Handbook of Gynecology [2 ed.] 3031148800, 9783031148804, 9783031148811

Table of contents :
Preface to the Second Edition
Preface to the First Edition
Acknowledgements
Contents
About the Editor
Section Editors of the First Edition
Contributors
Part I: General Office Gynecology
1 Anatomy of the Female Genital System
Introduction
Genital Structures
Vagina
Uterus
The Uterine Corpus
The Uterine Cervix
Adenexal Structures
The Fallopian Tubes
The Ovaries
Support Structures
Blood Supply
Innervation
Lymphatics
The Ureter
The Vulva and Erectile Structures
The Pelvic Bones
Pelvic Bones and Ligaments
Avascular Planes
Cross-References
References
2 Gynecologic History and Examination of the Patient
Introduction
History
Gynecologic History
Obstetrical History
Medical and Surgical History
Family History
Social History
Focused History/Common GYN Complaints
Abnormal Uterine Bleeding
Vaginal Discharge/Itching
Pelvic Pain
Contraceptive Counseling
Infertility
Pelvic Organ Prolapse
Physical Examination
When to Start?
Components of the Physical Exam
Breast Exam
Abdominal Exam
Pelvic Exam: Bimanual and Speculum Examination
Tests Performed on Exam
Pap Smear
STD Testing
Conclusion
Cross-References
References
3 Contraception
Introduction
Principles of Contraceptive Counseling
Starting Contraception
Assessments Required Before Starting Contraception
Contraception in Clients with Complex Medical Conditions
Contraceptive Efficacy
Tier 1: Long-Acting Reversible Contraception
Copper IUD
Hormone-Releasing IUDs
Hormone-Releasing Subdermal Implants
Tier 1: Permanent Contraception
Male Vasectomy
Female Permanent Contraception
Tier 2: Short-Acting Reversible Contraception
Combined Hormonal Contraceptives (CHCs)
Progestin-Only Oral Contraception
Progestin-Only Injectable Contraception: Depot Medroxyprogesterone Acetate (DMPA)
Tier 3: Fertility Awareness-Based and Barrier Methods
Fertility Awareness-Based Methods
Lactational Amenorrhea Method (LAM)
Withdrawal, Spermicides, and Vaginal pH Modulators
Barrier Methods
External Condoms
Internal Condoms and Barriers
Postpartum Contraception
Emergency Contraception
Oral Formulations
Intrauterine Devices
Conclusion
References
4 Preconception Care: In the Continuum of Women´s Healthcare
Introduction
Definition and Rationale of Preconception Care
Reproductive Life Plan
Components of Preconception Counseling
Family History
Maternal Genetic Conditions
Infections and Immunizations
Chronic Medical Conditions
Neurologic
Cardiovascular
Pulmonary
Gastrointestinal
Renal
Hematological and Immune
Endocrine
Mental Health
Oral
Medications
Environmental Exposures
Weight
Bariatric Surgery
Weight Gain
Nutrition
Folic Acid
Exercise
Age
Assisted Reproductive Technologies
Social and Lifestyle History
Cancer Survivors
Reproductive and Sexual Health Equity
Prenatal Care
Summary
References
5 Management of Intraepithelial Lesions of the Cervix
Cervical Cancer Screening
Cytology
HPV Testing
Screening Risk Evaluation and Triage to Surveillance or Assessment and Therapy
Abnormal Cytology
ASC-US
LSIL
ASC-H
HSIL
AGC
Other
Management of Histopathology
Therapeutic Modalities
LEEP
CKC
Cryosurgery
Laser Ablation
Colposcopic Results and Histopathology
No Lesion
Discordant Cytology and Histology
CIN 1
CIN2-3
AIS
Special Populations
Patients Younger Than 25 Years
Patients with Immunosuppression
Pregnant
Patients After Hysterectomy
Patients Over 65 with Abnormal History
Conclusion
References
6 Impact of Obesity on Gynecological Diseases
Introduction
Obesity and the Menstrual Cycle
Puberty
PCOS and Insulin Resistance
Infertility and ART
Fertility
Miscarriage
Assisted Reproductive Technology (ART)
Contraception
Combination Oral, Transdermal, and Vaginal Contraceptives
Progestin-Only Contraceptives
Intrauterine Devices (IUD)
Surgical Risk
Surgery in the Obese Patient
Anesthesia in the Obese Patient
Urinary Incontinence
Endometrial Cancer and Other Malignancies
Pelvic Imaging in the Obese Patient
Ultrasound
Computed Tomography (CT)
Magnetic Resonance Imaging (MRI)
Weight Loss
Diet
Exercise
Pharmacotherapy
Bariatric Surgery
Conclusion
Cross-References
References
7 Urinary Tract Infections and Asymptomatic Bacteriuria
Introduction
Epidemiology
Microbiology and Pathogenesis
Diagnosis
Presentation
Testing
Voided Specimen Collection Technique
Treatment
Uncomplicated Cystitis
Pyelonephritis
Recurrent UTI
Catheter-Associated UTIs
Asymptomatic Bacteriuria
Prevention: Nonantimicrobial
Conclusion
References
8 Reproductive Effects of COVID-19: A Journey Through COVID-19 Pathogenesis
General Pathogenesis of COVID-19
COVID-19 Pathogenesis: The Lung Is a Common Primary Target
Spike Protein Binding to AC2 Receptors and TMPRSS2 Activation
Synthesis of Viral Proteins
Host Cytokine Response
COVID-19 and CNS: Nervous System
COVID-19 and the Cardiovascular System
COVID-19 in Other Tissues: Gastrointestinal Tract, Liver, Kidneys, and Skin
COVID-19 and the Hematologic System
COVID-19: Multiple Attacks on the Cortisol Stress Response
COVID-19 Conclusion
References
9 Reproductive Effects of COVID-19: COVID Manifestations on the Endocrine and Reproductive Systems
COVID-19 and the Hypothalamic-Pituitary Axis
COVID-19 and Gonadal Function in Women
Risks Associated with Polycystic Ovary Syndrome
COVID-19 and Gonadal Function in Men
Decreases in Testosterone, Sperm Count, and Testicular Damage
Biphasic Effect of Testosterone Levels on Severity of Disease
Sexual Transmission
Orchitis
Poorer Response in Men to COVID-19
COVID and the Endometrium
Expression of SARS-CoV-2 Entry Genes Across the Menstrual Cycle
COVID-19 and Infertility
COVID-19 and Pregnancy
Fetal and Newborn Risks
Beneficial Pregnancy Responses
Adverse Pregnancy Responses
Pregnancy Recommendations: Not Necessary to Deliver Unless Other Factors Present
COVID-19 Conclusion
Cross-References
References
10 Pregnancy Termination
Introduction
Counseling and Consultation
Pre-abortion Evaluation
Procedural Abortion
Dilation and Curettage (D&C)
Dilation and Evacuation (D&E)
Pain Management (for Both D + C and D + E)
Antibiotics for Procedural Abortion
Complications of Procedural Abortion
Medication Abortion
The First-Trimester Medication Abortion
Candidate Selection
Pharmacology
Anticipatory Guidance
Antibiotics in Medication Abortion
Contraindications
Complications in Medication Abortion
Telehealth Considerations
Follow-up
The Second-Trimester (and Third-Trimester) Induction
Postabortion Counseling
Conclusion
Cross-References
References
Part II: Gynecologic Care of the Adolescent
11 Congenital Adrenal Hyperplasia in the Adolescent
Introduction
Background
Classical Congenital Adrenal Hyperplasia
Nonclassical Congenital Adrenal Hyperplasia
Puberty/Adolescence
Medical Management
Daily Medication Management
Sick-Day Management
Other Medications
Interdisciplinary Team Approach and Transition to Adult Care
Fertility and CAH
Comorbidities in CAH
Bone Mineral Density
Adrenal Rest Tumors
Cardiovascular Disease Risk Factors
Other Potential Morbidities
Surgical Considerations
Conclusion
Cross-References
References
12 Common Problems in Adolescent Medicine
Introduction
Consent
Confidentiality
Access to Care for Adolescents
Getting to Know the Adolescent Through the HEEADSSS Exam
Stages of Adolescent Sexual Development
Pubertal Development
Normal Menstruation
Specific Patterns of Abnormal Menstruation
Amenorrhea
Eating Disorders and Disordered Eating in Adolescents
Female Athlete Triad
PCOS in the Adolescent
Gender and Sexuality
Helping Adolescents Choose Effective Contraception
Emergency Contraception
Sexually Transmitted Infections: Special Considerations in Adolescents
Expedited Partner Therapy in Adolescents
Cervical Cancer Screening in Adolescents
HPV Infection and Vaccination
Special Consideration: Intimate Partner Violence and Sexual Assault
Conclusion
Cross-References
References
13 Management of Abnormal Bleeding in the Adolescent
Introduction
Overview of Hemostasis
Inherited Bleeding Disorders
Von Willebrand Disease
Hemophilia Carriers
Rare Factor Deficiencies
Disorders of Fibrinolysis
Inherited Platelet Disorders
Connective Tissue Disorders
Acquired Bleeding Disorders
Immune Thrombocytopenia Purpura
Thrombotic Thrombocytopenia Purpura
Liver and Renal Failure
Laboratory Evaluation
Treatment/Management
Medications to Avoid
Conclusion
Cross-References
References
14 Management of Pelvic Pain
Introduction
Neuroanatomy and Physiology
Acute Pelvic Pain
Acute Pelvic Pain Evaluation and Management
Chronic Pelvic Pain
Chronic Pelvic Pain Evaluation and Management
Important Elements of the History When Evaluating Chronic Pelvic Pain
Important Elements of the Physical Exam When Evaluating Chronic Pelvic Pain
Evaluation and Management of Chronic Pelvic Pain
Cyclic Menstrual-Related Pelvic Pain
Chronic Non-menstrual-Related Pelvic Pain
Conclusion
References
15 Treatment of Amenorrhea
Introduction
Primary Amenorrhea
Secondary Amenorrhea
History
Physical Exam
Genitourinary Exam
Normal Pelvic Anatomy
Abnormal Pelvic Anatomy
Ovarian Function
Laboratory Workup
Estrogen Measurement
Gonadotropin Measurement
Endometrial Stripe on Ultrasound
Progesterone Challenge
Positive Test
Negative Test
Normal Gonadotropin Levels
Ovarian Disorders Related to Chronic Anovulation
Polycystic Ovary Syndrome (PCOS)
Endometrial Sampling
Thyroid Dysfunction
Treatment
Hyperprolactinemia
Treatment
Elevated Gonadotropin Levels
Primary Ovarian Insufficiency
Initial Workup
Genetic Abnormalities
Low Gonadotropins
Hypothalamic Amenorrhea
Specific Causes of Amenorrhea
Disorders of Amenorrhea by Compartment
Anatomic Causes of Amenorrhea (Table 5)
Disorders of the Outflow Tract and Uterus
Asherman Syndrome
Cervical Stenosis
Androgen Insensitivity Syndrome
Imperforate Hymen
Transverse Vaginal Septum and/or Cervical Atresia
Müllerian Agenesis (Mayer-Rokitansky-Küster-Hauser Syndrome: MRKH)
Endocrine: Ovarian Disorders
Abnormal Chromosomes
Gonadal Dysgenesis
Turner Syndrome
Hormone Replacement Therapy
Swyer (46 XY Gonadal Dysgenesis)
46,XX Gonadal Dysgenesis
Fragile X Premutations (FMR1)
Normal Chromosomes
Autoimmune POI
Other Etiologies for POI
Radiation
Chemotherapy
Galactosemia
Resistant Ovary Syndrome
17-Hydroxylase Deficiency
Follicular Development Failure
Counseling and Management of POI
Pituitary Disorders
Pituitary Adenomas
Lab Testing
Gonadotroph Adenomas
Thyrotroph Adenomas
Somatotroph Adenomas
Corticotroph Adenomas
Lactotroph Adenomas (Prolactinoma)
Treatment
Medical Therapy
Surgical Therapy
Radiation Therapy
Fertility and Pregnancy
Empty Sella Syndrome
Sheehan Syndrome
Infiltrative Lesions
Hemochromatosis
Lymphocytic Hypophysitis
Hypogonadotropic Hypogonadism
Hypothalamus
Hypothalamic Amenorrhea
Eating Disorders
Exercise
Congenital GnRH Deficiency
Kallmann´s Syndrome
GnRH Receptor Mutations
Dosing
Conclusion
Cross-References
References
16 Treatment of Gynecological Congenital Anomalies
Introduction
Embryology
Molecular Origin
Classification for Müllerian Anomalies
Imaging Modalities
Reproductive Outcomes and Management Options
Non-ASRM Classifications
Conclusion
Cross-References
References
Part III: Gynecologic Care During the Early Reproductive Years
17 Diagnosis and Treatment of Premenstrual Syndrome
Introduction
Epidemiology
Clinical Presentation
Diagnosis
Pathophysiology
Treatment
Non-pharmacologic Treatment
Oral Contraceptives
Selective Serotonin Reuptake Inhibitors
Other Management
Conclusions
References
18 Abnormal Vaginal Bleeding During the Early Reproductive Years
Introduction
Definitions and Current Terminology
Disorders of Menstrual Timing
Primary Amenorrhea
Precocious Puberty
Secondary Amenorrhea
Infrequent Menses
Intermenstrual Bleeding
Postcoital/Post-traumatic Bleeding
Excessive Volume Disorders: Heavy/Prolonged Menstrual Bleeding
Definitions and Prevalence
PALM-COEIN Classification System of Abnormal Uterine Bleeding
Acute Excessive/Prolonged Menstrual Bleeding
Causes of Acute, Excessive Menstrual Bleeding
Assessment of Acute, Excessive Menstrual Bleeding
Treatment of Acute Excessive Menstrual Bleeding
Inpatient Therapies
Estrogen-Based Therapies in Inpatient Setting
Nonhormonal Adjuctive Therapies in Inpatient Setting
Outpatient Therapy
Chronic Heavy/Prolonged Menstrual Bleeding
Causes of Chronic, Heavy/Prolonged Menstrual Bleeding
Treatment of Chronic Heavy Menstrual Bleeding
Nonhormonal Therapies
Therapies to Suppress Endometrium Including COCs, Ring, Patches and Hormonal IUDs, Injections, Implants, GnRH Agonists and Ant...
Associated Menstrual Problems
Issues of Special Groups
Underserved, Resource-Poor AYA Women
AYA Women with Developmental Delays and Physical Disabilities
Transgender AYA
Conclusion
Cross-References
References
19 Sexually Transmitted Diseases: Diagnosis and Work-Up (GC, Chlamydia, Herpes, HPV)
Introduction
Chlamydia trachomatis
Epidemiology
Screening and Testing
Sites for Testing
Treatment
Expedited Partner Therapy in Management of Chlamydia and Gonorrhea Infection
Neisseria gonorrhoeae
Epidemiology
Screening and Diagnostic Testing
Sites for Testing
Treatment
Herpes Simplex Virus Types 1 and 2
Background
Testing for HSV-1 and HSV-2
Treatment
Human Papillomavirus (HPV)
Background
Screening and Diagnosis
Treatment
Conclusion
Cross-References
References
20 Diagnosis and Treatment of Vulvovaginitis
Introduction
Pathogenesis
Etiologies
Candidal vulvovaginitis
Bacterial Vaginosis
Vaginal Trichomoniasis
Other Etiologies of Vulvovaginal Symptoms
Atrophic Vaginitis
Desquamative Inflammatory Vaginitis
Vulvovaginal Dermatitis
Evaluation
History
Physical Exam
Diagnostic Studies
Treatment
Bacterial Vaginosis
Trichomoniasis
Other Causes of Vulvovaginal Symptoms
Women Without a Diagnosis After the Initial Evaluation
Post Diagnostic Management
Conclusion
Cross-References
References
21 Management of Chronic Recurrent Vulvovaginitis
Introduction
Pathophysiology
Presenting Symptoms
Physical Examination
Vulvovaginal Candidiasis
Bacterial Vaginosis
Trichomonas vaginalis
Threadworms
Atrophic Vaginitis
Lichen Sclerosus
Lichen Planus
Contact Dermatitis
Lichen Simplex Chronicus
Vulvar Care
Emotional Care
Summary
Conclusion
References
22 Pelvic Inflammatory Disease and Other Upper Genital Infections
Introduction and Epidemiology
Anatomic Considerations
Pathogenesis and Microbiology
Risk Factors
Clinical Manifestations
History and Physical Exam
Diagnosing PID
Complications of PID
Perihepatitis or Fitz-Hugh-Curtis Syndrome
Tubo-ovarian Abscess
Long-Term Sequelae
Diagnostic Testing
Pregnancy Test
Other Laboratory Tests
Microbiology
Histopathology
Pelvic Imaging
Pelvic Ultrasound
Additional Imaging
Treatment
Outpatient Management
Criteria for Outpatient Management
Inpatient Management
Criteria for Inpatient Management
Inpatient Course of Treatment
Drainage of Tubo-ovarian Abscess
Surgical Intervention
Intraoperative Findings
Other Management Considerations
Patient Counseling and STI Testing/Reporting
Intrauterine Device (IUD) in Place
Follow-Up
Long-Term Complications
Conclusion
Cross-References
References
23 Diagnosis and Treatment of Urinary Tract Infections
Introduction
Definitions (Table 1)
Epidemiology
Pathogenesis
Risk Factors (Table 2)
Microbiology
Resistance Trends
Complications of UTI
Prevention
Diagnosis and Management
Conclusion
Cross-References
References
24 Diagnosis and Management of Endometriosis
Introduction
Pathogenesis
Proposed Theories
Immune Alterations in Endometriosis
The Role of Estrogen
Pathophysiology of Pelvic Pain
Pathophysiology of Infertility
Risk Factors
Clinical Diagnosis
Patient Evaluation
Diagnostic Surgery
Screening for Endometriosis
Classification/Staging of Endometriosis
Treatment of Endometriosis
Interventions for Endometriosis-Associated Infertility
Natural History of Endometriosis
Conclusion
Cross-References
References
25 Diagnosis and Management of Ectopic Pregnancy
Introduction
Epidemiology
Pathogenesis
Risk Factors
Diagnosis
Ultrasound
Serial Beta HCG
Uterine Curettage
Treatment
Expectant Management
Medical Management with Methotrexate
Mechanism of Action
Adverse Effects
Candidates for Medical Therapy
Laboratory Evaluation
Multidose Regimen
Single-Dose Regimen
Two-Dose Regimen
Posttreatment Monitoring
Surgical Management
Salpingectomy
Salpingostomy
Adjunctive Use of Methotrexate
Conclusions
Cross-References
References
26 Diagnosis and Management of Pregnancy Loss
Introduction
Etiology
Genetic Factors
Thrombophilic Factors
Immunological Factors
Anatomic Factors
Endocrinologic Factors
Infectious Factors
Male Factors
Lifestyle, Environmental, and Chemical Factors
Evaluation
Genetic Assessment
Thrombophilia Assessment
Anatomic Assessment
Endocrine Assessment
Management
Karyotype Abnormalities
Thrombophilia
Anatomic Abnormalities
Endocrine Abnormalities
Conclusion
Cross-References
References
27 Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass
Introduction
Ovarian Torsion: Etiology and Risk Factors
Ovarian Torsion: Presenting Symptoms
Ovarian Torsion: Workup and Treatment
Ectopic Pregnancy
Tubo-Ovarian Abscess
Ruptured Ovarian Cysts
Conclusion
References
Part IV: Gynecologic Care During the Early and Late Reproductive Years
28 Management of Adnexal Masses
Introduction
Presenting Symptoms
History
Physical Exam
Laboratory and Imaging Studies
Imaging Studies Interpretation
Management
Conclusions
Follow-Up
References
29 Breast Cancer Screening
Introduction
Who Is at Increased Risk for Breast Cancer?
Impact of Race and Ethnicity on Breast Cancer Risk
Breast Screening Techniques and Technologies
Breast Exam
Clinical Breast Exam
Mammography
Tomosynthesis
Breast Ultrasound
Breast MRI
Characterization of Image-Detected Breast Lesions
When to Conclude Breast Cancer Screening
Conclusion
References
30 Benign Diseases of the Vulva
Introduction
Vulvar Dermatoses
Contact Dermatitis
Lichen Simplex Chronicus
Lichen Planus
Lichen Sclerosus
Psoriasis
Neoplasms
Vulvar Intraepithelial Neoplasia
Conclusion
Cross-References
References
31 Management of Vulvodynia
Introduction
Nomenclature of Vulvodynia
Anatomy
Taking a Patient History
Differential Diagnosis
Physical Examination of Vulvodynia
Histology and Physiology of Vulvodynia
Population Findings in Vulvodynia
Theories of Causation of Localized Provoked Vulvodynia
Low Estrogen as a Cause of Vestibulodynia
Other Potential Causes of Vestibulodynia
Vulvodynia´s Place in the History of Medicine
Comorbidities with Vulvodynia
Therapeutic Efforts: General Points
Specific Therapies for Vulvodynia
Conclusion
Cross-References
References
32 Management of Pelvic Pain, Dyspareunia, and Endometriosis
Introduction
Terminology
Pain Physiology: Basic Concepts
Sensitization
Convergence
Modulation
Neuropathic Pain and Nociceptors
Understanding Pain Physiology: Summary
Pelvic Pain Management
Pelvic Pain Story: The Initial Visit and Continued Care
Laboratory and Radiologic Studies
Chronic Pelvic Pain: Notes on Specific Assessment, Management, and Treatment of Various Causes
Dyspareunia
Dyspareunia and Sexual Physiology
Management of Dyspareunia
Endometriosis
Pathophysiology
Management of Endometriosis: Pelvic Pain
Management of Endometriosis: Infertility
Endometriosis Laboratory and Diagnostic Studies
Endometriosis Treatment
Reassessment
Conclusion
References
33 Management of Benign Breast Disease
Introduction
Clinical Breast Exam
Palpable Mass
Breast Pain
Nipple Discharge
Mastitis
Conclusion
References
34 Management of Fibroids
Introduction
Pathology and Epidemiology
Risk Factors
Oncogenic Potential
Effects on Fertility and Pregnancy
Management of Uterine Fibroids
Clinical Evaluation
Patient History
Physical Examination
Imaging
Expectant Management
Medical Management
NSAIDS
Tranexamic Acid
GnRH Agonist
GnRH Antagonists
Levonorgestrel Intrauterine Device
Ulipristal Acetate
Surgical Management
Myomectomy
Abdominal Myomectomy
Laparoscopic and Robotic Myomectomy
Hysteroscopic Myomectomy
Endometrial Ablation
Laparoscopic Radiofrequency Volumetric Thermal Ablation (LRVTA)
Uterine Artery Occlusion
Transcervical Radiofrequency Ablation
Hysterectomy
Radiologic Management
Uterine Artery Embolization (UAE)
MRI-Guided Focused Ultrasound (MRgFUS)
Conclusion
Cross-References
References
35 Management of Abnormal Uterine Bleeding: Later Reproductive Years
Introduction
Structural (PALM)
Polyp
Clinical Manifestations
Diagnostics
Treatment
Adenomyosis
Clinical Manifestations
Diagnostics
Treatment
Leiomyoma
Clinical Manifestations
Diagnostics
Treatment
Malignancy
Clinical Manifestations
Diagnostics
Treatment
Nonstructural (COEIN)
Coagulopathy
Clinical Manifestations
Diagnostics
Treatment
Ovulatory Dysfunction
Clinical Manifestations
Diagnostics
Treatment
Endometrial
Iatrogenic
Not Yet Specified
Conclusion
Cross-References
References
Part V: Work-Up and Management: Reproductive Endocrinology and Infertility
36 Workup and Management of Polycystic Ovary Syndrome
Introduction
Epidemiology
Etiology
Diagnostic Criteria
Evaluation
History
Examination
Laboratory Tests
Pelvic Ultrasound
Screening for Comorbidities
Clinical Manifestations and Management
Menstrual Regulation
Subfertility
Hyperandrogenism
Obesity
Metabolic Syndrome
Cancer Risk
Conclusion
References
37 Management of Recurrent Pregnancy Loss
Introduction
Causes and Management of Recurrent Pregnancy Loss
Karyotypic Abnormalities
Other Genetic Causes
Uterine Abnormalities
Immunologic Factors
Antiphospholipid Syndrome
Celiac Disease
Endocrine Dysfunction
Thyroid Dysfunction
Hyperprolactinemia
Luteal Phase Defect
Polycystic Ovarian Syndrome
Infectious/Microbial
Unexplained
Miscellaneous
Conclusion
References
38 Hyperandrogenism: Acne and Hirsutism
Introduction
Pathogenesis
Gonadotropins
Hyperinsulinemia
Androgen Excess
Hirsutism
Alopecia
Acne
Sex Hormone-Binding Globulin (SHBG)
Etiologies of Hirsutisms and Acne
Etiologies
PCOS
Idiopathic Hirsutism
Congenital Adrenal Hyperplasia (CAH)
Ovarian Tumors
Adrenal Tumors
Cushing´s Syndrome
Drugs
Evaluation
History
Physical Examination
Diagnostic Studies
Treatment
Weight Reduction
Hair Removal Treatments
Oral Contraceptives (OCPs)
Antiandrogens
Insulin-Sensitizing Agents
Other Treatment Modalities
Postmenopausal Women
Treatment of Acne
Conclusion
Cross-References
References
39 Hyperprolactinemia, Galactorrhea, and Pituitary Adenomas
Introduction to the Pituitary and Pituitary Adenomas
Prolactin
Galactorrhea
Signs and Symptoms of Prolactinomas
Diagnosis of Hyperprolactinemia
Imaging
Diagnosing the Cause of Hyperprolactinemia
Management of Hyperprolactinemia Due to Medications
Medical Management
Surgical Management
Pregnancy
Conclusion
References
40 Basic Management of Infertility
Introduction
Epidemiology
Age and Infertility
Fecundity
Definition of Infertility
Causes of Infertility
Male Infertility
Female Infertility
Ovulatory Causes of Infertility
Structural Causes of Infertility
Tubal
Uterine
Cervical
Endometriosis
Unexplained Infertility
Diagnosis
History and Physical Exam
Physical Exam
Diagnostic Tests
Diagnostic Test for Ovulation Confirmation
Ovulation Prediction Kits
Basal Body Temperature Charts
Serum Progesterone
Diagnostic Tests for Tubal Patency
Hysterosalpingogram
Chromotubation
Diagnostic Tests to Evaluate the Uterine Cavity
Transvaginal Ultrasound
Hysterosalpingogram
Sonohystogram
Hysteroscopy
Tests for Ovarian Reserve
Serum Follicle Stimulating Hormone
Antral Follicle Count
Antimullerian Hormone
Other Laboratory Tests
Diagnostic Tests for Evaluation of Male Infertility
Semen Analysis
Treatments
Optimizing the Window of Fertility
Treatment for Ovulation Dysfunction: Ovulation Induction
Treatment for Decreased Ovarian Reserve
Egg Donation
Gestational Surrogate
Treatment for Male Infertility
Treatment for Unexplained Infertility
Intrauterine Insemination
Assisted Reproductive Technology
In Vitro Fertilization
Intracytoplasmic Sperm Injection
Gamete Intrafallopian Transfer and Zygote Intrafallopian Transfer
Surgical Treatments
Laparoscopic Treatment of Endometriosis
Tubal Reversal
Conclusion
References
Part VI: Gynecologic Care During the Perimenopausal and Menopausal Years
41 Management of the Symptoms of Perimenopause
Introduction
Menstrual Irregularity
Combination Hormonal Contraception
Progestin-Only Methods
Vasomotor Symptoms
Lifestyle Modifications
Combination Hormonal Contraception
Hormone Replacement Therapy
Compounded Bioidentical Hormones
Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Gabapentin
Complementary Alternative Medicine
Vaginal Atrophy
Water-Based Lubricants and Vaginal Moisturizers
Vaginal Estrogen
Urinary Incontinence
Lifestyle Modifications and Behavioral Therapy
Estrogen
Mood Changes
Lifestyle Modifications
Pharmacotherapy
Conclusion
References
42 Management of Menopausal Symptoms
Introduction
Vasomotor Symptoms
Hormonal Therapies
Nonhormonal Therapies
Nonmedication Therapies
Genitourinary Syndrome of Menopause
Bone Strength
Libido
Neuropsychological Changes
Hormonal Therapies
Nonhormonal Therapies
Conclusion
References
43 Diagnosis and Management of Postmenopausal Bleeding
Introduction
Presentation
Epidemiology
Risk Factors for Endometrial Cancer
Etiology
Diagnostic Evaluation
History and Physical Examination
Endometrial Evaluation
Diagnostic Pap Test
Management
Conclusion
Cross-References
References
44 Management of Risks Factors for Older Women: Osteoporosis and Cardiovascular Disease (CVD)
Introduction
Osteoporosis
Epidemiology
Diagnosis
Pharmacological Management
Prevention of Osteoporosis and Bone Loss
Treatment for Established Osteoporosis
Risk Factors and Nonpharmacological Prevention
Cardiovascular Disease (CVD)
Background
Risk Factors: Prevention and Interventions
Hypertension
Cholesterol
Groups Benefiting from Statin Therapy (``Statin Benefit Groups´´)
Grade definitions
Risk Factors Unique to Women
Polycystic Ovary Syndrome (PCOS)
Menopause
Pregnancy Complications
Conclusion
Cross-References
References
45 Menopausal Hormone Therapy
Introduction
Physiology of Perimenopausal Transition
Climacteric Symptoms
Types of Hormone Replacement Therapy
Estrogen Therapy and Estrogen-Progestin Therapy
Oral Therapy
Transdermal
Vaginal Preparations and Rings
Conjugated Estrogen + Bazedoxifene
Selective Estrogen Receptor Modulators
Bioidentical Hormones
Other Potential Benefits
Lower Urinary Tract Symptoms
Urinary Tract Infection
Sexual Function
Dermatologic Aging
Special Populations
Endometrial Cancer
Breast Cancer
Uterine Leiomyomas
Liver Disease
Conclusion
References
46 Management of Vaginal and Vulvar Lesions in the Postmenopausal Women
Introduction
Presentation
Initial Assessment: History and Physical Examination
Biopsy
The Vulvar Dermatoses
Vulvovaginal Atrophy
Lichen Simplex Chronicus
Lichen Sclerosus
Lichen Planus
Psoriasis
Premalignant and Malignant Lesions
Vulvar Intraepithelial Neoplasia (VIN)
Vulvar Squamous Cell Carcinoma
Vulvovaginal Melanoma
Vaginal Carcinoma
Paget Disease
Conclusion
Cross-References
References
47 Management of Ovarian Masses in Older Patients
Introduction
Epidemiology
Clinical Presentation
Differential Diagnosis
Cystic Masses
Solid Masses
Evaluation
History
Physical Examination
Serum Tumor Markers
Cancer Antigen 125 (CA 125)
Human Epididymis Protein 4 (HE4)
Other Markers
Multiple Biomarker Tests
Radiological Studies
Pelvic Ultrasound
Computed Tomography
Magnetic Resonance Imaging
Management
Conservative Management
Operative Management
Conclusions
References
48 Management of Pelvic Pain in Older Women
Introduction
Clinical Assessment
Management Strategies
Pelvic Inflammatory Disease (PID)
Adenomyosis
Gastrointestinal Causes
Urological Causes
Musculoskeletal Causes
Pelvic Congestion Syndrome (PCS)
Pain After Surgery
Adhesions
Endometriosis
Physical Therapy Intervention
Conclusion
References
49 Management of Sexual Dysfunctions
Introduction
Definition and Classifications
Prevalence
Etiology
Screening
History
Partner Assessment
Physical Examination
Laboratory Evaluation
Advanced Testing
Treatment
Educating Patients on Sexual Health
Assess the Patient´s Goals
Optimizing General Health
Use a Team Approach
Make a Treatment Plan
Treatment of Female Sexual Interest/Arousal Disorder
Nonpharmacological
Pharmacological
Treatment of Female Orgasmic Disorder
Genito-Pelvic Pain/Penetration Disorder
Conclusion
References
Part VII: Gynecologic Office and Minimally Invasive Procedures
50 Office Procedures: Endometrial, Cervical, and Vulvar Biopsy
Common Causes of Abnormal Bleeding
Evaluation: Endometrial Biopsy
Contraindications
Sampling Technique
Treatment Options
Complications and Side Effects
Evaluation: Cervical Biopsy
Differential Diagnosis
Contraindications and Complications
Follow-Up Care
Evaluation and Procedure: Vulvar Biopsy
Biopsy Techniques
Indications
Contraindications
Approach Considerations
Dressing
Aftercare
Conclusions
References
51 Operative Hysteroscopy
Introduction
Equipment
Patient Preparation
Technique
Prevention of Cervical Trauma and Perforation
Distension Media
Hysteroscopic Treatment of Fibroids
Submucous Fibroids
Endometrial Preparation
Hysteroscopic Equipment for Removal of Fibroids
Technique
Electrosurgical Resection
Tissue Removal Systems
Hysteroscopic Polypectomy
Endometrial Polyps
Hysteroscopic Equipment for Removal of Polyps
Technique
Electrosurgery
Mechanical
Endometrial Destruction for Abnormal Uterine Bleeding
Endometrial Destruction
Technique of Transcervical Resection of the Endometrium and Endometrial Electrocoagulation
Technique for Second-Generation Endometrial Ablation
Hysteroscopic Treatment of Acquired Uterine Abnormalities
Intrauterine Adhesions
Technique
Retained Products of Conception
Technique
Hysteroscopic Treatment of Congenital Uterine Anomalies
Uterine Septum
Technique
Hysteroscopic Sterilization
Hysteroscopic Tubal Cannulation
Equipment
Technique for Tubal Cannulation
Outpatient Procedures
Equipment and Technique
Safety of Operative Hysteroscopy
Complications
Case Selection
Teaching
Clinical Governance and Audit
Future Developments
Conclusion
Cross-References
References
52 Laparoscopic Ovarian Cystectomy
Introduction
Ovarian Cysts
Functional Cysts
Benign Cystic Ovarian Neoplasms
Workup
Imaging
Serum Markers
Management
Observation
Surgical Intervention
Laparoscopy
Aspiration of Cyst
Laparoscopic Ovarian Cystectomy
Standard Closed Entry
Contraindications to Laparoscopic Ovarian Cystectomy
Oophorectomy
Conclusion
References
53 Laparoscopic Myomectomy
Introduction
Indications for Myomectomy
Benefits of Laparoscopy
Patient Selection
Preoperative Evaluation and Preparation
History and Physical Exam
Laboratory Tests
Imaging Studies
Managing Preoperative Anemia
Informed Consent
Discussing Morcellation
Operative Technique
Anesthesia and Patient Positioning
Prophylaxis
Laparoscopic Port Placement
Strategies to Decrease Intraoperative Blood Loss
Uterine Incision and Leiomyoma Removal
Repair of Uterine Defects
Morcellation of Leiomyomas
Closure
Complications
Postoperative Care
Outcomes
Improvement of Symptoms
New Leiomyoma Formation
Pregnancy After Myomectomy
Interval to Conception
Risk of Uterine Rupture
Conclusion
Cross-References
References
54 Robotic Surgery in Gynecology: Indications, Advantages, Avoiding Complications, Training, and Future Platforms-Update 2022
Introduction
Early Days
Single Site
Robotic Advantages
Gynecology Adoption
Hysterectomy
Myomectomy
Sacrocolpopexy and Pelvic Support Procedures
Endometriosis and Chronic Pelvic Pain
Reproductive Surgery
Ovarian Cysts
Special Populations
Complications
Direct and Indirect Injuries
Preventing Complications
Credentialing and Privileging
Training
Future Robotic Surgery Platforms
Summary and Conclusions
Cross-References
References
55 Minimally Invasive Procedures for Incontinence and Lower Urinary Tract Disorders: Indications and Avoiding Complications
Introduction
Indications for Surgery
Mid-Urethral Sling
Retropubic Mid-Urethral Sling
Technique
Anesthesia and the Cough Stress Test for the Retropubic Mid-Urethral Sling
Retropubic Mid-Urethral Sling Compared to Open Burch Colposuspension
Bottom-Up Versus Top-Down Retropubic Sling
Complications of Retropubic Mid-Urethral Sling
Transobturator Sling
Technique
Retropubic Versus Transobturator Sling
Voiding Dysfunction After Mid-Urethral Sling
Laparoscopic Retropubic Colposuspension (Burch)
Technique
Laparoscopic Burch Compared to Open Burch
Laparoscopic Burch Compared to Mid-Urethral Sling
Conclusion
Cross-References
References
56 Laparoscopic Hysterectomy
Introduction
Types of Hysterectomy
Benefits and Risks
Benefits
Risks
Alternatives
Patient Selection
BMI
Pelvic Adhesive Disease
Uterine Size and Shape
Concurrent Procedures
Preoperative Workup
Imaging
Surgery
Intraoperative Preparation
Laparoscopic Entry and Port Placement
Types of Entry
Surgical Procedure
Intraoperative Considerations
Instruments
Bowel Injury
Bladder Injury
Ureteral Injury
Morcellation
Cross-References
References
Part VIII: Gynecologic Operative Procedures
57 Vaginal Hysterectomy: Indications, Avoiding Complications
Background
Indications and Patient Selection
Contraindications
Technique
Vaginal Prep
Antimicrobial Prophylaxis
Patient Positioning
Vasopressin
Preemptive Techniques to Minimize Postoperative Pain
Surgical Steps
Energy-Based Sealing Devices
Vaginal Salpingo-Oophorectomy
Culdoplasty
Cuff Closure
Post-op Care
Outcomes Compared to Other Types of Hysterectomy
Complications
Conclusion
Cross-References
References
58 Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications
Introduction
Anatomy/Pathophysiology
Level 1: The Cardinal and Uterosacral Ligament Complex
Level 2: The Endopelvic Fascia
Level 3: The Perineal Body
Risk Factors
Diagnosis
Patient History
Physical Exam
Sensory Exam
Pelvic Exam
Complications of Prolapse
Nonsurgical Management of Prolapse
Pessary
Pessary Fitting
Types of Pessaries
Complications
Pelvic Floor Muscle Training
Surgical Management
Anterior Prolapse
Anterior Colporrhaphy
Vaginal Paravaginal Repair
Site-Specific Repair
Graft and Mesh Augmentation
Types of Grafts
Biologic Grafts
Transvaginal Mesh for Anterior/Apical Prolapse
Concomitant Hysterectomy
Apical Prolapse
Vaginal Approach for Apical Prolapse
Mayo/McCall Culdoplasty
Uterosacral Ligament Suspension
Technique
Outcomes and Complications
Sacrospinous Ligament Fixation
Technique
Outcomes and Complications
Alternative Vaginal Approaches
Abdominal Approach to Apical Prolapse
Sacral Colpopexy
Outcomes and Complications
Abdominal Uterosacral Ligament Suspension
Obliterative Procedures
Technique/Considerations
Total Colpectomy/Colpocleisis
Partial/LeFort Colpocleisis
Posterior Prolapse
Technique
Midline Plication
Site-Specific Repair
Graft or Mesh Augmentation
Outcomes and Complications
Conclusion
Cross-References
References
59 Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications
Introduction
Diagnosis and Evaluation
History
Physical
Additional Testing
Urodynamics
Stress Incontinence
Pathophysiology/Anatomy
Treatment
Conservative
Behavioral Modifications
Pelvic Floor Muscle Training (PFMT)
Incontinence Pessary
Urethral Inserts
Surgery
Mid-urethral Sling (MUS)
Transobturator
Pubovaginal (Autologous Sling)
Retropubic Urethropexy
Urethral Bulking Agents
Urgency Incontinence
Conservative
Pharmacologic Management
Percutaneous Tibial Nerve Stimulation
Intradetrusor Onabotulinum Toxin A
Sacral Neuromodulation
Mixed Urinary Incontinence
Conclusion
Cross-References
References
60 Diagnosis and Management of Delayed Postoperative Complications in Gynecology: Neuropathy, Wound Complications, Fistulae, T...
Introduction
Delayed Complications Presenting in the Immediate Postoperative Period (Within 2 Weeks)
Neurologic Injury
Femoral Nerve
Lateral Femoral Cutaneous Nerve
Ilioinguinal and Iliohypogastric
Genitofemoral
Common Peroneal
Sciatic Nerve
Obturator Nerve
Wound Complications
Cuff Infection
Cuff Evisceration
Delayed Complications Presenting in the Early Postoperative Period (Within 3 Months)
Urinary Tract Fistulae
Postoperative Recognition
Rectovaginal and Enterovaginal Fistulae
Thromboembolism
Delayed Complications Presenting in the Late Postoperative Period (Months to Years)
Pelvic Organ Prolapse
Cuff Complications
Granulation Tissue
Fallopian Tube Prolapse
Conclusion
References
Part IX: Management of Gynecologic Neoplasms and Cancers
61 Diagnosis and Management of Gestational Trophoblastic Disease
Introduction
Epidemiology
Presentation
Treatment Overview
Management of Primary GTN
Low-Risk GTN: Chemotherapy
Low-Risk GTN: Adjuvant Surgery
Second Curettage
Adjuvant Hysterectomy
High-Risk GTN: Chemotherapy
Management of PSTT/ETT
Management of Refractory/Persistent Disease
Low-Risk Refractory GTN
High-Risk Refractory/Recurrent GTN
Non-gestational Trophoblastic Tumors (Non-GTT)
Experimental Therapies for Chemoresistant GTN: Immunotherapy, High-Dose Chemotherapy, and Molecularly Targeted Agents
Special Considerations
Vaginal Metastases
Brain Metastases
Reproductive Outcomes After Treatment for GTN
Post-molar Prophylactic Chemotherapy
Phantom Beta-hCG, Quiescent GTD, and Physiologic Beta-hCG
Surveillance/Follow-Up
References
62 Diagnosis and Management of Vulvar Cancer
Introduction
Diagnosis and Staging
Tumor Imaging
Prognostic Factors
Prevention
Vaccination
Screening
Treatment of Early Stage Disease
Surgical Therapy
Surgical Management of the Primary Tumor
Management of Lymph Nodes
Adjuvant Radiotherapy
Management of Advanced Stage Tumors
Surgery Advanced Disease
Management of Groin Lymph Nodal Metastasis
Role of Chemo-Radiation Therapy
Role of Chemotherapy
Recurrence and Prognosis
Follow-Up
Melanoma of the Vulva
Vulvar Cancer in Pregnancy
Conclusion
Cross-References
References
63 Diagnosis and Management of Vaginal Cancer
Introduction
Vaginal Anatomy
Natural History
Epidemiology
Signs and Symptoms
Diagnosis
Evaluation and Staging
Screening and Prevention
Histologic Subtypes and Management
Vaginal Intraepithelial Neoplasia (VAIN)
Invasive Squamous Cell Carcinoma
Adenocarcinomas
Melanoma
Mesenchymal Tumors
Other Histologies
Conclusion
Cross-References
References
64 Cervical Cancer: General Overview
Introduction
Epidemiology
Prevalence
The Role of Human Papillomavirus and Vaccines Against It
Risk Factors
Diagnosis
Clinical Manifestations
Diagnosis
Taging
Clinical Staging
Diagnostic Studies
Tumor Size and Local Spread
Lymph Node and Distant Metastases
Histology
Spread and Metastasis
Direct Invasion
Lymphatic Spread
Hematogenous Metastasis
Surgical Staging of the PALN
Treatment
Surgical Treatment
Classification of Radical Hysterectomy
Morbidities Associated with Radical Surgery for Cervical Cancer
Nerve-Sparing Radical Hysterectomy
Radiotherapy
Prognosis
Conclusion
References
65 Fertility-Sparing Treatment for Early-Stage Cervical Cancer
Introduction
Candidate Selection
Conization
Conization Alone
Conization Plus Pelvic Lymphadenectomy
Neoadjuvant Chemotherapy Before Conization Plus Pelvic Lymphadenectomy
Radical Tracherectomy Plus Pelvic Lymphadenectomy
Outcomes
Surgical Outcomes
Surgical Complications
Intraoperative Complications
Postoperative Complications
Oncological Outcomes
Prognostic Factors
Surgical Procedures
Adjuvant Treatments
Neoadjuvant Chemotherapy Followed by Radical Trachelectomy for Tumors 2-4 Cm in Diameter
Hysterectomy in the Post-Childbearing Period
Reproductive Issues
Fertility Issues
Obstetric Outcomes
Cesarean Section for Women Who Undergo Radical Trachelectomy
Oocyte Cryopreservation for Women with Advanced Disease
Conclusion
Cross-References
References
66 Management of Early-Stage and Locally Advanced Cervical Cancer
Introduction
Early-Stage Cervical Cancer
Stage IA
Stage IA1
Stage IA2
Stage IB1-IIA
Surgery and Radiotherapy
Neoadjuvant Chemotherapy Before Radical Surgery
Risk Factors for Recurrence
Tailored Postoperative Adjuvant Radiotherapy Based on Pathological Risk Assessments
Minimally Invasive Approaches
Laparoscopic and Robotic Surgery
Less Radical Surgery
Sentinel Lymph Node Biopsy
Locally Advanced Disease (IIB-IVA)
Primary Surgical Approach for FIGO Stage IIB Disease
Radiotherapy
Definitive Radiotherapy
Adjuvant Chemotherapy After Definitive Radiotherapy
Neoadjuvant Chemotherapy
Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiotherapy
Neoadjuvant Chemotherapy Followed by Radiotherapy
Neoadjuvant Chemotherapy Followed by Chemoradiotherapy
Prognostic Factors for Survival
Follow-Up After Primary Treatment
Conclusion
Cross-References
References
67 Management of Metastatic, Recurrent, and Unusual Cervical Cancer
Introduction
Stage IVB Cervical Cancer
Recurrent Cervical Cancer
Diagnosis
Treatment
Chemotherapy
Immunotherapy
Surgical Treatments
Pelvic Exenteration
Radical Hysterectomy
Radiotherapy
Invasive Cancer that Is Detected After Simple Hysterectomy
Cancer of the Cervical Stump
Cervical Bleeding
Invasive Cervical Cancer with Bulky Lymph Nodes
Ureteral Obstruction
Cervical Cancer in Pregnancy
Incidence
Symptoms
Diagnosis
Distribution by Stage
Staging
Management
Cases in Which Pregnancy Preservation Is Not Desired
Cases in Which Pregnancy Preservation Is Desired
Before 20 Weeks´ Gestation
After 20 Weeks´ Gestation
Prognosis
Unusual Histological Types
Glassy Cell Carcinoma
Clear Cell Carcinoma
Minimal Deviation Adenocarcinoma and Gastric-Type Mucinous Carcinoma
Minimal Deviation Adenocarcinoma (MDA)
Gastric-Type Mucinous Carcinoma (GAS)
Small Cell Carcinoma
Sarcoma
Lymphoma
Melanoma
Conclusion
Cross-References
References
68 Management of Cervical Dysplasia
Introduction
Cervical Cytology
Human Papillomavirus
Risk Factors
Management of Abnormal Screening Tests
Colposcopy
Types of Cervical Dysplasia
Cervical Intraepithelial Neoplasia
Adenocarcinoma In Situ
Management of Dysplasia
Observation
Ablation
Excision
Pharmacological Agents
Hysterectomy
Special Considerations
Dysplasia in Pregnancy
Fertility-Sparing and AIS
Human Papillomavirus Prevention
Conclusion
References
69 Endometrial Hyperplasia
Introduction
Histology and Classification
WHO Classification
EIN System
Epidemiology and Risk Factors
Obesity
Polycystic Ovarian Syndrome
Hormone Replacement Therapy (HRT)
Tamoxifen Use
Lynch Syndrome
Reproductive Factors
Clinical Presentation
Diagnostic Evaluation
Management
Surveillance
Medical Management
Surgical Management
Screening and Prevention
Conclusion
Cross-References
References
70 Conservative Management of Endometrial Cancer
Introduction to Conservative Management
Epidemiologic Considerations
Age: Young Women with Endometrial Cancer
Age: Older Age and Comorbidities
Obesity and Endometrial Cancer
Special Populations: Hereditary Syndromes
Ideal Candidates for Conservative Management
Endometrial Cancer Classification
Selection of Appropriate Cases
Pretreatment Evaluation: Diagnosis and Testing
Determining Extent of Disease
Treatment Options
Hormonal Therapy
Nonhormonal and Combination Modalities
Definition of Response
Oncologic Outcomes
Risk of Recurrence
Fertility Outcomes
Surveillance
Definitive Management
Medically Inoperable Patients
Conclusion
Cross-References
References
71 Diagnosis and Management of Epithelial Ovarian Cancer
Introduction
Presentation
Diagnosis
History and Assessment
Bloods
Imaging
Pathology
Staging
Management
Definition of Surgery in EOC
Tumor Dissemination Patterns at Relapse
Value of Secondary Cytoreduction
Value of Tertiary Cytoreduction
Salvage Surgery in Acute Situations: Bowel Obstruction and Intestinal Perforation in the Era of Targeted Antiangiogenetic Agen...
Systemic Treatment of Epithelial Ovarian Cancer
Early-Stage Disease (FIGO I-IIb)
Advanced Stage Disease (FIGO IIc-IV)
Intermediate Platinum Response (PFS 6-12 Months)
Platinum-Resistant/Platinum-Refractory EOC Relapse (PFI

Citation preview

Donna Shoupe Editor

Handbook of Gynecology Second Edition

Handbook of Gynecology

Donna Shoupe Editor

Handbook of Gynecology Second Edition

With 238 Figures and 199 Tables

Editor Donna Shoupe Department of Obstetrics and Gynecology Keck School of Medicine, University of Southern California Los Angeles, CA, USA

ISBN 978-3-031-14880-4 ISBN 978-3-031-14881-1 (eBook) https://doi.org/10.1007/978-3-031-14881-1 © Springer Nature Switzerland AG 2017, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

This book is dedicated to my Medical School, The Ohio State University College of Medicine. Go Buckeyes!

Preface to the Second Edition

The Handbook of Gynecology, second edition, is an even more comprehensive textbook designed to guide management and understanding of the wide range of issues surrounding women’s health. The book is divided into 10 parts and begins with general office gynecology. Issues such as gynecologic history and examination, contraception, pap smear protocols, urinary tract infection, abnormal bleeding, anatomy, examination of the patient, preconception care, and management of obesity are included. There are also new chapters on the pathogenesis of COVID-19 and the effects of the virus on reproductive function. Part II covers gynecologic care of the adolescent, including congenital adrenal hyperplasia, congenital anomalies, common problems, abnormal bleeding, pelvic pain, and amenorrhea. Part III contains chapters on gynecologic care in early reproductive years with an emphasis on STDs, genital and pelvic infections, endometriosis, pelvic pain, fibroids, ectopic pregnancy, PMS, and pregnancy loss. Part IV deals with gynecologic care during the early and late reproductive years, including adnexal masses, breast screening guidelines, breast disease, vulvar complaints, dyspareunia, fibroids, endometriosis, and bleeding problems. Work-up and management of reproductive endocrinology and infertility problems are addressed in Part V. The chapters cover recurrent pregnancy loos, hyperandrogenism, hyperprolactinemia, and management of infertility. Part VI discusses gynecologic care during the perimenopause and menopausal years, including perimenopausal and menopausal symptoms, management of risk factors for older women, estrogen deficiency-related disease, hormone replacement therapy, vulvar lesions in older women, ovarian masses, pelvic pain, and sexual dysfunction. Part VII covers gynecologic office and minimally invasive procedures, genital biopsies, hysteroscopic procedures, laparoscopic procedures, robotic surgery, and minimally invasive approaches for urinary incontinence and hysterectomy. Part VIII describes gynecologic operative procedures, including vaginal hysterectomy, treatment of prolapse and incontinence, and diagnosis and management of postoperative problems. Part IX describes management of gynecologic neoplasms and cancers, hyperplasia, cervical dysplasia, locally advanced cervical cancer, fertility sparing treatments, preinvasive epithelial vulvar disease, along with sentinel node mapping in vulvar cancer and survivorship issues. Part X discusses benign and vaginal pathology, malignant vulvar and vaginal pathology, lesion of the cervix or uterine corpus, immunohistochemistry of gynecologic malignances, and multiple types of ovarian cancers. vii

viii

Preface to the Second Edition

The authors, section editors, editor, and publisher hope that his new edition will continue to be a highly educational and valuable resource for its readers. For the sake of brevity and better readability, the word woman is generally used throughout the book, this word is inclusive and can refer to persons with various biological backgrounds. Los Angeles, USA October 2023

Donna Shoupe Editor

Preface to the First Edition

The Handbook of Gynecology is a comprehensive textbook that is designed to guide management and understanding of the many complex issues surrounding women’s health. The book addresses issues in adolescents such as congenital adrenal hyperplasia, amenorrhea, genital tract anomalies, or other common problems in adolescents. The book has separate chapters on the multiple issues of reproductive-aged women, including management of bleeding issues, sexually transmitted diseases, vaginitis and chronic recurrent vulvovaginitis, sexual issues, premenstrual syndrome, obesity, abnormal Pap smears, recurrent pregnancy loss, infertility, preconception management, and androgen excess. For the perimenopausal and menopausal women, chapters include assessment of risk factors for osteoporosis and cardiovascular disease, perimenopausal/menopausal symptoms, guidelines for hormone replacement therapy, management of pelvic pain, benign breast disease, vulvar disease, and abnormal bleeding and also on common office procedures such as endometrial, vulvar, or cervical biopsy. There are multiple chapters on surgical techniques such as operative hysteroscopy, robotic surgery, laparoscopic hysterectomy, minimal invasive procedures, stress incontinence procedures, avoiding surgical complications, and management of postoperative complications. There are also detailed chapters addressing vulvar, vaginal, cervical, uterine, and ovarian premalignant and malignant lesions as well as chapters on their management. Most importantly, the book includes chapters addressing fertility and ovarian sparing operative procedures for these premalignant and malignant lesions. The authors, section editors, and editor hope that this book will be highly educational and very valuable for its readers. June 2017

Donna Shoupe

ix

Acknowledgements

There were so many hardworking and outstanding contributors to both the first and now second edition of this book. The contributors are leaders in their fields, and I thank them for sharing their clinical experiences, relevant clinical studies, common practices, and society recommendations. I also thank my section editors for their many hours of work, their expertise, and their outstanding judgment on selecting the best authors. Thanks also to Springer and their representatives including Neha Thapa who tirelessly worked with me. I also give thanks to my entire family for their continued support.

xi

Contents

Volume 1 Part I

General Office Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

1

Anatomy of the Female Genital System . . . . . . . . . . . . . . . . . Dalal Eldick and Fausto F. Andrade

3

2

Gynecologic History and Examination of the Patient . . . . . . Alejandra Salazar and Fausto F. Andrade

11

3

Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melissa Myo, Katrina J. Heyrana, and Brian T. Nguyen

21

4

Preconception Care: In the Continuum of Women’s Healthcare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Megan Bernstein, Yalda Afshar, and Christina S. Han

39

5

Management of Intraepithelial Lesions of the Cervix . . . . . . Rasika R. Deshpande, Caroline J. Violette, Morgan Elizabeth Fullerton, and Marcia A. Ciccone

63

6

Impact of Obesity on Gynecological Diseases Laurice Bou Nemer

............

79

7

Urinary Tract Infections and Asymptomatic Bacteriuria . . . Elise Morocco and Tanaz Ferzandi

93

8

Reproductive Effects of COVID-19: A Journey Through COVID-19 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Donna Shoupe

9

Reproductive Effects of COVID-19: COVID Manifestations on the Endocrine and Reproductive Systems . . . . . . . . . . . . . 111 Donna Shoupe

10

Pregnancy Termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Emma Koltun-Baker, Katrina J. Heyrana, Melissa Myo, and Brian T. Nguyen

xiii

xiv

Contents

Part II

Gynecologic Care of the Adolescent . . . . . . . . . . . . . . . . . . . 137

11

Congenital Adrenal Hyperplasia in the Adolescent . . . . . . . . 139 Mimi S. Kim, Mark C. Liang, Paul J. Kokorowski, Teresa Tseng, Christina M. Koppin, and Mitchell E. Geffner

12

Common Problems in Adolescent Medicine . . . . . . . . . . . . . . 159 Terez A. Yonan and Claudia Borzutzky

13

Management of Abnormal Bleeding in the Adolescent . . . . . 187 Julie Jaffray and Kristina Haley

14

Management of Pelvic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Kaily Cox, Donna Shoupe, and Anna E. Reinert

15

Treatment of Amenorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Jacqueline R. Ho

16

Treatment of Gynecological Congenital Anomalies . . . . . . . . 243 Irene Woo

Part III Gynecologic Care During the Early Reproductive Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 17

Diagnosis and Treatment of Premenstrual Syndrome . . . . . . 255 Zachary Anderson

18

Abnormal Vaginal Bleeding During the Early Reproductive Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Anita L. Nelson

19

Sexually Transmitted Diseases: Diagnosis and Work-Up (GC, Chlamydia, Herpes, HPV) . . . . . . . . . . . . . . . . . . . . . . . 283 Antonio V. Castaneda

20

Diagnosis and Treatment of Vulvovaginitis . . . . . . . . . . . . . . 297 Mya Rose Zapata

21

Management of Chronic Recurrent Vulvovaginitis . . . . . . . . 319 Abigail Kingston and Emma Torbé

22

Pelvic Inflammatory Disease and Other Upper Genital Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Jessica Reid

23

Diagnosis and Treatment of Urinary Tract Infections . . . . . . 347 Austin Zanelotti, Amanda Barnes, and Anam Khaja

24

Diagnosis and Management of Endometriosis . . . . . . . . . . . . 363 Angela S. Kelley and Molly B. Moravek

25

Diagnosis and Management of Ectopic Pregnancy . . . . . . . . 373 Elizabeth Stephens Constance and Molly B. Moravek

Contents

xv

26

Diagnosis and Management of Pregnancy Loss . . . . . . . . . . . 387 Kavitha Krishnamoorthy and Youssef Mouhayar

27

Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass . . . . . . . . . . . . . . . . . . . . 397 Youssef Mouhayar and Michael Saad-Naguib

Part IV Gynecologic Care During the Early and Late Reproductive Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 . . . . . . . . . . . . . . . . . . . . . . 409

28

Management of Adnexal Masses Donna Shoupe

29

Breast Cancer Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Heather R. Macdonald

30

Benign Diseases of the Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Sigita S. Cahoon

31

Management of Vulvodynia Martha F. Goetsch

32

Management of Pelvic Pain, Dyspareunia, and Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Judy Hall Chen

33

Management of Benign Breast Disease Heather R. Macdonald

34

Management of Fibroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Valentina M. Rodriguez-Triana and William H. Parker

35

Management of Abnormal Uterine Bleeding: Later Reproductive Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 Yoko Takashima, Janet Bruno-Gaston, and Jennifer Israel

. . . . . . . . . . . . . . . . . . . . . . . . . . 439

. . . . . . . . . . . . . . . . . 485

Part V Work-Up and Management: Reproductive Endocrinology and Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 36

Workup and Management of Polycystic Ovary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529 Alexandra Regens, Gillian Mackay, and Jack Maxwell

37

Management of Recurrent Pregnancy Loss . . . . . . . . . . . . . . 539 Sana N. Khan

38

Hyperandrogenism: Acne and Hirsutism . . . . . . . . . . . . . . . . 545 M. Blake Evans and Micah Hill

39

Hyperprolactinemia, Galactorrhea, and Pituitary Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561 Kate C. Arnold and Caroline J. Flint

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40

Contents

Basic Management of Infertility . . . . . . . . . . . . . . . . . . . . . . . 569 Bree Anna Gibson and Jamie Wilkerson

Part VI Gynecologic Care During the Perimenopausal and Menopausal Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 41

Management of the Symptoms of Perimenopause . . . . . . . . . 589 Courtney Ketch, Elizabeth Weedin, and Bree Anna Gibson

42

Management of Menopausal Symptoms . . . . . . . . . . . . . . . . 601 Melissa Conklin, Dana Siegel, Elizabeth S. Ginsburg, and Cassandra Roeca

43

Diagnosis and Management of Postmenopausal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 Trevin C. Lau, Tina O’Shea, and Lisa B. Spiryda

44

Management of Risks Factors for Older Women: Osteoporosis and Cardiovascular Disease (CVD) . . . . . . . . . 623 Philipp Quaas, Katrina Wade, and Alexander M. Quaas

45

Menopausal Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . 639 Benjamin J. Barenberg and Stephanie D. Pickett

46

Management of Vaginal and Vulvar Lesions in the Postmenopausal Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649 Jacob Lauer, Tina O’Shea, and Lisa B. Spiryda

47

Management of Ovarian Masses in Older Patients . . . . . . . . 659 Alexander Melamed, Devin T. Miller, Monica K. Neuman, and Laila Muderspach

48

Management of Pelvic Pain in Older Women . . . . . . . . . . . . 671 Pouya Javadian, Mazdak Momeni, and Mikio A. Nihira

49

Management of Sexual Dysfunctions . . . . . . . . . . . . . . . . . . . 685 Luwam Ghidei, Pardis Hosseinzadeh, and Terri L. Woodard

Volume 2 Part VII Gynecologic Office and Minimally Invasive Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 50

Office Procedures: Endometrial, Cervical, and Vulvar Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 Donna Shoupe

51

Operative Hysteroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719 Paul P. Smith and T. Justin Clark

52

Laparoscopic Ovarian Cystectomy . . . . . . . . . . . . . . . . . . . . . 745 Caryl S. Reinsch

Contents

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53

Laparoscopic Myomectomy . . . . . . . . . . . . . . . . . . . . . . . . . . 757 Brianne D. Romeroso and William H. Parker

54

Robotic Surgery in Gynecology: Indications, Advantages, Avoiding Complications, Training, and Future Platforms–Update 2022 . . . . . . . . . . . . . . . . . . . . . . . . 773 John P. Lenihan Jr.

55

Minimally Invasive Procedures for Incontinence and Lower Urinary Tract Disorders: Indications and Avoiding Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801 Begüm Özel

56

Laparoscopic Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . 817 Varun U. Khetan and Anna E. Reinert

Part VIII

Gynecologic Operative Procedures . . . . . . . . . . . . . . . . . . 831

57

Vaginal Hysterectomy: Indications, Avoiding Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 Begüm Özel

58

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849 Christina E. Dancz, Amin Tavakoli, and Morgan Elizabeth Fullerton

59

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881 Renee Rolston and Begüm Özel

60

Diagnosis and Management of Delayed Postoperative Complications in Gynecology: Neuropathy, Wound Complications, Fistulae, Thromboembolism, Pelvic Organ Prolapse, and Cuff Complications . . . . . . . . . . . . . . . . . . . . . 893 Christina E. Dancz, Amin Tavakoli, and Anastasiya Shabalova

Part IX Management of Gynecologic Neoplasms and Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911 61

Diagnosis and Management of Gestational Trophoblastic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913 Jocelyn Garcia-Sayre, Antonio V. Castaneda, Lynda D. Roman, and Koji Matsuo

62

Diagnosis and Management of Vulvar Cancer . . . . . . . . . . . 931 Satoshi Nakagawa, Mariko Shindo, Yutaka Ueda, Tadashi Kimura, and Koji Matsuo

63

Diagnosis and Management of Vaginal Cancer . . . . . . . . . . . 951 E. Clair McClung, Ardeshir Hakam, and Mian M. K. Shahzad

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Contents

64

Cervical Cancer: General Overview . . . . . . . . . . . . . . . . . . . . 969 Seiji Mabuchi, Mahiru Kawano, Yuri Matsumoto, and Tadashi Kimura

65

Fertility-Sparing Treatment for Early-Stage Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981 Seiji Mabuchi, Hiromasa Kuroda, K. Kozasa, and Tadashi Kimura

66

Management of Early-Stage and Locally Advanced Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989 Seiji Mabuchi, Mahiru Kawano, Tomoyuki Sasano, and Hiromasa Kuroda

67

Management of Metastatic, Recurrent, and Unusual Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 Seiji Mabuchi, Mahiru Kawano, Ryoko Takahashi, and Hiromasa Kuroda

68

Management of Cervical Dysplasia . . . . . . . . . . . . . . . . . . . . 1017 Laurie L. Brunette, Katherine E. Tierney, Lynda D. Roman, and Koji Matsuo

69

Endometrial Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029 Catherine Hermann, Kristina Williams, and Emily M. Ko

70

Conservative Management of Endometrial Cancer . . . . . . . 1049 Alexandra Huttler, Lindsey Buckingham, and Emily M. Ko

71

Diagnosis and Management of Epithelial Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069 Katherine Nixon and Christina Fotopoulou

72

Fertility-Sparing Treatment for Ovarian Cancer . . . . . . . . . 1089 Katherine Nixon and Christina Fotopoulou

73

Diagnosis and Management of Nonepithelial Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095 Erin A. Blake, X. Mona Guo, Saketh R. Guntupalli, and Koji Matsuo

74

Diagnosis and Management of the Cancer of the Uterus . . . 1121 Kristy K. Ward and Amy R. Carroll

75

Preinvasive Epithelial Disease of the Vulvar . . . . . . . . . . . . . 1131 Aida Moeini, Hiroko Machida, Sigita S. Cahoon, and Koji Matsuo

76

Sentinel Node Mapping in Vulva Cancer . . . . . . . . . . . . . . . . 1145 Mamoru Kakuda, Eiji Kobayashi, Kiyoshi Yoshino, and Tadashi Kimura

77

Survivorship of Gynecologic Malignancy . . . . . . . . . . . . . . . 1153 Kristy K. Ward, Alexandra Walker, and Amy R. Carroll

Contents

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Part X

Pathology of the Female Gynecologic System . . . . . . . . . 1169

78

Benign Vulvar and Vaginal Pathology . . . . . . . . . . . . . . . . . . 1171 Pouya Javadian, Daman Samrao, and Mazdak Momeni

79

Malignant Vulvar and Vaginal Pathology . . . . . . . . . . . . . . . 1187 Grace N. Kim, Neda Jooya, X. Mona Guo, Monica K. Neuman, and Laila Muderspach

80

Lesions of the Uterine Cervix . . . . . . . . . . . . . . . . . . . . . . . . . 1199 Saloni Walia and Paulette Mhawech-Fauceglia

81

Pathology of the Uterine Corpus . . . . . . . . . . . . . . . . . . . . . . 1215 Helena Hwang and Paulette Mhawech-Fauceglia

82

Germ Cell Tumors of the Ovaries . . . . . . . . . . . . . . . . . . . . . . 1233 Mohamed Mokhtar Desouki and Oluwole Fadare

83

Immunohistochemistry of Gynecologic Malignancies . . . . . . 1245 Yan Wang and Paulette Mhawech-Fauceglia

84

Surface Epithelial Neoplasms of the Ovary . . . . . . . . . . . . . . 1255 Paulette Mhawech-Fauceglia

85

Sex-Cord Stromal Tumors of the Ovary . . . . . . . . . . . . . . . . 1267 Mohamed Mokhtar Desouki and Oluwole Fadare

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289

About the Editor

Donna Shoupe, M.D., M.B.A., is a professor in the Department of Obstetrics and Gynecology and the Keck School of Medicine, University of Southern California. She graduated from Massachusetts Institute of technology in 1974 and The Ohio State College of Medicine. She also graduated from the Marshall School of Business at the University of Southern California in 2002. She completed a residency in Obstetrics and Gynecology and a Reproductive Endocrinology and Infertility Fellowship at Los Angeles CountyUniversity of Southern California School of Medicine and was appointed to the faculty in 1984. She has received many awards and served in many leadership positions. She has published over 100 peer reviewed papers, more than 65 book chapters, and has edited 9 books. She is also the editor of the journal Contraception and Reproductive Medicine and Associate Editor for the journal Menopause. She is currently a Co-Investigator on a 3-year NIH grant evaluating cardiovascular benefits of hormone replacement therapy. Her main interests include menopause, ovarian conservation, contraception, osteoporosis, the menopause transition and cardiovascular disease, dementia, polycystic ovarian syndrome, insulin resistance, hormone therapy, uterine anomalies, androgen excess, and management of bleeding abnormalities in women.

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Section Editors of the First Edition

Part I: General Office Gynecology Part III: Gynecologic Care During the Early Reproductive Years Marc Gualtieri Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Southern California, Los Angeles, CA, USA Part VII: Gynecologic Office and Minimally Invasive Procedures Jennifer Israel Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Part IX: Management of Gynecologic Neoplasms and Cancers Koji Matsuo Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Southern California, Los Angeles, CA, USA Part X: Pathology of the Female Gynecologic System Paulette Mhawech-Fauceglia Department of Pathology, Division of Gynecologic Oncologic Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Part IV: Gynecologic Care During the Early and Late Reproductive Years Part VIII: Gynecologic Operative Procedures Begüm Özel Department of Obstetrics and Gynecology, Division of Female Pelvic Medicine and Reconstructive Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Part V: Work-Up and Management: Reproductive Endocrinology and Infertility Part VI: Gynecologic Care During the Perimenopausal and Menopausal Years Alexander M. Quaas Department of Obstetrics/Gynecology, Section of Reproductive Endocrinology and Infertility, Oklahoma University Health Science Center, Oklahoma City, OK, USA Part II: Gynecologic Care of the Adolescent Donna Shoupe Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

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Contributors

Yalda Afshar Division of Maternal Fetal Medicine; Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA Zachary Anderson Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Fausto F. Andrade Department of Obstetrics and Gynecology, University of Miami/Jackson Memorial Hospital, Miami, FL, USA Kate C. Arnold Department of OBGYN, University of Oklahoma Health and Science Center, Oklahoma City, OK, USA Benjamin J. Barenberg The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Amanda Barnes University of Miami Miller School of Medicine, Miami, FL, USA Megan Bernstein Division of Maternal Fetal Medicine; Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA Erin A. Blake Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Claudia Borzutzky Department of Pediatrics, Division of Adolescent and Young Adult Medicine, Keck School of Medicine of USC/Children’s Hospital Los Angeles, Los Angeles, CA, USA Laurice Bou Nemer Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA Laurie L. Brunette Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Janet Bruno-Gaston Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA xxv

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Lindsey Buckingham Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Novant Health Cancer Institute, New Hanover, Wilmington, NC, USA Sigita S. Cahoon Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Amy R. Carroll WellStar Gynecologic Oncology, Austell, GA, USA Antonio V. Castaneda Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Judy Hall Chen Obstetrics and Gynecology, Tucson Medical Center, Tucson, AZ, USA Marcia A. Ciccone Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA T. Justin Clark Birmingham Women’s NHS Foundation Trust, Edgbaston, UK Melissa Conklin Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA Elizabeth Stephens Constance Reproductive Endocrinology & Infertility, Heartland Center for Reproductive Medicine, Omaha, NE, USA Kaily Cox Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Christina E. Dancz University of Southern California, Los Angeles, CA, USA Rasika R. Deshpande Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Mohamed Mokhtar Desouki Department of Pathology, Roswell Park Comprehensive Cancer Center, Administrative Services Buildings (ASB), Buffalo, NY, USA Dalal Eldick Department of Obstetrics and Gynecology, University of Miami/Jackson Memorial Hospital, Miami, FL, USA M. Blake Evans Oklahoma State University Department of Obstetrics and Gynecology, Tulsa, OK, USA Oluwole Fadare Division of Anatomic Pathology, University of California San Diego Health System, La Jolla, CA, USA Tanaz Ferzandi Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Caroline J. Flint Department of OBGYN, University of Oklahoma Health and Science Center, Oklahoma City, OK, USA

Contributors

Contributors

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Christina Fotopoulou Department of Gynaecological Oncology, West London Gynecological Cancer Centre, Imperial College NHS Trust, Queen Charlottes and Hammersmith Hospital, London, UK Morgan Elizabeth Fullerton Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Jocelyn Garcia-Sayre Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Mitchell E. Geffner Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Luwam Ghidei Baylor College of Medicine, Houston, TX, USA Bree Anna Gibson University of Oklahoma Health Science Center, Oklahoma City, OK, USA Elizabeth S. Ginsburg Division of Reproductive Endocrinology, Brigham and Women’s Hospital, Boston, MA, USA Martha F. Goetsch Center for Women’s Health, Oregon Health and Science University, Portland, OR, USA Saketh R. Guntupalli Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA X. Mona Guo Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Ardeshir Hakam Department of Pathology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA Kristina Haley Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA Christina S. Han Division of Maternal Fetal Medicine; Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA Catherine Hermann Division of Gynecologic Oncology, New York University Langone Health, New York, NY, USA Katrina J. Heyrana Division of Family Planning, Department of Obstetrics and Gynecology, Cedars-Sinai, Los Angeles, CA, USA Katrina J. Heyrana Section of Family Planning, Department of Clinical Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Micah Hill Reproductive Endocrinology and Infertility/Obstetrics and Gynecology, USU, National Institutes of Health and Walter Reed Natl. Military Medical Center, Bethesda, MD, USA

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Jacqueline R. Ho Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Pardis Hosseinzadeh Baylor College of Medicine, Houston, TX, USA Alexandra Huttler Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia, PA, USA Helena Hwang Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA Jennifer Israel Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Julie Jaffray Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Pouya Javadian Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Neda Jooya Department of Gynecologic Oncology, University of Southern California, Los Angeles, CA, USA Mamoru Kakuda Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Mahiru Kawano Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Angela S. Kelley Department of Obstetrics and Gynecology, University of Michigan Health System, Ann Arbor, MI, USA Courtney Ketch University of Oklahoma Health Science Center, Oklahoma City, OK, USA Anam Khaja University of Miami Miller School of Medicine, Miami, FL, USA Sana N. Khan Wayne State University, Detroit, MI, USA Varun U. Khetan Department of Obstetrics and Gynecology, LAC+USC Medical Center, Los Angeles, CA, USA Grace N. Kim Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Mimi S. Kim Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Tadashi Kimura Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan

Contributors

Contributors

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Abigail Kingston Great Western Hospitals NHS Foundation Trust, Swindon, UK Emily M. Ko Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania Health System, Philadelphia, PA, USA Eiji Kobayashi Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Paul J. Kokorowski Division of Pediatric Urology, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Emma Koltun-Baker Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Christina M. Koppin Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA K. Kozasa Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Kavitha Krishnamoorthy Department of Obstetrics and Gynecology, University of Miami, Miller School of Medicine/Jackson Health System, Miami, FL, USA Hiromasa Kuroda Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Trevin C. Lau Massachusetts General Hospital, Boston, MA, USA Jacob Lauer Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, NY, USA John P. Lenihan Jr. Department of Obstetrics and Gynecology, University of Washington School of Medicine, Surgical Science North America, Seattle, WA, USA Mark C. Liang Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Seiji Mabuchi Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan Heather R. Macdonald Hoag Hospital, Orange County, CA, USA Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Hiroko Machida Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA

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Gillian Mackay University of California San Diego, San Diego, CA, USA Yuri Matsumoto Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Koji Matsuo Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Jack Maxwell Health Sciences Center, University of Oklahoma, Oklahoma City, OK, USA E. Clair McClung Department of Obstetrics and Gynecology, Stanford University, Palo Alto, CA, USA Alexander Melamed Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA Paulette Mhawech-Fauceglia Department of Pathology, Sonic Healthcare, Las Vegas, NV, USA Devin T. Miller Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA Aida Moeini Department of Radiology, Women’s imaging, Cedars Sinai Medical Center, Los Angeles, CA, USA Mazdak Momeni Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Loma Linda University Medical Center, Loma Linda, CA, USA Molly B. Moravek Department of Obstetrics and Gynecology, University of Michigan Health System, Ann Arbor, MI, USA Elise Morocco Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Youssef Mouhayar Department of Obstetrics and Gynecology, Jackson Memorial Hospital, Jackson Health System, Miami, FL, USA Laila Muderspach Department of Gynecologic Oncology, University of Southern California, Los Angeles, CA, USA Melissa Myo Section of Family Planning, Department of Clinical Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Satoshi Nakagawa Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Anita L. Nelson Department of Obstetrics & Gynecology, Western University of Health Sciences, Pomona, CA, USA Department of Obstetrics & Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Contributors

Contributors

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Monica K. Neuman Department of Gynecologic Oncology, University of Southern California, Los Angeles, CA, USA Brian T. Nguyen Section of Family Planning, Department of Clinical Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Mikio A. Nihira Department of Obstetrics and Gynecology, UC Riverside School of Medicine & KPC Healthcare, Riverside, CA, USA Katherine Nixon Department of Gynecology, Imperial College NHS Trust, Queen Charlottes and Hammersmith Hospital, London, UK Tina O’Shea Obstetrics and Gynecology, University of Florida, College of Medicine, Gainesville, FL, USA Begüm Özel Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA William H. Parker Department of Obstetrics, Gynecology, and Reproductive Services, UC San Diego School of Medicine, La Jolla, CA, USA Stephanie D. Pickett The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Alexander M. Quaas Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology and Infertility, University Hospital Basel, Basel, Switzerland Philipp Quaas Department of Obstetrics and Gynecology, University Hospital Basel, Basel, Switzerland Alexandra Regens Health Sciences Center, University of Oklahoma, Oklahoma City, OK, USA Jessica Reid Oregon Health & Science University, Portland, OR, USA Anna E. Reinert Department of Obstetrics and Gynecology, LAC+USC Medical Center, Los Angeles, CA, USA Department of Obstetrics and Gynecology, Keck University School of Medicine, Los Angeles, CA, USA Caryl S. Reinsch Kaiser Permanente Southern California, San Diego, CA, USA Valentina M. Rodriguez-Triana University of California Los Angeles, Los Angeles, CA, USA Cassandra Roeca Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA Shady Grove Fertility, Greenwood Village, CO, USA Renee Rolston Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

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Lynda D. Roman Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Brianne D. Romeroso Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Michael Saad-Naguib Department of Obstetrics and Gynecology, Jackson Health System, Jackson Memorial Hospital/University of Miami Miller School of Medicine, Miami, FL, USA Alejandra Salazar Department of Obstetrics and Gynecology, University of Miami/Jackson Memorial Hospital, Miami, FL, USA Daman Samrao Laboratory Medicine Consultants, Las Vegas, NV, USA Tomoyuki Sasano Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Anastasiya Shabalova University of Southern California, Los Angeles, CA, USA Mian M. K. Shahzad Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA Mariko Shindo Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Donna Shoupe Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Dana Siegel Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO, USA Paul P. Smith Birmingham Women’s NHS Foundation Trust, Edgbaston, UK Lisa B. Spiryda Obstetrics and Gynecology, Phelps Hospital-Northwell Health; Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA Ryoko Takahashi Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Yoko Takashima Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Amin Tavakoli Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA

Contributors

Contributors

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Katherine E. Tierney Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Northwest Permanente Physicians and Surgeons, Clackamas, OR, USA Emma Torbé Great Western Hospitals NHS Foundation Trust, Swindon, UK Teresa Tseng Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Yutaka Ueda Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Caroline J. Violette Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA Katrina Wade Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Ochsner Medical Center, New Orleans, LA, USA Saloni Walia Department of Pathology and Laboratory Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA Alexandra Walker Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, FL, USA Yan Wang Department of Pathology, Kaiser Roseville Medical Center, Roseville, CA, USA Kristy K. Ward Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, West Virginia University, Morgantown, WV, USA Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Florida College of Medicine Jacksonville, Jacksonville, FL, USA Elizabeth Weedin University of Oklahoma Health Science Center, Oklahoma City, OK, USA Jamie Wilkerson Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OK, USA Kristina Williams Department of Obstetrics and Gynecology, Cooper University Health Care, Camden, NJ, USA Irene Woo Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Terri L. Woodard Baylor College of Medicine, Houston, TX, USA The University of Texas MD Anderson Cancer Center, Houston, TX, USA Terez A. Yonan Department of Pediatrics, Division of Adolescent Medicine, Children’s Health of Orange County, Orange, CA, USA

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Kiyoshi Yoshino Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Austin Zanelotti University of Miami/Jackson Memorial Hospital, Miami, FL, USA Mya Rose Zapata UCLA Medical Center, University of California, Los Angeles, CA, USA

Contributors

Part I General Office Gynecology

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Anatomy of the Female Genital System Dalal Eldick and Fausto F. Andrade

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Genital Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adenexal Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Support Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Ureter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Vulva and Erectile Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Pelvic Bones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Bones and Ligaments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Avascular Planes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4 4 5 6 6 7 7 8 8 8 9 9

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Abstract

Female pelvic anatomy requires a great deal of comprehensive knowledge that can often seem unattainable. This chapter focuses on the basics of this arena into thirteen sections that may be easier to understand once separated. These 13 sections will cover the uterus, adnexa, and vulvar organs as well as the pelvic

bones, vessels, and innervation. With the addition of specific and important surrounding structures and planes, there is emphasis on clinical and surgical application. This information is geared toward a better understanding of the female anatomy for the gynecologist, internist, and family physician, but it is particularly directed to the pelvic surgeon performing laparotomy and/or laparoscopy within this area. Keywords

D. Eldick (*) · F. F. Andrade Department of Obstetrics and Gynecology, University of Miami/Jackson Memorial Hospital, Miami, FL, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_14

Female pelvic anatomy · Pelvis · Gynecology · Surgical gynecology

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Introduction The word “gynecology” was first used in the middle of the nineteenth century. Gynecological anatomy was first explored in Alexandria by the Roman physician, Soranus. Soranus was interested in the disease of women and children, and one of his most important textbooks was named Gynecology. He focused his textbook on normal and abnormal anatomy, care of the newborn, and care of abnormal pregnancy but is particularly remembered for describing the anatomy of the anatomy of the gravid uterus. It was the Hungarian obstetrician, Dr. Ignaz Semmelweis, who pioneered the way with the importance of hygiene in preventing postsurgical sepsis. Two fathers in the world of surgical gynecology that need recognition are Dr. Ephraim McDowell who performed the first ovarian cystectomy and Dr. James Marion Sims who performed the first vesicovaginal fistula repair. These are the leaders that paved the way for a modern understanding of gynecological anatomy in the nongravid woman and the techniques of surgical repair. It is interesting that the first recorded surgery in history is a cesarean section that remarkably showed a fairly contemporary understanding of gynecological anatomy. This dichotomy can be better understood by the words of medical historian Howard Kelly when he stated “the history of gynecology seems to me more full of dramatic interest than the evolution of any other medical or surgical specialty.” However, before understanding the gravid state or the pathology that can affect this system, it is important to know the foundation of its anatomy. This chapter is divided into 13 sections. The anatomy of the female genital system including the uterus, adnexa, and vulva along with the blood vessels, lymphatics and nervous system is addressed below (Baggish 2011; Howard and Rock 2015).

Genital Structures Vagina • The vagina is a flexible viscus that is shaped by its surrounding structures and its attachments to its adjacent walls.

D. Eldick and F. F. Andrade

• The vagina is bent at a 120 angle at the distal one third and proximal two third junction at the level of levator ani attachment. It is typically 7–9 cm in length with the anterior wall typically shorter by 3 cm than the posterior wall as this is where the cervix lies. But these dimensions vary between individuals. • The vagina’s anatomical relations can be best understood by dividing it into thirds. The distal one third is fused anteriorly with the urethra and posteriorly with the perineal body and laterally to the levator ani by the fibers of Luschka. The mid one third portion of the vagina is comprised of the vesicle neck and trigone anteriorly, the rectum posteriorly, and the levators laterally. The proximal one third of the vagina is adjacent to the bladder and ureters anteriorly, posteriorly to the cul-de-sac, and laterally to the cardinal ligaments. • The wall of the vagina is compromised of the same layers of all hollow viscera which include the mucosa, submucosa, muscularis, and adventitia. This holds true for all parts of the vagina excluding the segment covered by the cul-de-sac which contains no serosal layer. The vaginal mucosa is nonkeratinized squamous epithelium. The submucosa is a dense, dermis-like layer and is fused with the muscularis in a bihelical arrangement. Outside the muscularis is the adventitia which is the connective tissue labeled “endopelvic fascia.”

Uterus The Uterine Corpus • The uterus is a fibromuscular organ that varies in shape and size according to the amount of estrogen stimulation and previous parity. It is divided into two parts: the upper muscular corpus and the lower, fibrous cervix. The corpus is generally much larger than the cervix in women of reproductive age (particularly in gravid women). However, in prepubescent girls and menopausal women, the sizes of both these structures are more equal. • The uterus is divided into three layers: the endometrium, a surrounding thick muscular wall called the myometrium, and the top layer

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called the serosa. The endometrial cavity is triangular in shape. The top of the endometrial cavity is called the fundus. The endometrium is comprised of glandular columnar epithelium and specialized stroma. The myometrium is the thickest part of the uterus and is comprised of smooth muscle. The serosa consists of the visceral peritoneum.

The Uterine Cervix • The cervix is a tubular structure that serves as a channel between the vagina and uterine corpus. It is comprised of two portions: the portio vaginalis which protrudes into the vagina and the superior portion called the portio supravaginalis that is above the vagina but below the corpus. The portio vaginalis is made up of nonkeratinized squamous epithelium. Its endocervical canal is made up of columnar mucussecreting epithelium. • The proximal border of the cervical canal is defined by the internal os that opens into the endometrial cavity. The distal border is defined by the external os that incorporates the squamous epithelium of the portio vaginalis and the glandular epithelium of the endocervical canal. This squamocolumnar junction is termed the “transition zone” and is particularly subject to malignant transformation. • The cervix is covered laterally by the broad ligament and anteriorly by the bladder and posteriorly serves as the anterior boundary of the posterior cul-de-sac (pouch of Douglas). The posterior segment of the cervix is the only part that has a serosal covering.

Adenexal Structures The Fallopian Tubes • The fallopian tubes are paired tubular structures that serve as highways between the ovaries and uterus. They typically range 7–12 cm in length. Each tube is divided into four parts. The portions include the interstitium, where the tube passes through the uterine cornu, the isthmus that is the narrowest segment of the

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tube comprised of a thin lumen and a thick muscular wall, the ampulla that contains an expanding lumen and muscular folds, and the infundibulum located at the end of the tube forming smooth muscle projections to increase the surface area for facilitating ovulated ova pick-up. The lumen of the fallopian tube thus connects the uterine cavity to the abdominal cavity. • The inner layer of the fallopian tube, the internal mucosa (endosalpinx), is comprised of three types of columnar epithelium: secretary, ciliated, and peg cells. The endosalpinx is arranged in folds that increase in number toward the fimbria. • The middle muscular layer (myosalpinx) of the fallopian tube is composed of an outer layer of longitudinal smooth muscle fibers and an inner circular layer. A third layer is added in the interstitial portion. • The outermost layer of the fallopian tube, the serosa, is composed of an epithelial layer that is histologically the same as peritoneal cells. The mesosalpinx is part of the broad ligament that stretches from the ovary and wraps round the fallopian tube forming the serosal layers.

The Ovaries • The ovary is suspended laterally to the pelvic wall by the infundibulopelvic (IP) ligament. The IP contains the ovarian artery and vein. The ovary is connected medially to the uterus by the utero-ovarian ligament. It measures about 2.5–5 cm long, 1.5–3 cm thick, and 0.7–1.5 cm wide depending on its activity or suppression during reproductive life. • The ovary’s external epithelial layer is composed of cuboidal germinal cells. For ovulation, this layer is ruptured. Beneath this layer is a layer of dense connective tissue, the tunica albuginea. The external layer or ovarian cortex contains ovarian follicles with stroma between them. The cortex also contains corpora lutea and corpora albicantia. • The innermost layer is the ovarian medulla. The medulla is fibromuscular with many blood vessels and connective tissue.

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• The mesentery of the ovary is called the mesovarium. The mesovarium is the portion of the broad ligament that reflects onto and holds the ovary in place. The mesovarium does not cover the ovary. • The round ligaments extend from the uterus laterally and are a homolog of the gubernaculum testis. After moving laterally from the deep inferior epigastric vessels, they become rounded and enter through the inguinal canal to the subcutaneous tissue of the labia majora. The mesentery of the round ligament and uterus is called the mesometrium. The ovaries and fallopian tubes form the adnexa.

Support Structures • The parametrium is composed of the fibrous tissues that connects to the uterus and separate the supravaginal portion of the cervix from the bladder. The parametrium extends laterally between the two layers of the broad ligament. The uterosacral and cardinal ligaments form the medial and lateral borders of the parametrium. These ligaments extend laterally from the cervix to the pelvic wall. These ligaments form the suspensory tissues that hold the cervix posteriorly in a position over the levator plate of the pelvic diaphragm. • The uterosacral ligament marginates the culde-sac of Douglas. It is formed by a combination of smooth muscle, autonomic nerves, connective tissues, and blood vessels. The uterosacral ligament extends from the posterior base of the uterus to the anterior sacrum. • The cardinal ligament attaches at the isthmus above the cervix and attaches to the pelvic wall over the piriformis muscle in the greater sciatic foramen. The cardinal ligament provides support for the uterus, cervix, and upper portion of the vagina, whereas the uterosacral ligament only provides support for the uterus and cervix.

D. Eldick and F. F. Andrade

Blood Supply • The aorta provides the blood supply to the pelvic structures through both the iliac branches and the ovarian artery. The aorta bifurcates at spinal level L4–L5 into the right and left common iliac arteries. The common iliac arteries are only about 4 cm long as they run along the psoas muscles and bifurcate at the pelvic brim forming the external and internal (hypogastric) iliac arteries. The internal iliac artery is the main blood supply to the pelvic organs. The branches of the iliac artery are variable but include the uterine, vaginal, obturator, inferior vesical, middle rectal, and internal pudendal arteries: – The uterine artery enters the uterus at the junction of the corpus and cervix and rises laterally. It also flows into the marginal artery on the side of the uterus and thus is able to provide upward and downward flow to the uterus. – The vagina receives its blood supply from the uterine artery and the vaginal branch of the internal iliac artery, and they anastomose at 3 o’clock and 9 o’clock positions of the vagina. The distal vagina also receives blood from the pudendal and hemorrhoidal vessels. – Bifurcation of the internal and external iliac blood vessels occurs within the sacroiliac joint. Before descending under the inguinal ligament, the external iliacs give form to the deep circumflex and deep inferior epigastric vessels. The internal iliac artery supplies the pelvic structures and splits into anterior and posterior divisions about 3–4 cm after leaving the common iliac artery. The posterior division is comprised of the iliolumbar, lateral sacral, and superior gluteal vessels that supply the pelvic wall and gluteal region. The anterior division is comprised of the obturator, internal pudendal, and inferior gluteal branches that supply pelvic muscles; the uterine, superior vesicle, inferior vesicle (vaginal), and middle rectal supply pelvic

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Anatomy of the Female Genital System

organs. Ligation of the internal iliac artery is helpful in the management of postpartum hemorrhage. • The adnexa blood supply consists of the ovarian artery, which is a branch of the aorta just below the renal artery. The venous plexus drain into the vena cava on the right and the renal vein on the left. The ovarian artery and vein also pass along the ovarian mesentery to connect with the upper part of the marginal artery of the uterus.

Innervation • Many of the pelvic structures are innervated by nerves originating from the sacral plexus, coccygeal plexus, and pelvic autonomic nerves: – The sacral plexus (innervated by the 4–5th lumbar spinal nerves) runs down the posterior pelvic wall anterior to the piriformis muscle. The nerves that form from the sacral plexus include pudendal nerves (clitoris), perforating cutaneous and posterior femoral cutaneous nerves, pelvic splanchnic nerves, sciatic nerve, superior and inferior gluteal nerves, as well as the nerve to the obturator internus, piriformis, and quadratus femoris muscles. – Coccygeal nerves (formed by the 4th and 5th sacral spinal nerves) innervate the coccygeus and levator ani muscles and that sacrococcygeal joint. – Pelvic autonomic nerves control blood flow, peristalsis, contraction of the bladder and rectum, and hormone levels. They include sacral sympathetic trunks, superior hypogastric plexus, inferior hypogastric plexuses, and pelvic splanchnic nerves. • The ovaries and fallopian tubes are innervated by the T10–11 renal plexus and the parasympathetics of the vagus nerve. • The superior hypogastric plexus (L1–2) receives input from the splanchnic nerves and afferent pain input from the pelvic viscera. Parasympathetic input derives from S2 to S4. • The inferior hypogastric plexus (L2–5) is comprised of three parts: vesical plexus, uterovaginal plexus, and middle rectal plexus.

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It can be affected during parametrial tissue dissection during hysterectomies and cause postoperative voiding dysfunction and urinary retention. • The uterus receives nerve innervation via the uretovaginal plexus called Frankenhauser ganglion. This plexus lies medical to the medial to the uterine vessels and lateral to the uterosacral ligament and receives sympathetic input from T10 to L1 and parasympathetic input from S2 to S4. Its caudal fibers also innervate the vestibule. • During surgery it is important to be cognizant of nerves that may be injured. Retraction during laparotomy can cause injury to the genitofemoral branch of the lumbosacral plexus (L1–L2), leading to anesthesia to the lateral labia and medial thigh. Retraction or hyperflexion of the hip while in lithotomy position can cause injury to the femoral cutaneous nerve (L2–L3), leading to anesthesia or abnormal sensation to the anterior thigh.

Lymphatics • Most of the lymph nodes of the pelvis follow the corresponding blood vessels. • The ovaries drain into the para-aortic lymph nodes. During dissection, the boundaries are the following: superiorly includes the origin of the inferior mesenteric artery, inferiorly is the midportion of the common iliac and laterally bordered by the ureters. • Lymph drainage from the uterus flows in the direction of its attachments, starting with the cardinal, uterosacral, and eventually round ligaments. These drain into internal iliac nodes. • Within the pelvis, lymph node chains can be divided into external iliac, internal iliac, common iliac, medial sacral, and pararectal nodes. The medial and pararectal nodes are rarely involved in gynecological diseases. • External iliac nodes receive drainage from the inguinal nodes from the leg. • Internal iliac nodes drain the pelvic viscera, and most of these nodes lie in adipose along the lateral pelvic wall.

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• The upper two thirds of the vagina and bladder drain into the uterine lymphatics into the internal iliac lymph nodes. The lower one third of the vagina and distal urethra drain into the inguinal nodes.

The Ureter • The ureter is medial to the ovarian vessels when it crosses over the bifurcation of the internal and external iliac arteries entering the pelvic brim. Upon entering the pelvis, it lies in connective tissue attached to the peritoneum of the lateral pelvic wall and medial leaf of the broad ligament. It then passes under the uterine artery at 1.5 cm lateral to the cervix. It then lies on the anterior wall of the vagina where the cervix is detached during a hysterectomy.

The Vulva and Erectile Structures • The bony outlet of the pelvis is bordered by the ischiopubic rami anteriorly and the coccyx and sacrotuberous ligaments posteriorly and divided into anterior and posterior triangles. These triangles share a base between the ischial tuberosities. The layers of the anterior triangle mimic that of the abdominal wall. The superficial layer is composed of the vulva, overlying the fascial layer that is the perineal membrane and deep to that is the muscular layer comprised of the levator ani muscles. • The structures of the vulva consist of the mons, labia, clitoris, vestibule, and associated erectile structures. The mons lies on the pubic bone in a layer of adipose and hair-covered skin. Posteriorly from the mons lies the labia majora which also shares the same hair-covered skin. The labia minora, vestibule, and glans clitoris lie between the labia majora. The labia minora are skin folds that split anteriorly over the clitoris. • The vestibule is the area between the labia minora, where the urethral introits and vaginal introituses are located. The hymenal membrane is a ring that surrounds the vaginal orifice. The ducts of the bartholin’s glands are

D. Eldick and F. F. Andrade

located posterior laterally of the vestibule at 4 o’clock and 8 o’clock. The ducts of the Skene’s glands are located laterally of the urethra within the vestibule. Blockage of these ducts can cause cysts or abscesses. • The pudendal nerve (S2–S4) supplies sensory and motor innervation to perineum. The blood supply originates from the pudendal artery. The nerve and artery are differentiated into three branches: the clitoral, perineal, and inferior hemorrhoidal.

The Pelvic Bones • In order to assume an upright position, without pelvic organs descending out through the abdominopelvic cavity, a support system is crucial. This system is called the pelvic floor and consists of the levator ani muscles and perineal membrane. • The perineal membrane, formally called the urogenital diaphragm, forms the inferior portion of the anterior pelvic floor. It provides support to the posterior vagina by forming the attachment between it and the perineal body and then from perineal body to the ischiopubic rami. It can be torn during parturition and that can result in abnormal descent of the pelvic floor. • Cephalad to the perineal membrane are the compressor urethral and urethral vaginal sphincter that help the two urethral sphincter muscles to compress the distal ureter. It is controlled by a branch of the pudendal nerve. • The perineum is the genital skin between the thighs including the external genitalia and anus. The perineal body consists of the lower vagina and skin of the perineum and anus. • The ischiorectal fossa forms the posterior triangle of the pelvis and lies between the levator ani muscles (they lie medially and superior) and the obturator internus muscle (lies laterally). It contains the external anal sphincter and the pudendal neurovascular trunk. • The external anal sphincter is attached to the coccyx posteriorly and attaches fibers to the perineal body superiorly. The internal anal sphincter is a smooth muscle that can be torn during labor and delivery (fourth degree laceration).

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• The levator ani muscles are composed of the pubococcygeus, puborectalis, and iliococcygeus muscles. The medial area that contains the openings of the urethra, vagina and rectum is called the urogenital hiatus. The sling of anterior support for this area is formed by the pubococcygeal and puborectal muscles. The posterior portion of support is formed by the iliococcygeus muscle.

Pelvic Bones and Ligaments • The bones of the pelvis are comprised of the ilium, ischium, pubis, sacrum, and coccyx. • In a standing woman, the anterior superior iliac spines (ASIS) and front of the pubic symphysis are in the same plane, perpendicular to the floor, tilting the pelvic inlet anteriorly and making the urogenital hiatus and ischiopubic rami parallel to the ground. • The ischial spines can be palpated vaginally and rectally and serve as a point of fixation for pelvic support structures such as levator ani muscles and sacrospinous ligament. The ischial spine is also palpated to determine fetal station during labor. • Beneath the pubic symphysis, two pubic bones form the pubic arch which can vary between 44 and 110 (mean angle is 75 ). The pubic arch in men is generally 50–60 and that of women is around 70–90 . A narrow pubic arch can result in dystocia during labor and delivery. • The pubic symphysis normally has a 4–5 mm gap, but it has increased mobility during pregnancy. It can become abnormally separated during childbirth called pubic diastasis. Greater than a 2 cm gap requires surgical intervention. • The sacrospinous ligament is a strong, triangular shaped ligament that divides the lateral pelvic outlet into the greater and lesser sciatic foramen. It is an attachment point for the vaginal apex in the treatment of vaginal prolapse. • The sacrotuberous ligament is also triangular shaped and forms the inferior lateral border of the lesser sciatic foramen. The apex is attached to the medial ischial tuberosity.

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Avascular Planes • The anterior cul-de-sac, also known as the vesicouterine pouch, is the space that separates the uterus from the dome of the bladder. During hysterectomy the vesicouterine peritoneal fold is dissected off the bladder to enter the vesicovaginal space. • The posterior cul-de-sac, also known as the pouch of Douglas or rectouterine pouch, is the space between the uterus and rectum. • The prevesical space of Retzius separates the bony pelvis and rectus muscles. It is bounded dorsally by the proximal urethra and bladder. • The rectovaginal space is located dorsally to the vagina and it begins at the apex of the perineal body. The lower urinary and lower genital tracts are separated by the vesicovaginal space and vesicocervical space.

Cross-References ▶ Benign Vulvar and Vaginal Pathology ▶ Laparoscopic Hysterectomy ▶ Management of Intraepithelial Lesions of the Cervix ▶ Operative Hysteroscopy ▶ Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications ▶ Vaginal Hysterectomy: Indications, Avoiding Complications

References Baggish MS. Introduction to pelvic anatomy. In: Baggish MS, Karram MM, editors. Atlas of pelvic anatomy and gynecologic surgery. 3rd ed. St. Louis: Elsevier Saunders; 2011. Howard JW, Rock JA. Te Linde’s operative gynecology. 11th ed. Philadelphia: Wolters Kluwer; 2015. http://www.uptodate.com/contents/surgical-female-pel vic-anatomy http://www.uptodate.com/contents/surgical-female-urogen ital-anatomy

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Gynecologic History and Examination of the Patient Alejandra Salazar and Fausto F. Andrade

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gynecologic History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obstetrical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical and Surgical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Family History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Social History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12 13 13 13 14 14

Focused History/Common GYN Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abnormal Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaginal Discharge/Itching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contraceptive Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Organ Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14 14 15 15 15 16 16

Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 When to Start? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Components of the Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Tests Performed on Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Pap Smear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 STD Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Abstract

A. Salazar (*) · F. F. Andrade Department of Obstetrics and Gynecology, University of Miami/Jackson Memorial Hospital, Miami, FL, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_15

Gynecologists are primary care providers for women. It is very important that a complete, comprehensive history and physical examination are performed and that every aspect of the patient’s health is addressed during the gynecologic visit. The patient interview should 11

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A. Salazar and F. F. Andrade

include gynecologic and obstetrical histories, as well as past medical, surgical, family, and social history. Once an overview of the patient’s health history is completed, focus can then be turned into specific complaints. In gynecology, these often are vaginal complaints, abnormal uterine bleeding, contraception counseling, fertility issues, urinary incontinence and prolapse, menopausal symptoms, or problems during intercourse. Attention should be also placed on complaints that can be associated with increased risk for gynecologic malignancies. Physical exam will then complete the encounter. The exam is focused on the patient’s chief complaint but should also include a general overview. At this time, appropriate screening testing can be performed and specific issues addressed. The goal of the gynecologic visit is to address all of the woman’s concerns, to obtain significant information that will guide diagnostic testing and treatment recommendations, and to develop a relationship between the practitioner and patient that will benefit the patient’s health status and future well-being. Keywords

Interview · Medical history · Gynecological history · Abnormal bleeding · Vaginal discharge · Physical examination · Pelvic examination · Speculum examination · Pap smear · Sexually transmitted diseases · Well woman exam · Gynecologic exam

when it is time for their Pap smear testing. In recent years, early establishment of gynecologic care before a Pap smear is needed and has been encouraged, as women become sexually active earlier, and there are many bleeding problems that can arise after menarche and during puberty. Today, women are encouraged to have their first gynecologic appointment at around age 13–15. This visit will be the most important and will create an impression that the patient will carry for the future. Accurate and complete history and physical examination are the most important tools in screening, diagnosis, and counseling that are performed by a healthcare provider. A detailed review of a patient’s health status, previous medical conditions, and gynecologic history provides pertinent and important information that guides the physical and pelvic examination, furnishes the indications for screening, and directs the selection of diagnostic testing and imaging studies needed to arrive at a correct diagnosis and treatment plan. Care of each patient should be individualized and tailored to each woman’s specific needs. Every aspect of the history and physical examination that should be addressed in the initial visit as well as the most common complaints seen in a gynecologic visit is outlined in this chapter. The goal of the physician-patient encounter is to provide a safe environment in which the patient can be honest and open and to ensure that all her concerns are addressed appropriately. After requisite knowledge of the patient is obtained, diagnostic and treatment recommendations can be made with confidence.

Introduction

History

Every woman at some point in her life will have a gynecologic complaint. With the passing of time, gynecologists have become primary health providers, available for firsthand general healthcare. As women usually go to the gynecologist every year, it is important that a good relationship is established between the patient and the healthcare provider with a level of trust that will allow for a complete and effective history and physical examination. Traditionally, women visit the gynecologist

Learning about a person’s medical history can aid the physician in coming up not only with a differential diagnosis for the presenting complaint but it may also discover other abnormalities that need further investigation. It is very important, as a clinician, to take relevant but at the same time complete histories that are complementary to the patient’s chief complaint. In gynecology, there are several topics that particularly need to be addressed.

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Gynecologic History and Examination of the Patient

Gynecologic History Components of a complete gynecologic history generally first include bleeding history: • For premenopausal women, age of menarche, frequency, regularity, and length of the menstrual period are documented. It is important to address amount of flow as well, the number of pads used per day, and the occurrence of intermenstrual bleeding. Amenorrhea, irregular periods, dysmenorrhea (painful periods), and menorrhagia (heavy periods) may signal ovulatory dysfunction, structural abnormalities, or endocrine problems. All this information allows the practitioner to interpret these patterns based on the female’s age and comorbidities and to determine which problems can be easily managed (NSAIDs or OCPs) or those that may be more serious and require immediate attention (bleeding disorders, Müllerian disorders). • Once the female is over 35 or perimenopausal, the pattern and frequency of bleeding may direct the provider toward performing endometrial sampling to rule out hyperplasia or cancer diagnosis. For postmenopausal women, the occurrence of unexplained bleeding generally requires endometrial sampling. • The next part of the gynecologic history involves questions related to sexual intercourse. At this time in the interview, it is vital that the patient is comfortable with the interviewer so responses are accurate and detailed: – For younger, reproductive-aged patient, information on coitarche, as well as number of sexual partners currently and in the last year, is documented. Contraceptive history, present use, side effects, reasons for discontinuation, as well as condoms for STD protection are also important information. – For perimenopausal and postmenopausal women, emphasis is placed more on problems of dyspareunia or changes in sexual desire. In both younger and older patients with sexual problems, questions related to vulvovaginal lesions, discharge, pain, or itching are pertinent.

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Finally, the interview includes history of Pap smears including dates and results. Documentation in the chart includes results of the patient’s last Pap smear, when and where it was performed, HPV status, and whether there have been any abnormalities in her cytology in the past. • As this is the most important screening tool that gynecologists have for cervical cancer, it is necessary to collect enough information so the guidelines can be followed and patients can be screened correctly, avoiding unnecessary testing.

Obstetrical History Obstetrical history should include number of total pregnancies and the outcomes of each pregnancy, including full term, preterm, abortions (medical or surgical), miscarriages, and number of live children. For reproductive-aged patients, details pertaining the types of delivery, complications such as preeclampsia, and desire for future fertility are documented. This information provides the clinician with the tools necessary to counsel the patient about the risks of future pregnancies or the need for cesarean section. For example, women with previous ectopic pregnancy have a higher probability of having another ectopic pregnancy in the future.

Medical and Surgical History Existent medical conditions are basic components of a complete patient interview. In gynecology, it is primordial to know about history of coagulopathies; history of easy bruising; epistaxis, which can explain irregularities in the menstrual period; endocrine or developmental disorders, which can explain problems like infertility; hirsutism; as well as history of malignancies, which can show genetic predisposition to gynecologic cancers. It is also important to review the medical problems of each patient, the medications they are on, and their compliance with medical care:

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• Treatment for some conditions can cause gynecologic symptoms or problems in women. An example of this is tamoxifen, an estrogen receptor antagonist used to treat breast cancer, which can cause thickening of the endometrium. • Patients should be asked about recent weight gain, weight loss, or any other symptoms of thyroid dysfunction. Inquiry should be also made for any signs/symptoms of anemia. History of previous surgeries will clue the practitioner into the source of a woman’s pain, helping to either rule out causes in which organs have been surgically removed, or attribute the pain to the fact that the patient has had previous abdominal surgeries. The location of previous surgery, type (laparoscopic vs open), and procedures performed will give the surgeon the necessary tools needed in case new surgical intervention is needed. This information will also tailor the physical examination to specific parts that are relevant to the individual being seen.

Family History Many gynecologic conditions have genetic components that predispose patients to serious diseases, particularly as they become older. Thus, it is important to obtain a detailed family history of first-degree relatives: • It is known that women with Lynch syndrome have an increased risk of developing endometrial cancer. This is why gynecologists need to inquire about family history of breast, colon, and endometrial cancer. • Ovarian and breast cancer may have genetic component [BRCA mutations]. • Clotting problems, diabetes, osteoporosis, and dementia can also have a genetic or familial component.

A. Salazar and F. F. Andrade

consumed, (how many drinks per week and specific type of drink as alcohol content and effects change), cigarettes smoking (pack per year history and desire to quit), as well as any other drug use: • If the patient admits to alcohol use, a CAGE questionnaire can be used to determine if the patient is alcohol-dependent or addicted so that the right referrals can be made. This can also lead to the discovery that the patient has an underlying psychiatric disorder, such as depression, that she is self-treating with alcohol. The use of drugs such as marijuana, cocaine, crack, and methamphetamines can have serious consequences in the overall well-being of an individual. As physicians, gynecologists have the obligation to offer addiction counseling to all patients who are dependent on any substance. This can improve their overall health status as well as avoid future medical emergencies. Tobacco use should be addressed with every patient. If there is a desire to quit, women can be referred to a quit-line and/or given prescriptions such as nicotine patches or gum, as well as antidepressants to aid in this difficult process. • Patients need to be counseled about the fact that smoking is proven to increase the risk of lung, throat, bladder, colon, rectum, blood, mouth, stomach, esophagus, kidney, and cervix cancer as well as preterm labor, low birthweight, or birth defects. Social history also includes domestic violence screening. Specific questions are important to obtain accurate information and make the appropriate referrals. The well-being of the individual in all aspects is the ultimate goal of the health-provider-patient relationship.

Focused History/Common GYN Complaints Abnormal Uterine Bleeding

Social History Gynecologists are the main care providers for many women. Important questions pertaining to social behavior include amount of alcohol

• For reproductive-aged women, uterine bleeding becomes abnormal when it differs from a woman’s usual cycle. Heavy menstrual bleeding is defined as >80 mL blood loss per period,

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changing a pad or tampon after less than 2 h, passing clots the size of a quarter or larger, or periods lasting longer than 7 days. It is important to ask how many pads are used during the day with a period and the duration of the period every month (American College of Obstetricians and Gynecologists 2012). In the adolescent female, abnormal bleeding is most likely secondary to immaturity of the hypothalamicpituitary axis. However, it can also indicate an underlying bleeding disorder (Mullins et al. 2015). In reproductive-aged women, the algorithm of PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) is used to determine the etiology for abnormal uterine bleeding. The most common causes of bleeding in perimenopausal women include uterine pathologies and anovulatory bleeding.

volume of discharge along with sexual history. A complete picture is obtained once a pelvic examination is performed.

Postmenopausal bleeding should raise concern for endometrial carcinoma until proven otherwise (Moodley and Roberts 2004). Menopause is defined as 12 months of amenorrhea after the last period. Any bleeding after this should be evaluated immediately. This complaint accounts for about 5% of office gynecologic visits. • A common cause of postmenopausal bleeding is vaginal atrophy. Other etiologies include hyperplasia, polyps, and fibroids as well as liver, thyroid, or kidney disease.

Vaginal Discharge/Itching Vaginal discharge can be physiologic and found in every woman during the physical exam. However, vaginal discharge is one of the most common complaints that brings patients to the gynecologist’s office. Physiologic discharge is clear, cloudy, white or light yellow. Generally, it is scant, watery or very thin, asymptomatic and not foul smelling. Abnormal discharge may represent vaginitis or a sexually transmitted diseases. During the interview, the patient is asked about the onset, duration, consistency, color, odor, and

Pelvic Pain Pelvic pain is a vague and common complaint. Because there can be multiple causes, important questions need to be asked at the time of interview to guide the physical exam. The gynecologist needs to know about the type of pain; exact location and radiation; timing, including if pain occurs during periods or becomes worse during periods; and severity. The effect of associated factors such as sexual activity, menstruation, or physical activity may provide clues as to the etiology of pelvic pain (Reiter 1990). Associated urinary or gastrointestinal symptoms may guide the diagnosis away from a gynecologic cause and referral for further evaluation by other specialists: • Differential diagnosis for pelvic pain includes ovarian cyst, hemorrhagic cysts, ovarian torsion, endometriosis, adhesions, complication of pregnancy, or pelvic inflammatory disease. • A comprehensive interview guides the physician to evaluate particular aspects of the physical exam and to which diagnostic studies needed.

Contraceptive Counseling Even though there are multiple methods of contraception, not all of them are right for the same patient. It is important at the time of the interview to assess if the patient is using or wants to use contraception for protection against unintended pregnancy or against sexually transmitted diseases or both (Steiner 1999). The patient at this time of the interview needs to talk about prior contraceptive use, as well as medical conditions or social habits that will prevent her from using certain contraceptive methods: • Both the WHO and CDC have published eligibility criteria for the use of hormones for contraception, including relative and absolute

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contraindications for their use (US Selected Practice Recommendations for Contraceptive Use 2013; WHO 2009; Centers for Disease Control and Prevention 2010). Migraine headaches, smoking, and hypertension are common problems that limit the use of combination oral contraceptive pills. • Hormonal contraception such as the birth control pills or progestin IUD or injections can also be used to treat conditions such as menorrhagia secondary to anovulatory bleeding. • The presence of acne or PMS is often improved on selected combination oral contraceptive pills.

Infertility Not being able to conceive is a common gynecologic complaint. Most women think that getting pregnant is easy and that after trying for 1 month they should be able to get pregnant. Thus, it is primordial that patients are explained during their gynecologic visit that infertility is defined as failure to conceive after 12 months of regular intercourse (for 6 months if over 35 years of age). For women with regular cycles, an infertility work-up is generally initiated after 12 months of trying to conceive (Practice Committee of American Society for Reproductive Medicine 2012): • The gynecologist should inquire about the partner, if he has had any children in the past and if he has had his semen tested to rule out male infertility. • The initial work-up includes a day 21 progesterone, TSH, metabolic panel, CBC, and blood type and a day 3 FSH for women 35 and older. A pelvic ultrasound or hysterosalpingogram is used to assess tubal and uterine problems. • Ovulation induction with Clomid or letrozole is used for anovulatory patients.

Pelvic Organ Prolapse Pelvic organ prolapse is diagnosed primarily during the physical exam. However, the patient may

A. Salazar and F. F. Andrade

present complaining of urinary incontinence, looseness on intercourse, splinting, frequent urinary tract infections, vaginal pressure, or a vaginal “bulge.”

Physical Examination When to Start? ACOG recommends that the initial reproductive health visit should begin between the ages of 13 and 15 (Committee opinion 598 2014). This should include a complete history, as well as a physical examination including a general examination, visual examination of the breasts, and an external vaginal exam. Pelvic examination is only performed when the patient has a particular symptom or when screening with a Pap smear. An internal examination should be performed if the clinician is concerned about information elicited in the history of the patient Committee on Gynecologic Practice (2012): • Screening with Pap smear begins at 21 years of age and from then on following ASCCP guidelines. Some practices require that throughout the physical examination, a chaperone must be in the room.

Components of the Physical Exam Breast Exam The breast examination is performed visually first, noting any gross abnormalities, masses, or defects. Palpation is then performed with the preferred technique examining the breast in vertical strips beginning in the axilla and extending in a straight line down the midaxillary line to the bra line. The fingers are then moved medially and continued in an up and down movement between the clavicle and the bra line making circular motions with the pads of the middle three fingers. Each breast area is examined with three different pressures lasting for at least 3 min in each breast (Barton et al. 1999).

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Gynecologic History and Examination of the Patient

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Abdominal Exam Abdominal exam should include inspection, auscultation, palpation, and percussion. The patient is placed in a supine position with legs straightforward or flexed at the knees to avoid contraction of the abdominal muscles. The patient is then told to relax, and the examiner auscultates in the four quadrants listening for bowel sounds. He/she will then proceed to palpate, feeling for masses or tenderness to superficial and deep palpation. Lastly, the abdomen is percussed [tapping on the surface to determine the underlying structure]. A dull sound suggests the presence of a solid mass while a more resonant sound indicates a hollow, air-containing structure.

Bimanual examination can be performed at any point of the exam. It consists of inserting the index and middle finger of the dominant hand of the examiner into the vagina while the other hand is placed on the abdomen. The abdominal hand is then used to push downward while the pelvic hand is used to elevate the uterus and adnexa. Between the two hands, the pelvic organs are evaluated while, at the same time, palpating for masses, cervical or fundal tenderness, and adnexal masses or tenderness. At this point, orientation of the uterus should also be noted.

Pelvic Exam: Bimanual and Speculum Examination Pelvic examination begins with inspection of the external genitalia. For the first exam, the examiner should have explained to the patient the nature of the examination and the steps entailed. The patient should be comfortable with the examiner. Inspection will allow the practitioner to suspect developmental anomalies (hair distribution, clitoromegaly), vulvar dysplasia or HPV changes (discoloration, redness, growths), or infection (redness, discharge). The Bartholin’s glands cannot be palpated when they are healthy:

Pap Smear

• The examiner needs to look carefully at the introitus, labia minora, labia majora, clitoris, and perineal body. Once the external genitalia have been inspected, a speculum examination is used to evaluate the vaginal canal and the cervix. It is important to notice vaginal lesions, signs of atrophy, presence of any growths, or gross lesions. Attention is now turned to the cervix, which is then inspected for lesions, bleeding, or abnormal discharge. • Cultures should be collected at this point if infection is suspected. • Cytology is done at the time of the speculum examination.

Tests Performed on Exam

As previously mentioned, cervical cancer screening starts at 21 years old and after that following ASCCP guidelines depending on results. There are also ACOG and US Preventive Task Force guidelines that are similar. Cervical cancer screening guidelines for average-risk women is shown below: • HPV testing is generally not recommended in women aged 65 with no or low risk for cervical cancer and adequate screening history may stop screening.

STD Testing STD testing should be performed when there is high suspicion for a sexually transmitted infection based on history (multiple sexual partners, unprotected intercourse) and examination (abnormal discharge, pelvic pain) or when the patient requests it. STDs such as HIV, syphilis, and hepatitis B and C can be tested in the blood. Chlamydia and gonorrhea are most easily tested in the urine and in a vaginal culture:

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• CDC recommended all adults and adolescents from ages 13 to 64 be tested at least once for HIV. • CDC also recommends that sexually active women 80 cm, respectively, is considered abnormal. In patients with a BMI >35 kg/m2, measuring waist circumference is unnecessary since these individuals are already at high risk. Obese individuals are at increased risk of all-cause mortality, in addition to many serious illnesses including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, some types of cancer, sleep apnea, osteoarthritis, and mental disorders such as depression and anxiety. Obese women have a separate set of complications from men resulting from their elevated BMI. The effect of obesity on women’s gynecologic health is reviewed in this chapter. Table 1 BMI classification in Western countries Underweight – BMI 29 kg/m2 (van der Steeg et al. 2008). The mechanisms related to this decrease in fertility in obese ovulatory women are not completely understood.

Miscarriage There is evidence that obesity increases the rate of spontaneous abortions by almost threefold compared to women of normal weight. In a retrospective study of 712 egg donation cycles (Bellver et al. 2007), showed the rate of miscarriages to be 13.3% in normal-weight women, 15.5% in overweight women, and 38.1% in obese women. Various theories have been proposed to explain this increased rate. Obesity and the associated endocrine alterations may affect corpus luteum function (Sherman and Korenman 1975; Fedorcsak et al. 2001), early embryo development (Kawamura et al. 2002; Fedorcsák and Storeng 2003), or endometrial receptivity (Alfer et al. 2000; Gonzalez et al. 2000) hence affecting embryo implantation and early development.

Assisted Reproductive Technology (ART) In addition to affecting the chances of spontaneous pregnancy, obesity also diminishes success rates with ART. With increasing BMI, there is evidence

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Impact of Obesity on Gynecological Diseases

for an increase in in-vitro fertilization (IVF) cycle cancelation states, increasing gonadotropin requirements, a decrease in the number of oocytes collected, and an overall decrease in the rate of live births. An increase in body habitus also makes the procedure of oocyte retrieval technically challenging with increased rate of complications. At this point in time, many fertility practices will counsel their morbidly obese patients about weight loss prior to initiating ART aiming at a threshold BMI of less than 40 to qualify for IVF.

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• USMEC puts malabsorptive bariatric surgery into category 3 (risks generally outweigh benefits) although restrictive bariatric procedures [sleeves or bands] are category 2. • Obese women with hypertension or previous DVT/PE would fall into category 3/4 based on these factors.

Contraception

Accordingly, consideration should be given to a progestin-only contraceptive or to intrauterine devices. The levonorgestrel intrauterine device is a particularly attractive option for obese women given its non-contraceptive benefits of endometrial cancer risk reduction and decreased menstrual bleeding.

Combination Oral, Transdermal, and Vaginal Contraceptives

Progestin-Only Contraceptives

Obesity may impair the efficacy of combined contraceptives. There is evidence of a higher risk of oral contraceptive (OC) failure in obese women when compared to normal-weight women. In a study by Holt et al. (2005), it was shown that women with a BMI >27.3 had a 60% higher risk of OC failure and those with a BMI >32.2 had a 70% higher risk. Similar results were seen in clinical trials of the combination transdermal patch, showing increased failure in women weighing above 90 kg (Zieman et al. 2002). Also, combination OC (COC) and obesity are both independent risk factors for venous thromboembolism (VTE). A case-control study found that in women using oral contraceptives with a BMI greater than 25, the rate of VTE is tenfold higher than in lean women not using oral contraceptives (Abdollahi et al. 2003). While the American Congress of Obstetricians and Gynecologists (ACOG) (American College of Obstetrics and Gynecology 2006) does not label obesity an absolute contraindication for combined contraceptives, it states OCs should be used with caution in obese women above the age of 35. The CDC Medical Eligibility Criteria [USMEC] rate obesity with BMI 30 kg/m2 at category 2 [benefits generally outweigh the risks]; they also say the obese women who use COCs are more likely than obese women who do not use the pill to develop a VTE.

Progestin-only pills (POPs) are not as widely used as COC. They are particularly a good option for postpartum women, where the risk of thrombosis is elevated, since they do not increase the risk of VTE and do not negatively affect breast milk. Despite their increased safety profile, POPs used in the United States are associated with undesirable side effects such as irregular bleeding, and they have a very stringent daily timing (within 3 h). POPs do not reliably suppress ovulation; however, their effectiveness relies on the changes they exert on the cervical mucus and the endometrium. For obese women, and women with other contraindications to COCs, the POPs offer the advantage that they do not increase the risk of venous thromboembolism while they maintain a success rate similar to that of OC. Injectable progestins have mechanisms of action similar to POPs that include increased cervical mucus viscosity, creation of an endometrium unfavorable for implantation, and unpredictable ovulation suppression. Their use is very popular in the United States. Depot medroxyprogesterone acetate (DMPA) has a contraceptive efficacy equivalent or better than that of COC but has a much better safety profile. In obese women, DMPA is safe. There are studies showing possible weight gain with the use of DMPA; however, not all studies have shown this effect.

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Intrauterine Devices (IUD) IUDs are one of the most effective methods of contraception. There are currently five different IUDs available in the United States, and they include one copper containing IUD and four different levonorgestrel-releasing IUDs. The effectiveness of IUDs is not affected by BMI as the mechanism of action does not rely on systemic hormone levels. In the Contraceptive CHOICE project, the overall failure rates of IUDs were less than one per hundred woman-years with no differences between various BMIs (Xu et al. 2012). The levonorgestrel-releasing IUD is a particularly attractive option for obese women. It exerts its contraceptive function by rendering the endometrium atrophic and stimulating thick cervical mucus, but its non-contraceptive uses are equally attractive. Since obese women have high rates of dysfunctional uterine bleeding and endometrial hyperplasia (section “PCOS and Insulin Resistance”), the levonorgestrel-releasing IUD is often used in obese women to minimize vaginal bleeding and decrease the risk of premalignant endometrial lesions.

Surgical Risk Obese women are at higher risk of experiencing surgical and anesthetic complications. In a paradox referred to as the “obesity paradox” (Mullen et al. 2009), otherwise healthy obese patients undergoing non-bariatric surgery were found to have lower mortality and morbidity than normal-weight patients. However, obese patients commonly have comorbid conditions such as hypertension, obstructive sleep apnea, coronary artery disease, or a difficult airway, and these patients have an increased rate of surgical mortality and morbidity compared to the normal-weight patients.

Surgery in the Obese Patient Physical exam and particularly the bimanual exam may be difficult in the clinic setting to decide on the preferred route of surgery. In this

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case, further imaging such as MRI is recommended for guidance. As in all patients, the least invasive route should be considered for better outcomes. Abdominal surgery in obese women takes longer and has a higher blood loss and higher rate of wound complications and surgical site infections, increased risk of VTE, and increased hospital stay. As the BMI rises, so do the risk of surgical site infection (Olsen et al. 2009) and wound complications (Nugent et al. 2011). Some intraoperative considerations have been suggested for surgery in obese patients. First, placement of the skin incision needs to be tailored to each patient, as anatomy of the abdominal wall may be distorted. In cases where an abdominal fat pad covers the lower abdomen, one must be aware that an incision under the fat pad is subjected to an intense maceration. Also, surgical instruments must be adapted to the situation, using wide retractors to maintain the thick abdominal wall. Mass closure, subcutaneous drains, and prophylactic antibiotics can be considered in order to minimize wound disruption. The implications for laparoscopic surgery are also present. The position of the umbilicus relative to the aortic bifurcation and the rest of the abdomen vary and may make abdomen penetration with a Veress needle challenging. Open laparoscopic entry has been found to be safer in obese subjects (Byron et al. 1989). Also of concern is that operating in the pelvis requires the patient to be in the Trendelenburg position. This positioning is known to increase intrathoracic pressure and particularly for obese patient may be associated with impaired oxygenation and difficulty in ventilation. The use of longer trocars and instruments needs to be anticipated. Laparoscopic surgery in obese patients may be more complicated and the risk of conversion to laparotomy is elevated, but these obstacles can be partly overcome with surgical experience (Wattiez et al. 2002). As with all patients, efforts to choose the least invasive surgery should be exerted. If appropriate, the vaginal route for hysterectomy is preferred to reduce postoperative pain and morbidity. This technique can also be challenging because of the size of the obese patient’s legs and buttocks, as

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well as the presence of redundant vaginal sidewalls, all of which can make visualization and surgery more difficult. According to the American College of Chest Physicians, obese woman who undergo gynecologic surgery for longer than 45 min fall in the category of moderate risk of VTE and should receive some form of prophylaxis unless at high risk of major bleeding. VTE prophylaxis can either be low molecular weight heparin, low-dose unfractionated heparin, or mechanical prophylaxis with intermittent pneumatic compression. Appropriately positioning the obese patient is of paramount importance and can prove to be challenging. The operating table can usually accommodate a patient weighing up to 205 kg, and some tables can accommodate up to 455 kg. Positioning of the patient should take into account surgeon ergonomics and provide protection to the patient from nerve injury and pressure sores. If the patient is to be placed in the lithotomy position, the boottype stirrups are preferred for better lower extremity alignment and decreased pressure on the knees and hips as compared to the candy cane stirrups.

Anesthesia in the Obese Patient Risks of anesthesia are higher in obese women with most issues related to technical problems such as constructing an airway, gaining venous access, or providing effective ventilation. Before undertaking gynecologic surgery, a preoperative consultation with an anesthesiologist should be considered. The obese patient has an increase in cardiac output and a relatively lesser increase in blood volume, resulting in a relative hypovolemia with poor tolerance to fluid overloading and hemorrhage. Respiratory function is altered as well. There is a decrease in functional residual capacity and reserve expiratory volume, associated with an increase in the closure capacity and alveolar dead space. This results in a mismatch of ventilation and perfusion that can lead to hypoxia. The oral airway in the obese patient is suboptimal due to decreased neck mobility and narrowing of the pharyngeal space soft tissue effect. In addition, there is an increased risk of aspiration of gastric

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contents due to the higher intra-abdominal pressure. All of these concerns must be addressed at the preoperative consultation.

Urinary Incontinence Urinary incontinence, a loss of bladder control, affects more than 13 million women in the United States. The four main types of urinary incontinency include stress urinary incontinence (SUI), urge incontinence, overflow incontinence and functional incontinence. Patients often present with mixed symptoms. Obesity is an independent risk factor for the development of both stress and urge incontinence, with obese women having up to a 4.2-fold greater risk of than women of normal weight (Alling Moller et al. 2000). The severity of incontinence appears to be influenced by the duration and extent of obesity; which could be explained by the raised intra-abdominal pressure caused by central obesity conveying additional pressure on the pelvis and bladder. This association is further corroborated by studies showing that weight loss among obese women leads to a reduction in episodes of urinary incontinence (Subak et al. 2009). The mid-urethral sling procedure for the management of SUI has been found to be safe and effective in both obese and nonobese women, regardless of BMI (Weltz et al. 2015).

Endometrial Cancer and Other Malignancies Obesity is directly associated with a number of malignancies including colon cancer, kidney cancer, esophageal cancer, as well as endometrial cancer and postmenopausal breast cancer (Bianchini et al. 2002). The normal balance between cell proliferation and apoptosis in vulnerable tissues may be distorted by the endocrinopathies of obesity that includes fat cell alterations in the metabolism of sex steroids, insulin, and growth factors. Obese women are at a two-fourfold higher chance of developing endometrial cancer than

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women of normal weight. In obese women presenting for bariatric surgery, the rate of endometrial hyperplasia was found to be 10% (Modesitt et al. 2015). There are two types of endometrial cancer. Type I endometrioid adenocarcinomas are the most common, comprising 75% of all cases. They are estrogen-dependent and low-grade and are preceded by endometrial hyperplasia. On the other hand, type II endometrial cancers have a serous or clear cell histology and no precursor lesion and are generally more aggressive. Type I is the endometrial cancer that is more common in obese women; since obesity is often associated with hyperestrogenism due to peripheral aromatization of androgens to estrogen in the adipose tissue. More importantly, the chronic anovulatory status, which is frequently seen in obese women, results in the endometrium being exposed to unopposed estrogen. In the absence of progesterone-induced endometrial shedding, endometrial hyperplasia can frequently develop. While at this time performing an endometrial biopsy for all women with a BMI >30 is not recommended, ACOG recommends sampling the endometrium of all obese women with symptoms of heavy or irregular uterine bleeding regardless of age (ACOG 2012). Almost half of women with endometrial cancer or hyperplasia don’t know that obesity affects their cancer risk (Beavis et al. 2015), so it is the role of providers to identify these patients at high risk and provide them with the appropriate counseling and education.

Pelvic Imaging in the Obese Patient Ultrasound Ultrasound is often the imaging modality of choice in gynecology. However, transabdominal ultrasound is the radiologic modality that is the most affected by obesity because of the attenuation of the ultrasound beam by the layers of adipose tissue. Nonetheless, the availability of transvaginal imaging provides easier accessibility to the reproductive organs by bypassing the abdominal pannus. An often-used solution to the

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decreased penetration of the transvaginal ultrasound is by placing a hand on the pelvic organs to push them closer to the probe, which in some cases may afford better visualization. Abdominal scanning in the obese patient is often more challenging. The abdominal pannus limits visualization by both increasing the depth of insonation required and by attenuating the strength of the ultrasound beam. The abdominal pannus also increases the ergonomic challenge for the sonographer. Since the pannus is usually at its thickest between the pubis symphysis and the umbilicus, the patient or an assistant can be enlisted for help by lifting the fat pad upwards toward the patient’s head, thus providing a flatter and thinner abdominal wall and closer distance to the pelvic organs. The use of technology such as harmonic imaging, a nonlinear propagation of ultrasound through body tissues, can improve the quality of the image because fat will act to increase the harmonic waves created. Also, when available, the use of the preset “penetration” mode may result in higher quality image. When ultrasound imaging fails to provide adequate visualization of the pelvic organs, the imaging modality of choice is MRI when a gynecologic condition is suspected. CT scan is preferred in urologic and gastrointestinal conditions.

Computed Tomography (CT) CT imaging of the pelvis is generally adequate in obese patients. The main limiting factors for CT imaging in obesity are size of the patient relative to the machine, positioning, artifacts, and radiation exposure. In fact, CT scan manufacturers set a weight limit for the table beyond which the table can be damaged and the warranty is void. Also, the aperture through which the patient should go is set at a diameter of 70 cm, with newer enhanced models fitting up to an 80–90 cm diameter. The best practice in the case of patients with severe obesity is to obtain an exact weight and abdominal girth immediately prior to the procedure. In cases where the abdominal girth may be over the limit, there are abdominal binders that can be used for

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this purpose, also serving the additional benefit of preventing the pannus from hanging asymmetrically to the side causing artifacts. Another consideration in the use of CT scan is the quantity of contrast material used. The dose is typically obtained by considering the patient’s weight, and this may expose obese patients to a higher-thannecessary dose of contrast. A solution to this problem may be to use the lean body weight as opposed to the actual weight.

Magnetic Resonance Imaging (MRI) Compared with ionizing radiation or sound waves, the radiofrequency used by MRI penetrates large amount of fat. Hence, MRI is the modality least affected by obesity. Challenges for MRI, like for CT scan, are mostly related to the size of the patient and the problems with positioning and length of the procedure. The tight fit of the patient in the aperture can cause claustrophobia and even motion artifacts. Also, there is a risk of skin burn if the patient is tightly fitting in the gantry. This can be minimized by placing cloth protections at the areas of friction (Glanc et al. 2012).

Weight Loss More than two-thirds of adults in the United States are either attempting to lose weight or preserve their weight. For patients who are overweight or obese and at risk for obesity-associated disorders, a number of weight loss interventions are available, including lifestyle, diet, exercise, pharmacotherapy, and surgery. Even moderate weight loss of 5–10% is associated with a reduction in obesity-associated morbidity. The role of the physician is to identify patients who would benefit from losing weight, determining an ideal body weight, and educating the patient about available options. The initial management is a combination of diet, exercise, and lifestyle modifications with a goal to create an energy deficit by either decreasing intake or increasing expenditure or ideally both. Pharmacological agents can be a

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useful adjunct to diet and exercise, with bariatric surgery increasingly used as a final option.

Diet In a normal adult, approximately 22 calories are required to maintain a kilogram of body weight. Once a patient’s daily energy expenditure is calculated, one can calculate their daily caloric intake that generates a daily deficit. This is also used to estimate the resulting weekly weight loss. Diets providing less than 800 calories per day are not generally recommended. Balanced low calorie/portion-controlled diets are the most commonly recommended diets. They encourage the intake of foods with adequate nutrients, in addition to proteins, minimal carbohydrates, and essential fatty acids, while eliminating alcohol, sugar-containing beverages, and other sources of food that are high in carbs/ calories but poor in nutrients. • Low and very low carbohydrate diets have been popular for many years. Low carbohydrate diets contain 60–130 g of carbohydrates and very low carbohydrate diets contain up to 59 g of diets. They are based on the fact that restriction of carbohydrates leads to glycogen mobilization and rapid weight loss primarily due to glycogen breakdown. Hence, they are more effective for short-term weight loss than low-fat diets. • Low-fat diets are another commonly used strategy for weight loss, recommending a reduction in the daily intake of fat to less than 30% of total dietary intake. Considering a diet of approximately 1500 calories, this would mean about 45 g or less of fat, which can be counted using the nutrition information labels on food packages. • The Mediterranean diet is inspired from the traditional diets of Greece, Spain, and the south of Italy. It includes primarily plantbased foods, such as vegetables, fruits, whole grains, legumes, and nuts. It replaces butter with monounsaturated fats such as olive oil and contains a moderate amount of dairy products and low amount of meat. A meta-analysis

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of eight cohort studies demonstrated that patients that adhered to a Mediterranean diet had a significantly improved health status, with a reduction in overall mortality, mortality from cardiovascular diseases, incidence and decreased mortality from cancer, and incidence of Parkinson’s disease and Alzheimer disease (Sofi et al. 2008).

Exercise Exercise alone, without dietary changes, results in only modest reductions or no loss in weight. Adding exercise to diet has only slight additional benefits than diet alone. In a systematic review of 17 randomized trials, it was found that there was only a slight increase in weight loss in the diet and exercise group compared to the diet alone group and that this difference was statistically significant in only two of the studies (Catenacci and Wyatt 2007). However, adding exercise to diet has other important benefits independent of weight loss, such as attenuating the diet-induced loss of muscle mass.

Pharmacotherapy In addition to diet, exercise, and lifestyle modification, drug therapy can be a helpful adjunct to weight loss in overweight patients with comorbidities and obese patients. The role of medications for weight loss has been questioned because of concerns about efficacy and safety; hence, the decision to initiate medications should only be made after a thorough evaluation of risks and benefits. There are five drugs currently approved for long-term use: orlistat, lorcaserin, phenterminetopiramate, bupropion-naltrexone, and liraglutide. Phentermine, benzphetamine, phendimetrazine, and diethylpropion have only been approved for short-term use. • Orlistat alters fat digestion by inhibiting pancreatic lipases, resulting in incomplete hydrolysis of fat and increased fat excretion in feces. The efficacy of orlistat has been demonstrated

in many clinical trials demonstrating that initial weight loss is greater and that weight regain is slowed as compared with lifestyle/placebo. In addition, orlistat showed other beneficial effects such a reduction in HbA1c, improvement in blood pressure, and an improvement in lipid values more than what can be explained by weight loss alone. The predominant side effects are gastrointestinal, mainly cramps, flatus, fecal incontinence, and oily spotting. These side effects are high initially and then subside as patients learn to avoid them by avoiding high-fat diets. Absorption of fat-soluble vitamins (A, D, E, K) is lowered by orlistat therapy. • Lorcaserin is a selective agonist of the serotonin 2C receptor; it reduces appetite and therefore body weight. It appears to have similar efficacy as and fewer side effects than orlistat. In addition to weight loss, lorcaserin has other beneficial effects including decreases in blood pressure, lipid levels, fasting glucose, and insulin levels. Side effects are generally mild, and they include headache, upper respiratory infections, dizziness, and nausea. • Liraglutide is a long-acting glucagon-like peptide-1 analog that is available for use in the United States for treatment of type 2 diabetes. It is also approved for use at higher doses in the treatment of obese patients or patients with a BMI 27 kg/m2 with at least one weightrelated comorbidity. Liraglutide has been associated with a significant reduction in weight when compared to placebo in diabetes and non-diabetes trials. At the higher doses used for obesity treatment, liraglutide has higher rates of nausea and vomiting, side effects that may be partly responsible for the weight loss effect of the drug. Other side effects include diarrhea, hypoglycemia, and anorexia. • A preparation of combined phentermine and extended-release topiramate has been approved for obese adults or adults with BMI 27 kg/m2 with at least one weight-related comorbidity. This combination has been shown to increase weight loss in the first year of use. The most common side effect is dry mouth, constipation, and paresthesia.

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• The combination preparation of bupropion-naltrexone is not recommended as first-line therapy, but can be used for the obese smoker who desires therapy for smoking cessation and weight loss. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence, and bupropion is used for depression and the prevention of weight gain during smoking cessation. The combination reduces weight by 4–5% compared to placebo. Side effects include nausea, headache, and constipation. • The sympathomimetic drugs phentermine, diethylpropion, benzphetamine, and phendimetrazine are only approved for short-term treatment, up to 12 weeks. They reduce food intake by causing early satiety. Phentermine is the most widely prescribed weight loss drug; however, because of the potential side effects, potential for abuse, and limited duration of use, they are usually not recommended. They are contraindicated in patients with coronary artery disease, hypertension, and hyperthyroidism or in patients who have a history of drug abuse.

Bariatric Surgery Candidates for bariatric surgery include obese patients with a BMI 40 kg/m2 or patients with a BMI 35 kg/m2 with at least one serious comorbidity, such as type 2 diabetes or hypertension. Adults with BMI between 30 and 34.9 kg/m2 can also be candidates if they suffer from uncontrolled type 2 diabetes or metabolic syndrome. Bariatric surgical procedures cause weight loss through two main mechanisms: malabsorption and restriction. Some procedures have both components. Malabsorptive procedures shorten the length of the functional small intestine and decrease the absorption of nutrients. Restrictive procedures work by limiting the caloric intake by reducing the stomach’s capacity. • The Roux-en-Y gastric bypass (RYGB) is the most commonly performed bariatric procedure. It involves the creation of a small gastric pouch that is divided and separated from the distal stomach and anastomosed to a limb of

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small bowel. While it is mainly a restrictive procedure, it also has a malabsorptive component that participates in weight loss. • The laparoscopic adjustable gastric banding is a restrictive procedure where an adjustable silicone ring is placed around the entrance of the stomach. Saline can be injected through an infusion port into the band to reduce its diameter, to increase the amount of restriction. • Another restrictive procedure, the sleeve gastrectomy is a partial resection of the greater curvature of the stomach, which creates a tubular stomach. This procedure is easier to perform than the RYGB. The created tubular stomach is small and resistant to stretching due the absence of the fundus.

Conclusion The impact of obesity on women’s reproductive health is significant with harmful effects noted on the menstrual cycle, fertility, contraception, urinary incontinence, surgical risk, imaging studies, and certain malignancies. Weight loss is a difficult but an achievable solution to many of these consequences. Weight loss can be achieved best in a multidisciplinary approach.

Cross-References ▶ Conservative Management of Endometrial Cancer ▶ Workup and Management of Polycystic Ovary Syndrome

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L. B. Nemer Glanc P, O’Hayon BE, Singh DK, Bokhari SA, Maxwell CV. Challenges of pelvic imaging in obese women. Radiographics. 2012;32(6):1839–62. Gonzalez RR, Caballero-Campo P, Jasper M, Mercader A, Devoto L, Pellicer A, Simon C. Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab. 2000;85:4883–8. Hedley AA, Ogden CL, Johneson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among U.S children, adolescents, and adults, 1999–2002. JAMA. 2004;291:2847–50. Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005;105:46–52. Kawamura K, Sato N, Fukuda J, et al. Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology. 2002;143:1922–31. Modesitt S, et al. Women at extreme risk for obesity-related carcinogenesis: baseline endometrial pathology and impact of bariatric surgery on weight, metabolic profiles and quality of life. Gynecol Oncol. 2015;138(2): 238–45. Mullen JT, Moorman DW, Davenport DL. The obesity paradox: body mass index and outcomes in patients undergoing nonbariatric general surgery. Ann Surg. 2009;250:166–72. Nugent EK, Hoff JT, Gao F, Massad LS, Case A, Zighelboim I, et al. Wound complications after gynecologic cancer surgery. Gynecol Oncol. 2011;121:347–52. Olsen MA, Higham-Kessler J, Yokoe DS, Butler AM, Vostok J, Stevenson KB, Prevention Epicenter Program, Centers for Disease Control and Prevention, et al. Developing a risk stratification model for surgical site infection after abdominal hysterectomy. Infect Control Hosp Epidemiol. 2009;30:1077–83. Onalan R, Onalan G, Tonguc E, Ozdener T, Dogan M, Mollamahmutoglu L. Body mass index in an independent risk factor for the development of endometrial polyps in patients undergoing in vitro fertilization. Fertil Steril. 2009;91(5):1056–60. Ramlau-Hansen CH, Thulstrup AM, Nohr EA, Bonde JP, Sorensen TIA, Olsen J. Subfecundity in overweight and obese couples. Hum Reprod. 2007;22:1634–7. Sanchez-Garrido MA, Tena-Sempere M. Metabolic control of puberty: roles of leptin and kisspeptins. Horm Behav. 2013;64:187–94. https://doi.org/10.1016/j. yhbeh.2013.01.014. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest. 1975;55:699–706. Sofi F, Cesari F, Abbate R, et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008;337:a1344. Subak LL, Wing R, West DS, et al. Weight loss to treat urinary incontinence in overweight and obese women. N Engl J Med. 2009;360:481–90. Van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al. Obesity affects

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Urinary Tract Infections and Asymptomatic Bacteriuria Elise Morocco and Tanaz Ferzandi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Microbiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Voided Specimen Collection Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96 96 96 97

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncomplicated Cystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyelonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recurrent UTI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97 97 98 98

Catheter-Associated UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Asymptomatic Bacteriuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Urinary tract infections are common in women and place a significant economic burden on our health care system. It is important for gynecologists to be familiar with

E. Morocco (*) · T. Ferzandi Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_95

distinguishing uncomplicated cystitis from more complicated infections, and when it is indicated to treat asymptomatic bacteriuria. This chapter will review the presentation, pathogenesis, diagnosis, and evidencedbased prevention strategies of UTIs. There is increasing antibiotic resistance, and the recommended treatments for uncomplicated cystitis, pyelonephritis, and recurrent UTIs are summarized.

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Keywords

Urinary tract infection · Pyelonephritis · Asymptomatic bacteriuria · Recurrent urinary tract infection · Antibiotic resistance

Introduction Urinary tract infection (UTI) is a general term referring to an infection in the upper (pyelonephritis) or lower genitourinary tract (cystitis). However, the term is often colloquially used to describe cystitis. It is an exceedingly common reason for women to seek medical care not only from primary care physicians and the emergency room, but also from gynecologists. UTIs are more common among women for anatomical reasons: the female urethra is shorter compared with the male urethra, and the distal third is often colonized with vaginal and enteric flora. As such, most cases of UTIs result from an ascending infection. The majority of UTIs are bacterial in origin, though they rarely can be fungal (American College of Obstetricians and Gynecologists 2008). UTIs are considered “uncomplicated” if they are in an otherwise healthy nonpregnant, premenopausal woman. Should there be an anatomic abnormality, or medical comorbidity, it would be considered “complicated.”

UTIs are distinguished from asymptomatic bacteriuria, which refers to the presence of bacteria in a patient’s urine that does not cause symptoms, and only requires treatment if the patient is pregnant. For many women, a single UTI may lead to others; studies have shown a range of recurrence of 30–50% per year (Foxman 2014). This chapter will review the terminology, risk factors, common pathogens, diagnosis, treatment, and prevention of UTIs. There has been increasing interest in hospital-acquired infections – and this chapter will briefly cover catheter-associated UTIs.

Epidemiology Urinary tract infections (UTIs) are an exceedingly common reason for women to seek medical care. In 2000, for instance, approximately 11 million outpatient visits were by adults above 20 years old with UTIs, and approximately nine million were women. In fact, UTIs are one of the most common bacterial infections encountered in the ambulatory setting in the USA; among women aged 18 years and older, 12.6% are diagnosed with a UTI annually. Up to 30–44% of women will go on to have one recurrent UTI (Brubaker et al. 2018), and a smaller subset will meet the criteria for diagnosis of recurrent UTI. While there are multiple definitions for recurrent UTIs, the American Urogynecologic Society recommends using the following clinical definition: two culture-proven UTIs in a six-month period, or three in one year. A relapse is when the same uropathogen causes a UTI within two weeks of initial diagnosis, while reinfection is a UTI caused by an infection beyond two weeks, after a sterile intervening culture (Table 1).

Unsurprisingly, this places a heavy burden on our health care system. The cost for diagnosis and treatment of UTIs has been estimated to be in the billions; the cost of hospitalizations alone related to UTIs were estimated to be approximately 2.8 billion in 2011 (Simmering et al. 2017). It is imperative that primary care providers and gynecologists be familiar with diagnosing and managing UTIs in women of all ages. Equally important is the need to serve as antibiotic stewards given widespread prevalence and increasing resistance rates.

Microbiology and Pathogenesis E coli is responsible for 70–95% cases of uncomplicated cystitis and pyelonephritis in women (Hooton 2012). Other uropathogens include but are not limited to: Staphylococcus saprophyticus

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Table 1 Definitions Asymptomatic bacteriuria

Acute uncomplicated cystitis Acute pyelonephritis

Relapse

Reinfection

Recurrent UTI

The presence of one or more species of bacteria growing 105 cfu/mL in a properly collected specimen in a patient without symptoms of a UTI (Nicolle et al. 2019). An infection of the lower urinary tract in an otherwise healthy, premenopausal nonpregnant woman (Hooton 2012) An infection that has ascended to affect the renal parenchyma, renal pelvis, and calices. Associated signs and symptoms reflect an infection that produces a more systemic inflammatory response than what is seen in acute cystitis: Fever and chills, flank pain, nausea, and leukocytosis in addition to the urinary symptoms associated with lower UTI. Chronic pyelonephritis results from persistent infection of the renal parenchyma causing scarring and fibrosis. End-stage renal disease can result. A UTI caused by the same uropathogen within two weeks of initial diagnosis after adequate treatment (Aydin et al. 2015) An infection beyond two weeks, after a sterile intervening culture (Aydin et al. 2015) 2 infections in 6 months or  3 infections in 1 year (Aydin et al. 2015)

(10% of uncomplicated UTIs), Klebsiella pneumoniae, Staphylococcus aureus, Proteus mirabilis, Enteroccocus faecalis (15% of nosocomial infections), and Streptococcus agalactiae (associated with diabetes mellitus). In voided specimens, Enterococcus and Streptococcus agalactiae may also represent contaminants. Pathogenic bacteria originating from bowel or vagina (potentially after inoculation during intercourse) colonize the mucosa surrounding the urethra, and travel into the bladder. In some cases, the infection ascends to the kidneys and pyelonephritis develops, though it is not exactly clear why this occurs in some cases and not others, as the majority of untreated UTIs do not progress to pyelonephritis.

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Lactobacilli are an important component of the healthy vaginal microbiome. They produce hydrogen peroxide and lend to the acidic pH (3.8–4.5) of a healthy premenopausal vagina. This pH environment helps inhibit bacterial growth. Lactobacilli are also steric inhibitors, blocking attachment sites from uropathogens. Decreased levels of estrogen in postmenopausal women decrease Lactobacillus, which predisposes them to infection. The extraintestinal strain of E coli that invades the genitourinary tract has several fitness and virulence factors that allow it to effectively evade the host immune system. Some strains of uropathogenic E coli (UPEC) can rapidly grow in urine, which has a uniquely high osmolality, and concentration of amino acids. UPEC has developed several molecular mechanisms to overcome one of the body’s innate immune responses: the sequestration of heavy metals required for bacterial growth. It therefore can obtain the iron, zinc, and manganese it needs to survive, and can also produce toxins that directly interfere with the host’s immune pathway. UPEC strains employ molecular mimicry, with capsules that appear similar to host cell molecules. A higher number of fimbriae allow UPEC to adhere to surfaces compared with other forms of E Coli. Flagella help the bacteria ascend into the genitourinary tract and both of these mechanisms allow the bacteria to flourish. Biofilms are thought to be implicated in catheter-associated UTIs (CAUTIs). These are aggregates of bacteria that produce an extracellular matrix that allow them to adhere to each other and a surface. They are known to be more antibiotic resistant, and UPEC biofilms have been shown to have factors that inhibit the growth of other bacteria. Lastly, there is ongoing research on how external stimuli can affect the expression of genes related to fitness and virulence at the molecular level, thus contributing to its pathogenic behavior (Subashchandrabose and Mobley 2015). It is not uncommon for the same pathogen to reinfect the patient despite treatment; two-thirds of women with recurrent cystitis have recurrences from the same strain of bacteria (Hooton 2012). There is evidence that the bacteria can persist in

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fecal flora, and there is ongoing research regarding the pathogenesis of recurrent UTIs. Risk factors for UTIs are listed in Table 2 and include behavioral factors, comorbidities, and genetic factors such as Lewis blood group antigen non-secretor phenotype. Fungal UTIs are rare, but candida albicans can be seen in patients who are immunocompromised including patients with diabetes, or those who have prolonged catheter use.

Table 2 Risk factors (Brubaker et al. 2018; Hooton 2012) History Prior UTI History of UTI in first-degree relative Sexual activity: Frequent, recent, or new sex partner within the last year* Spermicide use Use of diaphragms with spermicide Decreased functional ability* Bladder catheterization or recent instrumentation Urogynecologic surgery* Postmenopausal status (hypoestrogenism)* Comorbidities Obesity** Sickle cell trait Diabetes mellitus* Renal or bladder calculi Anatomic anomalies of GU tract Neurogenic bladder Vulvovaginal atrophy Increased post-void residual* Urinary and fecal incontinence* Anterior vaginal wall prolapse (aka cystocele) Immunocompromised state Genetic factors including Lewis blood group antigen non-secretor phenotype Factors not shown to be associated with UTIs*** Pre- and postcoital voiding patterns Beverage consumption Wiping patterns Tampon use Douching Hot tubs *Risk factors specifically for recurrent UTIs **conflicting data ***analyzed in a cross-sectional analysis and may misclassify when behaviors were initiated

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Diagnosis Presentation Dysuria is the most reliable symptom of cystitis. Patients also commonly present with suprapubic pain, urinary frequency, and sometimes with hematuria. In many cases, the diagnosis of an uncomplicated UTI can be made based upon symptoms alone. One study showed that a patient reporting dysuria without vaginal discharge or irritation has a 90% probability of having a UTI (Hooton 2012). Because the symptoms may overlap with sexually transmitted infections, it is important to evaluate for vaginal discharge, dyspareunia, and vulvar lesions. Older patients may present differently: with new onset incontinence, mental status changes, or, in extreme circumstances, septic shock. There is obvious symptom overlap of patients who have urogynecologic disorders such as overactive bladder, incontinence, and interstitial cystitis, especially in the older patient population, and these comorbidities should be taken into consideration. We also caution that the simple symptom of dysuria in a postmenopausal patient might be due to severe vulvovaginal atrophy, and not a UTI. Symptoms of pyelonephritis include fevers (>38  C) and costovertebral angle tenderness in addition to lower urinary tract symptoms. It is important to evaluate for symptoms of nephrolithiasis, which is more characterized by colicky flank pain that radiates to the groin, and calculi are an important risk factor for the development of an infection.

Testing

Urine dipstick is a fast, inexpensive screening test. It is best used to help rule out a diagnosis of UTI if there is a low pretest probability of an infection. The presence of leukocyte esterase (seen with pyuria) or nitrites is 75% sensitive and 82% specific for diagnosing a UTI (Hooton 2012). The

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Voided Specimen Collection Technique presence of nitrites is more useful than leukocyte esterase, but notably only positive when the infection is due to gramnegative bacteria (Simati et al. 2013). The utility of using a dipstick in a symptomatic person is low because there can be false negatives; a urine culture should be obtained if a patient has symptoms with a negative dipstick.

Urinalysis with microscopy can be used to help elucidate if there is a true infection, as a high number of leukocytes (generally, >10 cells/ microL) should be positive in a true bacterial infection. Urinalysis can also help evaluate if there is sterile pyuria, which may indicate contamination of a specimen, prior microbial treatment, or infection with atypical organisms such as Chlamydia. Hematuria is also commonly present in a patient with an active infection. Urine cultures are used to confirm the presence of bacteria and to obtain sensitivities for antimicrobial treatment. Traditionally, the presence of 100,000 cfu/mL of bacteria in a urine culture is considered clinically significant bacteriuria. However, of note, 30–50% of women with cystitis have colony counts anywhere from 100–10,000 in voided urine, and laboratories often do not quantify concentrations lower than 10,000 (Hooton 2012). Thus, if a culture reports no growth in a patient who is symptomatic, clinical judgement should be used when deciding to provide treatment.

If pyelonephritis is suspected, an in-person exam and urinary cultures should be performed. In postmenopausal patients with recurrent UTI, catheterized specimens for urine culture should be used to diagnose and guide treatment as dipstick is even less sensitive in this population (Jung and Brubaker 2019).

Most patients can provide a urine sample with the clean-catch technique. The patient should be instructed to spread her labia to minimize contamination. A nonfoaming antiseptic solution (e.g., diluted sodium hypochlorite 0.5%) can be used to disinfect the urethral meatus, and the area subsequently dried. The specimen should be obtained midstream. There is not strong data to support or discourage cleansing, and the most important factors to decrease contamination seem to be spreading the labia and midstream collection (LaRocco et al. 2016). The specimen should be sent immediately to the lab for analysis to minimize the time that bacteria can multiply in a warm environment. If this is not possible, the specimen can be stored at 4  C.

Treatment Uncomplicated Cystitis Interestingly, 25–42% of cases of acute uncomplicated cystitis resolve without intervention (Christiaens et al. 2002; Ferry et al. 2007). It may be appropriate to provide empiric treatment over the phone in a patient experiencing characteristic symptoms of uncomplicated cystitis without vaginal discharge or irritation. But treatment should be delayed for an in-person exam or culture results should they report any concurrent symptoms, or if it is a recurrent infection. There is increasing concern over antibiotic resistance and so treatment choice should take into consideration local resistance rates. The Infectious Disease Society of America (IDSA) recommends nitrofurantoin, trimethoprim-sulfamethoxazole DS, Fosfomycin, or pivmecillinam (not available in the USA) as first-line treatment for uncomplicated cystitis with the caveats detailed in Table 3 (Gupta et al. 2011). If the above cannot be used due to availability, allergy, or patient tolerance, then fluroquinolones or ß lactams can be used. The IDSA recommends

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Table 3 First-line treatment of uncomplicated cystitis, nonpregnant Regimen Nitrofurantoin monohydrate/ macrocrystals 100 mg po BID x 5 days Trimethoprimsulfamethoxazole 160/800 mg (DS) po BID x 3 days Fosfomycin trometamol 3gm po x 1 dose Pivmecillinam 400 mg po BID x 5 days

Consideration Avoid if early pyelonephritis is suspected, given it primarily functions in the lower urinary tract Avoid if resistance is >20% or if used to treat a UTI in the prior 3 months Lower efficacy, and avoid if early pyelonephritis suspected Lower efficacy and avoid if early pyelonephritis suspected. Not available in the USA

Table 4 First-line treatment of outpatient pyelonephritis Ciprofloxacin 500 mg po BID x 7 days +/ ciprofloxacin 400 mg IV x 1

Ciprofloxacin 1000 mg ER po daily x 7 days Levofloxacin 750 mg po daily x 5 days Trimethoprimsulfamethoxazole 160/800 mg (DS) po BID x 14 days

If resistance rate > 10% for fluoroquinolones, use ceftriaxone 1gm IV x 1 or gentamicin 50-7 mg/kg x 1 instead of ciprofloxacin IV If resistance rates >10%, add ceftriaxone or aminoglycoside IV x 1 as above If uropathogen known to be susceptible. Add ceftriaxone or aminoglycoside IV x 1 as above if susceptibilities are not known

Recurrent UTI

against ampicillin and amoxicillin alone due to lower efficacy and resistance rates.

Pyelonephritis Treatment for pyelonephritis depends on whether the patient is stable to be treated as an outpatient or if she requires hospitalization. Cultures should be obtained to determine speciation and sensitivities, but outpatient regimens include oral fluoroquinolones and trimethoprim-sulfamethoxazole, with or without a loading parental dose, depending on resistance rates (Table 4) (Gupta et al. 2011). If the patient meets criteria for inpatient hospitalization, the intravenous antimicrobial options include: a fluoroquinolone, aminoglycoside with or without ampicillin, extended spectrum cephalosporin or penicillin with or without an aminoglycoside, or a carbapenem. Local resistance rates should inform empiric treatment choice. Oral ß lactams are less effective, but if they must be used, a dose of intravenous ceftriaxone or aminoglycoside should be added for a total treatment course of 10–14 days.

If the patient has a recurrence that occurs within 6 months of a successfully treated UTI, a short course (4.5, and (4) positive whiff test – release of a fishy odor on adding alkali (10% KOH). If a gram-stained vaginal smear is taken, BASHH recommends evaluating this by the Hay/Ison criteria (Ison and Hay 2002). Hay/Ison criteria are defined as follows: grade 1 (normal), Lactobacillus morphotypes predominating; grade 2 (intermediate), mixed flora with some Lactobacilli present, but Gardnerella or Mobiluncus morphotypes also present; and grade 3 (BV), predominantly Gardnerella and/or Mobiluncus morphotypes, few or absent Lactobacilli. BV is caused by a complex change in normal vaginal bacterial flora making a vaginal culture generally useless. Additionally, G. vaginalis can be cultured in up to 50–60% of asymptomatic, healthy women. The Affirm VP III [DNA probe] test can detect high concentration of G. vaginalis. Treatment Most patients will initially respond to pharmacological treatments to BV; however, recurrence is common with more than half recurring by 12 months (Bradshaw et al. 2006). Metronidazole or clindamycin administered either vaginally or orally results in 70–80% of cure rates. Tinidazole 2 g once daily for 2 days or 1 g once daily for 5 days has been approved for treatment of bacterial vaginosis. Options for treatment of recurrent bacterial vaginosis include suppressive treatment with metronidazole vaginal gel used twice a week, oral antibiotics followed by boric acid, and then suppressive therapy with metronidazole vaginal gel. Probiotic therapy may be considered but optimal treatment has not been established. Acidifying gels [boric acid] may be effective (FSRHC 2012). Women using a copper intrauterine contraceptive device may consider changing to an alternative method of contraception (FSRHC 2012). Oral combined contraceptive pills and condoms are associated with a reduced risk of BV (Calzolari et al. 2000). Symptomatic pregnant women should be treated in the usual way. Women with BV with additional risk factors for preterm birth may benefit from treatment before 20 weeks of gestation, and therefore screening such high-risk groups should be considered. Treatment of choice is

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metronidazole and is not associated with teratogenicity (BASHH 2012). Metronidazole alters the taste of breast milk, so breastfeeding mothers should receive clindamycin or be advised to stop feeding during the course and for 24 h after.

Trichomonas vaginalis Trichomonas vaginalis (TV) is a flagellated anaerobic protozoan. It is rarer than RVVC and BV. It is sexually transmitted. TV can increase the risk of getting or spreading other sexually transmitted infections including HIV. Diagnosis Up to 50% of women are asymptomatic with a third becoming symptomatic within 6 months. Those with symptoms complain of vaginal and vulvar discomfort, characteristically soreness or burning, dyspareunia, and vaginal discharge. Occasionally women complain of abdominal pain or vulvar ulceration. The typical vaginal discharge described as copious yellow green, frothy, and foul smelling only occurs in up to 30% of women. The discharge can range from thin and scanty to profuse and thick (Fouts and Kraus 1980; Wolner-Hanssen et al. 1989). On examination the cervix may have the classic “strawberry appearance” as a result of punctate cervical microhemorrhages. This can be seen by the naked eye but more commonly picked up at colposcopy (Fouts and Kraus 1980; WolnerHanssen et al. 1989). Vaginal pH is generally greater than 5.0 and often greater than 6.0. T. vaginalis may be seen on Papanicolaou smears. Trichomonads are seen by a light field microscopy of the vaginal discharge on wet mount. Vaginal discharge is collected and mixed with saline on a glass slide and a coverslip is placed on top. The wet preparation slide should be scanned at both low and high magnification to confirm trichomonads [oval- or pear-shaped protozoans with a flagella] and to visualize the flagella. The slide must be read in under 10 min as trichomonads quickly lose their motility and after this time are more difficult to identify (Kingston et al. 2003). Microscopy can be performed in a clinic setting, near to the patient.

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Point of care tests are available [such as rapid antigen tests and nucleic acid amplification] that do not require instrumentation. They can provide a result in 30 min and so can be performed in the clinic setting near the patient. It is a suitable alternative to culture or molecular testing. These tests have a high sensitivity (greater than microscopy) and specificity (Nye et al. 2009). In difficult-to-diagnose cases, culture of TV or nucleic acid amplification tests could be considered as they have a higher sensitivity compared to microscopy (BASHH 2014a). Several culture mediums are available. Specimens should be incubated anaerobically and growth detected in 48 h. Treatment T. vaginalis is a multifocal infection of the vaginal epithelium. Vaginal epithelium, Skene’s glands, Bartholin’s glands, and urethra can all be affected, so systemic treatment is essential for complete cure. Nitroimidazole drugs [metronidazole] given in either single dose or over a prolonged period result in cure in over 90% of cases (Forna and Gulmezoglu 2003). Therefore recommended regimes are metronidazole 2 gm orally in a single dose or metronidazole 400–500 mg twice daily for 5–7 days (BASHH 2014a). Recurrent TV can be due to drug resistance but is more commonly due to reinfection due to failure to treat all sexual partners or a new sexual contact. Therefore it is important to reconfirm the diagnosis in patients who return with recurrence of symptoms. Partner notification is required and all parties treated. To best achieve this, sexual health services should be involved. Patients should be advised to avoid sexual contact for at least a week and until their partners have completed treatment and follow-up (BASHH 2014a). A strain of T. vaginalis exists that is resistant to metronidazole and other nitroimidazoles (Kirkcaldy et al. 2012). Therefore for patients that continue to have T. vaginalis despite therapy and in which reinfection is excluded, increased doses and longer duration of therapy may be required. Regimes include metronidazole or tinidazole 2 gm a day for 5–7 days (BASHH 2014a). In women who continue to not respond, resistance

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testing should be considered. Treatment protocols guided by resistance testing results have improved outcome (Bosserman et al. 2011). For women with recurrent symptoms, a test of cure is then recommended (BASHH 2014a). Concomitant treatment with an antifungal can also be considered.

Threadworms Threadworms are nematode infection with Enterobius vermicularis. It is also known as pinworm or enterobiasis. It is the most common helminthic infection in the United Kingdom. It is most commonly seen in children aged 5–9 years but can affect any age, frequently affecting family groups or institutions. Overcrowding and poor hygiene contribute to spread and reinfection. The female threadworm is 1 cm long and a little under 1 mm in diameter. It is white and pointed at each end. The male threadworm is much smaller at only 4 mm long and is rarely seen. Female threadworms may be seen at night emerging from the anus to lay eggs. The female lays on average over 10,000 eggs outside around the anus, vagina, and urethra. The eggs are so small that they are invisible to the naked eye and are accompanied by an irritant mucus, which causes intense itching and scratching. Scratching transmits the eggs from the perineal and perianal skin to the hands. Then these are transmitted to the mouth, swallowed or inhaled, and then ingested. The larvae hatch in the small intestine and migrate to the colon where they reach maturity over 2 weeks. Adult worms live for up to 6 weeks. Its only host is humans (Ibarra 2001). Transmission may occur through handling of contaminated food, clothing, and bed linen. Diagnosis Women present with itching of the vulva or anus, especially at night. Itching can cause loss of sleep. Threadworms do not move much and so can be easily missed, but if seen are diagnostic. Eggs can be detected by the adhesive tape test. Transparent wide hypoallergenic adhesive tape is applied to the perianal skin first thing in the morning, before wiping or bathing. It does

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not have to be left on overnight. The tape is then examined microscopically and the eggs are seen adherent to the tape. Treatment Mebendazole kills the threadworms. It is administered as a single oral dose and is best repeated after 2–3 weeks in case reinfection has occurred. Other possible drugs include albendazole and pyrantel pamoate. Asymptomatic infections can occur and so all the family and close contacts should be treated at the same time, regardless of symptoms. Drug treatment is not mandatory. The life cycle of threadworms is 6 weeks and the eggs remain viable for further 2 weeks. Excellent hygiene over this time frame will lead to the threadworms dying out without a chance to reinfect. Hygiene measures include: • Wash each morning especially around the anus and vulva. • Keep fingernails short and clean. • Wash hands and scrub under the nails first thing in the morning. Wash hands and nails prior to preparing food and eating. • Wash hands and nails after using the toilet. • Put toothbrushes in a closed cupboard and rinse them well before use. • Do not share towels or beds. If possible wash towels and bed linen daily. • Change and wash underwear and nightwear daily. • Do not shake the laundry as this can spread eggs.

Atrophic Vaginitis The storage of glycogen by the vaginal epithelium is under the influence of estrogen. If women have extremely low endogenous estrogen production such as after the menopause or bilateral salpingo-oophorectomy, gonadotrophin-releasing hormone analogues, radiation, chemotherapy, or immunological disorders, the glycogen content of the vaginal epithelium drops resulting in atrophy

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(Summers and Hunn 2007). It has been estimated that up to 50% of women experience symptoms due to atrophic vaginitis at 5 years postmenopause (Sturdee and Panay 2010). Postpartum women can also experience atrophy because of the decline in estrogen levels in conjunction with the loss of placental estrogen, and prolactin produced during lactation has an antagonistic effect on estrogen. Reduced endogenous estrogen reduces the glycogen content of the epithelium which in turn reduces lactic acid production and increases the vaginal pH leading to a reduction in Lactobacillus. Diagnosis History and physical examination will usually lead to a diagnosis. Symptoms of atrophic vaginitis include soreness, postcoital burning, dyspareunia, dryness, vulvar or vaginal itching, leucorrhea, pressure, yellow discharge, and occasional spotting. There are often associated urinary tract symptoms such as dysuria, frequency, leaking, and infection. The vaginal epithelium appears thin, smooth, pale, or shiny. The vaginal rugae will have disappeared. Petechiae and increased friability or erythema may be present. There can be fusion of the labia minora, introital stenosis, thin vulvar skin with patch erythema, or discolored lesions. Vaginal pH will be raised and a wet mount shows white blood cells and a lack of Lactobacillus (Kingston 2009). Treatment Many women with vaginal atrophy are not symptomatic, so treatment may not be desired. For symptomatic women treatment with vaginal estrogens is effective. Tablets and creams can be used nightly for 2 weeks and then twice weekly. Twice weekly maintenance dose can be continued long term and should be continued for as long as women have distressing symptoms. Systemic absorption is minimal and so progesterone is not required (BMS 2016). Some women may prefer to switch to oral or patch therapy after a few weeks or months of vaginal treatment. Those patients presenting with symptoms while already taking systemic HRT may show improvement in symptoms with the addition of vaginal estrogens (NICE 2015).

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Lichen Sclerosus Lichen sclerosus (LS) is an inflammatory dermatosis of unknown etiology. It is a chronic relapsing disease. There is evidence to suggest that autoimmune factors may be involved in its pathogenesis, and recent evidence has shown autoantibodies to extracellular matrix protein 1 (Oyama et al. 2003). There is an increased frequency of other autoimmune disorders in females with lichen sclerosus (Meyrick-Thomas et al. 1988). Diagnosis Presentation is usually with intense vulvar itching, but soreness, burning, or pain may be the primary symptom, particularly where there has been chronic itch. Pruritus is often worse at night and many women have disturbed sleep. If the introitus has narrowed, they may disclose dyspareunia and sexual dysfunction. On examination LS classically appears as porcelain-white plaques on the vulva, perineum, and perianal skin. The texture of “parchment” or “cigarette paper” skin is characteristic and helps to distinguish lichen sclerosus from lichen planus or vitiligo. Changes may be localized or distributed in a “figure of eight” around the perianal skin figure involving the labia minora and majora, vestibule, clitoral hood, and perineum. Other features include fissuring, hyperkeratosis, and erosions. Loss of architecture may be manifest as loss of the labia minora and/or midline fusion. The clitoral hood may be sealed over the clitoris so that it is buried or a clitoral pseudocyst may have formed. The vagina and cervix are spared, but extragenital lesions can be seen in around 10% of cases. Clinical diagnosis of lichen sclerosus is accepted as standard practice (Neill et al. 2002). Outpatient biopsy under local anesthesia is well tolerated. Histology shows epidermis thinning with subepidermal hyalinization and deeper inflammatory infiltrate. It is useful in diagnostically difficult cases, those which fail to respond to treatment and suspicious areas. The lifetime risk of squamous cell carcinoma (SCC) in cases of lichen sclerosus is less than 5% (BASSH 2014b), and this may be higher than actual risk owing to the probable high prevalence of undiagnosed lichen sclerosus (Neill et al. 2002).

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Investigation for autoimmune disease should be considered, especially thyroid dysfunction (i.e., T4 and TSH) as it is often asymptomatic. Treatment Women are treated symptomatically. Recommended treatment is by ultrapotent topical steroids, e.g., clobetasol propionate. Various regimens are used with no evidence of an optimal regime (BASSH 2014b). One of the most common regimes is to use the treatment daily for 1 month, then alternate days for 1 month, then twice weekly for 1 month, followed by reviewing the patient after the 3 months. It can then be used as needed depending on symptoms (Neill et al. 2002). Ointment bases are much better to use on the anogenital skin because of the reduced need for preservatives in an ointment base and hence less risk of a secondary contact allergy (BASHH 2014b). Topical steroids are safe to use while pregnant or breastfeeding. Women with active LS should have dermatology involvement. Those with complex conditions, such as developed vulvar intraepithelial neoplasia (VIN) or SCC on a background of LS, should be seen and followed up by an experienced clinician or in a specialized vulvar clinic. Surgery should only be used for the treatment of coexistenting abnormality requiring excision or to release labial fusion. Disease tends to recur around the scars (BASSH 2014b). Patients should be informed about the condition and given written information. Women must be made aware of the small risk of neoplastic change. They should be advised to contact the doctor if they notice a change in appearance or texture (e.g., lump or hardening of the skin), or if there is a major change in symptoms. Good vulvar hygiene may be helpful.

Lichen Planus Lichen planus (LP) is a rare inflammatory disorder of unknown but probably autoimmune pathogenesis. It has manifestations on the skin, genital and oral mucous membranes, and more rarely the lacrimal duct, esophagus, and external auditory meatus. It affects 1% of women.

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Diagnosis Vulvar LP presents with intense itching, pain, soreness, dyspareunia, and bleeding. A purulent discharge caused by desquamative vaginitis is common when the vagina is involved (Goldstein and Metz 2005). The heterogenous appearance can be divided into three groups: • Erosive LP is the most common subtype to cause vulvar symptoms. The mucosal surfaces are eroded looking “red raw”; the edges of the erosions are mauve. The lesions consist of friable telangiectasia with patchy erythema which are responsible for the common symptoms of postcoital bleeding, dyspareunia, and a variable discharge which is often serosanguinous. As erosions heal synechiae and scarring can develop, therefore vaginal lesions should be recognized and treated early to prevent scarring, stenosis, and introital narrowing (Genadry and Provost 2006). This type is also seen in the oral mucosa although synechiae are uncommon. Wickham striae are pathognomonic. On the vulva they appear as white reticular or linear papules and they may also be found on the buccal mucosa of the mouth. Vulvovaginal gingival syndrome describes erosive disease occurring in the vulva, vagina, and mouth. • Classical LP usually presents wellcircumscribed papules which are flat topped. They are found on the trunk, extremities, and the keratinized anogenital and vulvar skin, with or without striae. Hyperpigmentation frequently follows their resolution, particularly those with dark skin. This type of lichen planus may be asymptomatic. • Hypertrophic LP is relatively rare and can be difficult to diagnose. Lesions particularly affect the perineum and perianal area, presenting as thickened warty plaques which may become ulcerated, infected, and painful. Because of these features, they can mimic malignancy. They do not appear to be accompanied by vaginal lesions. Skin changes elsewhere can be helpful to aid diagnosis. Histology of a vulvar biopsy is diagnostic and shows irregular saw-toothed acanthosis, increased granular layer and basal cell liquefaction,

and band-like dermal infiltrate which is mainly lymphocytic (BASSH 2014b). Biopsy is essential if diagnosis is uncertain or to exclude coexisiting VIN or SCC. The incidence of developing SCC is as high as 3% (Cooper and Wojnarwowska 2006). Treatment Good vulvar care (see below) should be recommended. Potent or ultrapotent topical steroids constitute first-line treatment and suppositories can be used for vaginal disease. Daily application for up to 3 months has been advocated, reducing as required (Goldstein). However there is not an evidence-based optimal regime. Maintenance can be achieved by either regular application of a weaker steroid or less frequent use of a potent steroid. Delivery of corticosteroids to the vagina is a challenge. A proprietary preparation containing hydrocortisone (Colifoam) is introduced with an applicator. Prednisolone suppositories may be used in more severe cases (BASHH 2014b). There is not any good evidence in systemic therapy. Vaginal dilators should be used early in vaginal involvement to prevent adhesions and topical local anesthetic gel can help with discomfort. Surgery is reserved for reversal of severe scarring, particularly for younger or sexually active women. Lichen planus is very often misdiagnosed as lichen sclerosus because of similarities in the presentation and the presence of white plaques. However, vaginal involvement precludes lichen sclerosus as a diagnosis. Lichen sclerosus and lichen planus are thought to be present simultaneously in some cases, perhaps those with more resistant disease (Neill et al. 2002). Referral to a multidisciplinary vulvar clinic should be considered for any woman with erosive disease, coexisting diseases, intractable symptoms, or scarring complications.

Contact Dermatitis Contact dermatitis resulting in inflammation commonly affects the vulva. Inflammation of the skin occurs after exposure to an allergen (allergic dermatitis) or an irritant (irritant dermatitis).

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Management of Chronic Recurrent Vulvovaginitis

Allergic reactions are a cell-mediated (type 4) immunological response that occurs on reexposure after an initial sensitizing episode. The history of symptoms may reveal the diagnosis. Patch testing can be performed to determine the allergen among women in ongoing symptoms. Common allergens include nail polish, latex preservatives, and lanolin. There are also reports of semen rarely causing symptoms, and absence of symptoms following intercourse with a condom may lead to a suspicion of this. Irritant-induced contact dermatitis can be acute or chronic. It may occur from acute exposure to a potent irritant or after repeated exposure to a weak irritant. The postmenopausal vulva is particularly susceptible to irritation. Possible irritants include detergent, panty liners, moisturizers, chronic wetness from vaginal discharge or urine, topical medications, antifungals, latex, lubricants, spermicides, cosmetics, fragrances, cleansing products, and washing powders/liquids (Kingston 2009). Diagnosis A history of itching is the most common symptom. However, a potent stimulant causing acute reactions involving the mucosa can cause symptoms of burning, rawness, and pain. Persistent scratching in chronic conditions will also frequently lead to pain. On examination the skin can be red and edematous with exudation and weeping and rarely erosions and ulcers. If the exposure to the stimulant is prolonged, then lichenification, scaling, and thickening of the skin can occur with fissuring (see lichen simplex chronicus below). Treatment Where possible, identify and remove the exacerbating agent. Provide women with written information on good vulvar care (see below). Aqueous cream has been shown to be a potential irritant when it is used as an emollient, so it’s recommended as a soap substitute only. Consider topical corticosteroids in ointments for 7–10 days to treat the inflammation. In severe, rare cases, oral steroids could be considered. Any superimposed infection may need treating with antibiotics or antifungals as appropriate (Kingston 2009).

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Lichen Simplex Chronicus Lichen simplex chronicus results from an itchscratch-itch cycle caused by another pathology making LSC a secondary condition. The original itch can be triggered by (BASHH 2014b): • Underlying dermatosis – atopic dermatitis and superficial fungal (tinea and candidiasis) infections • Environmental factors causing irritant or allergic dermatitis • Systemic illness – obstructive biliary disease (primary biliary cirrhosis and primary sclerosing cholangitis), renal failure, hyper- or hypothyroidism, Hodgkin’s lymphoma, and polycythemia rubra vera • Psychiatric disorders – obsessive-compulsive disorder, anxiety, depression, and dissociative experiences Diagnosis Patients characteristically describe an intractable itching and scratching, especially during sleep at night. Examination reveals lichenification, i.e., thickened, slightly scaly, pale, or earthy-colored skin, exaggerated skin markings, and excoriations, maybe more obvious on the side opposite the dominant hand. There may be erosions and fissuring. Pubic hair can be lost as a result of scratching (BASHH 2014b). Treatment To treat the women, the cycle must be broken by treating the underlying cause, if known, and good vulvar care. Use a soap substitute for all washing and an emollient regularly. Emphasizing daily drying techniques may be helpful. If needed sedating antihistamines at night can be used to reduce the itch and aid sleep (such as hydroxyzine). Potent or ultrapotent topical corticosteroids can reduce the inflammation and treat the lichenification. These should be in ointment form as creams can cause irritation. Secondary infection is possible and so must be screened for and treated, if present, with an antifungal or antibiotic as necessary. Cognitive behavioral therapy may be helpful if there are coexisting mental health issues (BASHH 2014a).

Reduced lactobacilli with overgrowth of anaerobic species Metronidazole

Yeasts

Antifungals, vulvar care

>4.5

4.5 typically 5–6 Trichomonads

Trichomonas vaginalis Scanty to profuse, frothy yellow Fishy Present

Mebendazole

Nematode infection

Vaginal and vulvar discomfort, burning, dyspareunia Worms may be seen Eggs can be collected on adhesive tape 38.3  C, and sepsis). 5. Tubo-ovarian abscess. 6. Pregnancy.

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with clindamycin 450 mg four times daily or doxycycline 100 mg twice daily. However, patients with diagnosis of TOA should also be given doxycycline 100 mg twice daily in addition to metronidazole 500 mg twice daily or clindamycin 450 mg four times daily to ensure effective anaerobic coverage.

Inpatient Course of Treatment

Drainage of Tubo-ovarian Abscess

Recommended parenteral antibiotic regimens are shown in Table 2. Intravenous antibiotics should be given for at least 24 h. After 24–48 h with improvement in clinical symptoms (afebrile, improved pain, and able to tolerate oral intake), patients may be transitioned to an oral antibiotic regimen to complete a 14-day antibiotic course. Oral regimens after parenteral treatment:

Drainage of tubo-ovarian abscess may be considered in a patient who does not respond to intravenous antibiotics and may be necessary in abscesses larger than 7 cm (Beigi 2022b). TOAs are usually drained transvaginally or transabdominally with imaging guidance. Often, a short-term indwelling catheter remains in place for continued drainage. Laparoscopy may be used for drainage without surgical removal of infected structures.

• If using the standard regimens, patients should be discharged with doxycycline 100 mg twice daily and metronidazole 500 mg twice daily. • If using the clindamycin/gentamycin alternative regimen, patients should be discharged Table 2 Parenteral treatment (CDC 2021) Standard regimens OR Cefotetan 2 g IV every 12 h Cefoxitin 2 g IV every 6 h Ceftriaxone 1 g IV every 24 ha PLUS Doxycycline 100 mg orally or IV every 12 hb a PLUS Metronidazole 500 mg orally or IVevery 12 hb Alternative regimen (if severe B-lactam allergy) Clindamycin 900 mg IV every 8 h PLUS Gentamycin: 2 mg/kg IV or IM loading dose followed by 1.5 mg/kg IV or IM every 8 h (single daily dosing may be given 3–5 mg/kg/ day) Alternative regimen Ampicillin-sulbactam 3 g IV every 6 h PLUS Doxycycline 100 mg orally or IV every 12 hb IV intravenous, IM intramuscular, and BV bacterial vaginosis a Metronidazole should be added if using ceftriaxone as the cepahlosporin. b If a patient is able to tolerate oral doxycycline, it should be given orally. Intravenous doxycycline is associated with irritation and phlebitis. Oral and IV doxycycline and metronidazole have similar bioavailability.

Surgical Intervention Surgery is usually not indicated in the diagnosis or treatment of acute PID. Surgery may be indicated to rule out other surgical conditions that could not be excluded clinically (i.e., ovarian torsion). In cases not improved by conservative measures including antibiotics with or without drainage of abscess, or in cases of TOA rupture, surgery may be indicated to remove purulent material and necrotic tissue. Ruptured TOAs require immediate surgery. Surgery may also be indicated for source control in a patient who is not improving with IV antibiotics and abscess drainage (or when drainage is not feasible). Operating in the setting of acute infection can be associated with high surgical morbidity and loss of future fertility – traditionally a total hysterectomy and bilateral salpingooophorectomy (Beigi 2022b). Surgical approach should be guided by surgeon expertise, while also taking into account patient preferences and informed decision-making. Surgery may also be indicated in postmenopausal patients with TOA when malignancy cannot be excluded, though this is usually deferred

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until after completion of treatment for acute infection. Likewise, surgery is considered for any persistent adnexal mass after adequate antibiotic therapy.

J. Reid

The patient should be counseled on the use of condoms or other barrier contraception to prevent future sexually transmitted infection and should be offered additional contraceptive options if needed.

Intraoperative Findings Intrauterine Device (IUD) in Place If surgery is performed, laparoscopy can confirm or incidentally detect acute PID if salpingitis or pyosalpinx is seen but is not sensitive in detecting PID in a patient with only endometritis or mild intraluminal tubal disease. Salpingitis may be identified by tubal serosal hyperemia, tubal wall edema, or purulent discharge from the fimbria of fallopian tubes or collection in the cul-de-sac. In patients with perihepatic inflammation (Fitz-Hugh-Curtis syndrome), the classic intraoperative findings are violin string adhesions between the diaphragm and liver capsule that may be seen during acute PID or may suggest past infection.

Other Management Considerations Patient Counseling and STI Testing/Reporting Patients should be counseled about PID as a sexually transmitted infection. The patient should be offered testing for other STIs including HIV, syphilis, and hepatitis B and C. PID, N. gonorrhoeae, and C. trachomatis should be reported to the local public health department as a sexually transmitted infection. If the patient had positive testing for N. gonorrhoeae or C. trachomatis, they should be retested in 3 months. Repeat testing should not be performed prior to 6 weeks as NAAT results can be difficult to interpret. Sexual partners within the last 60 days, or the most recent sexual partner, should also seek evaluation and treatment. Expedited partner therapy should be considered if available in the practice setting. Patients should abstain from sexual intercourse while undergoing treatment until symptoms resolve and partners have been evaluated and treated. Adherence and completion of antibiotics should be emphasized.

If an IUD is in place at the time of diagnosis of PID, the IUD may remain in place. It does not need to be removed. If the patient does not demonstrate clinical improvement after 48–72 h of appropriate antibiotic treatment, removal of the IUD may be considered (CDC 2021).

Follow-Up For outpatient treatment of PID, patients should be seen within 48–72 h for repeat pelvic exam. In all patients, strict return precautions should be given for worsening symptoms. For TOA, repeat the pelvic ultrasound in 6 weeks to confirm resolution of the mass. Surgery may be indicated based on follow-up findings. A persistent adnexal mass, particularity in a postmenopausal patient, should prompt further evaluation for malignancy.

Long-Term Complications Prompt diagnosis and treatment are important to reduce the risk of long-term sequelae (Peipert and Madden 2021 (Fig. 6). Tubal inflammation damages both the secretory and ciliated endothelial cells within the tubal lumen, flattens mucosal folds, and also causes distortion of the fimbria leading to tubal clubbing, blockage, and adhesions. Hydrosalpinx or enlarged fluid-filled tubes may form secondary to blockage. Tubal damage and blockage may lead to infertility, ectopic Fig. 6 Long-term complications

-

Recurrent PID Hydrosalpinx Pelvic adhesions Chronic pelvic pain Infertility Ectopic pregnancy

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Pelvic Inflammatory Disease and Other Upper Genital Infections

pregnancy, and chronic pelvic pain. Patients are also at risk for recurrent PID. Pain may develop due to hydrosalpinx or pelvic adhesions and may affect up to one-third of patients after PID. In a cohort that followed 100,000 patients with PID between the ages of 20 and 24 years, there were 18,600 cases of chronic pelvic pain, 16,800 cases of infertility, and 8550 ectopic pregnancies (Yeh et al. 2003). Studies also indicate that the rates of ectopic pregnancy and infertility increase with the number of episodes and severity of disease (Wiesenfeld et al. 2012). One in eight patients with a history of PID experience difficulty with fertility (Kreisel et al. 2017). It is important to note that even mild PID can lead to long-term complications. Thus, early recognition, prompt treatment, and prevention of recurrence are necessary to minimize long-term complications.

Conclusion Pelvic inflammatory disease (PID) is an infection of the upper genital tract and is commonly encountered by healthcare providers in a variety of care settings, including obstetrics and gynecology, primary care, and emergency medicine/urgent care. The signs and symptoms of PID can be vague, and the diagnosis is made clinically. Given the significant long-term complications of delayed treatment or untreated PID, a low threshold for diagnosis and treatment is recommended. Healthcare providers may reference treatment guidelines developed by the CDC for both inpatient and outpatient management of PID and antibiotic regimens.

Cross-References ▶ Anatomy of the Female Genital System ▶ Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass ▶ Sexually Transmitted Diseases: Diagnosis and Work-Up (GC, Chlamydia, Herpes, HPV)

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References Beigi RH. Epidemiology, clinical manifestations, and diagnosis of tubo-ovarian abscess. 2022a [updated 2022 Feb 7; accessed Jan 2023]. Available from: www. uptodate.com Beigi RH. Management and complications of tubo-ovarian abscess. 2022b [updated 2022 Apr 19; accessed Jan 2023]. Available from www.uptodate.com Centers for Disease Control and Prevention (CDC). Pelvic inflammatory disease (PID). 2015 [updated 2015 Nov 17]. Available from: http://www.cdc.gov/std/pid/ stats.htm Centers for Disease Control and Prevention (CDC). Sexually transmitted infection treatment guidelines, 2021: Pelvic Inflammatory Disease (PID) [updated 2021]. Available from: https://www.cdc.gov/std/treatmentguidelines/pid.htm Hoffman BL, Schorge JO, Schaffer JI, Halvorson LM, Bradshaw KD, Cunningham FG. Chapter 3: gynecologic infection. In: Williams gynecology. 2nd ed. New York: McGraw Hill Medical; 2012. Kreisel K, Torrone E, Bernstein K, Hong J, Gorwitz R. Prevalence of pelvic inflammatory disease in sexually experienced women of reproductive age — United States, 2013–2014. MMWR Morb Mortal Wkly Rep. 2017;66:80–3. https://doi.org/10.15585/mmwr. mm6603a3External. Ness RB, Soper DE, Holley RL, et al. Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) randomized trial. Am J Obstet Gynecol. 2002;186:929–37. Peipert JF, Madden T. Long-term complications of pelvic inflammatory disease. 2021 [updated 2021 Jul 26; accessed Jan 2023]. Available from: www. uptodate.com Ross J. Pelvic inflammatory disease: pathogenesis, microbiology, and risk factors. 2022 [updated 2022 Dec 5; accessed Jan 2023]. Available from: www. uptodate.com Ross J, Chacko M. Pelvic inflammatory disease: clinical manifestations and diagnosis. 2022 [updated 2022 Apr 20; accessed Jan 2023]. Available from: www. uptodate.com Wiesenfeld HC. Pelvic inflammatory disease: Treatment in adults and adolescents. 2022 [updated 2022 Mar 14; accessed Jan 2023]. Available from www. uptodate.com Wiesenfeld HC, Hillier SL, Meyn LA, et al. Subclinical pelvic inflammatory disease and infertility. Obstet Gynecol. 2012;120:37–43. Yeh JM, Hook EW III, Goldie SJ. A refined estimate of the average lifetime cost of pelvic inflammatory disease. Sex Transm Dis. 2003;30:369–78.

Diagnosis and Treatment of Urinary Tract Infections

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Austin Zanelotti, Amanda Barnes, and Anam Khaja

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 Definitions (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 Risk Factors (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 Resistance Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 Complications of UTI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 Diagnosis and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360

Abstract

Urinary tract infections (UTI) are common among women of all ages and can vary in

A. Zanelotti (*) University of Miami/Jackson Memorial Hospital, Miami, FL, USA e-mail: [email protected] A. Barnes · A. Khaja University of Miami Miller School of Medicine, Miami, FL, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_28

severity from uncomplicated, acute cystitis to pyelonephritis leading to urosepsis. There are various etiologies and risk factors for developing these infections across different population groups. Diagnosis is generally made based on the clinical presentation in conjunction with the presence of bacteriuria on urinalysis or urine culture. Depending on the classification of the UTI, management and treatment will vary. Preventive measures can also be undertaken to address risk factors. Most infections can be treated successfully and patients can expect to make a full recovery. 347

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Keywords

Urinary tract infection · Cystitis · Pyelonephritis · Asymptomatic bacteriuria

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difficult to initiate and maintain. An adept understanding of this prevalent condition is essential in gynecology and other primary care fields, with attention paid to both the physical and psychosocial sequelae.

Introduction Urinary tract infections (UTIs) are common reason for women to seek gynecologic care. UTI can be caused by viruses or fungi like Candida, but the huge majority are bacterial in nature. In fact, UTI is one of the most common bacterial infections encountered in the ambulatory setting in the United States; 11% of US women report at least one physician-diagnosed UTI each year. According to the Centers for Disease Control and Prevention (CDC), more than six million women visited a medical provider for UTI in 2007; approximately 20% of those visits are to an emergency department. This pattern contributes to the large cost burden associated with UTI, with some studies estimating these infections cost upward of $1 billion annually. UTIs in young, otherwise, healthy women who are not pregnant are generally considered to be uncomplicated. They can be treated with empirical antibiotics (discussed below), usually on an outpatient basis. A UTI is considered complicated if a structural or functional abnormality of the genitourinary tract is present. Simple UTI in pregnant women is not considered complicated. This distinction is important, because complicated UTI may need different empiric antibiotics and is more likely to require inpatient treatment. UTI is widely regarded as a benign disease among medical practitioners because of the relatively innocuous natural history and because treatment of the majority of women with antibiotics is generally successful. However, patient perception of this health complaint is not always so benign. For example, when compared to women without UTI, women suffering from UTI rate their quality of life significantly lower with regard to general health perception, physical functioning, emotional health and well-being, vitality, pain, and social functioning. Lifestyle and behavior modifications may be suggested to prevent recurrent infection, and while effective, these can be

Definitions (Table 1) • Asymptomatic bacteriuria Traditionally, 100,000 colony-forming units (cfu)/mL are considered significant bacteriuria. This definition is highly specific but only 50% sensitive. Some sources advocate lowering that cutoff to 1000–10,000 cfu/mL in order to improve sensitivity of diagnosis. As the name implies, these women will have no symptoms of UTI regardless of the numerical definition of the term. • Acute cystitis Acute cystitis is an infection of the lower urinary tract, namely, the bladder. Associated symptoms are produced by a local inflammatory response to bacterial infection: dysuria, hematuria, urinary frequency and urgency, and occasionally suprapubic pain. The natural history of acute cystitis is resolution in approximately 50% of cases, even without antibiotic treatment. Interstitial cystitis is a distinct entity in the spectrum of chronic pelvic pain not to be Table 1 Risk factors for urinary tract infection Premenopausal History of UTI Frequent or recent sexual activity Diaphragm use Use of spermicide Increasing parity Diabetes mellitus Obesity Sickle cell trait Anatomic abnormalities of the urinary tract Urinary tract calculi Requirement for bladder catheterization

Postmenopausal History of UTI Vaginal atrophy Incomplete bladder emptying Poor perineal hygiene Pelvic organ prolapse Type I diabetes mellitus

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•

• •

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Diagnosis and Treatment of Urinary Tract Infections

confused with acute cystitis discussed in the context of UTI. It is defined generally as pain/ pressure/discomfort perceived to be associated with the urinary bladder for more than 6 weeks duration. There is no detectable infection or identifiable cause (i.e., urine cultures will be negative). Acute pyelonephritis Pyelonephritis implies infection that has ascended to affect the renal parenchyma, renal pelvis, and calices. Associated symptoms reflect an infection that produces a more systemic inflammatory response than what is seen in acute cystitis: fever and chills, flank pain, and leukocytosis in addition to the urinary symptoms associated with lower UTI. Chronic pyelonephritis results from persistent infection of the renal parenchyma causing scarring and fibrosis. End-stage renal disease can result. Persistent or relapse refers to UTI with the same organism after adequate treatment. Reinfection or recurrent refers either to a UTI with a different organism than that which was originally isolated or reinfection with the same isolate after an intervening negative culture. Either state might prompt a change in antibiotic therapy for that woman. Recurrent UTI. – Defined as 2 infections in 6 months or 3 infections in 1 year. – Most recurrences are thought to represent reinfection rather than relapse. Recurrence due to relapse warrants a more extensive urological workup, because a persistent nidus may be responsible requiring longer therapy or even surgery to eradicate it. This distinction is rarely clinically important in young healthy adult women (the most common UTI patient).

Epidemiology Fifty percent of all adult women self-report having been diagnosed with UTI by that age of 32. The lifetime probability that a woman will suffer from

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a UTI is 60%. Prospective cohort studies estimate the incidence of acute cystitis between 0.5 and 0.7 cases per person-year among young sexually active women; incidence of culture-confirmed acute cystitis among postmenopausal women is 0.07 episodes per person-year (Hooton et al. 1996; Jackson et al. 2004). Generally, the risk for UTI increases with age. UTI in the pediatric population is often due to congenital abnormalities of the urinary tract. Vesicoureteral reflux and constipation are also common causes of UTI in infants and children. Infrequent diaper changing promotes bacterial colonization. In young boys, posterior urethral valves are a well-described congenital variant that predisposes to UTI via obstructed urine flow from ureters to bladder. Circumcision has been shown to significantly reduce rates of UTI in male babies in the first year of life: one study showed a rate of 2.15% in uncircumcised boys versus 0.22% in circumcised boys (Schoen et al. 2000). Gram-negative rods (E. coli) are the most common causative agents, but Candida species (which cause tinea cruris, known colloquially as diaper rash) are important pathogens in this age group. • Two notable spikes in incidence above baseline occur at age 18–30 years and in the postmenopausal stage. The former is attributable in increased coitus and pregnancy; the latter is associated with atrophic changes in the vagina, a shift in vaginal flora composition, bladder or uterine prolapse, and increased comorbid illnesses like diabetes. Acute pyelonephritis is less common than acute cystitis, with annual incidence estimated to be 12–13 cases per 10,000 women. Recurrent uncomplicated UTIs are common in young healthy women: in one study, 27% of college women experienced a recurrence within 6 months of their first UTI, with an additional 2.7% experiencing a second recurrence in that time period (Foxman 1990). The chances of a recurrence increase with each subsequent recurrent infection. Recurrences are usually acute cystitis due to E. coli; recurrent pyelonephritis is rare

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in healthy patients and no prevalence data is available. Pregnant women are an important subset when considering UTI. While the incidence of bacteriuria is approximately the same in pregnant and nonpregnant women, pregnant women are more likely to have recurrent bacteriuria. Asymptomatic bacteriuria occurs in up to 7% of pregnant women and is most common in the first trimester, with 75% of cases occurring during this time. More than one-third of pregnant women with bacteria in the urine will develop UTI (cystitis or pyelonephritis); however, this risk is reduced by 70–80% if the bacteriuria is treated with antimicrobials. Asymptomatic bacteriuria in pregnancy is associated with preterm birth and consequently low birth weight infants. Therefore, it is recommended to treat this condition in pregnant women in order to improve pregnancy outcomes and reduce the risk of pyelonephritis (more on this below). Acute cystitis occurs in 1–2% of pregnant women; pyelonephritis has an incidence of 0.5–2% in pregnancy and usually occurs in the second and third trimesters when the gravid uterus is most likely to occlude the ureters and predispose to stasis. Between 30% and 50% of renal transplant patients suffer from UTI. However, many of these infections are “silent” or asymptomatic because the immunosuppressive drug regimens required after transplant suppress the body’s inflammatory response to urinary tract bacterial colonization.

Pathogenesis The normal urinary tract is sterile. Several natural defense mechanisms exist to prevent disruption of this sterile environment. The normal vaginal flora is composed primarily of lactobacilli, coagulasenegative staph, corynebacterium, and streptococci (group B streptococci). This population maintains a homeostatic biosphere and prevents overgrowth of foreign bacterial pathogens. Lactobacilli in particular contribute to maintenance of a normal vaginal pH ~3.5–4.5. Reduced estrogen levels or use of antibiotics can decrease the density of

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lactobacillus population. Cervical production of IgA also prevents vaginal colonization with nonnative bacterial species. Normal urine has a high osmolality due to high urea concentrations. Urea is naturally antimicrobial and protects against infection. Organic acids like ammonium confer urine with a low pH, which is also protective. The urothelium is normally shed every few days, so adhered bacteria will also slough off and be excreted via the urine. Additionally, bladder epithelium expresses Toll-like receptors (TLRs). Surface-expressed TLRs, like those found in the bladder, respond primarily to cell wall components of bacteria. Upon recognition of a pathogen, TLRs trigger phagocytic and maturation signals to recruit immune cells, as well as providing co-stimulatory signals in CD80- and CD86- positive B cells. Host defenses in the kidney are primarily composed of IgG and IgA production. UTI occurs when one or more of these normal defenses are disrupted. Generally, three main mechanisms are responsible for UTI: Colonization with Ascending Spread • This is the most common mechanism. • Pathogens that cause urinary tract infection originate in either the bowel or the vagina (via direct inoculation, e.g., during sexual activity). The mucosa of the urethral meatus is colonized, and the bacteria ascend into the urethra and bladder from this point. • The female urethra is short compared to the male urethra and in close proximity to both the vagina and the anus. • Cystitis represents bacterial invasion of bladder mucosa and consequential local inflammatory response. E. coli is the most commonly implicated bacterial species in this type of UTI. Staphylococcus saprophyticus accounts for up to 15% of UTI in young sexually active women. Hematogenous Spread • This is a rare cause of UTI, usually seen in immunocompromised patients and neonates.

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Diagnosis and Treatment of Urinary Tract Infections

• Incompletely treated pyelonephritis, especially emphysematous pyelonephritis, can cause a relapsing UTI via hematogenous spread. • Hematogenous UTIs are more likely to be due to Staphylococcus species (especially S. aureus). Mycobacterium tuberculosis and Candida species can also cause UTI via hematogenous spread. Periurogenital Spread • An infection involving another organ in the genitourinary or gastrointestinal systems can spread to affect the bladder, causing acute cystitis. • E. coli is still the most common bacterial species to cause UTI via this mechanism, but pathogens which cause vaginitis and enteritis are also implicated. • Circumstances that delineate asymptomatic bacteriuria from actual UTI are not clear. Rates of UTI do not differ between groups with asymptomatic bacteriuria treated with antibiotics versus no treatment.

Risk Factors (Table 2) Risk factors for UTI can be categorized into three main subsections: 1. Factors which reduce urine flow (promote stasis) • Outflow obstruction can occur from urinary tract calculi. Inadequate fluid intake both predisposes to urinary tract calculi and contributes to low urinary flow. Urethral strictures can occur following urethritis or traumatic catheterization. Reduced activity of the detrusor muscle can occur following spinal cord injury to the sacral nerve roots at S2–S4, interrupting parasympathetic stimulation that normally contracts the bladder in the voiding phase. Diabetes mellitus can cause a similar clinical picture as glycated end products damage nerves and blood vessels resulting in cystic neuropathy. Most cases of UTI in diabetics are in the upper genitourinary tract because of reflux of urine

351 Table 2 Key definitions Asymptomatic bacteriuria Acute cystitis

Acute pyelonephritis Reinfection

Relapse Recurrent

•

•

•

• •

Significant bacteriuria in a woman with no symptoms Infection limited to the lower urinary tract (bladder) associated with dysuria, frequency and urgency of urination, and suprapubic pain Infection of the renal parenchyma and pelvicaliceal system associated with fever and flank pain Recurrent UTI caused by the same organism after adequate treatment and an intervening negative culture OR A recurrent UTI caused by a second, different isolate Recurrent UTI with the same organism after adequate therapy Two or more infections in 6 months or three or more infections in 1 year, usually representing reinfection rather than relapse

from a neurogenic bladder into the kidney. Glucosuria may also contribute to virulence of UTI pathogens in diabetics. Use of anticholinergic medications can decrease detrusor activity and cause urinary retention. Sickle cell anemia can be complicated by papillary necrosis as sickled red blood cells occlude the microvasculature to the renal pelvis. Necrosed papilla can break off of the calices and fall into the proximal ureter, causing obstruction. Pelvic organ prolapse becomes more common with age, especially if a woman has been pregnant and has had vaginal deliveries. Uterine or bladder prolapse can obstruct normal urine flow and cause urine retention. In children and adolescents, congenital abnormalities of the urinary tract can cause abnormal urine flow and predispose to UTI. In young girls, the most common cause is vesicoureteral reflux from incompetent valves at the ureteral orifice into the bladder. Chronic constipation can obstruct urine flow as the rectum dilates with stool and impinges on surrounding structures. Increased progesterone levels in pregnancy cause decreased ureteral peristalsis and

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contraction pressure. The gravid uterus lateralizes the ureter and increases tortuosity and in some cases contributes to ureteral compression. This combination of factors predisposes to urinary stasis. 2. Factors which promote colonization • Increased sexual activity (especially involving vaginal penetration) contributes to UTI as it provides more opportunities for inoculation of foreign bacteria into the urethrovaginal area. The female urethra is small and in close proximity to the vaginal introitus, so bacteria can access the urethra from the vagina with relative ease. • Increased sexual activity, especially with multiple partners, is a risk factor for sexually transmitted infections. If those infections are treated with antibiotics, the normal vaginal biosphere is disrupted. Changes in flora patterns and vaginal pH allow nonnative bacteria to grow unchecked and cause infection. Use of spermicide and vaginal lubricants facilitates bacterial binding to vaginal and urethral mucosa, allowing for ascent into the bladder and beyond. 3. Factors which facilitate bacterial ascent • The most important culprit in this category is the bladder catheter. Whether a patient lives with an indwelling or undergoes intermittent catheterization, this device provides a variable highway for bacteria directly into the bladder. Patients with indwelling catheters are frequently immobile and/or elderly and have difficulty with urogenital hygiene, making it more likely that uropathogenic organisms will be in the region. • Postmenopausal women are particularly predisposed to UTI because of changes related to decreased levels of circulating estrogens. Atrophic vaginal mucosa is less able to heal and fight infection, and the lactobacilli bacteria that maintain normal vaginal homeostasis premenopause are a smaller component of the genital flora. Estrogen deficiency also reduces the urethral mucus that serves as a barrier to bacteria getting into the bladder. Postmenopausal risk factors for recurrent

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infections include urinary incontinence and the presence of a cystocele. ABO blood group antigen secretor status is also important in the context of postmenopausal women and recurrent UTI. Most people (80%) secrete these antigens in their saliva, gastrointestinal mucous, tears, and other fluids. However, those who do not secrete these antigens have a more robust inflammatory response to urinary tract infection and are more likely to have recurrent infections. Of note, nonsecretor status is also associated with uncomplicated pyelonephritis in premenopausal women. • Diabetes, obesity, and sickle cell anemia are all associated with micro- and macrovascular disease. Damage to blood vessels (via glycated end products in diabetes mellitus, atherosclerotic changes in obesity, and occlusion in sickle cell anemia) impedes blood flow to the pelvic floor, preventing optimal immune response to bacterial colonization. • Women who suffer from recurrent acute cystitis generally have normal urinary tracts. Loss of lactobacillus is one of the most consistently identified risk factors for recurrent infection. Genetic determinants have also been identified, such as an increased propensity for uropathogens to adhere to the uroepithelium in women with recurrent UTI versus women without recurrent infection. Maternal history of UTI is also associated with recurrent infections, supporting a genetic component. Behavioral risk factors also play a large role, including spermicide use and/or new sexual partner(s) in the preceding year.

Microbiology • The most common cause of uncomplicated acute cystitis and pyelonephritis in women is Escherichia coli, accounting for 95% of all cases of UTI in women. • Staphylococcus saprophyticus is a coagulasenegative species that is a common causative

23

•

•

•

•

•

Diagnosis and Treatment of Urinary Tract Infections

agent in sexually active women of childbearing age. Resistance to novobiocin differentiates S. saprophyticus from other coagulase-negative staphylococci. Enterobacteriaceae species make up the remaining cases. Proteus mirabilis and Klebsiella pneumoniae are common culprits, especially in recurrent, complicated, and catheterassociated UTI. Uropathogenic or extraintestinal pathogenic E. coli (ExPEC) has virulence and fitness factors that enhance the bacteria’s ability to cause symptomatic infection. These factors include flagella, adhesins, toxins, polysaccharide coatings, and others. These diverse attributes allow the bacteria to avoid host defenses and adhere to uroepithelium. Invasion of or damage to host cells by the bacteria stimulates an inflammatory response, producing the constellation of symptoms characteristic of UTI. Specifically, bacterial expression of a specific adhesin, type I fimbriae, has been identified as a reproducible and important virulence factor in acute cystitis. Type I fimbriae facilitate tissue attack and adhesion to bladder mucosa. E. coli is still the most common causative agent in complicated UTI in women, although strains causing complicated infections tend to have atypical virulence characteristics. Ureaseproducing organisms like Proteus mirabilis, Providencia stuartii, and Morganella morganii are common among patients with indwelling urological devices like urinary catheters. Proteus infections are notorious for causing struvite renal calculi, which protect the bacteria from antimicrobial treatment and result in infection that is difficult to eradicate. Overall, complicated UTI in catheterized patients is most commonly polymicrobial. Pseudomonas aeruginosa infection (associated with diabetes mellitus) can also become persistent, as this organism has intrinsic resistance mechanisms that protect it from host defenses. Patient education on proper clean-catch urine sample acquisition is critical. Contamination with normal vaginal or skin flora clouds the clinical picture because (though rare) some of

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these isolates can cause infection in the case of recurrent or complicated UTI. Isolation of lactobacilli, enterococci, group B streptococci, and coagulase-negative staphylococci other than S. saprophyticus is likely contaminated. Repeated urine sampling is inconvenient for the patient and wastes healthcare system resources.

Resistance Trends • It is exceptionally important that a practitioner treating UTI be familiar with local patterns of antibiotic resistance. A working knowledge of this topic is a moving target, because resistance patterns vary widely based on geographical location and can change with relative rapidity. The Center for Disease Dynamics, Economics, and Policy has created an antibiotic resistance pattern map, with data for many countries including the United States. It can be found online at http://www.cddep.org/projects/ resistance-map. • These trends are essential especially with regard to E. coli resistance. Several studies have demonstrated more than 20% of E. coli strains causing UTI are resistant to ampicillin. Trimethoprim (a component of Bactrim, an important empiric antibiotic) also has high resistance rates, some studies suggesting close to 20% in certain geographic regions. • Fluoroquinolones still have low resistance rates in most of the United States, and current antibiotic stewardship recommendations attempt to protect that drug class against inappropriate use. Ciprofloxacin is a fluoroquinolone commonly prescribed for UTI, but bacterial (E. coli) resistance rates to this drug unfortunately increased from 3% to 17% from 2000 to 2010. • Resistance to first- and second-generation cephalosporins and amoxicillin-clavulanic acid is generally 20% is suggested as the cutoff at which TMP-SMX should not be used. At this threshold, mathematical modeling and clinical and in vitro data suggest risks outweigh the benefits of TMP-SMX use. • Multidrug resistant strains of bacteria are particularly prevalent among elderly and catheterized patients. This may be because these populations of patients tend to get more antibiotics (for UTI and otherwise), and drugresistant organisms are selected out as other pathogens are eradicated by the drug therapy.

Complications of UTI • In the vast majority of uncomplicated UTI, prognosis is excellent. The infection may resolve even without antibiotic therapy in some cases. Most morbidity associated with uncomplicated UTI emerges when the infections are recurrent. The disease is very uncomfortable, painful, and disturbing to women who suffer from it. The cost and loss of productivity associated with physician visits and therapy are a burden. Multiple cases of acute pyelonephritis can cause permanent damage to the renal parenchyma similar to the morbidity associated with chronic pyelonephritis. Glomerular filtration rates can be compromised as a result. • Complicated UTIs are more frequently associated with serious morbidity. Some of the most common complications are suppurative in nature: paraurethral, renal, or perirenal abscesses have been described. Infection can spread to the bones and joints causing osteomyelitis and/or septic arthritis. Endocarditis can also be caused by metastatic infection. At the extremes of age or in the case of

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immunocompromised, acute urinary tract infection can result in septic shock and even death. Complications are more likely in diabetics, chronic catheter use, and in cases of urinary obstruction.

Prevention • Especially in the context of recurrent disease, many behavioral changes and alternative pharmaceutical therapies have been proposed to prevent UTI. It is important to bear in mind that few of these have been adequately tested via research study, but it is reasonable to advocate for them in order to reduce antibiotic use. Most of them carry a very low risk for harm and may work for some patients via mechanisms not yet identified. • Women should avoid contraception with spermicide, especially in conjunction with a diaphragm or cervical cap. • Postcoital voiding has been suggested as a preventative measure, citing the theoretical mechanism that urine flow would “wash out” bacteria at the urethral meatus and prevent ascension. To facilitate increased voiding in general, liberal fluid intake to increase micturition is also advocated. • Cranberry juice. – Cranberry juice is one of the most wellknown methods to prevent UTI among the laywoman. The proposed mechanism is inhibition of bacterial adhesion. Fructose may interfere with type 1 fimbriated E. coli adhesion specifically (Zafriri et al. 1989). Proanthocyanidins, another component of cranberry juice, prevent adherence of P-fimbriated E. coli (Howell et al. 1998). – Some providers have strong biases (positive or negative) about the effectiveness of cranberry juice. Nevertheless, controlled trials have yielded equivocal data regarding the prevention of uncomplicated cystitis. Attempts to meta-analyze the abundance of research on this topic are limited by heterogeneity of the studies in terms of

23

Diagnosis and Treatment of Urinary Tract Infections

delivery method of the cranberry extract (tablets vs. liquid concentrate, etc.), lack of blinding, lack of placebo group, and lack of a uniform operational definition of UTI. – A trial of cranberry extract is probably safe for most women who want to try it. Because of the acidity of the juice, women may experience gastric acid reflux and other gastrointestinal complaints. This is especially true in patients using cranberry juice for prolonged periods of time. • Probiotics. – Lactobacillus probiotics have been proposed as a prophylactic measure for recurrent UTI sufferers. Suggested mechanisms include maintenance of a pH 90% probability that a woman who presents with at least two of the following symptoms, dysuria, frequency, or urgency in the absence of vaginal discharge, has acute cystitis. Moreover, studies have shown that in women with symptoms of acute cystitis, obtaining urinalysis or urine culture is not associated with improvements in symptom scores or time to reconsultation compared to immediate empirical therapy. In addition to office visits, women with suspected acute, uncomplicated cystitis may also be managed via telephone or with patient-initiated therapy. Telephone management involves screening patients for the symptoms of acute cystitis and for risk factors for complicated UTI, pyelonephritis, and sexually transmitted infections. Women who meet criteria for telephone management (Table 3) can thus be managed by avoiding an office visit and having a prescription called into the pharmacy. Patient-initiated therapy may be appropriate in women with a history of UTI who can identify symptoms, have an existing patient-clinician relationship, and are educated on when to seek additional care (new symptoms of vaginal discharge, back pain, fever, missed menstrual period, new sex partner,

A. Zanelotti et al. Table 3 Criteria for telephone management of acute cystitis Adult women with acute onset (1 of the following: dysuria, frequency, urgency, gross hematuria No flank or abdominal pain Afebrile (10^5 colony-forming units (cfu)/mL of the same bacterial strain on two consecutive voided urine samples or >100 cfu/mL of a single bacterial strain on one catheterized urine sample. However, clinically, only one voided urine sample is obtained, and diagnosis is made without a repeat culture if >10^5 cfu/mL are found. Management of asymptomatic bacteriuria during pregnancy consists of antimicrobial therapy, as well as with follow-up cultures to confirm eradication of the bacteriuria. Antimicrobial therapy is tailored to the urine culture results and susceptibilities with consideration taken to which antibiotics are safe to use during pregnancy. Although there is no optimal duration of therapy, a short course of antibiotics is typically preferred. One week after the completion of antibiotic therapy, a test of cure is performed, and monthly urine cultures are repeated until the end of the pregnancy due to the risk of persistent or recurrent bacteriuria. Persistent bacteriuria occurs when the first urine culture for the test of cure continues to have >10^5 cfu/mL of the same bacterial isolate. In these cases, the same antimicrobial is continued for a longer duration, or a different antibiotic is used in a standard regimen. If the bacteriuria persists after two or more courses of therapy, then a suppressive therapy for the duration of the

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A. Zanelotti et al. Asymptomatic Bacteriuria

Pregnant Not Pregnant

Antibiotic Therapy No treatment

Test of Cure 1 week later

Positive

Same Bacterial Isolate

Negative

monthly urine cultures for duration of pregnancy Different Bacterial Isolate

Persistent Bacteriuria Negative Antibiotic Therapy

Positive

Recurrent Bacteriuria

No treatment, continue monthly cultures

monthly urine cultures for duration of pregnancy

Recurrent Bacteriuria

Antibiotic Therapy Antibiotic Therapy Negative

Positive >2 times

monthly urine cultures for duration of pregnancy continue monthly urine cultures for duration of pregnancy Antibiotic suppressive therapy for duration of pregnancy (monthly urine cultures not indicated)

monthly urine cultures for duration of pregnancy

Fig. 1 Management of asymptomatic bacteriuria

pregnancy may be appropriate. If suppressive antimicrobial therapy is begun, monthly cultures are not necessary, but typically one later culture usually at the start of the third trimester is performed to ensure that the therapy is working. In the event that the follow-up culture while on suppressive therapy turns out positive, another course of antimicrobials based on

susceptibility data should be administered and the suppressive regimen readjusted if needed. Recurrent bacteriuria occurs when the test of cure comes back positive for a different bacterial isolate or when the test of cure comes back negative, but a subsequent culture is positive for either the same or a different species. Based on susceptibility

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Diagnosis and Treatment of Urinary Tract Infections

data, another course of antimicrobials is then administered. Antibiotic prophylaxis is generally not indicated for recurrent asymptomatic bacteriuria. – Acute Cystitis When a pregnant woman complains of new-onset dysuria, a urinalysis and urine culture should be performed on suspicion of acute cystitis. However, it is important to note that urinary frequency and urgency can be normal physiologic findings of pregnancy. If pyuria is found on urinalysis and symptoms are consistent with cystitis, empiric treatment with antibiotics can be given. Diagnosis is confirmed with bacterial growth on urine culture. There have been no studies defining the threshold for bacterial growth in pregnant women, but >10^3 cfu/ mL with symptoms is typically indicative of cystitis. However, if the isolated bacteria is not a typical uropathogen, generally a higher bacterial count of >10^5 cfu/mL is needed for diagnosis. Empiric therapy is generally begun with either cefpodoxime, amoxicillin-clavulanate, fosfomycin, or nitrofurantoin (if during second or third trimester), and then treatment is tailored based on the results of the urine culture and susceptibilities. The optimal duration of treatment is uncertain, but antibiotics are generally given for 3–7 days, and a test of cure is performed 1 week after completion of therapy. Monthly urine cultures are also performed for the duration of the pregnancy due to risk of persistent or recurrent bacteriuria. If cystitis is recurrent, daily prophylaxis is appropriate with either 50–100 mg PO nitrofurantoin or 250–500 mg PO cephalexin at bedtime or postcoitally (if thought to be sexually related). – Acute Pyelonephritis Acute pyelonephritis is diagnosed based on the clinical picture and confirmed by bacteriuria on urinalysis and urine culture. Clinically, a patient will present with flank pain, nausea/vomiting, fever, and/or costovertebral angle tenderness. Symptoms of cystitis may or may not be present. Given the adverse outcomes associated with

359

pyelonephritis in pregnancy such as preterm birth, anemia, sepsis, and respiratory distress, the threshold for evaluation of pyelonephritis is low. Imaging is not routinely performed; however, if needed, renal ultrasound is preferred. Pregnant patients are generally treated for pyelonephritis in the inpatient setting with intravenous antibiotics until symptomatically improved with no fever for 24–48 h. Broad-spectrum beta-lactams are preferred for empiric therapy with tailoring done to the urine culture results and susceptibility data. Although, fluoroquinolones and aminoglycosides are used to treat nonpregnant women, they should be avoided in pregnancy if possible. Once the patient has been afebrile for 48 h, therapy can be switched to oral antibiotics, and the patient can be discharged home to complete a total of 14 days of treatment. However, if fever and symptoms persist despite treatment, a repeat urine culture and renal ultrasound should be done to rule out renal abscess. Low-dose suppressive antimicrobial therapy is typically administered for the duration of the pregnancy to prevent recurrence of pyelonephritis. However, if suppressive therapy is not administered, monthly urine cultures should be done. • Older Women >65 years In older women, the diagnosis of UTI becomes more difficult as asymptomatic bacteriuria is common in the elderly, and older adults will often have genitourinary symptoms such as urgency, incontinence, and dysuria. If there is a clinical suspicion of UTI in women >65 years and they present with nonspecific symptoms and signs, management options include either oral or IV hydration, current medication modification (e.g., discontinuation of diuretic), or topical vaginal estrogen if the vaginal mucosa appears hypoestrogenic. If after 24–48 h of observation, there are changes in mental status or in the character of the urine, a urine dipstick should be performed. If the dipstick is positive, a urine culture should be obtained, but if it is negative, further evaluation for a UTI should be stopped, and other

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diagnoses should be considered. If the urine culture returns positive and the symptoms persist, a short course of antibiotics may be appropriate. However, if the symptoms resolve regardless of the culture results, no treatment is indicated. If the culture is negative with persistent symptoms, other etiologies must be evaluated. If there is a clinical suspicion of UTI and the woman presents with UTI-specific signs and symptoms such as fever, new or worsening dysuria, new urinary incontinence, or costovertebral angle tenderness, then a urine sample must be sent for urinalysis and culture with subsequent treatment with empiric antibiotics. If the urinalysis or culture returns negative, antibiotics should be stopped, but if positive, they should be continued for 3–14 days depending on the severity of the infection. If the symptoms resolve with antibiotic treatment, a test of cure is not necessary after the completion of therapy.

Conclusion • UTIs are a common complaint among women and have a spectrum of severity. They are typically diagnosed clinically and confirmed by the presence of bacteriuria. Asymptomatic bacteriuria is a benign condition and can be left untreated unless pregnant. Acute cystitis is generally uncomplicated and can be treated on an outpatient basis with a short course of antibiotics with management not always requiring an office visit. Pyelonephritis is the most severe of the UTIs and can be managed both in the inpatient and the outpatient setting. Generally speaking, UTIs have an excellent prognosis with most patients being successfully treated with antibiotics and making a full recovery.

Cross-References ▶ Management of Pelvic Pain in Older Women ▶ Sexually Transmitted Diseases: Diagnosis and Work-Up (GC, Chlamydia, Herpes, HPV)

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References American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 91: treatment of urinary tract infections in nonpregnant women. Obstet Gynecol. 2008;111(3):785–94. Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, DeBusscher J, Foxman B. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis. 2011;52(1):23. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin Ther. 2008;30(3):453. Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, Prins JM, Koeijers J, Verbon A, Stobberingh E, Geerlings SE. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012;172(9): 704. Ellis AK, Verma S. Quality of life in women with urinary tract infection: is benign disease a misnomer? J Am Board Fam Pract. 2000;13(6):392–7. Flores-Mireles A, Walker J, Caparon M, Hultgren S. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269–84. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health. 1990;80(3):331. Grigoryan L, Trautner BW, Gupta K. Diagnosis and management of urinary tract infections in the outpatient setting: a review. JAMA. 2014;312(16):1677–84. Gupta K. Emerging antibiotic resistance in urinary tract pathogens. Infect Dis Clin N Am. 2003;17(2):243. Gupta K, Hooton TM, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–20. Hooton T. Clinical practice uncomplicated urinary tract infection. N Engl J Med. 2012;366(11):1028–37. Hooton TM, Scholes D, Hughes JP. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med. 1996;335:468. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med. 1998;339(15):1085. Jackson SL, Boyko EJ, Scholes D. Predictors of urinary tract infection after menopause: a prospective study. Am J Med. 2004;117:903. Lomberg H, Jodal U, Leffler H, De Man P, Syanborg C. Scandinavian. J Infect Dis. 1992;24(1):L77–83. Mody L, Juthani-Mehta M. Urinary tract infections in older women: a clinical review. JAMA. 2014;311(8): 844–54.

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Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329(11):753. Schito GC, Naber KG, Botto H, Palou J, Mazzei T, Gualco L, Marchese A. The ARESC study: an international survey on antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections. Int J Antimicrob Agents. 2009;34(5):407. Schoen EJ, Colby CJ, Ray GT. Newborn circumcision decreases incidence and cost of urinary tract infections during the first year of life. Pediatrics. 2000;105(4): 789–93. Stapleton AE, Au-Yeung M, Hooton TM, Fredricks DN, Roberts PL, Czaja CA, Yarova-Yarovaya Y, Fiedler T,

361 Cox M, Stamm WE. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis. 2011;52(10):1212–7. Wang CH, Fang CC, Chen NC, Liu SS, Yu PH, Wu TY, Chen WT, Lee CC, Chen SC. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: a systematic review and metaanalysis of randomized controlled trials. Arch Intern Med. 2012;172(13):988. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eukaryotic cells. Antimicrob Agents Chemother. 1989;33(1):92.

Diagnosis and Management of Endometriosis

24

Angela S. Kelley and Molly B. Moravek

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proposed Theories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune Alterations in Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of Estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of Pelvic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

364 364 364 365 365 365 365

Clinical Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

366 366 367 367

Classification/Staging of Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Treatment of Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 Interventions for Endometriosis-Associated Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 Natural History of Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Abstract

Endometriosis is a chronic, benign gynecologic condition, affecting up to 10% of reproductive-

A. S. Kelley (*) · M. B. Moravek Department of Obstetrics and Gynecology, University of Michigan Health System, Ann Arbor, MI, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_29

age women. It is characterized by the abnormal presence of endometrial glands and stroma outside of the uterus. Clinically, endometriosis is associated with dysmenorrhea, pelvic pain, and/or infertility. The diagnosis of endometriosis can be suggested based on history and physical examination, but the gold standard for diagnosis is histologic confirmation from a surgical biopsy. The stages of endometriosis are determined based on the extent of disease intraoperatively. 363

364

However, the stages of disease do not always correlate well with symptom severity. Treatments include pain management, hormonal suppression, and/or surgical intervention. Treatment decisions must be individualized to each patient, taking into consideration her symptoms and her plans for future fertility. Endometriosis presents a challenging problem to affected women and their gynecologists. As such, there continues to be investigation into the pathogenesis and potential treatments of the condition.

A. S. Kelley and M. B. Moravek

Endometriosis is a chronic, benign gynecologic condition of reproductive-age women. Approximately 6–10% of premenopausal women are affected by this complex disorder. It is characterized by the presence of endometrial glands and stroma beyond the uterine cavity, occasionally at distant sites. The implantation and proliferation of endometrial cells in distant tissues can cause inflammation, fibrosis, and distortion of normal anatomy. The survival of endometriotic implants in ectopic sites is highly dependent on estrogen, in addition to the local immune response. Clinically, women affected with endometriosis may experience dysmenorrhea, dyspareunia, pelvic pain, and/or infertility. Endometriosis has been reported in up to 20–50% of infertile women and in 71–87% of women with chronic pelvic pain (ACOG 2010). This chapter will discuss the pathogenesis, evaluation, and treatment of women with endometriosis.

the pathogenesis of the condition; however, it is likely that no single theory can fully explain the complexities of the disorder (Fritz and Speroff 2011; Schenken et al. 2015). The oldest and most commonly accepted theory suggests that endometriosis is the result of endometrial glands and stroma migrating into the abdominal cavity via retrograde menstruation through the fallopian tubes. These endometrial cells then attach and implant onto the surface of pelvic organs, where they are resistant to apoptosis and induce local inflammation. The most frequent sites of implantation include the ovaries, anterior and posterior cul-de-sacs, uterosacral ligaments, and broad ligament. Endometriosis found in abdominal scars following a cesarean delivery, or in perineal or vaginal scars following an obstetrical laceration repair, may also be explained by this “implantation theory.” However, there is evidence that retrograde menstruation also occurs in women without endometriosis; thus, endometriosis cannot exclusively be explained by this theory. An alternative theory proposes that endometriosis is the result of metaplasia of multipotent cells found in the peritoneal cavity. Specifically, it is suggested that exposure to menstrual fluid may induce transformation of these multipotent cells into endometriotic lesions. The fact that endometriosis has been diagnosed, although infrequently, in young girls who have not yet started their menstrual cycles, lends support to this particular theory. A third hypothesis suggests that endometriosis is the result of vascular and/or lymphatic transport of endometrial cells. This may explain endometriosis found in distant organs such as lymph nodes, the thoracic cavity, and the umbilicus. Intriguingly, endometriosis has also been identified in such sites as the bone, lung, breast, and brain.

Pathogenesis

Immune Alterations in Endometriosis

Proposed Theories

There is existing evidence that endometriosis is associated with immune dysfunction (Fritz and Speroff 2008). For example, peritoneal fluid from women with endometriosis demonstrates increased numbers of immune cells. Interestingly,

Keywords

Endometriosis · Dysmenorrhea · Pelvic pain · Infertility · Endometrioma · Minimally invasive surgery

Introduction

Endometriosis is a complex disorder that continues to be the subject of research investigation. Several theories have been proposed to explain

24

Diagnosis and Management of Endometriosis

this local inflammatory response appears to promote, rather than suppress, endometriotic lesions. The cytokines and growth factors secreted by these immune cells in turn stimulate attachment and proliferation of the ectopic endometrium. These cytokines include interleukin-1, interleukin-6, interleukin-8 and tumor necrosis factors. Local angiogenesis is promoted by vascular endothelial growth factor (VEGF). There is also evidence for impaired natural killer cell activity in the ability to recognize and act upon ectopic endometrium (Burney and Giudice 2012).

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in both uterine and ectopic endometrial tissues and may partially explain the pain component of endometriosis. Pain from endometriosis may also be caused by cyclic bleeding from endometriotic lesions, in a manner that corresponds with a woman’s menstrual cycle. Adhesions from endometriosis may distort pelvic anatomy or be located in close proximity to pelvic nerves, also causing alterations in pain sensation and processing.

Pathophysiology of Infertility The Role of Estrogen It is well documented that endometriosis responds to hormonal stimulation. In particular, the steroid hormone estrogen promotes the survival and growth of endometriotic lesions. In premenopausal women, the ovaries secrete the majority of circulating estrogen; however, estrogen production also occurs in adipose and skin tissue by conversion of androgens to estrogens, via the enzyme aromatase. Intriguingly, in women with endometriosis, estrogen synthesis also appears to occur locally within the endometriotic tissue, further promoting abnormal growth (Burney and Giudice 2012).

Pathophysiology of Pelvic Pain Pelvic pain is a common complaint among reproductive-age women. Pelvic pain is complex and multifactorial and is not limited to gynecologic factors. Non-gynecologic etiologies for pelvic pain include the gastrointestinal, urologic, musculoskeletal, psychological, and neurologic systems (Shin and Howard 2011). Chronic pelvic pain can be severe enough to require treatment or cause functional impairment in affected women. In women with endometriosis, pelvic pain is a prominent complaint, thought to be related to the action of prostaglandins, substances involved in inflammation and pain. In women with endometriosis, PGE2 and PGF2a are two specific prostaglandins that are produced in increased amounts

There are several mechanisms underlying the infertility component of endometriosis (ASRM Practice Committee 2012; Macer and Taylor 2012). First, endometriosis may cause distortion of normal anatomy, particularly of the fallopian tubes. The altered anatomic relationships between the ovaries and the fallopian tubes may interfere with oocyte capture after ovulation. Fallopian tubes, which may be blocked at their distal fimbriated ends, may accumulate with serous fluid, causing a distended, swollen tube known as a hydrosalpinx. Hydrosalpinges are a well-known cause of tubal factor infertility. Second, chronic inflammation may interfere with normal endometrial, ovarian, or tubal function. These problems may disrupt follicular development, fertilization of an oocyte, or implantation of an embryo. Further, women with endometriosis often have diminished ovarian reserve or a lower quantity of oocytes remaining than may be expected for age.

Risk Factors Risk factors for endometriosis include early menarche (before 11 years old), short menstrual cycles (5000 mUI/mL Refusal to accept blood transfusion Inability to participate in outpatient follow-up

Intrauterine pregnancy Peptic ulcer disease Pulmonary disease Renal dysfunction Rupture ectopic pregnancy Sensitivity to methotrexate ACOG (2008) and ASRM (2013)

Single-Dose Regimen The single-dose regimen is the simplest treatment course available. It was developed in response to pitfalls of the multidose regimen, in order to reduce side effects, increase convenience of administration, and eliminate the need for folinic acid rescue (Barnhart et al. 2007). This regimen consists of administration of methotrexate 50 mg/m2 on treatment day 1 followed by monitoring of HCG levels on treatment days 4 and 7. If a minimum 15% decrease in HCG is observed between treatment days 4 and 7, no further treatment with methotrexate is required, and HCG

25

Diagnosis and Management of Ectopic Pregnancy

381

Fig. 2 Multidose methotrexate regimen Multidose MTX Regimen

MTX 1mg/kg IM (days 1,3,5,7)

Alternate with folinic acid 0.1 mg/kg IM (days 2,4,6,8)

Measure HCG on MTX treatment days

Continue MTX until HCG has decreased by 15%

If HCG level plateaus or increases, consider repeat MTX as above

Repeat weekly until negative

levels should be monitored weekly until negative. If a 15% decrease in HCG is not observed, a second dose of MTX 50 mg/m2 should be administered on treatment day 7 with HCG monitoring repeated on days 4 and 7 after the second dose (ACOG 2008). Up to 20% of women undergoing treatment with this regimen will require a second dose of methotrexate (Barnhart et al. 2007). This can be repeated as necessary; however, failure to obtain a 15% decrease in HCG after two doses should prompt consideration of surgical management (ACOG 2008). An initial rise in HCG may be observed on treatment day 4 in relation to the pretreatment baseline HCG and should not be a cause for concern (ACOG 2008). If, during the course of follow-up, HCG levels plateau or increase, repeat administration of methotrexate may be warranted (ACOG 2008) (Fig. 3).

Review of several observational studies show a failure rate of 14.3% or higher with the singledose regimen when pretreatment HCG levels exceed 5000 mIU/mL, compared to a failure rate of only 3.7% when the starting HCG level is below 5000 mIU/mL (ACOG 2008). Other studies have suggested an increased failure rate of the single-dose regimen at even lower HCG levels, above 1300 mIU/mL (Rabischong et al. 2011). Therefore, patients with higher initial HCG levels should be appropriately counseled regarding the potential need for more than one dose of methotrexate and possible treatment failure.

Two-Dose Regimen The two-dose regimen was developed to serve as a compromise between the previous regimens detailed above. The goal of this regimen is to

382

E. S. Constance and M. B. Moravek

Single dose MTX regimen

Day 1 MTX 50 mg/m2 IM

Days 4 & 7 Measure HCG

15% decrease in HCG

Less than 15% decrease

between Day 4 and 7

between Day 4 and 7

If HCG levels plateau or increase, consider repeat MTX as above (new treatment Day 1)

MTX 50 mg/m2 IM Follow HCG weekly until negative

Repeat as above (new treatment Day 1)

Fig. 3 Single-dose methotrexate regimen

maximize the number of doses administered without the need for folinic acid rescue while minimizing the number of medical visits required and optimizing patient convenience and treatment efficacy (Barnhart et al. 2007). This regimen consists of the administration of methotrexate 50 mg/m2, on each of treatment days 0 and 4, for a total of two doses. An HCG level is then obtained on treatment day 7. If a decline in HCG of at least 15% compared to the pretreatment value is achieved, no further methotrexate administration is required, and HCG levels are monitored weekly until negative. If the decline in HCG on treatment day 7 is less than 15% of the pretreatment level, a third dose of methotrexate is administered on treatment day 7 and the HCG level reevaluated on treatment day 11. If a 15% decline in HCG is still not achieved, a fourth dose is administered on treatment day 11 and the HCG level repeated on treatment day 14. Failure to obtain at least a 15% decline in HCG by treatment day 14 warrants discontinuation of medical

therapy and consideration of surgical management (Fig. 4). Laboratory evaluation including CBC, LFTs, and creatinine should be performed on treatment day 7, at the time of administration of the third and fourth doses of methotrexate if required, and 2 weeks posttreatment (Barnhart et al. 2007). Methotrexate administration should be discontinued if at any point in the treatment process the patient is found to have LFTs greater than 50% above the upper limit of normal, white blood cell count 15% decrease in HCG

Fig. 4 Two-dose methotrexate regimen

significantly higher even after controlling for initial HCG level and the presence of embryonic cardiac activity (Barnhart et al. 2007). However, subsequent papers have shown no difference in

failure rates between these two treatment regimens (Rabischong et al. 2011). Furthermore, a prospective study evaluating the efficacy of the two-dose regimen demonstrated high patient

384

satisfaction and few side effects (Barnhart et al. 2007). This study demonstrated an overall success rate of 87.1% with 72% of patients requiring a single two-dose course and only 5% requiring a total of four doses. Therefore, the risk of treatment failure should be balanced with the ease of medication administration and improved medication adherence with fewer doses when choosing a treatment regimen.

Posttreatment Monitoring With any of the above treatment regimens, once the initial HCG decline of 15% is achieved, serial HCG levels should be monitored weekly until negative. If at any time in the monitoring process the HCG level is found to increase or plateau, the diagnosis of persistent ectopic pregnancy should be made (ACOG 2008). Tubal rupture can still occur despite declining HCG levels; therefore, clinical suspicion should remain high until a negative HCG level is obtained. Signs of treatment failure or suspected rupture that are indications to proceed with surgical management (ASRM 2013) include hemodynamic instability, increasing pain regardless of HCG level, and rapidly increasing HCG level >53% in 2 days after four doses of the multidose or two doses of the single-dose regimen (ASRM 2013). Serial ultrasound exams are not necessary nor are they recommended during posttreatment monitoring. Ultrasound findings cannot predict or prove treatment failure unless evidence of tubal rupture is noted (ASRM 2013). Some patients will develop transient pain following administration of methotrexate regardless of the treatment regimen used. This pain, often referred to as “separation pain,” generally occurs 2–7 days following methotrexate administration (ASRM 2013; ACOG 2008). The pain is likely caused by the cytotoxic effect of the medication on trophoblastic tissue causing tubal abortion and generally resolves within 4–12 h after its onset (ACOG 2008; ASRM 2013). In the absence of other signs and symptoms of overt tubal rupture, such as hemodynamic instability or significant hemoperitoneum on ultrasound, this pain can be managed expectantly and does not necessarily indicate a surgical emergency. For pain that is severe and/or persistent, evaluation of serial vital signs and hematocrit levels is warranted.

E. S. Constance and M. B. Moravek

Exploratory surgery should be undertaken if at any time tubal rupture is suspected or the patient becomes hemodynamically unstable.

Surgical Management Due to rapid advances in minimally invasive surgical technologies, laparoscopic surgery is currently the gold standard for surgical management of ectopic pregnancy over open laparotomy (Rabischong et al. 2010). The two existing techniques of tubal surgery for removal of ectopic pregnancies are tubal-sparing salpingostomy or complete salpingectomy. The decision of which technique to employ depends both on surgeon preference and patient characteristics.

Salpingectomy Salpingectomy is the complete surgical removal of the affected fallopian tube. This technique allows for nearly certain removal of the abnormal pregnancy in its entirety. It also removes the damaged fallopian tube, excluding the possibility of a repeat ectopic pregnancy in that same fallopian tube in the future. If the woman retains a normally functioning fallopian tube on the contralateral side, she remains capable of achieving spontaneous pregnancy in the future. It is important to note that a normal appearance of the unaffected fallopian tube at the time of surgery does not guarantee normal function. Therefore, even with a history of treatment with salpingectomy, women with a previous ectopic pregnancy should still be treated as high risk for recurrent ectopic pregnancy in the contralateral tube in future pregnancies. Salpingostomy Salpingostomy consists of making a single 10–15 mm incision along the antimesenteric portion of the fallopian tube at the point of maximal bulge from the ectopic pregnancy. The pregnancy tissue is then removed using a combination of aspiration, irrigation, and traction. The tubal incision is subsequently left open to heal by secondary intention in lieu of suturing. This technique may be more costeffective and result in improved future fertility rates compared to salpingectomy (Rabischong et al. 2010). The primary risk associated with

25

Diagnosis and Management of Ectopic Pregnancy

salpingostomy is the incomplete removal of all trophoblastic tissue. It has been estimated that 5–20% of women will experience a persistent ectopic pregnancy following laparoscopic salpingostomy (ACOG 2008). A population-based study looking at 3196 ectopic pregnancies diagnosed from 1992 to 2008 found that 6.6% of women undergoing laparoscopic salpingostomy required subsequent treatment for persistent ectopic pregnancy; however, that rate increased to 8.6% when the preoperative HCG level was greater than 1960 IU/L (Rabischong et al. 2010). A prospective study following 289 patients 9 years after treatment of ectopic pregnancy found that, of those that underwent laparoscopic salpingostomy, 18.9% experienced a repeat ectopic pregnancy in a subsequent pregnancy with 42.9% occurring on the side of previous salpingostomy (Banz et al. 2010).

Adjunctive Use of Methotrexate The presence of persistent ectopic pregnancy following surgical treatment with laparoscopic salpingostomy can be treated with a single dose of adjunctive methotrexate (ASRM 2013). One randomized trial of 129 women demonstrated that empiric administration of a single dose of methotrexate immediately following laparoscopic salpingectomy essentially eliminated the risk of subsequent persistent ectopic pregnancy (Graczykowski and Mishell 1997). However, due to the relatively low incidence of persistent ectopic pregnancy following salpingostomy, many women would need to be treated to prevent one persistent ectopic pregnancy. Therefore, use of HCG monitoring postoperatively in order to identify those who would benefit most from subsequent methotrexate administration is the preferred strategy (ACOG 2008).

385

and ectopic pregnancy should be included in the differential diagnosis. Advances in serum beta HCG assays and high-resolution transvaginal ultrasonography allow for earlier diagnosis of ectopic pregnancy, leading to improvements in management options. When initial ultrasound fails to provide a definitive diagnosis regarding pregnancy location, serial beta HCG levels may be followed until the ultrasound discriminatory zone is reached. Uterine curettage may also be utilized to provide a definitive diagnosis in cases of abnormal pregnancy of unknown location. Whereas surgery has historically been the primary treatment for ectopic pregnancy, earlier detection prior to tubal rupture now allows for more conservative medical management with methotrexate in the outpatient setting as the first-line therapy when appropriate. Although multiple treatment regimens exist, close follow-up is warranted to ensure adequate treatment regardless of which regimen is utilized. For those patients in whom medical management fails or is contraindicated, laparoscopic surgery with either salpingostomy or salpingectomy is recommended for definitive treatment.

Cross-References ▶ Abnormal Vaginal Bleeding During the Early Reproductive Years ▶ Anatomy of the Female Genital System ▶ Contraception ▶ Diagnosis and Management of Gestational Trophoblastic Disease ▶ Diagnosis and Management of Pregnancy Loss ▶ Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass ▶ Pelvic Inflammatory Disease and Other Upper Genital Infections

Conclusions

References

Ectopic pregnancy remains a significant cause of maternal morbidity and mortality in the first trimester. Therefore, all reproductive age women presenting for vaginal bleeding with or without abdominal pain should be tested for pregnancy,

Alsuleiman SA, Grimes EM. Ectopic pregnancy: a review of 147 cases. J Reprod Med. 1982;27:101. American College of Obstetricians and Gynecologists (ACOG). Practice bulletin number 94: medical management of ectopic pregnancy. Obstet Gynecol. 2008;111:1479–85.

386 American Society for Reproductive Medicine (ASRM) Practice Committee. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013;100: 638–44. Banz C, Chalvatzas N, Kelling K, Beyer D, Hornemann A, Diedrick K, Kavallaris A. Laparoscopic management of ectopic pregnancy during a 9-year period. Fertil Steril. 2010;94:2789–2. Barnhart K, Hummel A, Sammel M, Menon S, Jain J, Chakhtoura N. Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy. Fertil Steril. 2007;87: 250–6. Barnhart K, van Mello N, Bourne T, Kirk E, Van Calster B, Bottomley C, Chung K, Condous G, Goldtein S, Hajenius P, Mol B, Molinaro T, O’Brien K, Husicka R, Sammel M, Timmerman D. Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril. 2011;95(3):857–66. Centers for Disease Control and Prevention (CDC). Current trends in ectopic pregnancy – United States, 1990–1992. MMWR CDC Surveill Summ. 1995;44: 46–8. Chang J, Elam-Evans LD, Berg CJ, Herndon J, Flowers L, Seed KA, Syverson CJ. Pregnancy-related mortality surveillance – United States, 1991–1999. MMWR CDC Surveill Summ. 2003;52:1–8. Dart R, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med. 1999;33(3):283–90. DeCherney A, Cholst I, Naftolin F. Structure and function of the fallopian tubes following exposure to diethylstilbestrol (DES) during gestation. Fertil Steril. 1981;36: 741–5. Furlong L. Ectopic pregnancy risk when contraception fails. A review. J Reprod Med. 2002;47:881–5. Goldner T, Lawson H, Xia Z, Atrash H. Surveillance for ectopic pregnancy – United States, 1970–1989. MMWR CDC Surveill Summ. 1993;42:73–85. Graczykowski J, Mishell D. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstet Gynecol. 1997;89: 118–22.

E. S. Constance and M. B. Moravek Green L, Kott M. Histopathologic findings in ectopic tubal pregnancy. Int J Gynecol Pathol. 1989;8:255–62. Guven E, Dilbaz S, Dilbaz B, Ozdemir D, Akdag D, Haberal A. Comparison of the effect of single dose and multiple-dose methotrexate on tubal patency. Fertil Steril. 2007;88:1288–92. Hoover K, Tao G, Kent C. Trends in the diagnosis and treatment of ectopic pregnancy in the United States. Obstet Gynecol. 2010;115:495–502. Kaufman R, Adam E, Hatch E, Noller K, Herbst A, Palmer J, Hoover R. Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring. Obstet Gynecol. 2000;96:483–9. Mol B, Ankum W, Bossuyt P, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception. 1995;52:337–41. Peterson H, Xia Z, Hughes J, Wilcox L, Tylor L, Trussell J. The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative review of Sterilization Working Group. N Engl J Med. 1997;336:762–7. Rabischong B, Larrain D, Pouly J, Jaffeux P, AubletCuvelier B, Fernandez H. Predicting success of laparocopic salpingostomy for ectopic pregnancy. Obstet Gynecol. 2010;116:701–7. Rabischong B, Tran X, Sleiman A, Larrain D, Jaffeux P, Aublet-Cuvelier B, Pouly J, Fernandez H. Predictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general populationbased analysis from the Auvergne Register, France. Fertil Steril. 2011;95:401–4. Skjeldestad F, Hadgu A, Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study. Obstet Gynecol. 1998;91:129. Stock R. Tubal pregnancy. Associated histopathology. Obstet Gynecol Clin N Am. 1991;18:73–94. Yao M, Tulandi T. Current status of nonsurgical management of ectopic pregnancy. Fertil Steril. 1997;67: 421–33. Zane S, Kieke B, Kendrick J, Bruce C. Surveillance in a time of changing health care practices: estimating ectopic pregnancy incidence in the United States. Matern Child Health J. 2002;6(4):227–36.

Diagnosis and Management of Pregnancy Loss

26

Kavitha Krishnamoorthy and Youssef Mouhayar

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombophilic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrinologic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infectious Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Male Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lifestyle, Environmental, and Chemical Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

388 389 389 389 390 390 391 391 391

Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombophilia Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

391 392 392 392 393

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Karyotype Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

393 393 393 394 394

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

K. Krishnamoorthy (*) Department of Obstetrics and Gynecology, University of Miami, Miller School of Medicine/Jackson Health System, Miami, FL, USA e-mail: [email protected] Y. Mouhayar Department of Obstetrics and Gynecology, Jackson Memorial Hospital, Jackson Health System, Miami, FL, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_31

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K. Krishnamoorthy and Y. Mouhayar Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

Abstract

Recurrent pregnancy loss (RPL) is a multifactorial condition encompassing physical and emotional burdens. Several risk factors contribute to spontaneous miscarriage, most commonly through previous history and chromosomal abnormalities. Other etiologies include uterine anomalies, immunologic and endocrine factors, thrombophilias, and environmental pathogens. However, approximately half of all patients with spontaneous pregnancy loss have no reason for these miscarriages (ACOG practice bulletin, Management of recurrent pregnancy loss. Number 24, February 2001, (Replaces technical bulletin number 212, September 1995). American College of Obstetricians and Gynecologists, 2001). Those who experience two or more consecutive losses warrant further evaluation. Assessment of each patient starts with a comprehensive history and physical examination, karyotype testing, imaging of the pelvic structures, and detailed medical workup of possible conditions. If a definite cause is identified, treatment is focused on correcting the abnormality. Psychological support may be crucial and even therapeutic; patients should be comforted that a subsequent live birth is possible with great success. Keywords

Recurrent miscarriage · Spontaneous abortion · Pregnancy loss · Antiphospholipid syndrome · Aneuploidy

Introduction Sporadic pregnancy loss is common, occurring in approximately 15–25% of all pregnancies (Hatasaka 1994). Normally, a miscarriage is not an anticipated event, and couples go through

emotional, physical, and traumatic experiences as a result of this occurrence. Recurrent pregnancy loss is one of the more challenging and difficult aspects of reproductive medicine. According to the American Society for Reproductive Medicine (ASRM), recurrent pregnancy loss is a distinct disorder defined by two or more failed clinical pregnancies documented by ultrasonography or histopathological examination and not necessarily consecutive (Practice Committee of ASRM 2013). The European Society for Human Reproduction and Embryology (ESHRE) defines RPL as three consecutive losses, not necessarily intrauterine (Kolte et al. 2015). At very early gestational ages (4cm

no chorionic villi surgical treatment

chorionic villi= miscarriage

hCGcurettage

repeat hCG in two days

rise or slow decline= ectopic

rapid decline

normal rise

miscarriage

repeat TVUS when hCG>2000

rapid decline-follow until 0

Fig. 3 Management of suspected ectopic pregnancy. (Fig. 1 from Fritz and Speroff 2010)

ultrasonography, TVUS can determine the presence of an intrauterine pregnancy (IUP) with a βhCG value between 1500 and 2500 IU/L. When the β-hCG level is above the discriminatory zone, but no intrauterine pregnancy is detected by TVUS, a dilation and curettage of the uterus is suggested to evaluate for the presence of chorionic villi (Fylstra 2008). If chorionic villi are not detected, then this is considered to be a pregnancy of unknown location and is subsequently treated as an ectopic pregnancy. Alternatively, β-hCG levels may be followed and should demonstrate a minimum drop of 15%. Within 12–24 h in cases of failing IUP. If this is not the case, then an ectopic pregnancy is most likely the diagnosis (Fylstra 2008). On the other hand, when the β-hCG level is below the discriminatory zone, the value should then be serially monitored for appropriate rise as long as the patient is hemodynamically stable. β-hCG levels normally rise by 53% over a 48 h period (Fylstra 2008). The previously used value of 66% increase was determined to be unsafe as it could result in the termination of possible viable pregnancies. In these situations, a TVUS should be performed as

soon as the β-hCG level is above the discriminatory zone. A decline or an inappropriate rise of the β-hCG levels indicates a nonviable pregnancy. A β-hCG level that does not decline by 21–35% over 48 h is indicative of an ectopic pregnancy rather than a spontaneous abortion and should be treated as such. MRI might aid in the diagnosis of an ectopic pregnancy when ultrasonography is equivocal. An ectopic pregnancy usually appears as a structure with a “three rings.” The affected tube usually demonstrated solid components with dilation and evidence of hematosalpinx as well as enhancement of tubal wall (Rosen et al. 2009). Treatment options for ectopic pregnancy include expectant, medical, or surgical management and vary according to different clinical scenarios. Expectant management can be offered to patients with pregnancy of unknown location or when there is concern for an ectopic pregnancy in the setting of low or decreasing β-hCG. A β-hCG that is over 2000 IU/ml is a contraindication for expectant management, and patients should be treated medically with methotrexate (MTX) or surgically (Fylstra 2008). Medical management with MTX is offered to hemodynamically stable

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patients without severe or persistent pain and without relative or absolute contraindications to MTX therapy (Teng et al. 2003). Methotrexate is administered as a single dose, double dose, or fixed multidose with serial β-hCG measurements depending on each specific protocol (Teng et al. 2003). Surgical management is reserved for when there is evidence of hemodynamic instability or contraindication for MTX therapy. A minimally invasive approach is preferred unless there is concern for hemodynamic shock and large hemoperitoneum or when there is suspicion for multiple adhesions or if the pregnancy is extratubal or intraabdominal (Fylstra 2008). Both, a laparoscopic and an open technique, are equally effective; however, laparoscopy is associated with less blood loss and shorter hospital stay. Decision to perform a salpingectomy or salpingostomy is usually made intraoperatively depending on the status of the tube. If the tube is ruptured or severely damaged, salpingectomy is preferred as tubal function might be compromised; however, the number of performed salpingostomies has been declining with an increase in in vitro fertilization (IVF) cycle success (Fylstra 2008). While both salpingostomy and salpingectomy procedures yielded a similar subsequent intrauterine pregnancy rates, there was a higher rate of subsequent ectopic pregnancy in patients who had a salpingostomy (10% vs. 15%) in some but not all reports (Fylstra 2008). Treatment with salpingostomy may also fail if the trophoblastic tissue is not completely resected from the tube, in which case the β-hCG levels must be monitored to ascertain their decline to normal. Future reproductive outcomes appear to be similar after either medical or surgical treatment. It has been shown that the risk of a repeat ectopic pregnancy in patients with previous ectopic is about 10%, regardless of whether the patient underwent MTX treatment or salpingostomy; these patients should be closely monitored for signs and symptoms of ectopic pregnancy (Tulandi 2015).

Y. Mouhayar and M. Saad-Naguib

Tubo-Ovarian Abscess Tubo-ovarian abscesses (TOAs) are inflammatory masses that involve the fallopian tube, ovary, and adjacent organs. The most common cause of TOA is ascending pelvic inflammatory disease (PID) or any upper genital tract infection (Beigi 2015a). Prior to the use of antibiotics and current surgical techniques, the mortality rate as a result of TOA was over 50% (Parelkar et al. 2014). Currently, the mortality rates are less than 5% for both ruptured and non-ruptured abscesses (Parelkar et al. 2014). Most women with TOA are of reproductive age, and the risk factors are the same as those for PID. These include a prior history of PID, multiple sexual partners, and age between 15 and 25 years. In addition, patients undergoing oocyte retrieval during ART are at an increased risk of developing TOAs (McNeely et al. 1998). The microbiology of PID is complex and often includes both aerobic and anaerobic organisms such as E. coli, aerobic streptococci, such as S. agalactiae, and Bacteroides fragilis. Although TOAs are often associated with microorganisms similar to those found in PID, Neisseria gonorrhea and Chlamydia trachomatis are not often seen in cases of TOA (Beigi 2015a). Patients with TOA often present with a similar clinical presentation as those with PID. Symptoms include lower abdominal pain, fever, chills, and vaginal discharge. Patients with a ruptured TOA are more likely to present with signs and symptoms of acute abdomen or sepsis (Beigi 2015a). On physical examination patients with PID or TOA may present with vaginal discharge, cervical motion tenderness, fevers, tachycardia, rebound tenderness and guarding on abdominal exam, as well as vaginal discharge. Workup of a patient with suspected PID/TOA should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), a pregnancy test, as well as nucleic acid amplification testing (NAAT) for N. gonorrhea and C. trachomatis (Parelkar et al. 2014). Abnormalities seen in these tests include elevated white blood cell count, ESR, and CRP levels. Rapid and accurate diagnosis of TOA is crucial since delaying treatment can lead to further sequelae such as infertility, future ectopic

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Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass

pregnancy, and chronic pelvic pain (Beigi 2015a). Imaging is indicated in patients with PID who are acutely ill or have severe abdominal tenderness, as well as when there is suspicion for a TOA. Ultrasound is the imaging modality of choice due to accuracy and cost efficiency. On ultrasound, TOAs appear as complex multilocular masses that often alter the normal architecture of the adnexa as seen in Fig. 4. They tend to have internal echoes that are consistent with inflammatory debris (Dupuis and Kim 2015). CT scan has increased sensitivity and may exclude other abdominal pathologies; however, the financial cost to the hospital is much greater. Findings on CT scan include thick-walled, rim-enhancing adnexal masses, with high-density fluid indicative of pus (McNeely et al. 1998). Management of TOA can be medical or surgical, based on the severity of the clinical presentation and the qualities of the abscess on imaging. Antibiotic therapy is sufficient in 70% of patients with TOA (Tan et al. 2014). Candidates for antibiotics are those who are hemodynamically stable without signs of rupture and have an abscess less than 9 cm and who show an initial adequate response to antibiotic therapy (Beigi 2015b). Patients undergoing medical treatment will often show signs of improvement within 48–72 h

Fig. 4 (a and b) A 47-year-old female with complex and solid cystic mass in the right adnexa with internal vascularity in this patient with tubo-ovarian mass. Patient

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of treatment (Beigi 2015b). Those who do not improve within this time period or worsen will require either drainage or surgery. Table 1 outlines the various inpatient and outpatient regimens for treatment of TOA, but triple therapy with ampicillin, gentamicin, and clindamycin has been shown to be superior to the standard regimen of cefoxitin or cefotetan, plus doxycycline (Beigi 2015b). The first 48–72 h period of antibiotics treatment is critical, as there is high risk of rupture and sepsis. There are no determined guidelines for the duration of antibiotic therapy; however, the most commonly reported is 10–14 days (Beigi 2015b). Surgical management is necessary when rupture is suspected, and antibiotic therapy should be initiated immediately even when surgical management is chosen. Laparotomy is the approach of choice for most physicians due to improved visibility of the entire pelvis; however, a minimally invasive approach has been employed successfully in patients without evidence of rupture and is generally performed by experienced surgeons (Beigi 2015b). A minimally invasive laparoscopic approach has been shown to have low complication rates when offered to patients who desire to preserve fertility (McNeely et al. 1998). Intraoperatively, excision of the abscess is carefully performed followed by copious irrigation of the peritoneal cavity to decrease the intensity of inflammation. A positive response is seen in 90–100% of patients who undergo immediate surgical treatment with laparoscopy, while 20–87%

underwent percutaneous transgluteal drainage under CT guidance (Swenson et al. 2014)

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Table 1 Antibiotic regimens for inpatient and outpatient treatment of tubo-ovarian abscess Regimen Inpatient treatment Cefoxitin and Doxycycline Cefotetan and Doxycycline Clindamycin and Gentamicin

Dose 2 g IV every 6 h 100 mg PO or IV every 12 h 2 g IV every 6 h 100 mg PO or IV every 12 h 900 mg IV every 8 h

Ampicillin and Clindamycin and Gentamicin

900 mg IV every 8 h

2 mg/kg loading dose ! 1.5 mg/kg every 8 h IV/IM 2 g IV every 6 h

2 mg/kg loading dose ! 1.5 mg/kg every 8 h IV/IM

Outpatient treatment Levofloxacin 500 mg PO daily and Metronidazole 500 mg PO twice daily Beigi (2015b)

of patients undergoing medical management will show a positive response (Beigi 2015b). Ultrasound- or CT-guided drainage of the TOA is another treatment option that is widely used. It has been shown that abscess drainage with antibiotic therapy has a higher rate of successful treatment when compared to antibiotics alone (McNeely et al. 1998). Image-guided TOA drainage secondary to PID has been shown to help avoid subsequent salpingo-oophorectomy in 94% of patients (McNeely et al. 1998).

a low-grade fever. Right lower-quadrant pain on palpation is most often seen as the sigmoid colon can have a protective effect over the left ovary (Seeber and Barnhart 2006). Some patients may present with signs of acute abdomen if sebaceous material or blood leaks into the abdomen. Blood may also leak into the ovary, which can cause the patient pain due to stretching of the ovarian cortex (Seeber and Barnhart 2006). Laboratory and imaging studies for these patients is similar to those performed in the pathologies mentioned previously. • As with any gynecologic workup, pregnancy must first be ruled out. • However, if the patient is pregnant, ectopic pregnancy must also be ruled out. In addition to hCG, CBC, urinalysis (UA), blood, and urine cultures should be obtained to determine if there is an infectious cause. • Ultrasound is also preferred in the evaluation of ruptured ovarian cyst for the same reasons of cost efficiency and diagnostic accuracy. On US, an adnexal mass and fluid in the pelvis will be seen as in Fig. 5 (Swenson et al. 2014). Of note, these findings can be similar to those found with ectopic pregnancy or pus from a TOA. If diagnosis is still unclear after US, CT may be performed due to improved visualization of the ovary.

Ruptured Ovarian Cysts Ruptured ovarian cysts can lead to gynecologic emergencies. When an ovarian cyst ruptures, the patient may be asymptomatic, or she can have sudden onset abdominal pain as is seen in the pathologies reviewed above. Upon evaluation of the patient, it is important to determine the risks for cyst rupture. These include ovarian cysts, endometriosis, PID, and coagulation abnormalities. On physical exam, the patient is usually hemodynamically stable, although she can present with

Fig. 5 Complex cystic structure in the right ovary with heterogeneous internal echoes and peripheral solid components with a peripheral ring of vascularity, consistent with a hemorrhagic corpus luteum cyst (Swenson et al. 2014)

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Management of Acute Pelvic Pain: Torsion, Infection, and Rupture of Tubal or Ovarian Mass

Management of ruptured ovarian cysts is dictated by whether the cyst is complex or simple and whether the rupture is complicated or not. Ovarian cyst rupture is classified as uncomplicated when the patient is hemodynamically stable without signs of acute abdomen or an expanding hemoperitoneum. Such patients may be treated on an outpatient basis with oral analgesia, allowing for the cyst fluid to be resorbed spontaneously within 24–48 h, with subsequent improvement of symptoms (Seeber and Barnhart 2006). If the cyst rupture is complicated by large and ongoing blood loss, then patients are usually hospitalized for serial monitoring of vital signs, abdominal exams, and monitoring of hemoglobin and hematocrit levels to determine whether or not further intervention is required (Seeber and Barnhart 2006). Surgical intervention is recommended when bleeding is ongoing or if there are signs of hemodynamic instability. Choosing an exploratory laparotomy or a minimally invasive laparoscopic approach depends on the hemodynamic stability of the patient and the expertise of the surgeon. In most cases laparoscopic ovarian cystectomy with control of bleeding is feasible and is the preferred method in premenopausal patients. An oophorectomy is an acceptable option for postmenopausal patients (Herman et al. 2015).

Conclusion Acute pelvic pain is common presenting complaint that could result from various pathologies. It is critical for clinicians to be able to combine clinical judgment with imaging and laboratory findings in order to make an accurate diagnosis and properly treat the patient. Prompt appropriate treatment is of utmost importance as the consequences of misdiagnosis or mistreatment can be devastating.

References Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing single dose and multidose regimens. Obstet Gynecol. 2003;101:778–84. Beigi RH. Epidemiology, clinical manifestations and diagnosis of tuboovarian abscess. [Cited September 2015a].

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http://www.uptodate.com/contents/epidemiology-clini cal-manifestations-and-diagnosis-of-tuboovarianabscess?source¼search_result&search¼tuboovarian +abscess&selectedTitle¼2~33 Beigi RH. Management and complications of tuboovarian abscess. [Cited September 2015b]. http://www. uptodate.com/contents/management-and-complica tions-of-tuboovarian-abscess?source¼search_result& search¼tuboovarian+abscess&selectedTitle¼1~33 Dupuis C, Kim Y. Ultrasonography of adnexal causes of acute pelvic pain in pre-menopausal non-pregnant women. Ultrasonography. 2015;34(4):258–67. Fritz M, Speroff L. Ectopic pregnancy. In: Clinical gynecologic endocrinology and infertility. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 1388–407. 978-0-7817-7968-5. Fylstra D. Medical management of ectopic pregnancy ACOG Practice Bulletin No. 98. Obstet Gynecol. 2008;111:1479–85. Herman H, et al. Clinical characteristics of adnexal torsion in premenarchal patients. Arch Gynecol Obstet. 2015;293(3):603–8. Karayalçın R, Özcan S, et al. Conservative laparoscopic management of adnexal torsion. J Turk Ger Gynecol Assoc. 2011;12(1):4–8. McNeely G, Hendrix S, et al. Medically sound, cost effective treatment for pelvic inflammatory disease and tuboovarian abscess. Am J Obstet Gynecol. 1998;178(6):1272–8. Parelkar SV, et al. Should the ovary always be conserved in torsion? A tertiary care institute experience. J Pediatr Surg. 2014;49(3):465–8. Pfeifer S, Goldberg J, Lobo R, et al. Fertil Steril. 2008;90: 206–12. Rosen M, Breitkpf D, Waud K. Tubo-ovarian abscess management options for women who desire fertility. Obstet Gynecol Surv. 2009;64(10):681–9. Schraga ED, Fleischer AC, Lin EC. Ovarian torsion. Medscape. May 17, 2016. https://emedicine.medscape. com/article/2026938-overview. Last assessed 11 Nov 2016. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol. 2006;107(2):399–413. Swenson D, et al. Ovarian torsion: case-control study comparing the sensitivity and specificity of ultrasonography and computed tomography for diagnosis in the emergency department. Eur J Radiol. 2014;83(4):733–8. Tan T, Tan K, et al. Practical obstetrics and gynaecology. In: Handbook for clinicians and general practitioners. Hackensack: World Scientific; 2014. p. 50. Teng SW, Tseng JY, et al. Comparison of laparoscopy and laparotomy in managing hemodinamically stable patients with ruptured corpus luteum with hemoperitoneum. J Am Assoc Gynecol Laparosc. 2003;10:474. Tulandi T. Ectopic pregnancy. Clin Manifestations Diagn. [Cited September 2015]. http://www.uptodate.com/ contents/ectopic-pregnancy-clinical-manifestationsand-diagnosis?source¼search_result&search¼ruptured +ectopic&selectedTitle¼1~150

Part IV Gynecologic Care During the Early and Late Reproductive Years

Management of Adnexal Masses

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Donna Shoupe

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Presenting Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 Laboratory and Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Imaging Studies Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416

Abstract

The differential diagnoses of an adnexal mass range from benign functional ovarian cysts to metastatic ovarian carcinoma. The goal of the clinician is to differentiate benign conditions from more serious life-threatening or malignant conditions. Workup of an adnexal mass demands a thorough history and physical exam followed by gray-scale transvaginal ultrasonography (Givens et al., Am Fam Physician 80(8): 815–820, 2009). Findings that are suspicious for

D. Shoupe (*) Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_92

carcinoma include symptoms of bloating, increasing pelvic or abdominal pain, weight loss coupled with the presence of a solid component or complex mass, positive Doppler flow in the mass, thick septations, mural nodules, or presence of ascites. In an asymptomatic postmenarchial woman, (regardless of age) with an adnexal mass, transvaginal ultrasonography is the initial imaging study of choice (Guideline Summary. American College of Obstetricians and Gynecologists NGC.006539 2007 Jul reaffirmed 2011. https://www.guideline.gov/ summaries/summary/12631. Assessed 2 Sept 2016). Simple ovarian “simple cysts” can be found routinely in both premenopausal and postmenopausal women (Healy et al., Menopause 15 (6):1109–1114, 2008), and hemorrhagic corpus 409

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luteum cysts (3–5 cm in size) can occur in early (within 5 years of) menopause women (Seungdamrong and Weiss, Fertil Steril 88(5): 1438 e1–2, 2007). A serum Ca-125 should not be used routinely in premenopausal women (US Preventive Service Task Force 2016; American College of Obstetricians and Gynecologists, Obstet Gynecol 110(1):201–214, 2007). Keywords

Adnexal mass · Endometrioma · Cystic teratoma · Dermoid · Ovarian cancer · Pelvic ultrasound · Simple cyst · Ectopic pregnancy · CA 125 · Tumor markers · Luteoma · Complex mass · Torsion · Functional cyst · Unilocular cyst · Septations · Solid mass · Papillary components · Color flow

Introduction The adnexal mass is one of the most common gynecologic conditions. It is estimated that US women have a 5–10% lifetime risk of undergoing surgery for a suspected adnexal mass (Nagell and Miler 2016). Adnexal masses may be suspected in both symptomatic and asymptomatic women. In premenopausal women, the most common adnexal masses include physiologic follicular cysts and corpus luteum, ectopic pregnancy, polycystic ovaries, endometrioma, benign neoplasm, or tubo-ovarian abscess. In postmenopausal women, common adnexal masses include fibroids and benign neoplasms (Table 1). The first approach of the clinician is to establish that the condition does not mandate immediate intervention (exclude ectopic pregnancy or torsion) and then to determine whether the adnexal mass is “almost certainly benign in nature,” likely or definitely malignant, or indeterminate.

Presenting Symptoms There is a large spectrum of symptoms that patients with an adnexal mass may have as presenting symptoms. Common presenting symptoms of an ectopic pregnancy include vaginal bleeding, unilateral pelvic

D. Shoupe

pain, and a positive pregnancy test. A patient complaining of intermittent severe pain aggravated by movement that may be associated with nausea or vomiting suggests ovarian torsion. These are both conditions that need immediate attention as they need immediate intervention. Patients presenting with fever, purulent vaginal discharge, and cervical motion tenderness may have pelvic inflammatory disease or a tubo-ovarian abscess. An endometrioma/endometriosis may be suspected in patients with infertility and long-standing severe dysmenorrhea and dyspareunia. Premenarchal bleeding or postmenopausal bleeding with an adnexal mass may suggest a granulosa tumor. Midcycle pain may indicate ovulation or Mittelschmertz. There are important factors in the history and nature of the presenting symptoms that are risk factors for ovarian cancer. These include age over 60, nulliparity, infertility, no use of oral contraceptives, family history of breast, colon or ovarian cancer, increased abdominal size, bloating, urinary urgency or frequency, difficulty eating, weight loss, back pain, lack of energy, and nonacute abdominal or pelvic pain (Goff et al. 2000; Olson et al. 2001).

History The history includes the following: • Identification and careful review of the patient’s symptomatology includes an evaluation of pain (location, severity, character, timing, radiating, and back pain), bleeding (amount, timing, and lightheadedness), GI problems (eating problems, bloating, and bowel function), bladder issues (frequency, dysuria, and urgency), presence of vaginal discharge (color and quantity), fever or chills, aggravating or mitigating factors, and other associated complaints. – Symptoms associated with ovarian cancer are often vague in nature. • Medication review (contraceptive history [IUD, OCPS, and pain meds]). • Surgical review (tubal ligation, adnexal surgery, and prior myomectomy). • Medical problems review (history of endometriosis, fibroids, and assess surgical risk).

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Table 1 Differential diagnoses of an adnexal mass Corpus luteum Follicular/Functional cyst, simple cyst

Mature cystic teratoma (dermoid) Ovarian torsion Polycystic ovaries Serous and mucinous cystadenoma, cystadenofibromas Theca-lutein cyst/luteoma of pregnancy Tubo-ovarian abscess

Gynecologic nonovarian benign

Gynecologic malignant nonovarian Nongynecologic benign

Borderline tumor Epithelial carcinoma (clear cell, serous, mucinous, and endometrioid) Ovarian sarcoma Ovarian germ cell tumors Sex cord or stromal tumor Endometrial cancer

Fallopian tube cancer Appendiceal abscess/appendicitis

Endometrioma Ectopic pregnancy

Diverticular abscess Pelvic kidney

Leiomyoma Hydrosalpinx Para-tubal cyst Endosalpingiosis Mullerian/Wolffian duct remnants (paramesonephric cysts [cyst of Morgagni])

Bladder diverticulum Nerve sheath tumor Peritoneal inclusion cyst Ureteral or bladder diverticulum Gastrointestinal cancer/ Krukenberg

Nongynecologic malignant

Metastatic cancer (colon, breast, etc.) Retroperitoneal, intraligamentous cancer Omental cysts Malignant peritoneal mesothelioma

• Obstetrical and gynecologic history (normal cycle length, pregnancy history, pain with intercourse, days and heaviness of menstrual flow, cramps, history of STIs, PID, new partner, and prior Gyn diagnoses). • Family history (breast, ovarian, or colon cancer, bleeding or clotting problems). • Weight changes, changes in eating pattern, and change in energy levels.

Physical Exam Physical exam includes the following: • Vital signs and general assessment (amount of distress, fast pulse rate, low blood pressure, fever, and ease of movement)

• Abdominal exam per four quadrants (tenderness, guarding, bloating, distension, bowel sounds, rebound, ascites, inguinal lymph nodes, and when appropriate cervical, axillary, and supracervical lymph nodes) • Pelvic exam – Careful visual exam of the vulva and vagina (discharge or bleeding, vulvar/vaginal/cervical mass, dilation, stricture, or discoloration) – Bimanual exam of the uterus (cervical motion tenderness, uterine size, shape, consistency, uterine tenderness, mobility, guarding, bladder tenderness, or pain) – Careful adnexal evaluation (adnexal mass, size, shape, mobility, consistency, tenderness, and guarding) – Rectovaginal exam (masses and uterosacral nodularity)

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Laboratory and Imaging Studies • In premenarcheal girls (infants, children, or adolescents) with an adnexal mass, referral should be made to pediatric gynecology (Hermans et al. 2015). • In reproductive-aged women: – Pregnancy test urine and CBC: if positive pregnancy test, then pelvic ultrasound and quantitative B-hCG are obtained: If B-hCG is over 2000 mIU/ml, there is presence of an adnexal mass, and no gestational sac is seen intrauterine, an ectopic pregnancy is suspected. • CBC along with vital signs establishes presence of anemia/amount of blood loss and urgency of intervention. Adnexal masses coincident with a viable intrauterine pregnancy have a low risk of malignancy and are generally asymptomatic. See below (American College Ob/Gyn 2007; Whitecar et al. 1999). – CBC and labs With pelvic pain, especially when there is cervical motion tenderness, yellow vaginal discharge, fever, or GI symptoms, pelvic inflammatory (PID) or tubo-ovarian abscess (TOA) may be suspected. • CBC indicated with suspected PID or tubo-ovarian abscess: WBC elevated with shift • Cervical cultures obtained for gonorrhea and chlamydia, STD screening If prolonged or acute heavy bleeding: • CBC, clotting studies (blood dyscrasias particularly important to rule out in young adolescent women with prolonged bleeding episodes). • Pelvic ultrasound may demonstrate uterine fibroids, adenomyosis. Routine screening with CA-125 in a premenopausal woman with an adnexal mass (American College of Ob/Gyn 2007) or without an adnexal mass (US Preventive Service Task Force 2004) is not recommended.

D. Shoupe

– Pelvic transabdominal and transvaginal ultrasound Patients presenting with pain or suspected adnexal mass need pelvic US to evaluated adnexa and uterus. • Pelvic ultrasound establishes the presence or absence of adnexal masses and characteristics of the masses or presence of uterine or tubal pathology. • Gray-scale transvaginal imaging is the recommended imaging modality for evaluation of an adnexal mass (Mitchel et al. 2009). Particular findings on pelvic ultrasound that are suspicious for cancer are discussed in imaging studies below and Table 3. With suspicious findings for malignancy, follow-up studies with MRI or CT along with CA 125 and other biomarkers (see below under postmenopausal women) are used to further characterize the mass. • In postmenopausal women: – Pelvic ultrasound is used to identify the nature of the adnexal mass (see below). Follow-up CT or MRI may be indicated based on ultrasound and clinical findings. – CA-125 and other tumor markers are not used for screening in the absence of an adnexal mass. CA-125 is elevated from a number of benign as well as malignant conditions (Table 2). CA-125 should be drawn in a postmenopausal woman with an adnexal mass to guide treatment (Royal College of Ob/Gyn 2016). CA-125 is also followed postoperatively to monitor treatment response. • Any elevation in CA-125 in postmenopausal women needs further evaluation (Guidelines 2016). • Only 50% of stage 1 cancers have elevated CA-125. • Ca-125 is elevated in 80% of ovarian epithelial cancers.

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Table 2 Causes of elevated CA-125 Benign conditions Endometriosis/Endometrioma Pelvic inflammatory disease Uterine fibroids Pleural, peritoneal fluid or disease: Presence of fluid in cul-de-sac, pelvis, abdomen representing blood, fluid, or ascites Diseases involving serosal surface

Malignant conditions Ovarian cancer Breast cancer Endometrial cancer Lung cancer

Pancreatic cancer

Cirrhosis with or without ascites

– If a granulosa cell tumor is suspected, inhibins A and B are drawn and followed postoperatively. – If a germ cell tumor is suspected, quantitative B-hCG and alpha-fetoprotein are drawn and followed postoperatively. – CEA may be elevated with mucinous cancer associated with the ovary or GI tract (also reported elevated in breast, pancreas, thyroid, and lung cancer) but can also be elevated with smoking, cholecystitis, cirrhosis, diverticulitis, or IBS. – OVA1, approved by the FDA in 2009, is a test that included five biomarkers. The results of the biomarkers are used to generate an ovarian malignancy risk score. – The Risk of Malignancy Algorithm (ROMA), approved by the FDA in 2001, combines HE4 and Ca 125 to assess the likelihood of malignancy in women with an adnexal mass.

Imaging Studies Interpretation On pelvic ultrasound adnexal masses may be characterized as simple, cystic, solid, or complex. Asymptomatic simple cysts 2000 mIU/ml), and the presence of an adnexal mass indicate a possible ectopic pregnancy. Appropriate and timely medical or surgical intervention or close follow-up is important. (i) Pregnant women may also present with an adnexal mass, almost always a luteoma of pregnancy. Luteomas regress after the pregnancy and are associated with complication in less than 2% of cases. (b) Asymptomatic premenopausal women (negative pregnancy test) diagnosed with a simple ovarian cyst 4

Familial

2.1–4

Personal medical history Reproductive Reproductive Reproductive Reproductive Reproductive Personal medical history Lifestyle Lifestyle Lifestyle Lifestyle

1.1–2

recommendations for genetic testing and counseling. The American Society of Breast Surgeons recommends genetic testing for all women with a history of breast cancer, due to data that demonstrates under identification of familial breast cancer syndromes when only age at breast cancer diagnosis and family history are considered in genetic testing recommendations (Beitsch et al. 2018). Table 3 includes characteristics of the most common familial breast cancer syndromes. Personalized breast cancer risk assessment is an important tool to guide physicians and patients in quantifying breast cancer risk and designing an appropriate screening regimen. Counseling should focus on lifestyle changes targeting highrisk behaviors (see lifestyle factors above) and estimating risk from intrinsic risk factors like family history, past medical history, and atypical cells on biopsy. Clinicians should be aware of the various familial breast cancer syndromes and refer patients with suspicious family history for genetic counseling and possible genetic testing. Table 3 describes the more common hereditary cancer

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Table 3 Familial breast cancer syndromes Syndrome

Abnormal gene BRCA1 BRCA2

Peutz-Jegher syndrome

STK11

PALB2 RAD51C, RAD51D Li-Fraumeni

TP53

Hereditary diffuse Cowden

CDH1 PTEN ATM, CHEK2, BARD1, NF1

Lifetime risk breast and ovarian cancer Breast >60% Ovarian 39–58% Breast >60% Ovarian 13–29% Breast 40–60% Ovarian (nonepithelial) >10% Breast 15–40% Ovarian 3–5% Breast 15–40% Ovarian >10% >60% Young onset 40–60% Lobular carcinoma >60% 15–40%

syndromes and relative risks of breast cancer. For further discussion of ovarian cancer, please see ▶ Chap. 71, “Diagnosis and Management of Epithelial Ovarian Cancer.” The US Preventive Services Task Force recommended in 2009 each patient consult their physician regarding their personal risk of breast cancer and designs an individualized screening program (Nelson et al. 2009). The American Society of Breast Surgeons recommends every woman should undergo an initial breast cancer risk assessment at age 25 (American Society of Breast Surgeons 2019), the American College of Radiology recommends the same at 30 years (Monticciolo et al. 2021), with updated risk calculations as the medical and reproductive history progresses (age of first birth, menopause, etc.). Several online calculators have been designed and made publicly available to assist in breast cancer risk assessment (see Table 4). They incorporate varying details of family history, population-based risk factors like menstrual history and age at first birth, as well as personal history of breast atypia. For the highest risk patients, if lifetime breast cancer risk exceeds 20%, annual screening breast MRI is recommended (National Comprehensive Cancer Network 2016). Please see “Breast MRI” section for further explanation.

Associated benign and malignant tumors Pancreatic cancer 15% Colorectal cancer Pancreatic cancer 5–10%

Pancreatic cancer 5–10% Brain cancer, sarcomas Diffuse gastric cancer (67–83% risk) Thyroid, endometrial, colon cancers (>30% risk) Pancreatic cancer 5–10% (ATM) Colon cancer (CHEK2)

Generally, when lifetime risk of breast cancer exceeds 20%, enhanced surveillance with breast MRI is recommended. For women with a family history of breast cancer, screening with annual mammography is recommended to begin 10 years younger than the youngest affected family member, although not before 30. In patients who carry an inherited breast cancer syndrome such as BRCA, screening with annual breast MRI are recommended to start at 25 years with the addition of annual breast mammogram at 30. Women who have a history of an atypical breast biopsy are recommended to undergo annual screening mammography starting at 40 or at the time of identification of the lesion. In women with dense breasts that limits sensitivity of mammography, adjunct screening with breast ultrasound or breast MRI is recommended, depending on individual breast cancer risk assessment. See Table 8 for summary.

Impact of Race and Ethnicity on Breast Cancer Risk Current breast cancer screening recommendations have been primarily based on screening trials of non-Hispanic White women of European origin.

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421

Table 4 Breast cancer risk assessment tools Risk assessment tool Gail

Claus

IBIS TyrerCuzick

BRCApro

Risk factors included Reproductive First-degree family history breast cancer Breast atypia Breast density (with Chen modification) Family history only First, second relatives, breast or ovarian cancer Differentiates between maternal/paternal Reproductive Family history breast or ovarian cancer (includes males, maternal vs paternal) BRCA testing Breast histology (atypia, proliferative) Estimates probability of carrying BRCA mutation Family history of breast or ovarian cancer (includes males)

Gene mutation estimation No

No

Yes

Yes

Growing evidence demonstrates breast cancer risk is influenced by race and ethnicity, rendering current screening recommendations less beneficial for women of color. For example, the peak incidence of breast cancer in non-Hispanic White women is in the mid-60s; for Black, Asian, or Hispanic women it is in their 40s (Seewaldt and Bernstein 2021). Black women have incidence of dense breasts than White women, an accepted risk factor for breast cancer. Among women diagnosed with breast cancer, women of color are more likely to be younger than 50: 31% among Black, 35% among Asian, 33% among Hispanic compared to 24% among non-Hispanic Whites (Stapleton et al. 2018). Similarly, women of color are more likely to present with advanced disease than non-Hispanic White women: 46% for Black, 35% for Asian, 42% for Hispanic compared to 37% for non-Hispanic Whites. Obstacles to accessing high-quality breast care has been held responsible for these health disparities but differing biology is believed to play a role as well. Black women are two times more likely to die of

breast cancers less than 2 cm in size than White women. Black women are known to have an increased incidence of more aggressive breast cancer subtypes, specifically triple-negative intraductal carcinoma (Hendrick et al. 2021). While initiating annual breast screening at 45 and continuing every 2 years until 74 was demonstrated to be the most efficient screening program, initiating screening at 40 and continuing every 2 years would provide Black women the same mortality benefit as afforded by White women if screening started at 50 (Chapman et al. 2021). The same analysis estimated initiating breast cancer screening 10 years earlier in Black women than White women would decrease the mortality disparity from breast cancer between the two groups by 57%.

Breast Screening Techniques and Technologies Breast screening modalities include breast exam, self-administered (self-breast exam or SBE) or by a clinician (clinical breast exam or CBE), mammography which can include full field, digital, or tomosynthesis (three dimensional), breast ultrasound, or breast MRI. Table 5 lists the sensitivities and specificities of each modality.

Breast Exam Breast exam is the most utilized breast screening tool but has fallen out of favor due to low sensitivity and specificity. Self-breast exam has been demonstrated to increase patient anxiety without improving cancer detection and is no longer routinely recommended. Breast self-awareness can be taught at a routine health maintenance visit. It entails being aware of the normal texture of one’s breast tissue, as well as knowledge of any benign masses or cysts that may be present, so a patient can seek medical attention if changes occur. Breast self-awareness should also involve education of menstrual patients regarding the expected fluctuations in breast tissue associated with phases of the menstrual cycle.

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Table 5 Sensitivites and specificities of common breast cancer screening modalities Modality Mammography Tomosynthesis Breast MRI

Sensitivity 77–95% 90% 71–100%

Specificity 94–97% 79% 81–97%

Clinical Breast Exam Clinical breast exam is perhaps the most utilized breast cancer screening tool as it is commonly included in well woman annual health screening. However, because of its low sensitivity, annual CBE is no longer recommended outside highrisk patient populations.

should undergo screening mammogram annually. Women with a family history of breast cancer should undergo screening mammography annually starting 5–10 years younger than the youngest affected family member or at age 30. For the women with extensive family history, MRI should be considered in addition to annual mammography (see “MRI” section). A careful reading of all published guidelines demonstrates an emphasis by each of personalized screening based on the patient’s risk factors and concern regarding cancer detection. Guidelines agree that average-risk women should have the option to start mammographic screening at 40 should they desire screening for early cancer detection and understand the risks of falsepositive studies.

Mammography Screening mammography is the mainstay of breast cancer screening. The identification of breast cancer before it becomes clinically apparent leads to improved survival, as demonstrated in several randomized control trials in the USA and Europe starting in the 1970s. Screen-detected cancers were diagnosed at earlier stage and led to lower cancer-related mortality (Andersson et al. 1988; Tabar et al. 1985; Tabar et al. 2000). This was confirmed in subsequent meta-analyses (Oeffinger et al. 2015). Controversy arose over screening guidelines for average-risk women, specifically at what age to initiate regular screening and at what frequency (Nelson et al. 2009). Concerns were raised by the US Preventive Services Task Force in 2009 regarding potential harms of overscreening including false-positive studies requiring additional imaging and/or biopsy and overdiagnosis leading to overtreatment and additional costs. The American Cancer Society stratified their screening recommendations by age-adjusted risk. The American College of Radiology has continued to recommend annual screening due to benefits of early detection. Table 6 summarizes recommendations from several major medical societies regarding screening mammogram for average-risk women. Women with a high risk factor like breast atypia

Tomosynthesis A major advance in mammographic screening has been three-dimensional digital breast tomosynthesis (DBT). Tomosynthesis takes a series of images that allows the mammographer to review images in thin reconstructed slices, allowing the viewer to scroll up and down or side to side through breast tissues. Radiation exposure is comparable to standard mammography (Gur et al. 2009). The technology is better able to discern overlapping normal tissues and underlying lesions (Lei et al. 2014). In a meta-analysis of breast imaging techniques tomosynthesis demonstrated a higher sensitivity and specificity (90% and 79%, respectively) than digital and plain field mammography. DBT was found to have reduced recall rate and improved detection of breast lesions, resulting in fewer false positives and false negatives. It has been found to be most effective with increased invasive cancer detection rate when used in conjunction with full-field digital mammography but requires two radiation exposures of the patient (Hodgson et al. 2016). Patients with dense breasts may particularly benefit from tomosynthesis as a screening technique. Dense breasts impede cancer detection on screening mammography as suspicious lesions can be obscured by overlapping dense

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423

Table 6 Summary of breast cancer screening recommendations Society American Cancer Society

Age 40–44 45–55 >55

US preventive services task force

40–49 50–74 >75 Offer at 40, initiate by age 50 >40 >40

American College of Obstetricians and Gynecologists American college of radiology National Comprehensive Cancer Network

tissues. By allowing mammographers to scroll through breast tissue in 1 mm slices, tomosynthesis has been shown to increase cancer detection and reduce false-positive studies in women with dense breasts (Houssami and Turner 2016).

Breast Ultrasound Breast ultrasound has been investigated as a breast screening tool due to its ease of use, minimal patient discomfort, and lack of radiation exposure. In average-risk women without dense breasts, screening breast ultrasound has been demonstrated to minimally improve cancer detection at the cost of increased false-positive studies (Berg et al. 2008). Its utility as a screening test is most useful in women with dense breasts, intermediaterisk women (lifetime breast cancer risk 15–20%), and in women with breast cancer risk >20% who cannot tolerate a breast MRI (due to contrast allergy, claustrophobia, anxiety, and financial barriers). Addition of screening breast ultrasound to annual mammography in these populations of women has increased detection of mammographically occult node-negative breast cancers (Brem et al. 2015). As handheld screening breast ultrasound is time and labor intensive, automated technologies may make this strategy more feasible. Breast ultrasound remains a mainstay of diagnostic workup of symptomatic patients, as well as mammographic and MRI abnormalities.

Recommended screening for average-risk women Optional annual screening mammogram Annual screening mammogram Screening mammogram every 2 years; screen until life expectancy is 20% risk, consider adding breast MRI Mammography; consider adding breast MRI if diagnosed younger than 50, or if have dense breasts Mammography

Mammography and breast MRI

Age at initiation 25–30 years

Frequency Periodic

40–50 years; Adjusted by race and patient’s wishes 40 years

1–2 years

Annual

Immediately after diagnosis of initial breast cancer

Annual

10 years younger than the youngest affected family member or 25 years 25 years (MRI) 30 years (mammography plus MRI)

Annual

Annual

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If the patient is in good health and has life expectancy of more than 5–10 years, then continuing screening mammography is reasonable.

Conclusion Despite controversy regarding the timing of breast cancer screening, early detection of breast cancer remains an important method to reduce breast cancer mortality and improve survival. Individualized breast cancer risk assessment allows physicians to educate patients about modifiable risk factors and design a personalized screening regimen. Screening guidelines are conflicting for average-risk women only; all guidelines agree that at-risk women should undergo annual screening mammography. By encouraging a dialogue between patients and providers regarding breast cancer risk, benefits of early detection and intervention, and harms of false-positive studies, providers can increase breast cancer awareness. Table 8 summarizes a reasonable approach to breast cancer screening.

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425 Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Bohm-Velez M, Pisano ED, Jong RA, Evans WP, Morton MJ, Mahoney MC, Larsen LH, Barr RG, Farria DM, Marques HS, Boparai K. ACRIN 6666 investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151–63. Brem RF, Lenihan MJ, Lieberman J, Torrente J. Screening breast ultrasound: past, present and future. Am J Roentgenol. 2015;204:234–40. Chapman CH, Schechter CB, Cadham CJ, TrenthamDietz A, Gangnon RE, Jagsi R, Mandelblatt JS. Identifying equitable screening mammography strategies for black women in the united states using simulation modeling. Ann Inter Med. 2021;174:1637. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146–51. Gur D, Abrams GS, Chough DM, Ganott MA, Hakim CM, Perrin RL, Rathfon GY, Sumkin JH, Zuley ML, Bandos AI. Digital breast tomosynthesis: observer performance study. Am J Roentgenol. 2009;193(2):586–91. Hendrick RE, Monticciolo DL, Biggs KW, Malak SF. Age distributions of breast cancer diagnosis and mortality by race and ethnicity in US women. Cancer. 2021;127: 1–9. Hodgson R, Heywang-Kobrunner SH, Harvey SC, Edwards M, Shaikh J, Arber M, Glanville J. Systematic review of 3D mammography for breast cancer screening. Breast. 2016;27:52–61. Houssami N, Turner RM. Rapid review: estimates of incremental breast cancer detection from tomosynthesis (3D-mammography) screening in women with dense breasts. Breast. 2016;30:141–5. Lauby-Secretan B, Scoccianti C, Loomis D, BenbrahimTallaa L, Bouvard V, Bianchini F, Straif K. NEJM’ N Eng J Med. 2015;372(24):2353–8. Lei J, Yang P, Zhang L, Wang Y, Yang K. Diagnostic accuracy of digital breast tomosynthesis versus digital mammography for benign and malignant lesions in breasts: a meta-analysis. Eur Radiol. 2014;24:595–602. Monticciolo DL, Malak SF, Friedewald SM, Leung JWT, Hendrick RE, Smetherman D, et al. Breast cancer screening recommendations inclusive of all women at average risk: update from the ACR and Society of Breast Imaging. J Am College Radiol. 2021;18:1280. https://doi.org/10.1016/J.JACR.2021. 04.021. National Comprehensive Cancer Network. Breast cancer screening and diagnosis version 1. 2016. Available from http://www.nccn.org Nelson HD, Tyne K, Nalk A, Bougatsos C, Chan B, Humphrey L. Screening for breast cancer: an update for the US preventive services task force. Ann Intern Med. 2009;151:727–37. Oeffinger KC, Fontham ET, Etzioni R, Herzig A, Michaelson JS, Shih YC, Walter LC, Church TR, Flowers CR, LaMonte SJ, Wolf AM, DeSantis C,

426 Lortet-Tieulent J, Andrews K, Manassaram-Baptiste D, Saslow D, Smith RA, Brawley OW, Wender R. American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314(15): 1599–614. Ryerson AB, Eheman CR, Altekruse SF, Ward JW, Sherman RL, Henley SJ, Holtzman D, Lake A, Noone AM, Anderson RN, Ma J, Ly KN, Cronin KA, Penberthy L, Kohler BA. Annual report to the nation on the status of cancer, 1975–2012, featuring increasing incidence of liver cancer. Cancer. 2016;122(9):1312–37. Seewaldt VA, Bernstein L. The perils of generalization: rethinking breast cancer screening guidelines for young women of color. Cancer. 2021;127:4359. Sickles EA, D’Orsi CJ, Basett LW, et al. ACR BIRADS mammography. In: ACR BI-RADS atlas, breast imaging reporting and data system. Reston: American College of Radiology; 2013. http://www.acr.org/QualitySafety/Resources/BIRADS/About-BIRADS/How-toCite-BIRADS.

H. R. Macdonald Silverstein M, LAgios M, Recht A, et al. Image-detected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg. 2005;201:586–97. Stapleton SM, Osent TO, Bababekov YJ. Race/Thnicity and age distribution of breast cancer diagnosis in the United States. JAMA Surg. 2018;153(6):594–5. Tabar L, Gad A, Holmberg LH, Ljungquist U, Fagerberg CJG, BAldetorp L, Grontoft O, Lundstrom B, Manson JC, Eklund G, Day NE, Pettersson F. Reduction in mortality from breast cancer after mass screening with mammography. Lancet. 1985;325(8433):829–32. Tabar L, Vitak B, Chen H, Duffy SW, Yen M, Chiang C, Krusemo UB, Tot T, Smith RA. The Swedish two-county trial twenty years later. Radiol Clin. 2000;38(4):625–51. Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer in the elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncol. 2007;8(12):1101–15.

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Sigita S. Cahoon

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 Vulvar Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen Simplex Chronicus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

428 428 429 429 431 434

Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Vulvar Intraepithelial Neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Abstract

Many benign diseases can affect the vulva. These varied conditions can present similarly, often with pain, burning, pruritus, vaginal discharge, and dyspareunia. Physical exam findings can be nonspecific, with erythema, excoriations, and lichenification. Contact dermatitis is a frequent cause of vulvar pruritus and pain, and nearly all topical vaginal products can cause irritation. Removal of common irritants usually results in disease resolution.

S. S. Cahoon (*) Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_75

Lichen simplex chronicus is a condition characterized by severe pruritus leading to a persistent itch-scratch cycle. Lichen planus is a chronic, immune-mediated dermatosis presenting with pruritic papules on the vulvar skin and white lacy striae on mucosal surfaces. Lichen sclerosus is an immune-mediated disorder that results in waxy white “cigarette paper” changes to vulvar skin and can also affect the perianal region resulting in a classic “figure of eight” appearance. Patients with lichen sclerosus should be followed closely due to an increased risk of vulvar squamous cell carcinoma. Psoriasis is a dermatologic condition which can manifest as painful and pruritic vulvar erythema. Topical corticosteroids are the first-line therapy for lichen 427

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simplex chronicus, lichen planus, lichen sclerosus, and vulvar psoriasis. Vulvar intraepithelial neoplasia (VIN) is a premalignant condition which can present variably with raised or flat lesions, ranging in color from white to red or black. It can be associated with carcinogenic human papillomavirus (HPV) infections as well as with vulvar dermatoses. All cases should be treated, and options range from excision, to laser ablation, to topical medical therapy with Imiquimod. Patients remain at risk for recurrence and require continued surveillance. Keywords

Vulva · Dermatoses · Contact dermatitis · Lichen simplex chronicus · Lichen planus · Lichen sclerosus · Psoriasis · Vulvar intraepithelial neoplasia · VIN

Introduction This chapter focuses on the diagnosis and management of common benign vulvar diseases. Benign vulvar disease encompasses numerous disorders, including infections, autoimmune diseases, topical irritation, dermatoses, neoplasms, cysts, and masses. Many of these varied diseases can present quite similarly. Patients often complain of vulvar irritation, burning, pain, pruritus, dysuria, dyspareunia, and vaginal discharge. On exam, many vulvar conditions appear similar, with erythema, edema, signs of excoriations leading to ulcerations, and lichenification in cases of chronic scratching. This chapter focuses primarily on dermatoses commonly affecting the vulvovaginal region, including contact dermatitis, lichen simplex chronicus, lichen planus, and lichen sclerosus, as well as psoriasis and vulvar intraepithelial neoplasia. Diagnoses are often made clinically after assessing for a history of medication and product use and ruling out common infections including vulvovaginal candidiasis. Treatment is usually initiated empirically, and most vulvar dermatoses are treated with topical corticosteroids. However,

S. S. Cahoon

clinicians should have a low threshold to obtain a biopsy in cases of unusual appearing lesions or in instances of treatment failure. Disease prevalence, common symptoms, physical exam findings, recommended diagnostics, treatments, and prognoses of common vulvar dermatoses will be reviewed here. Given that many of these conditions can become recurrent or chronic, it is important that physicians remain mindful of the potential impact on patients’ quality of life that these diseases can have and continue to work with patients to achieve good symptom control.

Vulvar Dermatoses Contact Dermatitis Contact dermatitis affects approximately 15–30% of the population (Crone et al. 2000; MoyalBarracco and Wendling 2014). Common causes of vulvar contact dermatitis are irritants and allergens. Fragrances, topical medications, and preservatives are the most frequent culprits (Hoang et al. 2014; O’Gorman and Torgerson 2013). Acute cases of contact dermatitis can present with erythema, edema, and even vesicles or erosions. Chronic contact dermatitis often presents as erythema with lichenified or excoriated areas. Patients complain of pruritus, pain, vulvovaginal dryness, burning, and dyspareunia (Fischer et al. 1995; Hoang et al. 2014). Irritant contact dermatitis is the most common subtype. Factors including moisture from sweat or urine, heat, friction from clothing or scratching, estrogen deficiency, or enzymes can damage the skin’s barrier properties and exacerbate irritation due to topical products (Margesson 2004; MoyalBarracco and Wendling 2014). The list of potential irritants is extensive and essentially includes anything that comes in contact with the vulvovaginal region. Common irritants include soaps and detergents, dyes, perfumes, deodorants, lotions, condoms, spermicides, lubricants, sanitary products including tampons and pads, topical medications including anesthetics, antibacterials, antifungal preparations, corticosteroids, and

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bodily fluids including semen, saliva, and urine (ACOG 2008; Margesson 2004; Marren et al. 1992). Allergic contact dermatitis is an immunemediated type IV hypersensitivity reaction to an allergen which occurs in sensitized patients (Margesson 2004; Moyal-Barracco and Wendling 2014). Numerous allergens have been identified; however, topical medications, including lidocaine, corticosteroids, and neomycin, as well as perfumes and metal such as nickel, are known to be causative agents (Marren et al. 1992; MoyalBarracco and Wendling 2014). Patch testing in conjunction with a dermatologist can be considered if the etiologic agent cannot be identified (Crone et al. 2000). Patients with vulvar contact dermatitis often complain of burning or pruritus, and the course can be either acute or chronic. Poorly defined erythema is often noted on exam, and associated findings including edema, erosions or ulcers, and papules or vesicles can be found, especially in the area covered by diapers or sanitary napkins. If pustules or crusting are noted, a superimposed bacterial infection may be present. In chronic cases of excoriation, changes in pigmentation and lichenification may be noted (Margesson 2004; Moyal-Barracco and Wendling 2014). On biopsy, contact dermatitis is characterized by histopathological findings of intraepidermal edema, spongiosis, acanthosis, parakeratosis, and infiltrating lymphocytes and eosinophils (Hoang et al. 2014; Moyal-Barracco and Wendling 2014). In cases of contact dermatitis, use of all topical products should cease, and patients should use only water to clean the vulva. Resolution of symptoms is expected once the causative factor is removed. Patients may feel greater symptomatic relief with the addition of petrolatum for moisturization, and systemic antihistamines can be added for relief of pruritus (Margesson 2004; Moyal-Barracco and Wendling 2014).

Lichen Simplex Chronicus Lichen simplex chronicus is a common dermatosis which causes severe vulvar pruritus. Initial

429

symptoms may have been triggered by a topical irritant, candidiasis, moisture, heat, or friction, or concurrent lichen sclerosus (ACOG 2008; Virgili et al. 1997). Subsequent scratching alleviates the itch but damages the skin, over time resulting in a thickened epidermis which can appear leathery with areas of hyper- and hypopigmentation. Patients complain of chronic recurrent pruritus, which often becomes worse at night. Frequent scratching results in erosions with accompanying pain and burning (ACOG 2008; Moyal-Barracco and Wendling 2014; Virgili et al. 2001). Lichen simplex chronicus predominantly affects the hair-bearing skin on the labia majora. Skin often appears thickened and may be erythematous, pigmented, or pale, and excoriations are frequently noted. This condition often exhibits a chronic, relapsing pattern; however, it has not been associated with an increased risk of squamous cell carcinoma (Moyal-Barracco and Wendling 2014; Stewart 2010). Potent topical corticosteroids are the mainstay of treatment for lichen simplex chronicus. Daily application for 3–4 weeks is recommended initially, followed by a taper or switch to a less potent topical steroid for the following 3–6 months to prevent recurrence (Lynch 2004; Moyal-Barracco and Wendling 2014). Topical calcineurin inhibitors such as tacrolimus or pimecrolimus ointment applied once or twice daily for 6 weeks, then tapered, are second-line therapies for patients who do not tolerate or do not respond to topical corticosteroids (Goldstein et al. 2007; MoyalBarracco and Wendling 2014).

Lichen Planus Lichen planus is an inflammatory condition which can affect the vulvovaginal region as well as oral mucosa. The epidemiology of lichen planus is not well studied, but prevalence estimates range from 0.22–5%, affecting both males and females (Gorouhi et al. 2014; Shiohara and Kano 2008). Vulvovaginal lichen planus most often affects peri- or postmenopausal women, though there have been reports of affected children (Gorouhi et al. 2014; McPherson and Cooper 2010).

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Lichen planus is thought to be a T-cell-mediated inflammatory autoimmune disease. Studies have suggested possible genetic susceptibility as well as environmental triggers associated with lichen planus. Associations have also been noted between lichen planus and coexisting stress, anxiety, and depression as well as hepatitis C infection, other autoimmune illnesses, dyslipidemia, and other viral infections (Gorouhi et al. 2014; Shengyuan et al. 2009; Vallejo et al. 2001). Several subtypes of lichen planus have been described, based on morphology as well as the primary site of involvement (Gorouhi et al. 2014). Oral involvement is the most common subtype of mucosal lichen planus, with vulvovaginal involvement being the next most common and esophageal, laryngeal, and conjunctival involvement being rare (Eisen 1999; Gorouhi et al. 2014). In addition to affecting the mucous membranes of the mouth, vulvovaginal and anogenital region, gastro intestinal tract, conjunctiva, and mouth, lichen planus can affect the skin, nails, and hair. Among patients with vulvar lichen planus, 43–100% also have oral lesions, and 25–57% of patients who initially present for oral lesions are found to also have vulvar lesions (Belfiore et al. 2006; Eisen 1999; Gorouhi et al. 2014). Approximately 17–22% of patients with vulvovaginal disease will also have skin lesions (Gorouhi et al. 2014; Simpson et al. 2012). Lichen planus can have a variable appearance. Classic dermatologic presentations include the “6 Ps”: “Pruritic, Purple, Polygonal, Planar, Papules, and Plaques” (Gorouhi et al. 2014; Lazar and Murphy 2009). When present on mucosal surfaces, the classic description is of white, lacy, or fernlike striae known as Wickham striae. Pruritic papules ranging in color from pink to violaceous can also be observed (Rogers and Eisen 2003; ACOG 2008). Vulvovaginal lichen planus has three major subtypes: erosive, papulosquamous, and hypertrophic, with erosive being the most common (Gorouhi et al. 2014). Erosive vulvar lichen planus affects only the mucous membranes and can lead to vulvovaginal scarring, agglutination, and resorption of the labia minora and clitoral hood, formation of synechiae, introital stenosis,

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Fig. 1 A case of erosive lichen planus with early vaginal agglutination. (Reprinted from Fairchild and Haefner 2016, with permission from Elsevier)

and vaginal obliteration in extreme cases (Fig. 1). Affected women often complain of dyspareunia, burning, vaginal discharge, and postcoital bleeding and can have significant psychological distress due to the condition (Gorouhi et al. 2014; Lewis 1998). Vaginal pH is frequently increased to 5 or 6 in lichen planus, and a wet mount often reveals numerous inflammatory cells as well as immature parabasal and basal epithelial cells (ACOG 2008; Rogers 3rd and Eisen 2003). Biopsy of the lesion confirms the diagnosis, and immunofluorescence staining can be used to distinguish between lichen planus and other similarly presenting immunobullous diseases. A dense continuous band of infiltrating lymphohystiocytes at the dermal-epidermal junction in the upper dermis is the classic histologic finding (Fung 2016; Gorouhi et al. 2014; Ramer et al. 2003). Other findings include hyperkeratosis, areas of wedgeshaped hypergranulosis, spongiosis in the spinous layer, and squamatization, as well as elongated and rounded rete ridges. However, erosive vulvovaginal lichen planus can often have nonspecific histopathological findings, lacking the classic markers (Fung 2016; Gorouhi et al. 2014). Topical application of super potent corticosteroids is the first-line treatment of vulvovaginal lichen planus with up to 55% of patients experiencing symptomatic improvement with topical corticosteroids alone, while some patients will require oral therapy with prednisolone or a combination of topical and oral corticosteroids

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(Schlosser and Microwski 2015). Topical corticosteroid therapy has been shown to be effective in treating symptoms including burning, pruritus, discharge, and dyspareunia; however, the symptoms caused by vaginal stenosis were not significantly improved by topical corticosteroid therapy (Anderson et al. 2002; Schlosser and Microwski 2015). A variety of systemic immunomodulators have been studied with limited benefits observed and often with significant adverse effects noted. As such, systemic treatments are often limited to use for severe disease or refractory cases (Lotery and Galask 2003; Schlosser and Microwski 2015). Vaginal dilators can be helpful in both treatment and prevention of adhesion and synechiae formation, which can occur in cases of inflamed, ulcerated vaginal mucosa. Dilators are often used in conjunction with topical corticosteroids, estrogen creams, or topical calcineurin inhibitors and can be used twice daily initially, then taped down to three times per week. Dilator therapy has been shown to be beneficial in helping patients resume sexual intercourse (Lotery and Galask 2003; Schlosser and Microwski 2015). In addition to dilators, use of vaginal hydrocortisone suppositories at a dose of 25 mg, initially used twice daily, then tapered down to twice weekly maintenance therapy, has been demonstrated to be effective for controlling symptoms of lichen planus (Anderson et al. 2002). If synechiae do form, surgical therapy should not be attempted until the inflammation due to lichen planus is well controlled. Lysis of adhesions and careful tissue dissection should be performed under general anesthesia, and vaginal dilators along with topical corticosteroids, with the addition of topical estrogen therapy in certain cases, must be used during the healing process to prevent scarring and additional adhesion formation (Kortekangas-Savolainen and Kiilholma 2007; Schlosser and Microwski 2015). Regarding prognosis, cutaneous lichen planus can resolve in about 6 months to 1 year; however, some types of oral lichen planus can become chronic and progressive. Erosive lichen planus, which is the most common subtype affecting the vulvovaginal region, can display a chronic, waxing and waning, cyclic pattern. Risk of

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malignant transformation of lichen planus has been suggested, but studies have been inconclusive, and further study is required (Cooper et al. 2004; Gorouhi et al. 2014).

Lichen Sclerosus Lichen sclerosus is one of the most common inflammatory dermatoses of the vulva. It is a chronic autoimmune inflammatory condition affecting the vulvovaginal region, thought to be mediated by lymphocytes. It is more common in women than men (Schlosser and Microwski 2015). Lichen sclerosus exhibits a bimodal age distribution. It occurs commonly in prepubertal girls with a prevalence of 1 in 900 and a mean onset at 5 years of age. Perimenopausal to postmenopausal women are usually affected between ages 45 and 55; however, it can also present in women of reproductive age. There is often a delay in diagnosis of approximately 2 years in young patients and 5–15 years in older women. Cutaneous lesions outside of the genital region can be present in 6–15% of patients affected by lichen sclerosus (Cooper et al. 2004; Schlosser and Microwski 2015). Reports suggest a familial predisposition, though the mode of inheritance has not been identified. Several genes have been studied with possible protective as well as predisposing genes under investigation. There is also a significant link between lichen sclerosus and autoimmune disorders, including autoimmune thyroid disease, as well as vitiligo, alopecia areata, pernicious anemia, and diabetes mellitus, among others (Meyrick et al. 1988; Schlosser and Microwski 2015). Additionally the role of estrogen and androgens in lichen sclerosus has been investigated but remains a subject for further study (Schlosser and Microwski 2015; Taylor et al. 2008). Patients commonly present with vulvar pruritus which can be more severe at night. They can develop painful vulvar and perianal erosions and fissures which lead to dysuria, dyspareunia, and dyschezia. Patients can develop urinary retention and constipation secondary to pain. As such, stool

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retention is commonly the presenting symptom of lichen sclerosus in young girls. Disease progression and labial agglutination are concerns for young girls diagnosed with lichen sclerosus, and abnormal voiding with weak urinary stream can result from labial agglutination (Powell and Wojnarowska 2001; Schlosser and Microwski 2015). Lichen sclerosus typically affects the labia majora and minora, clitoris and clitoral hood, and the posterior fourchette. The perianal area is affected in 30–60% of women, often with a classic hourglass or “figure of eight” pattern when both the vulva and perianal region are affected. The vaginal mucosa is usually spared. A white, hypopigmented vulvar skin with a waxy or wrinkled texture, classically described as appearing like “cigarette paper,” is the typical clinical exam finding. Patients may also have fissures, erosions, and ulceration as well as hyperkeratosis or purpura, and clitoral hood edema (Schlosser and Microwski 2015; Virgili et al. 2014).

Scarring can occur to varying degrees, most commonly affecting the clitoral hood and labia minora as well as the posterior fourchette and introitus (Fig. 2). Resorption of the labia minora has been observed, and scarring can result in stenosis of the vaginal introitus or urethral meatus to the point that intercourse and voiding are impaired. Lichen sclerosus can also result in areas of hyperpigmentation which can be difficult to differentiate from potential melanoma, and as such, biopsy is recommended. Extragenital lesions in cutaneous lichen sclerosus can also be observed and predominantly affect the trunk, though rare cases affecting the face, scalp, mouth, and nails have been reported (Schlosser and Microwski 2015). Treatment with topical corticosteroids is recommended if clinical signs are suggestive of lichen sclerosus. Biopsy is indicated if lesions do not respond to topical therapy; if there is concern for malignancy, including melanoma; or if

Fig. 2 Scarring of the vulva from lichen sclerosus. (Reprinted from the Goldstein and Burrows 2007, with permission from Elsevier)

ulcerated lesions are present (Schlosser and Microwski 2015). Hyperkeratosis, an atrophic epidermis, loss of rete ridges, and band-like lymphocytic infiltrate are classic histopathological signs of lichen sclerosus (Schlosser and Microwski 2015). Lichen sclerosus is associated with a nearly 300 times increased risk of development of vulvar squamous cell carcinoma, with a period of 4–10 years between diagnosis of lichen sclerosus and diagnosis of vulvar squamous cell carcinoma. It is unclear if successful treatment of vulvar lichen sclerosus decreases the risk of vulvar squamous cell carcinoma; however, carcinoma is seen typically in elderly patients and has not been reported in pediatric patients. Age greater than 70 years has been associated with treatment failure and disease recurrence (Carli et al. 1995; Schlosser and Microwski 2015). Topical treatments in ointment formulations are preferable as they have improved potency and absorption. Ointment formulations also have emollient properties and are less likely to contain vulvar irritants including preservatives, alcohol, and propylene glycol. Topical super potent

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corticosteroids are the mainstay of therapy for vulvar lichen sclerosus, and clobetasol propionate 0.05% ointment has demonstrated significant efficacy in randomized trials (Schlosser and Microwski 2015). An initial twice-daily application is recommended. As symptoms improve, the application can be tapered, and a less potent corticosteroid can be used. Maintenance therapy over a period of 6–12 months is commonly recommended. Side effects of long-term topical corticosteroid therapy include atrophy and thinning of the skin as well as development of striae and telangiectasias. Long term use can also increase susceptibility to superimposed candida infections and can be associated with reactivation of herpes simplex viral infection (Schlosser and Microwski 2015). Topical estrogen therapy may be beneficial in postmenopausal patients who experience significant atrophy with topical corticosteroid use. In addition, oral antifungals and antihistamines can be used to combat side effects rather than utilizing their topical formulations. Topical creams may exacerbate symptoms due to their potential to act as topical irritants. Second-line therapy includes a twice-daily application of topical calcineurin inhibitors, such as tacrolimus 0.1% ointment, which may be chosen for use in cases which demonstrate a lack of response to topical corticosteroids or in patients who develop side effects from corticosteroid therapy; however, their use has been associated with a reportedly increased risk of dermatologic malignancies (Fischer and Bradford 2007; Schlosser and Microwski 2015). Systemic retinoid therapy such as acitretin can be useful for patients with hyperkeratotic or hypertrophic vulvovaginal lichen sclerosus refractory to superpotent topical corticosteroids.

Oral acitretin regimens of 20–30 mg per day over a course of 16 weeks have been studied; however, as retinoids are teratogenic, they should not be used in women who might become pregnant. There is evidence that acitretin can reduce

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the incidence of squamous cell carcinoma in at-risk patients such as those who have undergone organ transplantation. It is suggested that there may also be a similar protective effect against squamous cell carcinoma in patients with lichen sclerosus; however, further study into this area is necessary (Bousema et al. 1994; Schlosser and Microwski 2015). Surgical therapy for severe vulvar and introital scarring affecting function should only be undertaken after resolution of inflammation with at least a 6-month, disease-free period. Superpotent topical corticosteroids must be used to prevent a postoperative lichen sclerosus recurrence due to the Koebner phenomenon (the development of new lesion areas secondary to trauma) as well as to prevent recurrence of labial agglutination and stenosis of the introitus (Schlosser and Microwski 2015). Additional supportive measures can be undertaken to help manage the pruritus, pain, and irritation. Patients should wash the vulvar area with water only, then pat dry and avoid rubbing. Sitz baths as well as ice packs and cool compresses can be utilized to ease burning symptoms.

Petroleum jelly or A and D ointment can act as soothing emollients and decreases friction in the affected areas. Some patients develop a secondary vulvodynia which may be treated with topical 5% lidocaine ointment, while other patients may benefit from systemic treatments for neuropathic pain including amitriptyline and gabapentin (Schlosser and Microwski 2015). In most patients, disease control should be attained within 3–4 months. Patients should then be followed every 6–12 months to monitor for disease recurrence as well as for the development of atrophy, scarring, or potential malignant changes. Cases that do not improve despite appropriate therapy should be reassessed, and alternate diagnoses such as contact dermatitis, a superimposed infectious process, or undiagnosed malignancy should be considered and further

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evaluated. Suspicious or unresponsive areas must be biopsied. A multidisciplinary approach should be considered for patients with refractory or multifocal disease as well as to help manage common psychological effects secondary to severe or persistent disease (Schlosser and Microwski 2015).

Psoriasis Vulvar psoriasis affects approximately 5% of women and 15% of girls with vulvar dermatosis. This chronic dermatosis is generally diagnosed clinically and has several presentations, including the classic form with well-demarcated thick scaly plaques, discrete pustules in the pustular form, or as erythema with minimal scaling in the inverse form which presents predominantly in the anogenital area and in flexural folds. Vulvar psoriasis affects the hair-bearing cutaneous regions of the vulva, especially the mons pubis and labia majora, and generally spares the mucosa (Hoang et al. 2014; Kapila et al. 2012). Biopsy frequently is nondiagnostic; however, areas of parakeratosis with neutrophils, known as Munro’s micro abscesses, as well as spongiosis are a common finding (Hoang et al. 2014). Treatment of vulvar psoriasis should focus on relief of symptoms and the minimization of kernelization. Use of soothing emollients and avoidance of topical irritants are recommended. Flares can be managed with topical mid- to high-potency topical corticosteroids. Topical corticosteroid therapy can then be followed with topical tar preparations, retinoids, calcineurin inhibitors, and low-potency topical corticosteroids for maintenance therapy. In rare cases of severe refractory disease, systemic therapy with methotrexate may be considered; however, limited efficacy has been demonstrated with this treatment (Kapila et al. 2012).

Neoplasms Vulvar Intraepithelial Neoplasia Vulvar intraepithelial neoplasia (VIN) is a premalignant squamous lesion with a peak incidence of 5 per 100,000 women which is observed primarily

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in Caucasian women in their forties (Preti et al. 2014). VIN was historically divided into three grades. However, after studies revealed that VIN 1 was predominantly a self-limited disease due to human papillomavirus (HPV) infection, the International Society for the Study of Vulvovaginal Disease (ISSVD) revised the classification system in 2004 such that now only a high-grade disease is classified as VIN, and what was previously called VIN 1 is now classed and treated as condyloma (Sideri et al. 2005).

VIN is now subdivided into usual-type VIN and differentiated VIN. Usual-type VIN is the most common type and is linked to carcinogenic HPV genotypes as well as states associated with persistent HPV infection including being immunocompromised and smoking. This grouping includes warty, basaloid, and mixed VIN. Differentiated VIN accounts for only 2–5% of cases of VIN. It is more commonly associated with vulvar dermatoses such as lichen sclerosus, a risk factor for squamous cell carcinoma, and is not associated with HPV infection (Preti et al. 2014; Sideri et al. 2005). There is no screening test specifically for VIN, which is diagnosed clinically. VIN has a variable presentation. Color can range from gray or white to red, brown, or even black. The majority of lesions are raised (Fig. 3); however, they can be flat as well. Vulvar colposcopy can be used to aid visual inspection of the area after applying cotton pads soaked with 3–5% acetic acid. Any suspicious or pigmented lesion, any areas refractory to treatment, or lesions found in a postmenopausal woman should be biopsied (ACOG 2011; Preti et al. 2014). All cases of VIN should be treated. If malignancy is suspected, VIN lesions should be surgically managed with wide local excision, using either a cold knife or loop electrode excision. In rare cases, such as in immunocompromised women with extensive disease, a skinning vulvectomy may be considered. Gross margins

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Fig. 3 (a) Vulvar SCC on the left labium minus, 9 mm diameter and with a depth of invasion of 4 mm; (b) lesion on the right labium minus, which turned out to be VIN on

histologic examination. (Reprinted from Simons et al. 2010, with permission from Elsevier)

of 0.5–1 cm are preferred when performing wide local excision, though adjustments can be made to avoid structures such as the urethra, clitoris, and anus. Negative margins on pathologic examination are preferred; however, risk of recurrence remains. If suspicion for malignancy is low, CO2 laser ablation or topical therapy with imiquimod 5% for 12–20 weeks, cidofovir 1%, or photodynamic therapy in conjunction with the photosensitizing agent 5-aminolevulinic acid (ALA) can be utilized (ACOG 2011; Preti et al. 2014). The quadrivalent HPV vaccine reduces the risk of developing VIN as it confers protection from HPV genotypes 6, 11, 16, and 18 (Muñoz et al. 2010). Smoking cessation should be stressed, as it is associated with usual-type VIN, and the diagnosis and treatment of vulvar dermatoses may reduce the risk of differentiated VIN and development of squamous cell carcinoma (ACOG 2011). Despite treatment, recurrence rates can be as high as 30–50%, and rates are even higher if positive margins were noted on excision. After treatment, patients should be reexamined at 6 months and 1 year and can then resume yearly monitoring if no new lesions are noted (ACOG

2011), though some studies suggest following patients more closely, with follow-up every 3 months for the first 2–3 years, then every 6 months subsequently (Preti et al. 2014).

Conclusion As reviewed above, numerous conditions can manifest as vulvar disease. When evaluating vulvar complaints, a thorough history and physical examination are essential, as well as an awareness of the wide range of potential diagnoses. The first steps in evaluation often involve assessment for and removal of potential irritants as well as testing for suspected infections. Discontinuation of topical products is often a crucial component in the management of symptoms, as nearly any product in contact with the vulvovaginal region has the potential to cause irritation. The common dermatoses reviewed in this chapter, including contact dermatitis, lichen simplex chronicus, lichen planus, lichen sclerosus, and psoriasis, are often treated with topical corticosteroids as a first-line therapy. However,

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providers should have a low threshold to obtain a biopsy for tissue diagnosis in refractory cases or unusual presentations to rule out underlying malignancy or alternate diagnoses. In severe and chronic cases of vulvar dermatoses, a long-term follow-up is often indicated to monitor for disease recurrence or progression, potential malignant transformation, as well as vulvovaginal scarring, labial agglutination, or introital stenosis. Cases of VIN must be monitored closely due to high rates of recurrence as well as risk of malignancy. Depending on the etiology of the vulvar disease, patients may have multifocal disease affecting more than one organ system. As such, a multidisciplinary approach should be taken to coordinate therapy. Additionally, patients can experience significant morbidity from vulvar dermatoses, which may have wide impacts on various activities ranging from normal sexual activity to basic voiding function. These morbidities can have significant psychological impacts on patients which should be addressed as a component of comprehensive gynecologic care.

Cross-References ▶ Benign Vulvar and Vaginal Pathology ▶ Diagnosis and Treatment of Vulvovaginitis ▶ Management of Chronic Recurrent Vulvovaginitis ▶ Management of Vaginal and Vulvar Lesions in the Postmenopausal Women ▶ Preinvasive Epithelial Disease of the Vulvar

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437 Schlosser BJ, Microwski GW. Lichen sclerosus and lichen planus in women and girls. Clin Obstet Gynecol. 2015;58(1):125–42. Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145(9):1040–7. Shiohara T, Kano Y. Lichen planus and lichenoid dermatoses. In: Bolognia JL, Jorizzo J, Rapini RP, editors. Dermatology. 3rd ed. New York: Mosby Elsevier; 2008. p. 183–202. Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD vulvar oncology subcommittee. J Reprod Med. 2005;50(11):807–10. Simons M, Van De Nieuwenhof HP, Van Der Avoort IA, Bulten J, De Hullu JA. A patient with lichen sclerosus, Langerhans cell histiocytosis, and invasive squamous cell carcinoma of the vulva. Am J Obstet Gynecol. 2010;203(2):e7–10. Simpson RC, Littlewood SM, Cooper SM, Cruickshank ME, Green CM, Derrick E, Yell J, Chiang N, Bell H, Owen C, Javed A, Wilson CL, McLelland J, Murphy R. Real-life experience of managing vulval erosive lichen planus: a case-based review and U.K. multicentre case note audit. Br J Dermatol. 2012;167(1):85–91. Stewart K. Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus, dermatologic clinic. 2010;28(4):669–80. Taylor AH, Guzail M, Al-Azzawi F. Differential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis. Br J Dermatol. 2008;158:319–28. Vallejo MJ, Huerta G, Cerero R, Seoane JM. Anxiety and depression as risk factors for oral lichen planus. Dermatology. 2001;203(4):303–7. Virgili A, Corazza M, Bacilieri S, Califano A. Contact sensitivity in vulval lichen simplex chronicus. Contact Dermatitis. 1997;37(6):296–7. Virgili A, Bacilieri S, Corazza M. Managing vulvar lichen simplex chronicus. J Reprod Med. 2001;46:343–6. Virgili A, Borghi A, Toni G, Minghetti S, Corazza M. Prospective clinical and epidemiologic study of vulvar lichen sclerosus: analysis of prevalence and severity of clinical features, together with historical and demographic associations. Dermatology. 2014;228(2):145–51.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Nomenclature of Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 Taking a Patient History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 Physical Examination of Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Histology and Physiology of Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Population Findings in Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Theories of Causation of Localized Provoked Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . 446 Low Estrogen as a Cause of Vestibulodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Vulvodynia’s Place in the History of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448 Comorbidities with Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Therapeutic Efforts: General Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Specific Therapies for Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

Abstract

Vulvodynia is the term assigned when a woman has a chronic condition of pain in the

M. F. Goetsch (*) Center for Women’s Health, Oregon Health and Science University, Portland, OR, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_76

inner or outer vulva that has lasted longer than 3 months and cannot be explained by a chronic skin condition or infection. The general diagnostic term vulvodynia is used to describe two subtypes of vulvar pain. One is localized to the vestibule of the vulva, generally is painful only when touched, and is the most common explanation for repeated pain with initiation of vaginal penetration. It is the most common form of 439

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vulvodynia, termed localized provoked vulvodynia (LPV) or vestibulodynia. The second form of vulvodynia causes a constant burning sensation in areas of the outer vulva, whether touched or not, and is less common. Localized provoked vulvodynia is often associated with tight pelvic floor muscles and was initially described in 1861 by Sims and named vaginismus. It has characteristic histologic findings of nerve hyperplasia and an infiltrate of lymphocytes and mast cells. A multitude of therapies has been tried for both types of vulvodynia, but careful comparative studies have been few. Because of the significant associated problem of dyspareunia, this condition has very deleterious effects on intimacy, development of relationships, and self-image. Therapeutic efforts should be multidisciplinary, including gynecologic assessment and treatment of local skin pain, physical therapy to retrain tight pelvic floor muscles, and skilled mental health counseling for emotional difficulties. Keywords

Vulvodynia · Localized provoked vulvodynia · Generalized vulvodynia · Dyspareunia · Female sexual pain · Chronic vulvar pain condition · Vestibulodynia

Introduction Vulvodynia has been a puzzling disorder with a checkered history of varying understandings, explanations, therapies, and research initiatives. It may be one of the most interesting of misunderstood medical conditions. Because localized provoked vulvodynia is a cause of repeatedly painful sexual intercourse affecting 12–14% of women in the premenopausal population, all care practitioners who see women should be conversant about vulvodynia and vulvar conditions in general. With steadily increasing ease of finding information using electronic search engines, more and more women are assigning a potential

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name to their own pain condition and then requesting help from their gynecologist. Additionally, pressure at the National Institutes of Health (NIH) to increase vulvodynia research funding has been increasing. Finally, as the population bubble of older women swells and as women have increasingly stopped using supplemental estrogen in postmenopause, there is evidence that the very prevalent problem of postmenopausal dyspareunia is a form of localized provoked vulvodynia.

Nomenclature of Vulvodynia In 2015 three specialty organizations produced a consensus document of terminology and classifications of persistent vulvar pain. The organizations were the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women’s Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) (Bornstein et al. 2016). “Vulvodynia is vulvar pain of at least 3-month duration, without clear identifiable cause, which may have potential associated factors.” Categories are further defined by descriptors: • Localized (e.g., vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized). • Provoked (e.g., insertional, contact) or spontaneous or mixed (provoked and spontaneous). • Onset (primary or secondary). • Temporal pattern (intermittent, persistent, constant, immediate, delayed). Associated factors are often “musculoskeletal,” such as pelvic floor myalgia; “psychosocial,” with feelings of inadequacy, grief, anxiety; or “comorbidities” such as painful bladder syndrome or fibromyalgia. Allodynia is a painful sensation from a stimulus that should be painless. This is in contrast to hyperalgesia, which is enhanced intensity of a pain sensation.

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The most common form of vulvodynia is localized provoked, and it is often referred to as vestibulodynia since it is localized to the vulvar vestibule. Studies have suggested that this form occurs in 90% of those diagnosed with vulvodynia.

The less common form of vulvodynia is generalized vulvodynia, which usually has a spontaneous and constant level of pain and describes 10% of those with vulvodynia (Lamvu et al. 2015).

Anatomy The vulva has distinct zones because of embryonic origins. The tissues comprising labia majora and minora are derived from ectodermal tissues and have an array of potential problems that must be ruled out in an assessment of vulvar pain. For instance, the dermatosis lichen sclerosus is an inflammatory disorder that affects the ectodermal skin primarily. The vulvar vestibule is a second distinct zone comprising mucosa from the inner labia minora to the hymen and from just under the clitoris to the fourchette.

This introital zone is endodermal in embryonic origin, perforated by the urethra, and related in development to the bladder. The demarcation of the ectodermal and endodermal zones is Hart’s line, named after an Edinburgh gynecologist in the 1880s who noted the visual landmarks. Figure 1 shows these landmarks with Hart’s line visible midway along the inner aspect of the labia minora. This vestibular zone of mucosa forms the entryway to the vagina, and the vestibule is supposed to be sensitive in a positive way, but has a capacity to develop localized exquisite tenderness, i.e., vulvar vestibulodynia, or become very symptomatic from an inflammatory trigger such as Candida.

Fig. 1 The photograph is from a 25 year-old with primary localized provoked vulvodynia who could never tolerate tampons, speculum exams or intercourse. The vestibule is the area medial to Hart’s line, seen here as the demarcation between somewhat ruddy coloration and a pale zone along the inner surface of the labia minora. The lateral labial tissue is of ectodermal origin and the pale zone is endodermal in origin. The vestibule extends from Hart’s line to hymen and from fourchette to clitoris. Her exquisite tenderness was immediately next to the hymen, with rednessvisible at 4-5:00 & 7-8:00. The redness in the ectodermal areas was nontender and normal coloration for her. (Goetsch 1996)

The structure representing the innermost point of the vulva is the hymen where the vaginal mucosa begins. The vagina is mesodermal in origin, with the vaginal mucosa having advanced upward from the urogenital sinus. Therefore, within about 1.5 in., three embryologic layers are represented. Each zone has different and unique tissue properties including different nerve sensitivities. Some systems of nomenclature refer to vulvar pain as a subcategory of pelvic pain. This can be confusing since vulvodynia is vulvar pain, not deeper pain from the pelvis. The common clinical problem associated with vulvodynia is pain with intercourse. Dyspareunia is a term derived from the Greek words for “badly mated.” It is important to distinguish entry dyspareunia, which is pain occurring at initial vaginal entry, from deep dyspareunia, associated with penetration deep into the vagina. The vagina itself does not usually account for pain in various female genital pain syndromes. Compared to the severity of typical introital symptoms of pain or itching or the severity of upper tract pain from uterine/tubal/abdominal structures, the vagina is relatively nontender. Structures just deep to the vaginal walls can be

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tender and will be discussed below. Causes of deep pelvic pain can be conditions such as adenomyosis, endometriosis, or pelvic scarring from prior infections or surgery. Vulvar pain might reasonably be segregated from pelvic pain in pain classifications. Another consideration regarding nomenclature is the difference between “chronic pain” and a “chronic condition” that causes intermittent pain. Localized provoked vulvodynia is a cause of exquisite pain on touch, as, for example, with repeated penetrative activity of intercourse. However, if a woman with this chronic condition refrains from intercourse, she may well have no pain. Generalized vulvodynia, on the other hand, is a condition of persistent spontaneous pain that is sometimes completely unremitting. The origin of -dynia is from the Greek oδύνη (odunē, “sorrow, grief, anguish, unhappiness”), which is used as a term meaning “painful.” Women’s descriptions of vulvodynia are usually those of a thermal nature. Generalized vulvodynia usually has a burning or tingling sensation, and localized vulvodynia has a burning, raw, or tearing sensation provoked by entry penetration. Generalized vulvodynia is an acquired condition. In contrast, the more common condition, localized provoked vulvodynia (LPV), is categorized by onset as either primary or secondary. The primary type will have been present with penetrative attempts for as long as the patient can recall – often from the first attempt to place a tampon, the first attempt at coitus, or the first speculum examination. This implies a presence before recognition, perhaps even since childhood, but there is not a body of information about prepubertal girls, since genital examinations are restricted in this age group so as not to cause emotional harm. Secondary vestibulodynia is a penetrative pain condition acquired after not having had prior pain with penetration.

Taking a Patient History For localized provoked vulvodynia (LPV), the usual patient complaint is pain with penetration. On taking a history, it is useful to ask about qualities of pain, timing of onset, and other

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associated issues. The pain is usually described as burning or tearing in nature. If milder, it is described as an irritation as if tissues are dry. The use of a lubricant can help in more minor cases but does not correct severe tenderness. Ask patients when they first experienced pain with sex, but questions about other examples of penetration are useful. Attempts with tampons usually antedate the first speculum examination or first coital attempts by years, indicating early presence of the disorder. Regarding pain with tampons, removal of an engorged tampon is often more painful than insertion. Those with severe LPVoften cannot use tampons due to pain. A clinical history should allow an assignment to primary versus secondary status, although the plan of therapy does not depend on the LPV type. Comorbidities such as psychosocial impairment are more common in women with primary LPV who have never known painless intimacy and often come to attention later than women with secondary LPV. The duration of time women have been suffering pain and continuing to have intercourse will also affect the likelihood that they have developed the secondary problem of pelvic floor myalgia as a reaction to entry pain. A family history may reveal a mother or sisters who have had a similar pain condition, but this very private information may not have been shared. Finally, it is useful to ask about bladder issues such as frequency, urgency, and nocturia, which are patterns that may reveal the comorbidity of bladder involvement either because of mucosal inflammation or due to tight pelvic muscles reducing filling capacity.

Differential Diagnosis Vulvar pain and dyspareunia can be caused by other vulvar or genital problems than vulvodynia. Infections should be ruled out before the diagnosis of vulvar vestibulodynia is assigned. Such problems can also be comorbidities with vulvodynia, however, so if treatment of the obvious problem does not return a patient to normal, the differential diagnosis should be expanded with a consideration of vulvodynia. Many vulvar pain sufferers have been to multiple practitioners before they get

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an accurate diagnosis, and they often give histories of having been treated multiple times with antifungals or antibiotics for a presumed vaginitis. Whereas it is true that a vaginitis such as candidiasis or an irritative bacterial vaginitis (desquamative inflammatory vaginitis) creates acute symptoms in the introitus, these symptoms will clear with appropriate therapy. Without evidence of a vaginitis on visual or microscopic examination, vaginal pathogens are an unlikely cause of introital pain symptoms. Of note, bacterial vaginosis (BV) is an imbalance of vaginal bacteria and not a cause of pain, typically causing just an odor (“halitosis” of the vagina?) and/or discharge. BV is too often blamed for the pain condition of vulvodynia, leading to inappropriate and ineffectual antibiotic use and delay in an accurate diagnosis. An exception to the accuracy of standard office microscopy is subclinical Candida albicans or Candida glabrata, due to vaginal colonization that causes vestibular symptoms. These pathogens can be diagnosed with office microscopy, the DNA probe, or vaginal culture. In the case of candida, oral antifungal treatment for a series of a few weeks can establish a baseline of vulvar sensations to help assess whether symptoms have cleared, or whether vulvodynia is also present. Dermatologic conditions of the vulva and vagina (lichen planus, LP, and lichen sclerosus, LS) can cause pain with intercourse. If vulvar scarring is noted, an inflammatory process is to blame, rather than vulvodynia or atrophy. In the setting of visual changes in the vulva, a biopsy may be indicated. A routine biopsy (with LS) or immunohistochemical staining (with LP) can establish the diagnosis unless the physical appearance is sufficient to classify the dermatosis. These inflammatory processes require steroid therapy for control.

Physical Examination of Vulvodynia Vulvodynia is often described as a diagnosis of exclusion with no physical findings. This is the case with generalized vulvodynia, but not with localized provoked vulvodynia. Care in doing a

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focused examination of the external vulva and vestibule is primary. First, the patient should be asked to clarify where she feels pain, pointing and touching the specific areas. A simple examination of the external vulva employs light probing touch by the examiner’s finger and can ascertain whether pain is elicited. A rolling swab touch test of the vestibule can then be performed, mapping the degrees of pain in specific zones. Findings in Generalized Vulvodynia Pain is usually in areas outside the vestibule, thereby distinguishing it from vestibulodynia. Locations can be confirmed by touch, but touch does not always provoke more pain during the examination process. There are no visual skin changes. Findings in Localized Provoked Vulvodynia The labial tissues must be gently but firmly drawn far enough apart to examine the entire vestibule including the crypts next to the hymen, especially at each Bartholin’s duct orifice. Normally, light touch in this zone is not tender. Allodynia is tenderness to types of touch that should not be painful, and this characterizes vestibulodynia. A physical finding of erythema is usually evident in portions of the vestibule. Redness can be very specific to the zone of allodynia, for instance, forming a U-shape from 3 to 9:00, referencing the hymen like a clock face. The most pronounced redness is often around each Bartholin’s duct orifice. Reddened spots can exist at tiny vestibular gland openings in the anterior vestibule. The erythema is not an erosion or ulcer but is from dilation of fine capillaries. Areas of redness without tenderness are a physiologic variant and not of concern. The “cotton swab test” utilizes a small cottontipped applicator, dry or moistened with water. The locations of pain are mapped using light rolling touch checking all surfaces of the vestibular mucosa. This technique reflects observations about this condition from an old text from 1885 stating that “the touch of a feather is insupportable.” The scoring can be 0–3: 0 ¼ nontender, 1 ¼ annoying touch, 2 ¼ stinging or burning sensation, and 3 ¼ very painful touch causing the patient to flinch.

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Some authors have utilized an algesiometer in research settings (Pukall et al. 2003). It measures the threshold of pain using calibrated swab pressure or calibrated touch with von Frey hairs. It should be noted that prodding actions require many touches to map painful areas; and poking maneuvers may inadvertently elicit pain from superficial submucosal structures like muscles. Therefore, light, rolling touch of a cotton swab is preferable and sufficient to examine mucosa (Stenson et al. 2021). Algesiometers or vulvalgesiometers are not readily available and the cotton swab therefore provides a simple tool for all practitioners to use. The “lidocaine test” helps to establish the mucosal nature of LPV because the application of aqueous 4% lidocaine for 1–3 min can extinguish the mucosal pain of LPV but does not ablate the pain of aberrant nerve function in centrally mediated generalized vulvodynia (see “Histology and Theories”). Both localized vulvodynia (vestibulodynia) and generalized vulvodynia can be present in a mixed form including the vestibule and outer vulva, although this is not the usual circumstance. Some women are so avoidant of an exam of the vestibule that touch is not possible on the first visit. This has confounded the elucidation of “vaginismus,” since women have been entered into studies without having undergone full examinations for the mucosal pain condition of LPV (Reissing et al. 2004). Lidocaine is extremely helpful in examining women with other causes of mucosal tenderness, like vulvitis or a lichenoid dermatosis. Quelling introital tenderness makes it possible to accurately examine upper genital structures without eliciting pain from the introitus from touch with fingers or a speculum.

Histology and Physiology of Vulvodynia No histologic changes have been documented in generalized vulvodynia. It is considered a condition of aberrant nerve function with central

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sensitization with no specific nerve abnormalities at the peripheral skin level. Biopsies are negative for pathology. Histologic studies of vestibulodynia (localized provoked vulvodynia) have found an excessive number of nerve endings in the vestibule mucosa and submucosa (Bohm-Starke et al. 1999). These nerves are pain nerves (nociceptors) that are the type targeted by local anesthetic agents such as lidocaine that block sodium channels. Additionally, the local neural hyperplasia is accompanied by an infiltrate of lymphocytes and mast cells. The inflammation is not the type responsive to therapy with topical steroids (Bohm-Starke et al. 2001). Immunohistochemical studies have elucidated the physiology in human LPV cases (Liao 2017). The various increased vestibule inflammatory cells provide the requisite substrates for a local renin-angiotensin system. Angiotensinogen from B and T cells and renin from T cells and macrophages interact to produce angiotensin I, and chymase from mast cells converts it to angiotensin II. Angiotensin II receptor 2 is what stimulates nerve axons. A culture medium from tender vestibule tissues stimulated axon sprouting in rat nerve cultures, but culture medium from non-tender tissues did not stimulate extra axon growth. The same researchers have shown that such axon sprouting has a plasticity depending on estrogen levels, with increased sprouting in lower estrogen situations and pruning of nerve endings in higher estrogen environments (Brauer 2015). Similar histopathologic studies have not explored postmenopausal vestibulodynia. Differences in degree of neural hyperplasia and lymphocytic infiltrate have been noted in different types of vestibulodynia. Nerve trunks and branches are most pronounced in tissues from women with primary LPV (Leclair et al. 2011). The lymphocytes are more numerous in tissues from women with secondary LPV, with the most marked lymphocyte infiltrates in postmenopausal women’s tissues (Leclair et al. 2013). Vulvodynia does not predispose to cancer and is not contagious.

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Population Findings in Vulvodynia Premenopausal Vulvar Vestibulodynia Several prevalence studies have established that 12–14% of young premenopausal women have LPV (Harlow et al. 2014). There are equal proportions of sufferers in primary and secondary categories. Localized provoked type comprises 90% of cases of vulvodynia (Lamvu et al. 2015). Women have typically consulted five clinicians about their problem before receiving an accurate diagnosis. Postpartum Vulvar Vestibulodynia Postpartum dyspareunia is a poorly studied phenomenon, but one prospective study found that 37% of women delivering babies developed introital pain with penetration in association with lowered hormones after delivery and during lactation (Goetsch 1999). The women’s complaints were similar whether their delivery had been vaginal or abdominal. The severity was equally apportioned between mild, moderate, or severe pain, and median duration was 5 months. For some women postpartum dyspareunia does not resolve with the return of natural estrogen and periods. Two prevalence studies have found that 25% of women with vestibulodynia described the onset as postpartum. It is unknown how many women need to deliver for one to develop chronic long-term vestibulodynia. Generalized Vulvodynia Population studies indicate that there is a stable prevalence of 8.3% of vulvodynia through age 70. For about 17%, however, symptoms may begin or remit spontaneously (Reed et al. 2012). Early studies termed this condition “essential vulvodynia” and described it as a complaint of postmenopausal women with constant sensations of irritation or stinging. It can be a co-morbidity in younger women with LPV and can develop rarely after a vestibulectomy. A large clinical study indicated that 10% of women with vulvodynia have generalized type (Lamvu et al. 2015).

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Postmenopausal Pain with Sex Dyspareunia is very common in postmenopause and has suffered from a lack of research (Kao et al. 2008). There has been a hesitation to classify postmenopausal dyspareunia as a form of vulvodynia since the vulvodynia definition states “without another identifiable cause,” and lack of estrogen is the cause of dyspareunia in this age group. Pain has commonly been ascribed to atrophy causing vaginal dryness. The newer term is genitourinary syndrome of menopause (GSM) and replaces the term “vulvovaginal atrophy” (NAMS 2020). GSM includes symptoms of dyspareunia, sensations of dryness, and urinary and vulvar irritation. Atrophy is a condition of thinned genital tissues from the lack of estrogen that characterizes menopause. Without estrogen, the uterus and cervix shrink, and vaginal, vestibular, and outer vulvar tissues thin. A problem with attributing menopausal dyspareunia to atrophy is that the intimacy tenderness is localized to the vestibule and not the vagina, despite both areas having developed atrophy (Goetsch et al. 2014). Additionally, not all women with genital atrophy have dyspareunia. Finally, in other circumstances of physiologic atrophy, such as muscle atrophy, there is no associated pain condition. For these reasons there is pressure to reconsider the definitional injunction against labeling a condition vulvodynia if the “clear identifiable” associated cause is estrogen loss (Kao et al. 2008). In women with postmenopausal dyspareunia, an examination indicates that the pain is at the entryway and is tenderness, not dryness. The use of lubricants can temper the sensation of irritation or pain, but they do not remove pain as should be expected if this were simple dryness. The use of lubricants is a good idea in menopause generally, for reasons of less natural lubrication, and a silicone lubricant is a good option. Postmenopausal dyspareunia fulfills the criteria of being localized to the vestibule and only painful when provoked, similar to the condition of vestibulodynia found in younger women. Postmenopausal vestibulodynia can be diagnosed with the cotton swab and lidocaine tests, which

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can demonstrate that there is extinguishable mucosal pain and no other cause of penetrative tenderness, this being demonstrated by painless post-lidocaine speculum and pelvic examinations. The lack of estrogen in menopause can therefore cause two concomitant problems: vestibulodynia and general genital atrophy. Estrogen therapy usually corrects both conditions, but not uniformly. For localized therapy the instructions are to apply estrogen into the vagina. However, this does not directly treat the important location of the vestibule, and low-dose vaginal therapy may not be strong enough to correct vestibular tenderness. Another example of chronic vulvar pain may be emerging now that years have passed after women were urged in national guidelines to forego postmenopausal estrogen. Women are presenting for care in the later years of menopause with constant burning pain arising from the vestibule. These women often have not used estrogen for years or they have used anti-estrogen medications (aromatase inhibitors) as treatment for breast cancer. Their burning pain is constant and debilitating. It is a very severe example of vestibulodynia and responds to prolonged estrogen therapy directed to the vestibule (Goetsch 2020). A final example of genital insertional pain that may be vestibulodynia is in the understudied population of transgender men (female to male). Testosterone therapy suppresses the ovaries, and the resulting lack of estrogen may cause the genital tissues to develop a pain syndrome probably equivalent to GSM (Goetsch and Ribbink 2021).

Theories of Causation of Localized Provoked Vulvodynia Current research is pursuing various possible triggers for both primary and secondary vulvar vestibulodynia. Scarring was an early theory to explain dyspareunia. It was proposed by Woodruff, who suggested that submucosal scarring from childbirth was causative. He demonstrated that a surgical procedure could be quite palliative, but because he believed scars to be the cause, his procedure advanced vaginal tissues out over the

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fourchette and down to mid-perineum so that there would not be a scar where penetration would occur. This prototype surgery has influenced surgical approaches since, although scarring is no longer the operant theory of causation. A counter to this theory of causative introital scarring is the fact that millions of women sustain tears around the introitus during vaginal childbirth, and these heal with only rare sequelae of tenderness and dyspareunia. In fact, keloids, which arise from pathologic thickening of scars in ectodermal skin, never involve the vestibule, which is endodermal. Psychological Etiologies By the early 1900s, with the new field of psychology experiencing increasing popularity, dyspareunia shifted from the category of a physical problem to being a sign of neurosis. See the “History” section below. This conceptualization meant that for much of the twentieth century, women with dyspareunia were referred to psychologists or psychiatrists for mental health therapy about maladjustment to being sexual. Modern psychologists have refined the research on etiologic psychological factors. Studies have reported mixed findings about the prevalence of antecedent depression or sexual abuse. One study found that severe childhood physical or sexual insecurity was associated with a threefold increase in vulvovaginal pain. Sexual pain is acknowledged to be a complex cause of distress (Bergeron et al. 2015). Irritant Exposure Many patients’ first symptoms are assumed to be from a yeast vulvovaginitis, and research is ongoing to assess a relationship between candida exposure and LPV. Clinically, episodes of severe vaginitis or a reaction to over-the-counter antifungals is a feature of some women’s histories of vestibulodynia. Episodes and treatments are common enough that cause and effect are hard to prove. Practical vulvar cleansing and drying techniques may be beneficial. The use of immune modulators such as imiquimod in the fourchette/vestibule area can elevate the risk that LPV will be triggered. Constant wetness can also lead to adverse changes in the vulvar tissue.

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Low Estrogen as a Cause of Vestibulodynia Low estrogen levels have been found to provoke growth of genital tract nociceptive nerves in animal studies. Additionally, lower and higher estrogen levels during estrus cycles are associated with repetitive cyclic proliferation and thinning of genital nerve density, respectively. The accompanying infiltrate of lymphocytes and mast cells may be responsible for reacting to low estrogen levels and releasing neurogenic messengers such as angiotensin II (Brauer and Smith 2015). The low-estrogen theory of causation holds that since vestibular tenderness is so specific to intercourse, it might be considered a strategic contraceptive condition. LPV makes intercourse intolerably painful in women who are otherwise healthy. Considering that species survival is a major rule of nature, dyspareunia during one period of reproductive life, lactation, could selectively increase survival of a newborn by postponing a next pregnancy. After high placental estrogen levels plummet with delivery, and ovarian function is suppressed during the period of lactation, low estrogen may constitute a trigger for temporary vestibular pain. Postpartum dyspareunia is common after ovarian estrogen levels fall. In a 1996 study, dyspareunia occurred in 38% of parturients, and if it continued beyond 5 months, its resolution was specifically associated with resumption of menses (Goetsch 1999). All cases were resolved by 1 year, but this provided a painful disincentive to have intercourse, thereby acting as a contraceptive by virtue of pain. Two early prevalence studies of vestibulitis (the old term for vestibulodynia) found that 25% of patients had first noted their dyspareunia postpartum, and it had not resolved. This is a useful piece of patient history to assess. Postmenopausal dyspareunia is also common after estrogen levels fall. Although this problem is usually attributed to vaginal atrophy, a new interpretation holds that both atrophy and vestibulodynia develop side by side, and the location of pain in patients with severe untreated vulvovaginal atrophy is the vestibule, not the vagina (Goetsch et al. 2015). A histologic study

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in this population has found the condition to be consistent with neurogenic inflammation and vestibulodynia (Leclair et al. 2013). Figure 2 shows an example of severe vestibulodynia in postmenopause. The theory of low-estrogen causation does not immediately seem to apply to premenopausal women, as this population has a 12–14% prevalence of LPV despite generous levels of estrogen. The theory holds that if the introital zone is genetically primed to become tender, nonhormonal triggers may be capable of setting the neurogenic process in motion. This would explain vestibulodynia that arises after bladder infections or topical irritant use. The theory of an estrogen trigger may also explain primary vulvar vestibulodynia (pain since first attempt at vaginal penetration in young women). Girls have scant estrogen until puberty. Many girls may be asymptomatic but have tender vestibules, something we don’t know since genital examinations are restricted in

Fig. 2 Severe vestibulodynia in a 64-year-old who has been without estrogen for 10 years and for whom estrogen is contraindicated due to a history of breast cancer for 3 years. The redness is severe erythema where she had exquisite tenderness to touch, tenderness extinguishable with 4% lidocaine topical solution. (Goetsch 2013)

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girls. Tenderness would then disappear with the rise of estrogen in puberty, only to return postpartum or many years later with menopause. If, for some girls, the hormone receptor mechanism in the vestibule is faulty and the tenderness does not resolve with puberty, they are left with primary vulvar vestibulodynia despite normal estrogen levels. Primary vulvar vestibulodynia is present in 7% of young women and may represent nature’s “error” rate, so to speak.

Other Potential Causes of Vestibulodynia Progesterone Effect Some researchers suggest that newer progestins with an androgenic nature be avoided. Genetic Predisposition Findings utilizing the Utah Population Database showed an extremely strong genetic linkage, with shared ancestry out to seven meioses among a set of women who had undergone corrective procedures for severe LPV (Morgan et al. 2016). Data show that there are genetic variants that cluster in women with LPV, and these relate to pro-inflammatory pathways, T-cell regulators, and serotonin and androgen receptors. Relationship to Bladder Pain Syndromes Not uncommonly, the clinical history in women with secondary vestibulodynia points to a bladder infection as a trigger. The bladder and the vulvar vestibule are both derived embryonically from the endodermal layer. A flare of bladder pain symptoms, also called interstitial cystitis, in bladder/ urethra tissues can be reflected in symptoms in the vestibule. In both entities there is sensory hyperinnervation and a lymphocyte infiltrate (Regauer et al. 2017). Triggering by Human Papilloma Virus (HPV) Investigators initially suspected HPV to be a causative agent of secondary vestibulodynia. However, there is rarely histologic or DNA evidence of the virus at biopsy, and academic consensus is that it is not causative. Patients can give a history of pain a few months into a new relationship, however, implicating a transmissible agent. HPV may

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therefore be acting as a “hit and run” actor. Therapeutic approaches are not altered even if HPV seems to have been a trigger. The early popularity of interferon injections for vestibulodynia faded when efficacy was questioned. Neuropathic Pain with Central Mediation Many researchers consider that both types of vulvodynia, localized and generalized, exhibit evidence of amplification of peripheral nerve impulses by intermediate synapses before they reach the brain, and are perceived as pain (Zolnoun et al. 2006). Several studies have demonstrated heightened sensitivity to noxious stimuli in anatomic sites distant from the vulva in women with LPV. Whether in LPV this reflects a variation in genetically determined pain sensitivity, or a product of peripheral LPV pain with development of central sensitization is not clear. Generalized vulvodynia is best described as a disorder with central sensitization and is most successfully treated with neuromodulators effective for peripheral neuropathy, but rigorous assessment of the many attempted therapeutic regimens awaits agreement regarding core outcome measures that would quantify benefits to patients.

Vulvodynia’s Place in the History of Medicine Textbooks of gynecology over one hundred years ago described and offered treatments for what is now realized to be vulvar vestibulodynia and pelvic muscle hypertonus. “Vaginismus” was the original name given to this condition by Marion Sims when he presented a descriptive paper to the Obstetrical Society of London in 1861. The term “vaginismus” included both mucosal and muscle problems. He described five patients with severe dyspareunia that prohibited coitus, noting this to be a moral issue because they had never been able to consummate holy matrimony due to their severe conditions. His term “vaginismus” would today be considered the duo of vestibulodynia with pelvic floor myalgia. He published a

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description of a minor surgery that revised the tissues of the introitus, and he instructed patients to follow this with the use of vaginal dilators. Over the next decades of the nineteenth century, authors of gynecologic textbooks such as Simpson, Skene, Huhner, and Kelly described this condition. When psychological diagnoses became popular in the 1880s, textbooks began introducing the consideration that women with dyspareunia were hysterical and neurotic. The description of mucosal hypersensitivity dropped out of the writings by the 1930s, and women were treated by psychologists for neuroses and by physical therapists offering dilator training. “Vaginismus” held on as a psychiatric diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM) until the newest version, 5. Before edition 5, “vaginismus” was characterized as a severe aversion to penetration without a mention of pain, noting only tight muscle spasms sufficient to obstruct penile entry. The latest DSM-5 edition has eliminated “vaginismus” in favor of “genitopelvic pain/penetration disorder” and emphasizes the distress that it causes.

Comorbidities with Vulvodynia Pelvic Floor Myalgia Pelvic floor muscle tightness is usually present in LPV and can be a source of pain with penetration. Repeated, protective contractions of pelvic floor muscles can easily develop as a response to exquisite vulvar tenderness and/or deeper pelvic pain. Patients with myalgia have lost the capacity to fully relax these muscles, and there is relative weakness of the muscles despite the constant contracted state. Physical therapy is very important to help patients retrain these pelvic floor muscles to be able to relax and contract volitionally. The American Physical Therapy Association has special certification for members who complete training to become skilled in pelvic floor therapy. These practitioners provide expertise about pelvic floor tightness and pain as well as about other problems such as pelvic relaxation and associated urinary incontinence.

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Bladder Issues There are two ways that localized vulvodynia patients can develop symptoms that relate to their bladder function. In the simpler example, the increased muscle tension elevates the hammock of muscles, thereby reducing filling capacity of the bladder and causing urinary frequency and perhaps urgency. Patients may have multiple episodes of nocturia and may complain of having a small bladder capacity. They don’t have bladder pain. As a second reason to develop bladder symptoms, there is a significant association between localized provoked vulvodynia and what has been called interstitial cystitis. Just as occurred with vulvar pain, the terminology of bladder pain has evolved. It is now termed “bladder pain syndrome/ interstitial cystitis (BPS/IC).” It is a poorly understood problem of nonspecific bladder inflammation with intermittent symptoms of voiding pain, frequency, and urgency. These symptoms mimic bladder infections but patients are negative for bacteriuria. The bladder and the vestibule derive from the same embryologic layer, the endoderm. Therefore, it is not uncommon to elicit a history that there is a relationship between the symptoms of these two urogenital tissues. For instance, women may relate the onset of vulvar pain to a bad bladder infection. And women with both conditions may note that when the bladder condition is worse, the vestibule has a flare of pain and vice versa. Both in vestibulodynia and interstitial cystitis, 17–20% of sufferers have both conditions. It is useful to become conversant in both conditions. A helpful measure is dietary restriction of bladder irritants such as caffeine, alcohol, citric acid foods such as cranberries, spicy foods, and artificial sweeteners. The Interstitial Cystitis Association has an informative website. Psychosocial Issues As can be expected, sexual pain has many difficult emotional consequences for women who experience it, and it affects their partners as well. Women with sexual pain have increased levels of anxiety and depression, catastrophizing, and lower levels of self-efficacy. Sex therapists are

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specialists in this area and can help with the complicated emotions and difficult communication that is so common with these pain problems. All aspects of sexuality are affected by sexual pain, including arousal and lubrication, desire, orgasmic success, and the ability to have penetration itself. Many women continue to have intercourse despite pain because the risk to their relationship seems too great if they abstain. Continued penetrative activity despite pain will likely cause and worsen pelvic floor myalgia. Atrophy After Menopause Although for decades the problem of postmenopausal dyspareunia has been assumed to be a symptom of atrophy, recent publications have concluded that this pain condition has more in common with LPV (Kao et al. 2012) and is located in the vestibule rather than the vagina. Atrophy in other organ systems is not a cause of pain (atrophied muscles, aged skin). Specialists in menopause and vulvar pain have not aligned their concepts; acknowledgment that neural hypertrophy is not typical for atrophy, but is for localized provoked vulvodynia, will allow research to proceed regarding neurogenic vestibular inflammation in GSM, a condition affecting millions of women. Chronic Pain Conditions Vulvodynia is considered by many pain researchers to be one of several conditions that exhibit central mediation and upregulation of pain processing. Other conditions often mentioned in this list are fibromyalgia, bladder pain syndrome, irritable bowel syndrome, and migraine syndrome. One confusion about research into such groupings of pain conditions is that often no distinction is made between generalized vulvodynia, probably a centrally mediated pain process, and localized provoked vulvodynia, felt by some vulvar researchers to be a chronic but peripheral condition.

M. F. Goetsch

therapeutic efficacy. This has resulted in a frustrating accumulation of anecdotal reports without rigorous science. Additionally, it is common that studies have failed to assign women to specific categories of generalized versus localized vulvodynia, and they have failed to group women into categories of primary versus secondary vestibulodynia or specifically defined the categories of severity. All of these factors mean that there are many answers awaiting elucidation. Treatment of the General Problem of Entry Dyspareunia When this complaint has become chronic, it is usually multifactorial. The triad of factors are mucosal allodynia, secondary tightening of pelvic floor muscles, and psychic stress. Therapeutic initiatives are required for each to achieve full treatment. Despite acknowledgment that dyspareunia requires multimodal therapy, there is not agreement about how to evaluate success. Researchers in the field have not established a uniform set of outcome measures. Using “dyspareunia” as an outcome, for instance, may be significant but still not complete (i.e., intercourse is now possible but shouldn’t intercourse be comfortable and enjoyable?). The IMMPACT group that has published criteria for evaluating improvement in chronic pain conditions suggests that a pain reduction of 50% is probably of clinical significance. However, for dyspareunia, an intolerable pain that is reduced 50% may still be unacceptable. Proportional improvement may need clarification by assessing features like the consistency of relief and the confidence associated with sexual function. As another general point, only in menopause is estrogen therapy helpful; in younger women estrogen may ameliorate pain in some, but the effect is not dramatic.

Specific Therapies for Vulvodynia Therapeutic Efforts: General Points Many therapies have been tried for vulvodynia. A criticism of most intervention studies is that they lack controls and randomization to compare

General Suggestions for Vulvar Hygiene Most reviews of vulvodynia emphasize reduction of local exposure to irritants or constant wetness, whether the irritants be sweat, soap residues in

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clothing, irritating body soaps, or over-the-counter genital products. Commonly used over-the-counter “intimacy” products like anti-itch or numbing benzocaine can be problematic because of skin hypersensitivity reactions and should be avoided. The use of an effective sexual lubricant is important to reduce friction across tender mucosal surfaces. Water-based lubricants are recommended when condoms are being used, but silicone lubricants can provide longer-lasting lubrication. Tips on cleaning and drying techniques for the vulva can be beneficial. Multiple Empiric Therapies Many pill and cream therapies have been tried empirically for all vulvodynias without scientific proof of efficacy. These include cortisone creams, hormone creams, anti-herpes therapies, antifungals, topical use of hot red pepper extract (capsaicin), and therapies used for shingles. A common impulse in response to seeing redness in the vestibule is to prescribe a course of topical steroids to the area. The inflammation of vestibulodynia, however, has been shown to be neurogenic and not a classic inflammation, and is unresponsive to topical steroids. One study combined injections of steroid and anesthetic and showed efficacy after a year of follow-up, but further studies were not forthcoming. A prolonged empiric course of an oral antifungal for several weeks is standard in some approaches to vulvodynia to check whether pain relief implicates low-grade fungal irritation as a cause. Topical Lidocaine Therapy For symptom relief of LPV, the most helpful therapy is topical lidocaine applied just before intercourse. Such therapy is not intuitive, as numbing a potentially erogenous area seems counterproductive. However, the numbing is applied very specifically, is only mucosal, and avoids the clitoris. It extinguishes the burning allodynia, and touch sensation remains. (It could be compared, in the case of aphthous mouth sores, to the difference between a rinse of oral lidocaine solution and a facial nerve block by a dentist.) If mucosal pain is

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prevented, women with this condition can learn to relax their pelvic floor muscles, thereby further reducing discomfort. Choices of product include a gel formulation with 2% lidocaine, an aqueous formulation with 4% lidocaine, and an ointment with 5% lidocaine. The benefits of the aqueous solution are its relative strength combined with a single preservative, making it less likely to sting on first application. Additionally, a liquid does not smear widely and risk numbing the partner. Patients must be shown with a mirror just where the tender zones are, and they avoid numbing the clitoris. Pretreatment with lidocaine for several minutes immediately before intimacy, plus the use of an effective lubricant, can help most women have comfortable intercourse even when affected with mild or severe vulvar vestibulodynia. Clinical experience teaches that premenopausal women find lidocaine use instructive to confirm the diagnosis, but unacceptable as an indefinite strategy. Lidocaine for Those Who Cannot Use Estrogen in Postmenopause Breast cancer survivors who cannot use estrogen products can get excellent results for severe dyspareunia by learning to use liquid lidocaine anesthetic applied for 3 min to the painful area (followed by lubricant) just before intimacy (Goetsch et al. 2015), Ninety-five percent of affected women in a randomized trial were able to enjoy comfortable intercourse after preventing entry dyspareunia with lidocaine. Half of the group had been abstaining because of the severity of pain. All aspects of sexual function improved when pain was prevented, independent of the length of time the couples had had to abstain, indicating that the adage “use it or lose it” serves simply to warn the patient to endure pain and is not an accurate or appropriate exhortation. In the 2015 randomized controlled trial, postmenopausal breast cancer survivors embraced liquid lidocaine as a long-term therapy, having previously found that the prohibition against estrogen gave them no effective therapy for severe genital pain after menopause.

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Treatment of the Vestibule Mucosa The most effective corrective therapy for LPV is superficial local excision of the affected mucosa (Tommola et al. 2010). More than 20 outcome series and one randomized comparative study show excision to be a successful and acceptable treatment for this condition. There has been great hesitation, however, to list this intervention as the most indicated. Review publications and specialty committee reports continue to suggest that it be offered as a last resort, only after other therapies have been exhausted. Delay, however, has been shown to increase the difficulty of treating associated muscle and emotional problems. Pain for 5 or more years prior to effective mucosal therapy has been associated with a worse prognosis for cure of dyspareunia. Early diagnosis and symptom relief are important to prevent sexual comorbidities. LPV may be a singular example of a focal unremitting inflammatory pain that is amenable to local excision. The procedures vary from performance of uniform excisions to instead making an individualized plan by mapping the localized pain areas and removing only painful mucosa. Some techniques remove the hymen and then undermine and advance vaginal tissues out to the perineum (vaginal advancement). Others leave the hymen and use it as a flap to close the resected zone of affected vestibule. Figure 3 shows an example prior to excision.

Fig. 3 This shows the mapped area of vestibulodynia before the procedure of localized mucosal removal in a patient with tenderness from 3 to 9:00. The hymen will be used as a flap to close the resected zone without advancing the vaginal tissues (Goetsch 2007)

M. F. Goetsch

The extent of surgery will determine the time needed to heal and the associated disfigurement to the vulva. Surgical techniques have not been directly compared to assess morbidity and rates of cure. Since all surgeries excise the apertures of the Bartholin’s ducts and cover them with a flap, there is a risk of developing Bartholin’s duct cysts at a future time, but this occurs in only 10% of cases and may not be apparent to patients. Postoperative physical therapy and dilator use help with the relaxation of tense muscles and the transition to comfortable sex. Another noninvasive therapy has employed the NgYag laser. It is a laser used by dermatologists for remodeling of skin collagen related to aging in nongenital areas. It is not clear what it targets in LPV, but there has been success in treating the anterior vestibule where surgical excision is not feasible. Multiple pulses of laser energy are directed to the painful zone during 1–3 treatment sessions. NgYag laser is not a destructive laser. The classic vaporizing CO2 laser was found to have a low success rate and risked worsening the LPV; it was quickly abandoned. Treatment of Pelvic Floor Myalgia Physical therapy is an important adjunct in the treatment of LPV (Bergeron et al. 2008). It addresses muscle pain (pelvic floor myalgia) and tight introital muscles that cause heightened penetrative friction. Physical therapy may be less important for generalized vulvodynia (GV), as this pain condition results less often in muscle tightening. Also, generalized V often affects older women who are more likely to be multiparas with laxer muscles compared to nulliparas who constitute a significant portion of LPV patients. The physical therapist must be specifically trained in pelvic floor muscle work. Techniques vary, and the consistent feature is to train women to recognize when muscles are tight and learn to relax them volitionally. On evaluation, muscles are usually in hypertonus but are actually weak. Biofeedback is provided either by the therapist while monitoring with a finger, or with a vaginal sensor that assesses electromyographic (EMG) data. The goal is muscle relaxation, increased

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blood circulation, and enlargement of the vaginal caliber. Successful physical therapy of myalgia can reduce the degree of dyspareunia by 50% even without addressing the vestibule tenderness. Soft or firm vaginal dilators of varying sizes can be helpful for home use so that therapy can continue for each woman independently. The ability to easily insert successive sizes of dilators confirms increasing success with relaxation. Physical therapists are a source of emotional support and patient education about anatomy and touch. Some use topical lidocaine to treat the mucosal pain of LPV in order to focus on muscle work. They can be effective teachers of home lidocaine use. Psychosocial Therapy Sexual pain, by its nature, complicates a woman’s sense of personal normalcy and sexual confidence. Professional counseling can be critical for patients and their partners, treating specific dysfunctions in addition to the pain itself. Researchers are exploring various approaches to therapy more specific than simple supportive therapy. Cognitive behavioral therapy (CBT) has successfully focused on pain management and sexual functioning with improvements maintained at a 2.5-year follow-up (Bergeron et al. 2008). Mindfulness is being proven valuable as well, in changing perceived intensities of pain and benefiting muscle relaxation in series of group sessions (Brotto et al. 2019). A sex counselor can be helpful by suggesting to couples a range of non-painful options for intimacy. Both parties are affected, and couples’ sex therapy is important to address the shared issues of guilt, inadequacy, and shame. Only a few studies report on therapeutic interventions that include the sexual partner. Hormone Therapies Generalized V is not considered to be hormonally sensitive. There is not a consensus about the benefit of manipulating the hormone milieu in patients with LPV. Researchers in Sweden have concluded that one in five patients with LPV is benefited to some degree by stopping their estrogen/progestin oral contraceptives. Some believe that the second-generation progestin drospirenone

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can trigger or worsen LPV and should be discontinued. Research is ongoing about the benefit of topical estradiol/testosterone cream. The one clear setting where estrogen therapy is definitely effective and appropriate is in postmenopausal dyspareunia. The therapy may need to be applied directly to the vestibule, but research lags in this area, as the general understanding of GSM assumes that the pain is from vaginal thinning. Vaginal and systemic estrogens in current FDA-approved regimens do not adequately correct GSM dyspareunia (Simon et al. 2013) (Nastri et al. 2013). A synthetic estrogen receptor modulator, oral ospemifene, a lower-vaginal estrogen gel, and a vaginally applied estrogen precursor DHEA are available as alternatives to older estrogen products for menopausal dyspareunia. Diet Therapy A low oxalate diet has not been shown to have benefit in vestibulodynia. A diet that restricts bladder irritants can help with bladder pain and urgency. Extreme adherence to a low oxalate diet does not provide healthy nutrition. Neuromodulators Oral medicines to treat the nervous system are commonly offered by many vulvar practitioners across the country, although results vary and good comparative studies are few (Foster et al. 2010). The placebo effect has been shown in controlled studies to be strong. Frequently-used medications include the tricyclic medicines (amitriptyline, desipramine, nortriptyline) and neuromodulators (gabapentin, pregabalin, and duloxetine). Some of these medicines have also been mixed into a cream and applied directly to the painful vestibule (Boardman et al. 2008). There are studies supporting the use of topical 5% lidocaine, 2% amitriptyline cream, and 6% gabapentin cream as helpful for some patients. Baclofen or valium has been offered as vaginal suppositories. Generalized Vulvodynia This disorder, characterized by aberrant nerve messaging, is not appropriately treated by surgery. Medical management is with neuromodulators.

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Conclusion Vulvar pain is a complicated sexual pain disorder affecting 8–15% of all young women, and it is a progressive problem for postmenopausal women, affecting 50% within 3 years of menopause. It can be expected to affect women who are warned not to supplement with estrogens after a diagnosis of breast cancer or transgender men who suppress estrogen from a young age. Although what we know to be vulvodynia was described in early gynecologic textbooks, it was then misunderstood for decades and then “rediscovered” in the 1980s. Research is ongoing to understand the physiology and why this affects so many women. Clinicians in many specialties should be familiar with this condition and its variations in order to offer accurate diagnoses and referral for treatment. Those whose practices include genital examinations should know how to pretreat with lidocaine in order to facilitate optimal examination assessments of the entire urogenital tract. Therapies for vulvodynia must address not only the physical pain but the emotional and psychological distress that results. An integrated multidisciplinary approach provides the best strategy for success.

Cross-References ▶ Benign Diseases of the Vulva ▶ Benign Vulvar and Vaginal Pathology ▶ Management of Menopausal Symptoms ▶ Management of Pelvic Pain, Dyspareunia, and Endometriosis ▶ Management of Sexual Dysfunctions ▶ Management of Vaginal and Vulvar Lesions in the Postmenopausal Women

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M. F. Goetsch Boardman LA, Cooper AS, Blais LR, Raker CA. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol. 2008;112(3):579– 85. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Investig. 1999;48:270–5. Bohm-Starke N, Falconer C, Rylander E, Hilliges M. The expression of cyclooxygenase 2 and inducible nitric oxide synthase indicates no active inflammation in vulvar vestibulitis. Acta Obstet Gynecol Scand. 2001;80:638–44. Bornstein J, et al. Consensus statement: 2015 ISSVD, ISSWSH and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. Obstet Gynecol. 2016;127:745–51. Brauer MM, Smith P. Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. Auton Neurosci. 2015;187: 1–17. Brotto LA, Bergeron S, Zdaniuk B, Driscoll M, Grabovac A, Sadownik LA, et al. A comparison of mindfulness-based cognitive therapy vs cognitive behavioral therapy for the treatment of provoked Vestibulodynia in a hospital clinic setting. J Sex Med. 2019;16:909–23. Foster D, Kotok M, Huang L, Watts A, Oakes D, Howard F, et al. Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled study. Obstet Gynecol. 2010;116(3):583–93. Goetsch M. Postpartum dyspareunia – an unexplored problem. J Reprod Med. 1999;44(11):963–8. Goetsch M. Severe postmenopausal genital pain treated successfully with prolonged estrogen therapy: a case series and narrative review. J Low Genit Tract Dis. 2020;24:405–10. Goetsch MF, Ribbink PJA. Penetrative genital pain in transgender men using testosterone: a survey study, vol. 226. Oct: AJOG; 2021. p. 264. Goetsch MF, Lim JY, Caughey AB. Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial. Obstet Gynecol. 2014;123(6): 1231–6. Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33(30):3394–400. Harlow B, Kunitz C, Nguyen R, Rydell S, Turner R, MacLehose R. Prevalence of symptoms consistent with a diagnosis of vulvodynia: population-based estimates from 2 geographic regions. Am J Obstet Gynecol. 2014;210:40.e1–8. Kao A, Binik Y, Kapuschinski A, Khalife S. Dyspareunia in postmenopausal women: a critical review. Pain Res Manag. 2008;13(3):243–54. Kao A, Binik Y, Amsel R, Funaro D, Leroux N, Khalife S. Challenging atrophied perspectives on postmenopausal dyspareunia: a systematic description and synthesis of pain characteristics. J Sex Marital Ther. 2012;38:128–50.

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Lamvu G, Nguyen R, Burrows L, Rapkin A, Witzeman K, Marvel RP, Hutchins D, et al. The evidence-based vulvodynia assessment project. A national registry for the study of vulvodynia. J Reprod Med. 2015;60(5–6): 223–35. Leclair C, Goetsch M, Korcheva V, Anderson R, Peters D, Morgan T. Differences in primary compared with secondary vestibulodynia by immunohistochemistry. Obstet Gynecol. 2011;117(6):1307–13. Leclair CM, Goetsch MF, Li H, Morgan TK. Histopathologic characteristics of menopausal vestibulodynia. Obstet Gynecol. 2013;122(4):787–93. Morgan TK, Allen-Brady KL, Monson MA. Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition. Am J Obstet Gynecol. 2016;214(5):609.e1–7. NAMS. The 2020 genitourinary syndrome of menopause position statement of the North American Menopause Society. Menopause. 2020;27(9):976–92. Nastri CO, Lara LA, Ferriani RA, Rosa-e-Silva ACJS, Figueiredo JBP, Martins WP. Hormone therapy for sexual function in perimenopausal and postmenopausal women. Cochrane Database Systemat Rev, Issue. 2013:6. Pukall C, Payne K, Binik Y, Khalife Y. Pain measurement in vulvodynia. J Sex Marital Ther. 2003;29(1):111–20. Reed B, Harlow S, Sen A, Legocki L, Edwards R, Arato N, et al. Prevalence and demographic characteristics of

455 vulvodynia in a population-based sample. Am J Obstet Gynecol. 2012;206:170.e1–9. Regauer S, Gamper M, Fehr MK, Viereck V. Sensory Hyperinnervaqtion distinguishes bladder pain syndrome/interstitial cystitis from overactive bladder syndrome. J Urol. 2017;197:159–66. Reissing E, Binik Y, Khalife S, Cohen D, Amsel R. Vaginal spasm, pain, and behavior: an empirical investigation of the diagnosis of vaginismus. Arch Sex Behav. 2004;33(1):5–17. Simon J, Nappi RE, Kingsberg SA, Maamari R, Brown V. Clarifying vaginal Atrophy’s impact on sex and relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on north American postmenopausal women and their partners. Menopause. 2013;21(2):137–42. Stenson AL, Leclair CM, Goetsch MF. Comparing vestibule examination techniques: light touch, serial forces, and the lidocaine test. J Low Genit Tract Dis. 2021;25 (3):236–42. Tommola P, Unkila-Kallio L, Paavonen J. Surgical treatment of vulvar vestibulitis: a review. Acta Obstet Gynecol Scand. 2010;89:1385–95. Zolnoun D, Hartmann K, Lamvu G, As-Sanie S, Maixner W, Steege J. A conceptual model for the pathophysiology of vulvar vestibulitis syndrome. Obstet Gynecol Surv. 2006;61(6):395–401.

Management of Pelvic Pain, Dyspareunia, and Endometriosis

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Judy Hall Chen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Pain Physiology: Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Convergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropathic Pain and Nociceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Understanding Pain Physiology: Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

462 462 463 463 464 464

Pelvic Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Pain Story: The Initial Visit and Continued Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory and Radiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Pelvic Pain: Notes on Specific Assessment, Management, and Treatment of Various Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

464 466 468 468

Dyspareunia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Dyspareunia and Sexual Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 Management of Dyspareunia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Endometriosis: Pelvic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Endometriosis: Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometriosis Laboratory and Diagnostic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometriosis Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

476 477 479 482 482 482

Reassessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Abstract

J. H. Chen (*) Obstetrics and Gynecology, Tucson Medical Center, Tucson, AZ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_78

Pelvic pain is an enigmatic diagnosis which often brings frustrations to both patient and practitioner. This chapter provides an introduction to the changing categorization of pain, a 457

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review of pain pathophysiology, and clinical approaches to three presentations of pelvic pain. Dives into the clinical approach for general pelvic pain, dyspareunia, and endometriosis stress the need for a thorough interview, documentation of history, and a detailed physical exam findings. If these parameters fail to give a clear explanation of the etiology, other techniques may be useful to elicit other common findings associated with pelvic pain, dyspareunia, or endometriosis. Despite the trend toward algorithmic clinical practice for many disease assessments, the diversity of diagnoses related to pelvic pain limits the effectiveness of an algorithmic approach. A focus on the reproductive status of the patient impact may help to guide both diagnostic and therapeutic options. Keywords

Pelvic pain · Dyspareunia · Endometriosis · Pain · Pain syndromes · Sensitization · Convergence · Neuronal cross-talk · Pelvic pain

Introduction Pain, as a symptom, provokes strong responses and emotions from both patients and physicians. Such reactions reflect the complex nature of diagnosing and treating pain. As a complex symptom arising out of multilevel activation process of neural feedback loops modified by both physiologic and psychological factors, the difficulty lies in isolating the exact location of the physiologic process involved in the disease. Yet, even if a physiologic process can be identified, the same multilevel activation neuronal process may not respond to treatment targeting the physiologic process. Added to the complexity of the pain response lies the complexity of the female pelvis and reproductive system. The cyclic and systemic nature of reproductive hormones impact disease triggers not only through endocrine modulation but also psychologic perceptions. Outside of these individual patient characteristics are societal factors related to fertility and femininity. Although

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scientific investigation continues to unveil new understandings related to these processes, the interplay and overlap of the factors above within patients with chronic pelvic pain, ultimately, demands individual customization.

Terminology Before diving into the aspects of pelvic pain, there is a need to outline two sources of difficulty within this area: nomenclature and physiology. Past terminology grouped pelvic pain by time constraints: less than 6 months (acute) versus more than 6 months (chronic). However, as the understanding of the different causes of pelvic pain has evolved so has the nomenclature. No longer does a general diagnosis of chronic pelvic pain suffice to guide treatment. It is now important to specify the suspected source, the progression or evolution, possible cyclic changes, and effects of interventions. “Chronic pelvic pain” (CPP) as a term should no longer be merely a diagnostic categorization of a patient complaint but an indication that persistent investigation and delineation continues.

The past combination of imprecise language and static understanding of pain pathology gave rise to a frustrating cycle of generalized history taking, imprecise differential diagnosis lists, indeterminate results, and failed empiric therapy. These factors potentially lend themselves to the frequently seen divide between patient and physician with the divide often leading to a change in physician. With a new physician, however, the process of investigation often repeats itself given the traditions of medical practice and diversity of language interpretation. Repeated cycles of these events often lead to frustration and distrust on both sides of the clinical experience: patients and clinicians. Using a more precise nomenclature assists in increased diagnostic accuracy, therapeutic precision, patient rapport, and professional communication.

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• Baranowski gives good scope to untangling the complexity of the current vague terminology by introducing CPP classifications related the three conditions of medical understanding: phenotyping, terminology, and taxonomy (Baranowski 2009). Expanding an understanding beyond a “symptom with multifactorial etiologies” is benefited from the detailed categorizations proposed by Baranowski. • Phenotyping is the process of identifying the pathophysiologic changes to understand the cause of the pain symptoms. • Terminology highlights the gap between the true definition of words and the varied use of practitioners when selecting words to describe both the cause and symptoms of pelvic pain. – Taxonomy separates terminology into two categories: known pathologic causes of pelvic pain versus syndromes of pain which have consistent symptom presentations but no known active associated pathologic process.

“[CPP is] associated with negative cognitive, behavioral, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor, myofascial, or gynecologic dysfunction.” Also recognized is the cyclic frequency with which CPP may present. In the figure (Fig. 1), the baseline definition promoted by ACOG is given a detailed eight-axis structure to work through the patients symptoms and possible etiologies related to a patient’s CPP complaint (Table 1).

Clinically, the baseline definition of CPP continues to be broad and nonspecific. ACOG in 2020 in the context of the reVITALize data starts with “pain symptoms perceived to originate from pelvic organs/structures typically lasting more than 6 months.” The practice bulletin #218 then goes on to reflect the complex nature of CPP etiologies,

*Where perceived indicates that the patient and clinician, to the best of their ability from the history, examination, and investigations (where appropriate), have localized the pain as being perceived in the specified anatomical pelvic area.

Chronic pelvic pain is chronic or persistent pain perceived* in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioral, sexual, and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor, or gynecological dysfunction.

Axis VIII: Psychological symptoms Axis VII: Associated Symptoms Axis VI: Character Axis V: Temporal Characteriscs Axis IV: Referral characteriscs Axis III: End-Organ pain syndrome Axis II: System Axis I: Region

Fig. 1 Eight axis structure for evaluating chronic pelvic pain

Axis I region Chronic Chronic secondary pelvic pelvic pain syndrome, formally pain known as specific disease associated pelvic pain OR Chronic primary pelvic pain syndrome, formally known as pelvic pain syndrome

Gastrointestinal

Gynaecological

Axis II system Urological

Axis III End-organ as pain syndrome as identified from Hx, Ex and Ix Prostate Bladder Scrotal Testicular Epididymal Penile Urethral Post-vasectomy Vulvar Vestibular Clitoral Endometriosis associated CPPPS with cyclical exacerbations Dysmenorrhoea Irritable bowel Chronic anal Intermittent chronic anal Axis IV referral characteristics Suprapubic Inguinal Urethral Penile/ Clitoral Perineal Rectal Back Buttocks Thighs

Table 1 European Association of Urology classification of chronic urogenital pain syndromes Axis V temporal characteristics Onset Acute Chronic Ongoing Sporadic Cyclical Continuous Time Filling Emptying Immediate post Late post Trigger Provoked Spontaneous

Axis VI character Aching Burning Stabbing Electric

Catastrophic thinking about Pain Depression Attributed to pain or impact of pain Attributed to other causes

Dysfunctional flow Urgency Incontinence Gynaecological Menstrual Menopause Gastrointestinal Constipation Diarrhoea Bloatedness Urgency Incontinence Neurological Dysaesthesia

Unattributed PTSD Symptoms Reexperiencing Avoidance

Axis VIII psychological symptoms Anxiety About pain or putative cause of pain

Axis VII associated symptoms Urological Frequency Nocturia Hesitancy

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Dyspareunia Pelvic pain with sexual dysfunction Any pelvic organ Pelvic floor muscle Abdominal muscle Spinal Coccyx

Pudendal pain syndrome

Reprinted with permission Fall et al. (2009) Hx history, Ex examination, Ix investigation, ESSIC European Society for the Study of IC/PBS, PTSD post-traumatic stress disorder

Psychological Musculoskeletal

Peripheral nerves Sexological

Fasciculation Cutaneous Trophic changes Sensory changes

Hyperaesthesia Allodynia Hyperalgesia Sexuological Satisfaction Female dyspareunia Sexual avoidance Erectile dysfunction Medication Muscle Function impairment

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Pain Physiology: Basic Concepts Pain as a symptom has two components. The first is concrete and has its basis within the anatomy of the nervous system. The second, more amorphous and incompletely defined, involves inflammatory protein peptides and neurotransmitters that modify the perception of pain. The peripheral nervous system contains fibers and receptors. The peripheral nerve fibers include three main types: large-diameter fibers known as A-beta (Aβ) fibers, small-diameter myelinated A-delta (Aδ) fibers, and unmyelinated axons (C) fibers. Although the Aβ fibers are the largest fibers in the peripheral nervous system, it is the small-diameter myelinated A-delta (Aδ) fibers and the unmyelinated axons (C) fibers which contribute the most to the detection and relay of pain signals from the pelvis to the central sensory cortex. Additionally, these two fibers innervate skin, deep somatic structures, and visceral structures. In addition to the fibers which transmit pain signals, pain activation begins with the pain receptors. Pain receptors are distinguished by specific trigger elements: chemoreceptors (receptors activated by an organic molecule) vs photoreceptors (receptors activated by photons of light) vs. mechanoreceptors (receptors activated by pressure changes) vs. thermoreceptors (receptors activated by changes in temperature). Primary afferent pain receptors specifically associated with the Aδ and C fibers transmit information related to mechanical, thermal, and chemical stimuli to the central nervous system. Also known as nociceptors, the primary afferent pain receptors signal their trigger information to the central nervous system through the dorsal root ganglion in the spinal cord and then onto the brain. Beyond the anatomy of the peripheral nervous system lie the inflammatory peptides, neurotransmitters, and (particularly in women) hormones that modulate the triggers and signaling found at the level of the primary sensory afferents and nociceptors.

These modulators can lead to variable expressions of pain, intensity, and symptom complaints. These variations in expression fall under the phenomena of sensitization, convergence, and modulation.

Sensitization Sensitization is a neuro-learning process where repeated stimuli result in a progressive amplification of a response. Enhancing the signal transmission of the peripheral nerves are the inflammatory markers produced during tissue injury including bradykinin, prostaglandins, and leukotrienes. The threshold for activating the afferent nociceptors is lessened and the frequency of firing is increased when intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissue. This may result in innocuous stimuli becoming noxious (Fields and Martin 2001). Sensitization can be triggered in an autocrine fashion via the pain receptor itself. Once triggered, pain receptors produce inflammatory factors which can then alter the original response and perpetuate it. Sensitization contributes to tenderness, soreness, and hyperalgesia. Any repetitive occurrence of tissue injury can further shape the response of pain receptors causing a new response not previously associated with such stimulation. This evolutionary neuronal response often leads to persistent stimulation of an “older” receptor despite a new stimuli source (Jones 2001). Primary afferent nociceptors may also activate an autocrine response through the production of substance P, a neuropeptide unique to neuronal tissue. Substance P impacts the transmission of pain signals by increasing vasodilation, degranulation of mast cells, release of leukocytes, and even production of inflammatory markers. This multimodal process increases sensitivity of pain signaling and interpretation and may contribute to evolving pain complaints and triggers.

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Convergence There are several theories describing the mechanisms behind referred pain. Convergence is where multiple primary afferent axons connect with multiple different central spinal neurons (the dorsal root ganglion) that in turn may also contact multiple different afferent axons. This “mixing” of transmitters and receptors within the nervous system leads to the phenomenon known as referred pain. The most common example of referred pain is the irritation of the diaphragm being perceived as shoulder pain. While each dorsal root ganglion is associated with a dermatomal section for skin innervation, it also receives signals from internal organs and/or deeper musculoskeletal structures. While sensitization can modulate an individual’s response to an activated pain receptor, convergence can obscure the origin of the pain receptor.

Convergence and sensitization within the pelvis have also been referred to as “neuronal cross talk,” where the activation of the neuronal system by one organ system within the pelvis alters the threshold as well as response of another organ system (Pezzone et al. 2005). Both the overlapping nature of the autonomic sacral plexus and the inflammatory markers of the paracrine system function to produce a “neuronal cross talk” within the pelvis. These cross talk elements effectively become both modulators and unique triggers of all primary afferent pain receptors within the pelvis.

Modulation Pain modulation is an increase or decrease in the sensation of pain due to outside stimuli. The “gate control” theory postulates that nonpainful input “closes the gates” to painful stimuli, thus blocking pain sensation from reaching the CNS. The “gate control” theory or the “gate theory” has led to development of transcutaneous electrical nerve stimulation (TENS) for pain relief.

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An observed example attributed to gate control theory is the well-known phenomena called “stress-induced analgesia” linked to situations on the battlefield or arena where wounded soldiers or injured athletes report that they feel no pain. Pain information heading to the CNS may be modulated by ascending and descending inhibitory systems through endogenous opioids, endogenous serotonin, spinal cord inhibition, peripheral nerve stimulation, or exogenous analgesics. Each patient has a complex response to pain stimuli that varies greatly from subject to subject. This perceived pain sensation is often heavily influenced by the emotional state.

Nonperipheral neural pathways that often modulate chronic pelvic pain are those associated with mood and emotion. Mood and emotions can strongly influence how pain is perceived. Multiple studies performed in the arena of psychiatry demonstrate how mood and emotions impact pain perceptions. In healthy volunteers, positive patient affects were associated with reduced pain, while negative moods were associated with amplification of pain sensations (Meagher et al. 2001). Psychiatric disorders have a good correlation with increased pain symptoms with depression occurring as a comorbidity about 30–40% of the time (Holdcroft and Jaggar 2005).

The exact molecular mechanisms in which psychiatric disorders modulate pain perception have yet to be delineated. However, evidence indicates that psychological variables such as expectation and anticipation influence “pain-modulating circuits” between the brain and pain transmission pathways. One such “pain-modulating circuit” links the hypothalamus, midbrain, and medulla with the spinothalamic and spinoreticulothalamic pathways (Jones 2001). In this circuit, the opioid receptors are responsible for both inhibiting pain responses as well as enhancing pain responses. This is possibly one of many contributors to the phenomenon of opioid-induced hyperalgesia (Jones 2001).

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Neuropathic Pain and Nociceptors Neuropathic pain is a result of damage anywhere along the peripheral nervous system, spinal, or supraspinal nervous system. Central neuropathic pain results from a lesion or disease in the central nervous system. Peripheral neuropathic pain results from lesion or disease in the peripheral nervous system. Neuropathic pain is often very difficult to manage because of the heterogeneity of its etiology, underlying mechanisms, and symptoms. Direct damage to the somatosensory nervous system may result in a type of pain called neuropathic pain. Neuropathic pain may include dysesthesia (abnormal sensations) or allodynia (normally nonpainful stimuli). Common qualities of neuropathic pain include burning or coldness, “pins and needles” sensations, tingling, numbness, and itching. In addition to nerve damage, however, these sensations can also be triggered by strong nociceptive stimulation (Berkley 2005). Nociceptors are the nerve endings found in high numbers in the skin and internal surfaces such as the periosteum, joint surfaces, and visceral organs. Damaging mechanical, thermal, and chemical stimuli trigger the firing of these receptors. The differentiation between the two sources of neuropathic pain (direct nerve damage or activation of nociceptors) currently requires direct testing of nerve conduction of the specific nerve in question. This becomes difficult when the specific nerve in question lies with a visceral organ and as is often the case, within the pelvis. Assessing neuropathic pain relies upon detailed, careful descriptions of pain complaints. Clinicians may find available pain scales useful. The Leeds assessment of neuropathic symptoms and signs scale (LANSS) may assist with teasing out the elements of history that increase the likelihood that true tissue damage has occurred. However, a clear separation of the overlap between the effects of persistently stimulated nociceptors versus true neuronal damage continues to be difficult.

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Understanding Pain Physiology: Summary Overall, understanding how sensitization, convergence, modulation, and neuropathic pain influence pain acuity and chronicity plays a vital role in guiding clinical evaluation. Accurate and detailed descriptions of pain symptoms, intensity, duration, site, modulating factors, type of pain, and response to medication coupled with a documentation of the changes in these parameters over time provide an optimal basis for accurate evaluation. Normal changes in the brain throughout a person’s life (process of sensitization and neuroplasticity) may cause confusing and changing patterns of complaints.

Pelvic Pain Management Other factors can be layered on top of the neuronal responses as discussed above. Like the overlapping neuronal pain responses, the female pelvic anatomy and hormonal cycling enhance the complexity of CPP etiologies and pain management options. Neuronal activation, pelvic anatomic structure, and hormonal contributions are important factors to consider as one works through the different axis of pain categorizations. Complaints of pain within the female pelvic region are common. The prevalence of chronic pelvic pain worldwide has been estimated to be about 16–82% for dysmenorrhea, 8–21% for dyspareunia, and 2–24% for noncyclical pain (Latthe et al. 2006). The wide range in prevalence speaks to the difficulties related to inconsistent diagnostic criteria as well as the underlying complexities affecting pain symptoms (Berkley 2005; Winnard et al. 2006). Within the anatomic pelvis, pain stimuli may arise from any of the following: the bony pelvis, the musculature of pelvic floor and/or abdominal wall, vasculature, nerves, reproductive organs, bowel, ureter, and bladder (see Fig. 2). In addition to each individual organ is the influence that one organ can have on another organ in the same region.

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Fig. 2 Female pelvis with relation of major organs. (Gray’s anatomy. 1918, www.bartleby.com/107/, plate 829) Rat models have demonstrated both mechanical as well as chemical “sensitization” of the urinary tract in response to colonic irritation. The frequency of bladder contractions increased while the threshold of firing decreased when exposed to inflammatory markers (Ustinova et al. 2006).

Studies highlight how pain perceptions may inaccurately point to the true physiologic process that is occurring at the visceral level. In other words, disease within one pelvic organ system may be the source of afferent nociception in a separate pelvic organ, thus the pain perceived may not reflect the origin of stimuli.

Reproductive Hormonal Effects on Pain Female patients have an added modulator of pain: the influence and fluctuation of reproductive hormones. Dr. Berkley and her team demonstrated in a rat model that the spread of inflammatory markers to the colon, uterus, bladder fluctuated with the cycling of progesterone (Winnard et al. 2006). Particularly, they demonstrated that cross-organ interaction increased during the proestrus stage (presence of progesterone), lending evidence to the difference between pain descriptions of women and of men – particularly the cyclic nature of pain.

Integrating an understanding of fluctuating inflammatory markers secondary to reproductive hormones into the concept of “neuronal cross

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talk” adds insight to the confusing and often changing pattern of chronic pelvic pain in reproductive women. This mix of neuronal cross talk and reproductive hormones suggest a possible link between pain symptoms over the course of a menstrual cycle. Correlating pain symptoms with menstrual cycling can offer additional options related to hormonal modulation for pain management. Establishing the status of patients as premenarchal, perimenarchal, reproductive age ovulatory, reproductive age nonovulatory, perimenopausal, and postmenopausal may add to the development of a specialized CPP management plan for patients in different reproductive states. As patients progress through these stages, their pain will likely change and require different treatment plans. The ability to communicate such factors to patients may assist with pain management compliance and expectations.

Pelvic Pain Story: The Initial Visit and Continued Care Many patients with pelvic pain have been seen multiple times by health-care providers (frequently different providers) and tell stories of multiple diagnosis and associated treatment failures. They bring with them not only their physiologic pain symptoms but also the emotional complexity related to cycles of hope and disappointment from previous evaluations. Thus, a primary key in caring for patients with pelvic pain is a tripod of patience, communication, and expectation management beginning with the first visit. The initial trust and cooperation established with the patient at the first visit becomes the cornerstone for all subsequent interactions and patient compliance. After this point, the ability to negotiate a new patient alliance during the process of investigation and therapeutic trials will be limited. The complex combination of the neuronal response, pelvic anatomy, and female hormonal status does not lend itself to quick and clear diagnoses within a few visits. Rather these complexities require the clinician and patient to commit to a long-term cooperative relationship. Recognizing

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the long-term nature of CPP acts as a reminder for both clinicians and patients that symptoms may wax and wane over a reproductive life course and thus a “cure” may be an unrealistic goal. Chronic pelvic pain should be considered another chronic morbidity like hypertension or diabetes and thus requires continued management.

Chronic Pelvic Pain: Initial Visit This view of chronic pelvic pain established at the initial visit not only manages expectations of patients but also physicians, thus allowing for cycles of treatment success and failure to contribute to the process of refining individual treatment/ management plans. Given the dual complaint of physiologic pain and a psychiatric primed pain, the goal of the first interview should be to first understand the contributing physiologic factors as well as the psychologic factors before determining the needed diagnostic exams or therapeutic interventions. Frequently the best care models for these patients are ones which approach the management of pelvic pain from a team perspective. Depending upon the resources available to a clinic, the medical team should not only include the primary physician and nurse evaluating the patient but also extend to other physician specialists, physical therapists, and mental health support (Chaitow and Jones 2012). Novel models may even extend the mental health support team to include social service support depending upon the nonmedical needs of the patient. Of primary importance to the clinician is an understanding of the “story” each patient with pelvic pain tells, particularly at the first visit. In no other diagnostic process (with possibly the exception of a psychiatric history) is the history intake so vitally essential and pivotal.

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During the initial visit, the history of present illness (HPI) should have sections of focus. • The classical description of the nature of the pain, noting emotional response, and specific details concerning the “seven attributes of a symptom” (below): – It is particularly helpful to note the emotional response of the patient as they describe each component in detail. The emotional response becomes an indicator as to the severity of each symptom and the overall impact on a patient’s lifestyle. • The time course or evolution of the pain, impact of specific events, aging, menopause, and pregnancy. • The history of the different diagnoses and effectiveness of prior treatments. • Specific medical problems that may modulate pain responses include diabetes, rheumatologic diseases, inflammatory diseases, or prior surgeries. – Reviewing medication history is also important and may add information such as highlighting pain modulation and behavior related to current or past medications. • A thorough gynecologic history including the last menstrual period, menarche, dysmenorrhea (now and in past), number of pregnancies, types of deliveries or terminations, delivery complications, regularity of cycle length, bleeding duration, flow of bleeding, prior sexual infection exposure and treatment courses, and current and/or past contraceptive usage. – A review of pap smear screening, while it usually does not add insight into the patient’s pain history, it may provide further information of the patient’s awareness of their own health status and needs. • It is worthwhile to spend some time understanding the patient’s psychiatric history particularly given the emotional component of pain. The classical process of investigating the “seven attributes of a symptom” has no greater relevance than with pain. Detailing

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the location, quality, severity, timing, remitting/exacerbating factors, associated manifestations, and environmental influences of the patient’s pain complaints is critical (Bickley and Szilagyi 2012).

After a complete history, a careful physical and pelvic exam is done. 1. Go slow. This cannot be stressed enough. Much of the “pain” reaction of patients during this exam is provoked by clinicians who perform this exam without much warning and with extreme rapidity or roughness. 2. Limit the amount of palpation to directive, purposeful movements. (a) Directive palpation of the external genitalia, vaginal entrance (hymenal ring), vaginal walls (anterior, posterior, and lateral), levator ani muscles, cervix, uterus, and adnexa may help to identify a precise area of provocation. Usage of a single digit or q-tip may help to further elicit a precise pain response and thus a specific diagnosis. (b) Bimanual assessment should focus on assessment of size, mobility, position, and tenderness within the pelvic cavity. Cervical motion tenderness should also be noted. Ovarian assessment` is primarily focused upon the presence or absence of fullness from a mass, coupled with assessing pain or tenderness. (c) When indicated: A rectovaginal assessment` allows for assessment of abnormal tissue growth (whether a mass or disease invasion), mobility of organs in contrast to bony pelvis, tenderness, and cul-de-sac disease. 3. Speculum assessment requires the proper size speculum (a) Both metal and plastic speculums have several large speculum designs which have a wider nose and thus more useful in parous women.

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(b) Both metal and plastic speculums have small Peterson’s design that have a narrow nose and are often useful in nulliparous patients or those with narrow or tight introituses.

Laboratory and Radiologic Studies Frequently blood work will include a complete blood count and a comprehensive metabolic panel. Additional laboratories may include inflammatory markers, sedimentation rate, or (hs)CRP or Ca-125 (occasionally useful when endometriosis is suspected). Rheumatologic disease screening is particularly good in patients with systemic pain complaints. In most cases evaluation of pelvic pain is done with a pelvic ultrasound. A pelvic ultrasound may confirm findings of enlarged pelvic organs or other masses found or not found on physical exam. An MRI or CT scan in the setting of chronic pelvic pain can assist with diagnosis and surgical planning.

Chronic Pelvic Pain: Notes on Specific Assessment, Management, and Treatment of Various Causes • Endometriosis: Risk factors for endometriosis include heavy monthly menstrual flow, menstrual outflow obstruction, and family history. Common symptoms include cyclic pelvic, lower back or rectal pain, severe menstrual cramps, deep dysmenorrhea, painful bowel movement, and primary infertility. The Ca-125 is often elevated. Pelvic ultrasound or MRI may show an endometrioma if present but will not show endometrial implants. – Laparoscopic confirmation of endometriosis is rarely recommended as the first-line treatments are Mirena IUD, progestin dominant oral contraceptive pills, and cyclic NSADs. Second-line treatments include gonadotropin agonists and contraceptive implants.

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• Dyspareunia on entry and/or deep penetration can be due to vulvovaginitis, STDs, herpetic lesion, injury to vulva or vagina, atrophic vaginitis, vaginal inlet obstruction, vaginismus, lichens sclerosis, or vulvodynia (chronic pain affecting the vulva). – Dyspareunia on deep penetration may be caused by uterine fibroid or mass, pelvic endometriosis, ovarian cyst, ectopic pregnancy, tubal disease, or pelvic adhesions. Evaluation of vulva or vaginal discharge, redness, injury, lesion, pregnancy test, ultrasound findings, and menopausal status along with detailed description of the complaint generally leads to the correct treatment option. • Systemic complaints, complaints present across multiple organ systems, require a thorough investigation of diseases which present in a systemic fashion (i.e., rheumatologic pathologies and immunologic pathologies). Treatments only targeting pain may palliate pain but does not often treat systemic disease problems. • Musculoskeletal complaints of the pelvic floor (ranging from spasms of vulvovaginal area to dyspareunia to incontinence) require a systematic and detailed physical exam. Through the combination of a thorough history and precise pelvic exam one can often consult with a physical therapist with a specialty in pelvic floor function to develop a treatment plan. – Surgical corrections are available in some instances. Use of NSAIDs can also be effective. • Myofascial trigger points have been associated with increased sensitization and crossactivation of other pain syndromes within the pelvis – particularly those related to urinary complaints, sexual dysfunction, and vulvovaginal pain (Chaitow 2007). Deactivation of these sites often decreases the pain perceived from the above-related sites. – Manual deactivation lies within the realm of the rehabilitation therapist; however, clinicians may also rely upon trigger point injections at sites of extreme tenderness.

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• Bulk symptoms (ranging from pressure to increasing abdominal girth) should also include a thorough investigation of associated gastrointestinal complaints, radiologic investigations, as well as consideration of a risk profile for carcinoma. Ultimately, treatment may involve surgical excision and a referral to a gynecologic surgeon. • Perimenopausal complaints require an understanding of the perimenopausal period. Perimenopause is defined as the 4–5 years before the onset of menopause punctuated by symptoms of hormonal fluctuations: irregular cycles, hot flashes, vaginal dryness, dyspareunia, headaches, as well as mood and sleep disturbances. As previously mentioned, the process of sensitization is modulated by the cyclic nature of estrogen and progesterone, thus any changes to this cycling may modify pain sensation. Low-dose hormonal replacement has efficacy for these symptoms, particularly mood. • Mental health and mood disorders can modify the perception of the severity of a patient’s disease. Descriptions of pain symptoms which appear out of proportion of believed triggers or persistent pain that does not fit a generalizable physiologic pattern may trigger closer inquiries into the state of the patient’s mental health. Having a therapeutic team available to assess these patients not only provides comprehensive care for difficult diagnoses but also assists in managing efficiencies within the medical system. • Neuropathic pain may not be easily diagnosed as true neuronal damage or persistent stimulation of the neuronal tissue. Modulation of neuronal tissue, however, can be done through the usage of both tricyclic antidepressants and neuromodulators such as gabapentin. Usage may not elicit the true pathophysiology and a thorough work up of the pain should be pursued. Consultations with physical therapy and neurology may enhance the therapeutic process. • All facets of the inflammatory processes can be nociceptive triggers. It is often difficult in isolating the original source of the inflammation. In some cases, NSAIDs or antibiotics are effective.

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– Given the potential severity of pelvic inflammatory disease it is always reasonable to treat for suspected PID, but close follow-up should be practiced. Persistence of pain may require further investigation into the proper diagnosis.

Dyspareunia The diagnosis of “dyspareunia” is complex and controversial. The World Health Organization in 2006 estimated that about 8–22% of sexually active females report painful intercourse and with 26% of them attributing their sexual difficulties to dyspareunia (Meana and Binik 2011). The variable reported prevalence of dyspareunia may arise from differing definitions used to define dyspareunia. In addition, characteristics of patients with complaints such as age, educational level, socioeconomic standing, and comorbid conditions, particularly urinary complaints, contribute to a diverse interpretation of causes of dyspareunia (Palacios et al. 2009). Estimates of dyspareunia prevalence increase when the study population is composed of a “high-risk” population such as chronic pelvic pain patients or patients with reported female sexual dysfunction. Traditionally, dyspareunia has been considered a part of the spectrum of female sexual dysfunction and described as pain with intercourse. The DSM IV defines dyspareunia as recurrent or persistent genital pain associated with sexual intercourse which causes personal distress (Mimoun and Wylie 2009). However, in analyzing the diverse symptom presentation associated with dyspareunia, Binik suggests that rather than a diagnostic category related to sexual dysfunction, dyspareunia should lie on the spectrum of genitopelvic pain syndromes (Binik 2010). • In 2015, the Consensus Vulvar Pain Terminology Committee (representing ISSVD, ISSWSH, IPPS, NVA, ASCCP, ACOG, and expert opinions) issued new nomenclature for persistent vulvar pain and vulvodynia based upon the increased scientific evidence from the

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beginning of the twenty-first century. While dyspareunia is not addressed specifically, the terminology and classification specifications demonstrate the multifactorial aspect of genitopelvic pain syndrome related to the anatomic area of the vulva and vagina, thus giving structure to etiologic investigations. With a better understanding of contributing etiologic factors, genito-pelvic pain syndromes previously treated in a haphazard manner have guidance related to possible specific interventions (Table 2).

Table 2 2003 ISSVD Terminology and Classification of Vulvar Pain guidance taken from ‘2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Vulvar pain caused by a specific disorder

Infectious (e.g., recurrent candidiasis and herpes)

Inflammatory (e.g., lichen sclerosus, lichen planus, and immunobullous disorders) Neoplastic (e.g., Paget disease and squamous cell carcinoma) Neurologic (e.g., postherpetic neuralgia, nerve compression, injury, and neuroma) Trauma (e.g., female genital cutting and obstetrical) Iatrogenic (e.g., postoperative, chemotherapy, and radiation) Hormonal deficiencies (e.g., genitourinary syndrome of menopause (vulvovaginal atrophy) and lactational amenorrhea)

Vulvodynia – vulvar pain of at least 3 months duration, without clear identifiable cause, which may have potential associated factors Localized (e.g., vestibulodynia and clitorodynia) or Generalized or Mixed (localized and generalized) Provoked (e.g., insertional and contact) or Spontaneous or Mixed (provoked and spontaneous) Onset (primary or secondary) Temporal pattern (intermittent, persistent, constant, immediate, and delayed)

The descriptors identify four areas: (1) the area affected, (2) provocateurs of pain, (3) associated onset factors, and (4) temporal pain patterns, to assist with not only etiologic understanding but also therapeutic targeting. Within the context of the 2015 consensus terminology for persistent vulvar pain and vulvodynia, one begins to understand the limitations of dyspareunia in its historical application. Rather than mere association with an activity, dyspareunia can be associated with specific disease disorders and/or descriptors which can assist with therapeutic recommendations and symptom management. While scientific investigations have added to the etiologic understanding associated with dyspareunia, other factors such as culture, personal morality/ethics, and societal norms/perceptions may influence, or worse inhibit, the patient or physician engagement required for investigations and serial therapeutic trials. Thus, in addition to the history and exam structure addressed previously, targeting areas of cultural, societal, and individual factors may have a large impact upon the patient/physician relationship and subsequent therapeutic outcome than previously acknowledged.

Dyspareunia and Sexual Physiology Following the updated genito-pelvic pain classification above, dyspareunia associated only with sexual activity not associated with a specific pain disorder requires contextualization within the different sexual stages. • The original work by Masters and Johnson described sexual physiology as a linear series of stimulation leading to ➔ excitement to ➔ plateau to ➔ orgasm and ending with resolution. – Kaplan relabeled and simplified this process into four sexual stages: desire, arousal, orgasm, and resolution. – Work from Basson in 2002 identified two aspects to sexual stimulation: a subconscious neurophysiologic response versus a cognitive registration of contextual cues (Basson 2002).

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• Current considerations now recognize that the female sexual physiology is cyclic in nature and does not always require an arousal stage (Steege and Zolnoun 2009). Basson explicitly identifies different psychosocial aspects and influences of emotional intimacy upon female sexual physiology (Basson 2002). Frequently, pain directly associated with a specific stage of the sexual physiology has limited treatment options other than to prevent entrance into that specific stage, thus treatment solely based upon the sexual stages may have limitations. Pain associated with the psychosocial component of sexual physiology alters the focus of management and therapeutics from a genito-pelvic arena to a psychiatric/behavioral approach. The diagnostic criteria of sexual dysfunction used by the DSM IV-TR is divided into multiple categories including sexual desire disorders, sexual arousal disorders, and orgasmic pain disorders. Specifically, DSM IV-TR divides sexual pain disorders into two types as seen below. When the suspected etiology of dyspareunia appears to arise from the psychosocial component of the sexual physiology, coordination with psychiatry may be required (Table 3). One common patient characteristic impacting sexual physiology in female patients is menopause. SWAN (Study of Women’s Health Across the Nation), the largest and most diverse crosssectional studies on menopausal women in the USA, describes six variables related to sexual outcomes in menopausal women (Avis and Green 2011): the importance of sex, sexual desire, frequency of activities and physical pleasure (both intercourse and masturbation), emotional Table 3 DSM IV-TR: sexual pain disorders Dyspareunia Recurrent or persistent genital pain associated with sexual intercourse causing marked distress of interpersonal difficulty

Vaginismus Recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal intercourse causing marked distress or interpersonal difficulty

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satisfaction with partner, arousal, and pain. Here again, aspects of neurophysiologic sexual response are countered with psychosocial contextual cues requiring recognition of the dual etiologic source of sexual disorders: physiology and psychosocial association. Addressing only the physiologic changes associated with menopause may be insufficient treatment if psychosocial changes associated with menopause are not also addressed. A discussion between clinician and patient regarding the level of distress is important. A conversation defining the goals of sexual function may have more impact than anticipated within the context of managing dyspareunia.

Given the variation in psychosocial etiologies of sexual disorders, specifically, only a weak association exists between individuals with sexually associated PTSD and dyspareunia (Steege and Zolnoun 2009); providers may search for contributions from neurophysiologic sexual reflexes. Current understanding has defined roles for both sex hormones and neurotransmitters within the stages of sexual desire/excitement and sexual arousal (Fig. 3). While specific female hormone–receptor combinations and cellular cascades have not been fully delineated, all the sexual hormones (testosterone, estrogen, and progesterone) play a part in increasing sexual desire and maintaining organs during arousal (Fig. 4). How each hormone interacts with the other and in which manner they interact continues to be an area of ongoing study. While no direct association has been made between changing levels of estrogen and decreasing sexual outcomes, there does appear to be an association between increasing vaginal dryness (known to be associated with decreased estrogen levels) and increasing complaints of dyspareunia. Dyspareunia can occur during the early stages of the perimenopausal period or late stages. Studies do show effectiveness of vaginal or systemic estrogen replacement with decreasing complaints of dyspareunia.

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Fig. 3 Central effects on sexual function. + indicates a positive effect; indicates a negative effect. (Reprinted with permission Clayton and Hamilton 2010)

Fig. 4 Peripheral effects on sexual function. + indicates a positive effect; indicates a negative effect. (Reprinted with permission Clayton and Hamilton 2010)

Other hormonal mechanism of action upon sexual physiology has yet to be fully delineated in human studies, but equivalent animal studies describe their anticipated role. Specifically, these studies demonstrate a role for dopamine in the stimulation of sexual desire, arousal, and drive (Hull et al. 1993). Norepinephrine is known to play a role in arousal while oxytocin is known to play a role in orgasms.

Management of Dyspareunia The fuller picture of dyspareunia can be described as a sexual pain syndrome which has components

within human physiology, neurophysiology, and psychosocial influences(See Fig. 5). Dyspareunia Complaint Triage A simplified complaint triage is often a good place to start when interviewing patients complaining of dyspareunia. The complaint triage includes deep (penetration), mid-vaginal, and superficial (entry) dyspareunia This designation is often a good place to begin when interviewing patients. Often deep dyspareunia is associated with pathology deeper within the vaginal canal, cervix, and pelvic cavity. Superficial dyspareunia is associated more with the external genitalia and vaginal entrance (hymen). (Meana and Binik 2011). Recent

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Fig. 5 Components within a sexual pain syndrome

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neuro-physiology (related to both pain physiology and hormonal influences)

systemic physiology

psychosocial influences

(related to vulvar pain caused by a specific disorder)

(related to both psychiatric and behavioral disorders)

Dyspareunia

dyspareunia reviews using a designation of deep versus superficial dyspareunia have developed a table of diagnosis, complaints, examination findings, testing options, and therapy (Hill and Taylor 2021) (Table 4). Dyspareunia Exam While the factors related to superficial dyspareunia tend to be more consistent in their presentation, the exam associated with delineating between deep and superficial is more detailed and extensive than a routine pelvic exam. • Examining these patients requires a preexam suspicion leading to a detailed exam of the external genitalia occasionally utilizing a Q-tip or finger for localization of pain responses along individual portions of the external genitalia. The portions of the external genitalia examined include mons pubis, labia majora, labia minora, clitoral hood, urethra, skene’s glands, hymen, Bartholin’s glands, introitus, and vulva. Special attention should be given to the specific areas of complaint by the patient. – Evidence of infection, lesions, erythema, swelling, color changes, and differential texture should also be noted. – During this pelvic exam, attention should be paid to any area of chronic skin changes or abnormal growths within the vagina or cervix

which necessitates a biopsy for complete assessment. • As the exam progresses to the speculum insertion, attention should be paid to the presence of normal vaginal mucosa, rugae, moisture, redness, pail color, discharge, lesions, strictures, and pain with speculum advancement. • Usage of a single digit at the beginning of the bimanual portion of the pelvic exam is recommended. – The bimanual exam includes a directive palpation of the vaginal canal along the anterior, lateral, and posterior walls in a sequential manner. Attention should also be placed upon the pelvic floor muscles and their associated tenderness or retraction during palpation. – Palpation of the cervix should be done in a manner to isolate the cervix from the vaginal walls thus decreasing any confounding response from vaginal tenderness. – Assessment of the uterus and adnexa should proceed noting any masses and/or tenderness. Attention is paid to abdominal findings of guarding or distention. Often the smallest Peterson billed speculum is better tolerated than a typical Graves speculum. One should not shy from frequent exams as they may be necessary to

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Table 4 Causes of dyspareunia (reprinted with permission from the American Academy of Family Physicians) Entry or Diagnosis deep Vulva and vagina Dermatologic Entry diseases (e.g., lichen sclerosus, lichen planus, contact dermatitis) Inadequate Both lubrication

Historical clues

Examination Findings

Additional testing

Treatment options

Burning, dryness, pruritus

Visible skin changes (dependent on condition)

Biopsy may be necessary to confirm diagnosis

Usually topical steroids; depends on diagnosis

Dryness; history of diabetes mellitus; history of chemotherapy or use of progestogens, aromatase inhibitors, tamoxifen, or gonadotropinreleasing hormone agonists Difficulty evacuating stool or emptying bladder; aching after intercourse: pain in lower back, thighs, or groin

Vulva may be normal or appear dry

Usually unnecessary

Discontinuation of causative medication if possible; use of vaginal moisturizers or lubricants

Painful vaginal muscles just inside of the hymen during single-digit examination

Usually unnecessary

Tissue may appear pale and dry (although may appear normal in early menopause) Involuntary contraction of pelvic floor muscles with attempted insertion of finger or small speculum

Usually unnecessary

Pelvic floor physical therapy, gabapentin (Neurontin), trigger point injections with local anesthetics or obabotulinumtoxinA {Botox), neuromodulation Vaginal moisturizers or lubricants, topical estrogen, ospemifene (Osphena), prasterone (Intrarosa) Multidisciplinary approach includes cognitive behavior therapy, psychotherapy, relationship and sexual counseling, lubricants, sequential vaginal dilators, and onabotulinurntoxinA injection

Pelvic floor dysfunction

Both

Vaginal atrophy

Both

Burning, dryness

Vaginismus

Entry

Vaginitis

Both

Difficulty achieving penetration; possible history of anxiety, sexual abuse or trauma, or other causes of painful penetration; sometimes no prior risk factors are present Discharge, burning, or odor

Vaginal discharge

Identify psychosocial factors, such as sexual abuse or anxiety

pH testing, microscopy, polymerase chain reaction swab as indicated

Antibiotic or antifungal therapy according to diagnosis (continued)

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Table 4 (continued)

Diagnosis Vulvodynia

Bladder Interstitial cystitis

Entry or deep Entry

Deep

Pelvis Adhesions or chronic pelvic inflammatory disease

Endometriosis

Examination Findings Vulva may be visually normal or may have focal areas of erythema around the vestibule and hymen that are painful, as elicited by a cotton swab

Additional testing Assess for comorbidities, such as depression, anxiety, a history of childhood sexual or physical abuse, fibromyalgia, irritable bowel syndrome. Interstitial cystitis, musculoskeletal disorders, or pelvic floor muscle dysfunction; as Indicated, rule out other etiologies (e.g., testing for vaginitis)

Treatment options Patient education about vulvar hygiene and using cotton underwear and pads, 2% lidocaine jelly or ointment applied by cotton ball placed on vulva at bedtime, amitriptyline, oral or compounded vaginal gabapentin, compounded vaginal muscle relaxants, estrogen, selective serotonin or norepinephrine reuptake Inhibitors, pelvic floor physical therapy, cognitive behavior therapy, amitriptyline, surgical excision

Urinary urgency, frequency, and nocturia

Pain with palpation of bladder base

Interstitial cystitis questionnaire; bladder instillation; cystoscopy

Dietary modification, antispasmodics; cimetidine (Tagamet); amitriptyline

Lateralized pain with intercourse

Pain with adnexal palpation

Transvaginal ultrasonography

Deep

Pain may be related to sexual position; may be associated with endometriosis

Retroverted uterus, may be painful when moved cephalad

Usually unnecessary; transvaginal ultrasonography helpful to rule out myomas

Observation or laparoscopy as indicated Modify sexual positions; vaginal pessary; hysterectomy

Deep

May have lateralized, sharp pain; history of pelvic inflammatory disease or pelvic surgery Family history; dysmenorrhea common

Possible fixation of pelvic organs on bimanual examination

Pelvic imaging to rule out other diagnoses

Nonopioid analgesics; laparoscopic adhesiolysis

Generalized pelvic tenderness; nodularity may be noted in cul-de-sac during rectovaginal examination

Generally unnecessary; laparoscopy if diagnosis uncertain or patient desires

Nonopioid analgesics, combined oral contraceptives, progestogens, levonorgestrelreleasing intrauterine system (Mirena), elagolix (Orilissa), laparoscopic excision

Uterus and adnexa Ovarian Deep masses Uterine retroversion

Historical clues Chronic burning, tearing, aching, or stabbing vulvar pain of at least three months’ duration

Deep

Information from references 1,2, and 10-19.

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narrow down the differential as complaints persist or alter.

Lastly, the role of pelvic floor physical therapy cannot be diminished in addressing complaints related to dyspareunia. The last 10 years has demonstrated a growth and maturation of pelvic floor physical therapy in addressing both primary muscular disorders and gynecologic muscular disorders (Steege and Zolnoun 2009). Given the tactile and immediate feedback nature of pelvic floor physical therapy, therapeutic targets may expand beyond the physical physiologic causes of genitopelvic pain syndromes to triggers rooted in psychosocial behavioral responses.

Cultures for sexually transmitted infections or wet mount can be performed to help differentiate possible infectious contributors to the complaints of dyspareunia. Vaginal smears can be used to assess for atrophy. Other laboratory investigations vary based on suspected systemic disease (such as diabetes). Radiologic investigations starting with pelvic ultrasound may be useful to confirm physical exam findings during the bimanual exam but are not mandatory in the process of evaluating dyspareunia.

Endometriosis

Dyspareunia Treatment Treatment should be targeted at the specific diagnoses including infection, neoplasm, or atrophy. Table 5 lists the therapeutic options for the listed conditions contributing to complaints of superficial dyspareunia. Conditions and therapeutic options associated with deep dyspareunia are shown in (Table 6).

The incidence of endometriosis in premenopausal patients with chronic pelvic pain (CPP) symptoms ranges from 35–50%, while the overall incidence in all women is about 10% (Burney and Giudice 2012). Conversely, the two most common complaints associated with endometriosis in premenopausal reproductive-aged women are pelvic pain and infertility. It is suggested that about

Table 5 Therapeutic options for the listed conditions contributing to complaints of superficial dyspareunia Conditions associated with superficial dyspareunia Vestibulodynia

Cyclical vulvovaginitis Sexually transmitted infections Vulvar dermatoses Congenital anomalies Obstetrical sequelae (i.e., episiotomy scars) Vulvovaginal atrophy Neurologic disorders Muscular abnormalities (i.e., pelvic floor hyper- or hypotonicity Neoplastic vulvar lesions Urologic disorders Bowel disorders

Therapeutic options Lidocaine gel prior to intercourse, capsaicin cream, anti-tricyclics (either oral or vaginal), and severe symptoms may benefit from trigger point injections, as a last resort – surgery may be indicated Suppression of cause of vulvovaginitis if infective versus steroidal creams for systemic inflammatory complaints Appropriate antibiotic/parasitic treatment Therapy should target pathology results Depending upon diagnosis: surgical intervention, vaginal dilators, hormonal therapy, etc. Vaginal dilators versus surgical intervention Vaginal estradiol preparations versus Premarin ®, systemic hormone replacement Consultation with neurologist for systemic manifestations is recommended Vaginal dilators, muscle relaxants via a vaginal route, relaxation techniques, pelvic floor physiotherapy, and antidepressants versus antipsychotics Treatment according to pathologic diagnosis Kegels, pelvic floor physiotherapy, and vaginal estrogen may consider comanagement with a urogynecologist depending on the diagnosis Treatment for constipation and consideration of comanagement with a gastroenterologist depending upon diagnosis

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Table 6 Treatment options for deep dyspareunia complaints Conditionsa associated with deep dyspareunia Lack of arousal necessary for vaginal lengthening

Chronic cervicitis Repeated cervical trauma Pelvic endometriosis

Pelvic adhesions (secondary to infection or surgery) Uterine fibroids

Pelvic inflammatory disease

Pelvic congestion Pelvic organ prolapse

Urologic disorders (i.e., painful bladder syndromes)

Bowel disorders (i.e., IBS)

a

Therapeutic options Counseling, selfexperimentation with arousal techniques, vaginal dilators, and vibrators Treatment as dictated by the CDC Surgical options for excision Hormonal suppression (oral vs. injection) and surgical excision Appropriate treatment if infective and surgical excision Medical therapy to decrease size, surgical excision, and ultrasonic options in certain institutions Treatment as dictated by the CDC, interventional drainage if abscess is present, and surgical excision Hormonal suppression and surgical excision Kegels, pessary, and surgical excision with repair Kegels, targeted medical therapy depending upon diagnosis, pelvic physiotherapy, and surgical interventions per urogynecologic recommendations Treatment targeting constipation and consultation of a gasteroenterologist

Inconsistently associated with deep dyspareunia

20–50% of patients with infertility have endometriosis and that about 30–50% of patients with endometriosis have infertility (The Practice Committee of the American Society for Reproductive Medicine 2006). In comparison to fertile women, infertile women have up to a six- to eightfold increased risk for endometriosis. Given the variable pain presentation of patients with

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endometriosis, an additional complaint of infertility should trigger considerations of endometriosis.. Despite the high incidence of endometriosis among symptomatic patients in their reproductive life, an average 6.7 years still often pass before a diagnosis of endometriosis is determined (Nnoaham et al. 2011). Such a discrepancy between incidence and rate of diagnosis suggests that endometriosis has a diverse presentation with CPP and infertility as common but not necessarily dominant features.

Pathophysiology Burney et al. give a thorough and well-written summary on “Pathogenesis and Pathophysiology of Endometriosis” from Fertility and Sterility Vol 98. No3. September 2012. They define endometriosis as “an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility” with multiple theories related to the “origin and molecular basis” of its disease process. Taken from their article, Fig. 6 demonstrates most of the current theories on the pathogenesis of endometriosis, the most well known being Sampson’s theory of retrograde menstruation. Support for this theory lies not only in laparoscopic studies of healthy women with patent fallopian tubes identifying retrograde menstruation in 90% of these patients, but also from observed correlations between women with Mullerian malformations and the increased prevalence of endometriosis among them. • Obstructive outflow pathology of mullerian malformations leads to “back flow” of endometrial tissue through the fallopian tubes into the intraabdominal peritoneal cavity. Additional theories find support in observed genetic susceptibilities, endocrine responses, immune system activation, epigenetic modifications, and emybrologic origins of endometriosis (Signorile and Baldi 2010). Proliferation of endometrial cells in the peritoneal tissues is not only an activation of

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Fig. 6 Theories regarding endometriosis pathogenesis. (Reprinted with permission Burney and Giudice 2012)

inflammatory markers but also a change in both the nature of the endometrial cells and the surrounding peritoneal cells. These inflammatory changes correlate with various implants and peritoneal scar tissue seen during surgical visualizations during laparoscopy. These lesions are often described by their coloring – black, red, white, or by the presence of adhesive tissue between pelvic organs. CPP associated with endometriosis most likely arises from a combination of activated inflammatory markers, change in the peritoneal environment, and scar tissue formation. Endometriosis targets all the modulators of neuroreceptor control: inflammatory provocation, threshold changes, and scar tissue–related nerve growth. Infertility in patients with endometriosis is thought to be due to several factors with the two most prominent related to tubal scarring and blockage leading to the interrupted passage of a mature ovum and unfavorable hormonal/inflammatory environment for either fertilization or implantation. • De Ziegler et al. break up the pathophysiology of infertility secondary to endometriosis into three categories (Fig. 7): pelvic fluid within the pelvic cavity, ovarian function at the level of

the ovary, and the endometrium (De Ziegler et al. 2010). Activation of inflammatory markers leads to a change in the peritoneal fluid which baths the reproductive organs. • The most favorable location of fertilization is the ampullary region of the fallopian tube, an area that is open to the exposure of free peritoneal fluid. Here a change in the peritoneal environment may impact the ability for fertilization to occur. • Altered ovarian function specific to endometriosis patients has yet to have an explanation or description of a specific pathologic process, but scientists have reported that endometriosis increased production of estradiol through prostaglandins as well as an abnormal response to progesterone. These same changes in estradiol/ progesterone production and reception may lead to impacts at the level of the endometrium. Endometriosis often has a misalignment between disease severity and symptom complaint. A disease state found in an individual may be replicated in another individual, but it may not confer the same or even similar symptoms. Efforts to create a staging system for endometriosis like a cancer staging system to unify the pathophysiology

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Fig. 7 Effects of endometriosis on human reproduction. (Reprinted with permission De Ziegler et al. 2010). ART: assisted reproductive technologies

and clinical presentation struggle with these differences. Although the American Society of Reproductive Medicine (ASRM) has the longest standing staging system for endometriosis, its limitations lie exactly within the divergence of disease stage and symptom presentation (Pearce et al. 2012). In addition, unlike staging systems for cancer, there is a lack of prognostic value associated with the ASRM staging for endometriosis. The primary benefit to the ASRM system has been within the realm of research and repeat surgical assessments. In 2010, Adamson and Pasta introduced a validated revision of the ASRM endometriosis staging system that is designed to correlate with non-in vitro fertility treatment outcomes and give clinicians an opportunity to

counsel patients on possible anticipated outcomes (Adamson and Pasta 2010). They describe a scoring system where an endometriosis fertility index, using history, surgical findings, and functional assessment of tubes and ovaries, is calculated. This index is then used to correlate with non-in vitro fertility treatment outcomes (Fig. 8).

Management of Endometriosis: Pelvic Pain The two complaints associated with endometriosis, pelvic pain and infertility, usually require a different approach during the initial patient interview and assessment. To begin, it may be more

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ENDOMETRIOSIS FERTILITY INDEX (EFI) SURGERY FORM LEAST FUNCTION (LF) SCORE AT CONCLUSION OF SURGERY Score

Left

Description

4 3

= =

Normal Mild Dysfunction

Fallopian Tube

2

=

Moderate Dysfunction

Fimbria

1 0

= =

Severe Dysfunction Absent or Nonfunctional

Ovary

To calculate the LF score, add together the lowest score for the left side and the lowest score for the right side. If an ovary is absent on one side, the LF score is obtained by doubling the lowest score on the side with the ovary.

Right

Lowest Score

+ Left

= Right

LF Score

ENDOMETRIOSIS FERTILITY INDEX (EFI) Historical Factors Factor Description Age

If age is ≤ 35 years If age is 36 to 39 years If age is ≥ 40 years

Surgical Factors Points

Factor Description

Points

LF Score 2 1 0

If LF Score = 7 to 8 (high score) If LF Score = 4 to 6 (moderate score) If LF Score = 1 to 3 (low score)

3 2 0

Years Infertile If years infertile is ≤ 3 If years infertile is > 3

2 0

AFS Endometriosis Score If AFS Endometriosis Lesion Score is < 16 If AFS Endometriosis Lesion Score is ≥ 16

1 0

Prior Pregnancy If there is a history of a prior pregnancy If there is no history of prior pregnancy Total Historical Factors

1 0

AFS Total Score If AFS total Score is < 71 If AFS total Score is ≥ 71 Total Surgical Factors

1 0

+

EFI = TOTAL HISTORICAL FACTORS + TOTAL SURGICAL FACTORS:

Historical

= Surgical

EFI Score

Fig. 8 Endometriosis fertility index surgery form. (Reprinted with permission Adamson and Pasta 2010)

approachable to start with those patients who have complaints of pain and then move to those who present with infertility. While the emotional carriage that accompany both complaints may be similar, the details of history and eventual investigations will vary based upon the patient’s primary complaint and goals. The defining pain description of endometriosis is cyclic pelvic pain with dysmenorrhea. Dysmenorrhea is pain associated with menses and can be separated into two categories: primary versus secondary. Primary dysmenorrhea occurs in about 40% of menstruating teenagers and is not consistently related to endometriosis. The pathophysiology linked to primary dysmenorrhea focuses on the prostaglandin pathway stimulated by the

shedding of the endometrial lining rather than the implantation of ectopic endometrial tissue. The cyclic pelvic pain most consistently correlated with endometriosis falls into the category of secondary dysmenorrhea, implying that there was a period in which the patient had menses without significant pain. This detail becomes essential in differentiating between treatment options and diagnostic options from an empiric approach. • Traditionally it is thought that pain associated with endometriosis occurs a day or two prior to the start of menstruation; however, it is not consistently demonstrative of endometriosis (highlighting the variation between pathology and clinical manifestation).

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• Other descriptions of pain associated with a disease process suggestive of endometriosis are pain with defecation, particularly if it worsens during menses. • The pain of dysmenorrhea worsens during menses, the most symptomatic time of endometriotic implants. • Some endometriosis can present with variable or constant, noncyclic, generalized, or localized pelvic pain. Since endometriotic tissue responds to hormonal changes, hormonal modulation is the primary medical therapy. Progestin IUDs or progestin-dominant OCPs are the primary firstline medical agents used to suppress pain symptoms. Gonadotropin agonists or antagonists, NSAIDs, progestin-only pills, Depo-Provera, contraceptive implants, and surgical resection are also options (Table 7). Other medical options have demonstrated potential in managing endometriosis through other molecular pathways: aromatase inhibitors (decreasing conversion of sex steroids to estrogen), immunomodulators and anti-inflammatory drugs (decreasing immune response and cytokine stimulation of pain pathways),

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antiangiogenic therapies (blocking vascular endothelial growth factor in order to limit the invasive growth of ectopic endometrial tissue), and selective progesterone receptor modulators (blocking the effect of progesterone, primarily, and estrogen, secondarily, on reproductive tissue). All these options while available are generally considered after standard hormonal modulatory therapy has been exhausted. While it has a high success rate in relieving pain complaints, surgically induced menopause is associated with often severe medical problems and difficult to treat hypoestrogenic symptoms. Immediate postoperative problems include menopausal symptoms, mood disorders, bladder problems, vaginal atrophy, and sexual problems. Serious long-term problems particularly in premenopausal women after removal of ovaries include higher rates of cardiovascular disease, osteoporotic fractures, muscle loss, CNS diseases, and death rates. Some individuals who have undergone radical therapy may still have microscopic disease that is symptomatic requiring continued medical therapy. Thus, extensive surgical counseling is required to match patient expectation to unpredictable and adverse surgical outcomes.

Table 7 Review of standard medical therapeutic recommendations, their benefits, and common concerns (Vercellini et al. 2011) Medical therapy options Combined oral contraceptives

Levonorgestrel-releasing intrauterine devices Progesterone-only oral therapy (i.e., norethindrone acetate) Progesterone-based intramuscular injections GnRH analogues Danazol

Benefits Ease of prescribing, prevalent, effective in both cyclic and continuous fashion, and diversity of hormonal combination to assist with side effect control One-time administration, long duration of effectiveness may induce amenorrheic state Ease of prescribing, minimal interaction with other medications, and minimal estrogenic side effects

Limitations/Concerns Cannot be used when estrogen is contraindicated

Three-month administration, very effective suppressor of endometrial gland proliferation

Office-based administration required, bone density changes occur during therapy Prominent hypoestrogenic side effects Prominent androgenic side-effects: Acne, hirsutism, etc.

Three-month administration, very effective suppressor of endometrial gland proliferation Very effective suppressor of endometrial gland proliferation

Requires trained personal to place implant within body Daily dosing required

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Management of Endometriosis: Infertility When investigating complaints of infertility, a review of definitions is beneficial. Infertility in patients less than 35 years of age is a period of greater than 12 months of regular timed intercourse without contraception that is not marked by pregnancy (note that it is merely pregnancy and not delivery that drives this definition). While a patient who is 35 years of age or greater may be considered to have issues of infertility if that period is greater than only 6 months. The urgency of investigation and exploration of patients presenting with infertility complaints increases as they age (refer to the chapter on infertility for details). The physical examination in a patient with a suspicion for endometriosis does not vary greatly from the physical exam of a patient with general complaints of chronic pelvic pain. On the bimanual assessment, attention should be paid to areas of pain or tenderness as well as the mobility of the uterus in comparison to the anterior abdominal wall, adnexas, and rectum. Rectovaginal assessment may add information related to obliteration of the posterior cul-de-sac and/or dissection of the endopelvic fascia between the rectum and vagina.

Endometriosis Laboratory and Diagnostic Studies • Thus far serum markers for endometriosis have been more experimental rather than practical (Burney and Giudice 2012). Clinically, the most common serum marker has been CA 125 in the setting of an endometrioma (endometriotic mass of the ovary). As often noted in the literature specific to CA 125, this is a serum marker which is nonspecific and thus frequently elevated in cases of endometriosis in general. There may be a role for following CA 125 serially (as with the cases of concurrent ovarian malignancies [Pearce et al. 2012] and also possibly for disease monitoring and response to therapy [Mol et al. 1998]).

J. H. Chen

Ultrasonography has had more clinical impact than the investigations into serum markers. General pelvic assessment with ultrasound for ovarian masses, endometriomas, has become undisputed in the initial investigation and assessment of patients for which suspicion for endometriosis is high. Clinicians who specialize in endometriosis often recommend transvaginal ultrasonography to assess for invasive endometriotic lesions on the bladder and bowel allowing for a noninvasive manner of confirming a diagnosis of severe endometriotic disease as well as monitoring disease progression (Young 2014). • CT or MRI may be useful to assess local tissue invasion but are not necessary for the initial assessment of endometriosis.

Endometriosis Treatment Medical therapy primarily utilizes the pathophysiologic understanding that endometriosis is a disease that responds to hormonal fluctuations. Thus if the cyclic nature of estrogen and progesterone can be controlled, it is assumed that the disease progression and impact of endometriosis can also be controlled. (Standard medical therapeutic recommendations, their benefits, and common concerns are reviewed in Table 5.) However, controlling the cycling of estrogen and progesterone directly conflicts with any treatment related to complaints of infertility, thus medical therapy may not be the first therapeutic option should infertility be the primary concern. Surgical intervention for moderate to severe endometriosis may improve fertility rates although advances in advanced fertility are generally first line for these patients. With the advancement of minimally invasive techniques (laparoscopic and robotic) and instruments, the ability to offer fertility preserving surgery to all symptomatic patients has increased and become the standard. In approaching patients with suspected endometriosis complaining of infertility, surgical options may allow for symptom relief/control along while allowing patients to seek fertility. However, such surgical intervention

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Management of Pelvic Pain, Dyspareunia, and Endometriosis

should be undertaken soberly given the invasive nature of the endometriotic pathology. Removal of uterus with ovaries and tubes is associated with severe medical complications and symptoms and is not generally a standard option.

Reassessment Chronic pelvic pain patients require close monitoring during early treatment and any period of uncertainty. While the frequency of close monitoring may differ depending upon overall assessment and treatment plan, a monthly follow-up for the first couple of months adds an early reassessment of treatment effectiveness and importantly adds to patient rapport and trust. At the point in the therapeutic process that the patient’s pain symptoms have improved or are resolved, lengthening of the interval of followup is appropriate. However, if the patient’s symptoms continue, worsen, or change in nature, a reassessment process mirroring the initial visit inquiry should be utilized and follow-up shortened and maintained appropriately.

Conclusion The changing course of terminology and understanding of pain physiology has allowed for improved clinical assessment and therapeutic targets. Matching clinical findings with a detailed history, directed physical and pelvic exam, appropriate laboratory, or radiologic assessment are supported by consistent application of precise terminology and physiology. Such a transition in describing and diagnosing pelvic pain allows for systematic and algorithmic approaches to CPP treatment.

References Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2010;94(5):1609–15. Avis NE, Green R. The perimenopause and sexual functioning. Obstet Gynecol Clin N Am. 2011;38(3): 587–94.

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Baranowski AP. Chronic pelvic pain. Best Pract Res Clin Gastroenterol. 2009;23(4):593–610. Basson R. A model of Women’s sexual arousal. J Sex Marital Ther. 2002;28:1–10. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272–80. Bickley L, Szilagyi PG. Bates’ guide to physical examination and history-taking. Philadelphia: Lippincott Williams & Wilkins; 2012. Binik YM. The DSM diagnostic criteria for dyspareunia. Arch Sex Behav. 2010;39:292–303. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9. Chaitow L. Chronic pelvic pain: pelvic floor problems, sacro-iliac dysfunction and the trigger point connection. J Bodyw Mov Ther. 2007;11(4):327–39. Chaitow L, Jones R. Chronic pelvic pain and dysfunction: practical physical medicine. London: Elsevier Health Sciences; 2012. Clayton AH, Hamilton DV. Female sexual dysfunction. Psychiatr Clin N Am. 2010;33(2):323–38. De Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–8. Fall M, Baranowski AP, Elneil S, Engeler D, Hughes J, Messelink EJ, Oberpenning F, de Williams AC. EAU guidelines on chronic pelvic pain. Eur Urol. 2009; https://doi.org/10.1016/j.eururo.2009.08.020. Fields HL, Martin JB. Pain: pathophysiology and management. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 15th ed. New York: McGrawHill Medical Publishing Division; 2001. Hill DA, Taylor CA. Dyspareunia in women. Am Fam Physician. 2021;103(10):597–604. Holdcroft A, Jaggar S, editors. Core topics in pain. Cambridge, UK: Cambridge University Press; 2005. Hull EM, Eaton RC, Moses J, Lorrain D. Copulation increases dopamine activity in the medial preoptic area of male rats. Life Sci. 1993;52(11):935–40. Jones JB. Pathophysiology of acute pain: implications for clinical management. Emerg Med. 2001;13(3):288–92. Latthe P, Latthe M, Say L, Gülmezoglu M, Khan KS. WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health. 2006;6(1):177. Meagher MW, Arnau RC, Rhudy JL. Pain and emotion: effects of affective picture modulation. Psychosom Med. 2001;63(1):79–90. Meana M, Binik YM. Dyspareunia: causes and treatments (including provoked vestibulodynia). In: Chronic pelvic pain. Oxford: Blackwell; 2011. p. 125–136. Mimoun S, Wylie K. Female sexual dysfunctions: definitions and classification. Maturitas. 2009;63(2):116–8. Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, van der Veen F, Bossuyt PM. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril. 1998;70(6):1101–8.

484 Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco NF, de Cicco NC, Jenkinson C, Kennedy SH, Zondervan KT, Study WE. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2): 366–73. Palacios S, Castaño R, Grazziotin A. Epidemiology of female sexual dysfunction. Maturitas. 2009;63(2): 119–23. Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, Nagle CM, Doherty JA, Cushing-Haugen KL, Wicklund KG, Chang-Claude J. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies. Lancet Oncol. 2012;13(4):385–94. Pezzone MA, Liang R, Fraser MO. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005;128(7):1953–64. Signorile PG, Baldi A. Endometriosis: new concepts in the pathogenesis. Int J Biochem Cell Biol. 2010;42(6): 778–80. Steege JF, Zolnoun DA. Evaluation and treatment of dyspareunia. Obstet Gynecol. 2009;115(5):1124–36.

J. H. Chen The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril. 2006;86(supplement 4):S156–60. Ustinova EE, Fraser MO, Pezzone MA. Colonic irritation in the rat sensitizes urinary bladder afferents to mechanical and chemical stimuli: an afferent origin of pelvic organ cross-sensitization. Am J Physiol Ren Physiol. 2006;290(6):F1478–87. Vercellini P, Eskenazi B, Consonni D, Somigliana E, Parazzini F, Abbiati A, Fedele L. Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Hum Reprod Update. 2011;17(2): 159–70. Winnard KP, Dmitrieva N, Berkley KJ. Cross-organ interactions between reproductive, gastrointestinal, and urinary tracts: modulation by estrous stage and involvement of the hypogastric nerve. Am J Phys Regul Integr Comp Phys. 2006;291(6):R1592–601. Young SW. Imaging as the gold standard for diagnosis of endometriosis: TVUS techniques for deep endometriosis. 43rd AAGL Global Congress on Minimally Invasive Gynecology; 2014 Nov 17–21; ENDO-604: 12–36.

Management of Benign Breast Disease

33

Heather R. Macdonald

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 Clinical Breast Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 Palpable Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 Breast Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Nipple Discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 Mastitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

Abstract

The purpose of identifying and treating benign breast disease is twofold: to identify underlying breast cancer or exclude its presence and treat symptoms. The most common breast complaints are breast masses, breast pain, nipple discharge, and breast infections. A palpable breast mass should be evaluated by the triad of clinical breast exam (CBE), imaging (ultrasound in all patients with the addition of mammogram in patients over 30), and biopsy. Mastalgia is the most common breast complaint. A thorough evaluation should be performed to exclude malignancy.

H. R. Macdonald (*) Hoag Hospital, Orange County, CA, USA Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_79

Nipple discharge may be physiologic, especially if bilateral, and involves multiple ducts, seen only with expression and clear, green, or black. Medications, especially centrally acting or psychotropic drugs, and nipple stimulation are potential causes of nonpathologic discharge. Nipple discharge that is spontaneous, unilateral, single duct, clear or bloody, or associated with a palpable mass is especially concerning for underlying malignancy. Mastitis is a common occurrence even in nonlactating women. Inflammatory cancer must be ruled out, especially in an inflammation not responding to antibiotics and supportive measures. Lactating women with a breast infection must drain the breast regularly to prevent milk stasis that encourages bacterial growth. Antibiotic therapy should be guided by what is safe for the nursing infant. Skin flora is the most common pathogen. Referral for specialty services should be 485

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provided to patients with atypical biopsies, discordant biopsies, breast cancer, biopsy findings that require excision, nonhealing abscesses, and hereditary breast and ovarian cancer syndromes. Keywords

Clinical breast exam · Breast mass · Fibroadenoma · Mastalgia · Nipple discharge · Mastitis · Galactorrhea

Introduction The purpose of identifying and treating benign breast disease is twofold: to identify underlying breast cancer or exclude its presence and treat symptoms. Breast complaints are common in gynecologic practice, and benign breast conditions are within the scope of practice of a general ob-gyn. Referral for specialty services should be provided to patients with atypical biopsies, discordant biopsies, breast cancer, biopsy findings that require excision, nonhealing abscesses, and hereditary breast and ovarian cancer syndromes. Elsewhere in this book, breast cancer screening in the asymptomatic woman is described. This chapter focuses on the evaluation and treatment of the symptomatic patient. Focus will be on the most common breast complaints: breast masses, breast pain, nipple discharge, and breast infections. Table 1 lists conditions for which specialty care is required, and the patient should be referred.

Clinical Breast Exam Clinical breast exam (CBE) should be part of a well woman health evaluation when indicated by medical history or patient symptoms, per the Table 1 Indications for referral to a breast specialist Indications for referral to a breast specialist Atypical breast biopsy Malignancy Histologic findings on biopsy that require excision Nonhealing breast abscess or inflammation Familial breast cancer syndromes Discordant breast biopsy results

H. R. Macdonald

American College of Obstetricians and Gynecologists (ACOG Committee Opinion 755). The clinical breast exam should encompass all breast tissue from the clavicles to the inframammary folds and from the midaxillary lines to the sternal borders. Axillary and supraclavicular lymph nodes should be included in the field of examination. On clinical breast exam, dominant masses should be described by size, position on the clockface (with the nipple at the center, 12 o’clock superior, 6 o’clock inferior, etc.), and distance from the nipple (e.g., 2 cm mass at 4:00 3 cm from the nipple). The mobility of the lesion or lack thereof should be described as well as any overlying skin changes. The presence or absence of lymphadenopathy in the axillary or supraclavicular beds should be noted. Findings on clinical breast exam concerning for malignancy include tethering to the skin or underlying muscle, relative immobility of the mass, irregular or indistinct borders of a dominant mass, the presence of a mass with single duct bloody nipple discharge, overlying skin changes including erythema or induration, and the presence of axillary or supraclavicular adenopathy.

Palpable Mass A palpable mass is a three-dimensional finding distinct from the surrounding breast tissue and is a common breast complaint. When a patient presents with suspicions of a palpable mass, she should be asked to describe when and how it was first discovered, how long it has been present, if it is still palpable, does it change with her menstrual cycle, has she appreciated it before (i.e., does it come and go), is it painful, are there skin changes or nipple discharge, and has she had a breast mass previously in either breast. Masses that wax and wane with menstrual cycles are consistent with fibrocystic changes and are rarely pathologic. History of a previous breast cyst or fibroadenoma may be informative as patients may develop additional lesions. Alternatively, a palpable mass in conjunction with bloody nipple discharge is highly concerning for carcinoma. Overlying skin changes indicate an inflammatory process but can also be concerning for inflammatory carcinoma.

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Management of Benign Breast Disease

Table 2 describes what should be documented when examination reveals a mass distinct from the surrounding breast tissue. A palpable breast mass should be evaluated by the triad of clinical breast exam (CBE), imaging (ultrasound in all patients with the addition of mammogram in patients over 30), and biopsy. Between 9% and 22% of palpable breast cancers are not apparent on breast imaging (Morrow 2000). In young patients with a benign clinical breast exam and benign appearing imaging (BIRADS 2), tissue sampling may be omitted, but as breast carcinoma or cancerous lesions metastasizing to the breast (lymphoma, sarcoma) can present in teenaged patients, careful consideration should be given to securing a definitive diagnosis of any dominant mass with tissue sampling. Tissue sampling should be accomplished with a needle wherever possible (Silverstein et al. 2009). Surgical excision of a previously unsampled breast mass should be rare. The majority of lesions will be benign and not need excision. The uncommon malignant lesion will not be completely treated by simple excision (if breast cancer) or may not be treated surgically at all (if lymphoma or metastatic sarcoma). A concordant diagnostic triad of benign CBE, benign imaging, and benign biopsy carries a false-negative rate (or the chance that an underlying cancer may be missed) of less than 1% (Ariqa et al. 2002). Concordance of all three elements of the diagnostic triad is key. Any discordance between the clinical exam, imaging

Table 2 Pertinent findings when documenting a breast mass Pertinent findings when documenting a breast mass Laterality Location expressed as clockface position and distance from the nipple Size Associated skin changes (edema, erythema, and retraction) Fixation Texture (smooth, lobulated) Tenderness Presence or absence of axillary or supraclavicular lymphadenopathy

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impression, and biopsy results should trigger a second biopsy or surgical excision. Management of the lesion is guided by the biopsy results. Asymptomatic benign masses less than 3 cm in size can be followed with serial ultrasounds to demonstrate stability every 6 months for 2 years. Any patient who is bothered by the sensation or presence of a mass should be offered excision. Surgical excision should be considered for lesions larger than 5 cm due to sampling concerns as breast lesions can be heterogeneous. Additionally, larger lesions can be cosmetically destructive even if benign and are better excised before they require more extensive dissection if not reconstructive surgery. If atypia is identified within any lesion, surgical excision is warranted for definitive diagnosis and cancer risk reduction. Table 3 summarizes benign breast histology by risk of breast cancer as well as treatment considerations. Not all lesions listed will present as a palpable mass. For example, radial scar is most often identified by stereotactic core biopsy after a mammographic finding. However they are including Table 3 as a reference for interpreting breast biopsy results. Table 4 includes benign causes of palpable breast abnormalities and recommendations for management. Common benign causes of palpable breast masses include simple cysts and fibroadenomas. Cysts appear as empty black circles on ultrasound as cyst fluid allows free passage of ultrasound waves without reverberating back to the transducer. They often grow suddenly and are painful at first detection. They may be symptomatic with menses. They may be aspirated to alleviate tenderness. Cyst fluid should only be sent for cytology only if it is frankly bloody, as analysis of cyst aspirate has not been shown to be sensitive or specific for malignancy (Ciatto et al. 1987). Green, black, dark brown, yellow, and clear fluid may be discarded. After cyst aspiration if any mass remains, it should be biopsied to avoid missing the solid component of a complex cyst. Cysts should only be surgically excised if they recur after multiple aspirations. Fibroadenomas are the most common solid benign mass, occurring in up to 25% of asymptomatic patients (El-Wakeel and Umpleby 2003).

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Table 3 Breast histology stratified by risk of breast cancer Breast histology DCIS, LCIS Proliferative lesions with atypia Atypical ductal hyperplasia Atypical lobular hyperplasia

Lifetime risk of breast cancer 30–50% Intermediate risk 15–30% 15-30%

Proliferative lesions without atypia

Low risk

Fibroadenoma Moderate/florid ductal hyperplasia of the usual type Radial scar/complex sclerosing lesiona Papillomaa Papillomatosis Sclerosing adenosis Flat epithelial atypia Nonproliferative lesions (cysts) Duct ectasia Papillary apocrine changes Nonsclerosing adenosis Periductal fibrosis Mild epithelial hyperplasia of the usual type Lipoma

30 cm/kg, a bimanual exam to assess uterine size has been shown to correlate well with the actual pathologic size and weight of the uterus (Cantuaria et al. 1998). Most clinically significant subserosal and intramural, or FIGO 3–5, fibroids will be detected as bulky, and irregularly shaped on physical examination (ACOG Practice Bulletin 2000). As part of the evaluation, the clinician should assess the location of the top of the fundus. This will help determine the type of skin incision that is used for laparotomy, or whether placement of an umbilical port would be feasible during laparoscopy. It is also important to determine how broad the uterus palpates in relationship to the pelvic sidewall. If the fibroid uterus feels very broad and difficult to elevated off the sidewall, laparoscopic surgery may be more technically difficult. Imaging Imaging should be included as part of the evaluation of uterine fibroids. The most commonly used imaging modalities for fibroids are transvaginal ultrasound, saline-sonohysterography (SSH), and magnetic resonance imaging (MRI). In one study evaluating the preoperative use of transvaginal ultrasound, SSH, hysteroscopy, and MRI in patients who were scheduled to undergo hysterectomy for symptomatic fibroids, MRI was 100% sensitive and 91% specific at detecting submucosal fibroids (Dueholm et al. 2001). Transvaginal ultrasound had 83% sensitivity and 90% specificity, and SSH had 90% sensitivity and 89% specificity. MRI provides the additional benefit of identifying adenomyosis and adenomyomas (Dueholm et al. 2002a, b). Focal areas that appear non-well delineated and that have high or low intensity signals within the myometrium are very characteristic of adenomyosis. Of the above imaging modalities available for evaluation of fibroids, ultrasound continues to be the least expensive and most accessible. Fibroids on ultrasound appear as regularly shaped,

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Management of Fibroids

hypoechoic masses. For uteri 80% in African-American women and almost 70% in white women (Baird et al. 2003). AfricanAmerican women are diagnosed at a younger age compared to Caucasian women, 37.5 years versus 41.6 years. African-American women were also found to have a greater number of leiomyomas, higher incidence of anemia, and more likely to report severe pelvic pain (Kjerulff

et al. 1996b). Other risk factors include increasing parity, early menarche, and use of oral contraceptives before 16 years of age (Stewart 2015; Marshall et al. 1998). Symptomatology varies based on size, number, and location of fibroids. The FIGO classification system is used to describe fibroid location (Fig. 1) (Munro et al. 2011). Uterine myomas can be asymptomatic or present with one or more of the three common manifestations: AUB, pelvic pain and pressure, and reproductive dysfunction. AUB is the most common symptom of fibroids and can cause heavy or prolonged menstrual periods. Of greatest concern, submucosal fibroids (fibroids that protrude into the uterine cavity) commonly cause abnormal bleeding and have been found to be associated with higher risk of anemia (Puri et al. 2014). Submucous fibroids are also strongly linked to infertility and recurrent miscarriages. Patients with fibroids can also complain of dysmenorrhea, dyspareunia, abdominal protrusion,

Coagulopathy

Polyp

Ovulatory dysfunction

Adenomyosis

Submucosal

Leiomyoma

Other

Endometrial Iatrogenic

Malignancy & hyperplasia

Not yet classified

Leiomyoma subclassification system 3

2-5

5

O - Other

4 1

0 6

SM - Submucosal

2 7 Hybrid leiomyomas (impact both endometrium and serosa)

Fig. 1 FIGO leiomyoma subclassification system

0

Pedunculated intracavitary

1

10 cm3. Ultrasound evaluation also has a role outside of diagnostic purposes. Transvaginal ultrasound is recommended for patients who are ready to conceive to monitor ovulatory

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Workup and Management of Polycystic Ovary Syndrome

status (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015a), PCOS is associated with a 2.7-fold increased risk of developing endometrial cancer. Endometrial surveillance by transvaginal ultrasound or endometrial biopsy should be considered based on clinical suspicion. Indications for surveillance include women with PCOS who have thickened endometrium, prolonged amenorrhea, unopposed estrogen exposure, or abnormal uterine bleeding (Barbieri and Ehrmann 2015a; Dumesic and Lobo 2013).

Screening for Comorbidities PCOS is associated with an increased prevalence of a metabolic syndrome, including type 2 diabetes, dyslipidemia, and coronary heart disease, as well as mood disorders and sleep apnea. Screening for the presence of these comorbidities is recommended and can be performed as a part of the initial workup. Evaluation should include a 2 h oral glucose tolerance test and measurement of fasting lipid profile (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015a). Measurement of fasting insulin levels may be considered in women who are young, have signs of severe insulin resistance or hyperandrogenism, or are undergoing ovulation induction (ACOG Practice Bulletin No. 194 2018). A lipid profile may also be obtained, regardless of age, as well as liver function tests in patients with obesity or marked hyperinsulinism (Azziz 2018; ACOG Practice Bulletin No. 194 2018). Lipid abnormalities have been reported in up to 70% of women with PCOS. (Anagnostis et al. 2017; Berdnarska and Siejka 2017). Women with PCOS should continue to be screened periodically for cardiovascular disease risk factors because new development of impaired glucose tolerance approaches 20% per year (ACOG Practice Bulletin No. 194 2018). Mood disorders can be screened for using validated tools such as the PHQ-9 for depression and GAD-7 for anxiety (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015a; Hussain et al. 2015). Women should be asked about excessive daytime sleepiness and

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other signs of sleep apnea, and appropriately referred to a sleep medicine specialist (Barbieri and Ehrmann 2015a).

Clinical Manifestations and Management Menstrual Regulation Up to 95% of women with PCOS experience irregular menses. Amenorrheic women tend to have a more severe overall phenotype, with more profound hyperandrogenism and higher antral follicle counts, compared with oligomenorrheic women or those with regular cycles. Despite these irregularities, spontaneous ovulation may still occur and has been reported in up to 32% of menstrual cycles. Menstrual cycles tend to become more regular later in life as women approach menopause (Fauser et al. 2012). Obesity perpetuates reproductive abnormalities in women with PCOS. Even modest weight reduction with loss of 5–10% of body weight has been shown to lower circulating levels of androgens and can result in spontaneous resumption of menses. In women not desiring pregnancy, combination low-dose hormonal contraceptives are recommended as the first-line treatment to achieve cycle control and offer many benefits, including suppression of pituitary release of LH, suppression of ovarian androgen secretion, and increased circulating SHBG (ACOG Practice Bulletin No. 194 2018; Fauser et al. 2012; Barbieri and Ehrmann 2015b; Mendoza et al. 2014). In patients who are not candidates for estrogen-containing medications, cyclic progestins may be considered. Progestin-only contraceptives and progestincontaining intrauterine devices (IUDs) are associated with high rates of abnormal bleedings and are therefore suboptimal for cycle regulation. Insulin-sensitizing agents such as metformin are an acceptable second-line therapy, restoring ovulatory cycles in 30–50% of patients (Barbieri and Ehrmann 2015b). Given the improvement in ovulation rates, it is important to discuss effective contraceptive options if pregnancy is not desired. Metformin is not currently approved by the US

534

Food and Drug Administration (FDA) for the treatment of PCOS-related menstrual abnormalities, although it appears to be a safe option.

Subfertility Women with PCOS may be subfertile. It is important to optimize the patient’s health prior to conception. Preconception counseling should focus on the importance of weight loss and exercise, smoking cessation, reducing alcohol consumption, and folic acid supplementation (Thessaloniki 2008; Fauser et al. 2012). Modest weight loss of 5–10% of total body weight is associated with improved pregnancy rates (ACOG Practice Bulletin No. 194; Barbieri and Ehrmann 2015b) and even a 5 kg weight gain was associated with a 3% risk of pregnancy loss (Vitek et al. 2020). For many years, the recommended first-line treatment for ovulation induction in PCOS patients was the anti-estrogen clomiphene citrate. However, subsequent randomized controlled trial data and Cochrane systematic review findings show that the aromatase inhibitor letrozole is superior in PCOS patients with increased ovulation rates, clinical pregnancy rates, and live birth rates compared with clomiphene. All ovulation induction agents are associated with increased risks of multiple gestations. Twin rates are similar for letrozole and clomiphene citrate (Legro et al. 2014, Franik et al. 2018). Aromatase inhibitors, such as letrozole, are effective agents for ovulation induction, although their use is off-label and patients should be counseled on this prior to commencing therapy. Letrozole was shown in a randomized controlled trial to be more effective than clomiphene citrate in PCOS patients with a higher live birth rate (27.5% vs. 10.1%) and cumulative ovulation rate (61.7% vs. 48.3%) (Legro et al. 2014). Live birth rates following 6 months of clomiphene therapy range from 20% to 40%, and approximately 50% of patients who ovulate on clomiphene citrate will conceive after 3–5 cycles of treatment (Azziz 2018). Most pregnancies will occur within the first six ovulatory cycles, but there may be some benefit to a longer course.

A. Regens et al.

For patients who fail oral ovulation induction therapy, exogenous low-dose gonadotropins or laparoscopic ovarian surgery may be considered (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015b; Donesky 2015). Insulinsensitizing agents, preferably metformin due to its favorable safety profile, have not been supported as first-line therapy for ovulation induction but can improve ovulation rate when used in conjunction with clomiphene, particularly in obese patients (ACOG Practice Bulletin No. 194 2018; Johnson 2014). Finally, PCOS patients who fail ovulation induction or prefer not to proceed with laparoscopic treatment or gonadotropin treatment can choose to proceed with in vitro fertilization and embryo transfer (Azziz 2018). When women with PCOS do become pregnant, they are at an increased risk for adverse pregnancy outcomes. PCOS is associated with increased rates of gestational diabetes, gestational hypertension, alterations of birth weight, early pregnancy loss, and newborn morbidity and mortality (Fauser et al. 2012; Lentscher et al. 2021).

Hyperandrogenism Hyperandrogenism can manifest as hirsutism, acne, or alopecia. About 70% of women with PCOS experience hirsutism. Acne and alopecia are less prevalent (Fauser et al. 2012). Overall, treatment of hirsutism tends to be palliative rather than curative and there is no agreed-upon first-line treatment. Due to the slow rate at which terminal hair turns over, treatment requires at least 6 months before expecting a response (Fauser et al. 2012). Weight loss decreases hirsutism by decreasing circulating androgen levels (ACOG Practice Bulletin No. 194 2018). Pharmacological treatment of hirsutism is focused on decreasing free testosterone and limiting the activity of androgens in the hair follicles. Oral contraceptive pills increase the levels of sex hormone-binding globulin levels and, therefore, decrease free testosterone. They are often prescribed in combination with an antiandrogen, such as spironolactone, flutamide, or finasteride. Spironolactone is the preferred

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Workup and Management of Polycystic Ovary Syndrome

first-line agent, and, in patients who do not tolerate spironolactone, flutamide might be considered. It is important that antiandrogens are only used with effective contraception due to their potential teratogenic effects. Topical eflornithine hydrochloride can be used to decrease the development of new unwanted facial hair growth. Hair may also be removed physically through electrolysis or laser therapies. For severe acne, isotretinoin may be effective. There is currently no effective treatment for androgenic alopecia (Fauser et al. 2012).

Obesity In the United States, about 60–70% of women with PCOS are obese (Fauser et al. 2012). Diet and lifestyle changes must be emphasized as modest weight loss of as little as 5% of initial weight can improve reproductive and metabolic abnormalities. Although there is no definitive study regarding which type of diet is best for PCOS patients, smaller studies and clinical experience suggest that diets lower in simple carbohydrates and sugars are preferred (Azziz 2018). When these interventions fail, improvement in ovarian function has been seen with the use of pharmacological agents, such as orlistat and sibutramine. Morbidly obese women with PCOS may consider gastric bypass. It is not known whether weight loss is beneficial for normal-weight women with PCOS (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015b).

Metabolic Syndrome As well as a high prevalence of obesity in this population, PCOS patients tend to have upperbody fat distribution with greater abdominal or visceral adiposity. This puts these patients at increased risk for insulin resistance, impaired glucose tolerance, gestational diabetes, and type 2 diabetes (Fauser et al. 2012). Women with PCOS have a two- to fivefold increased risk of diabetes compared with control populations with up to 40% demonstrating glucose intolerance.

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Metabolic syndrome, consisting of hypertension, increased waist circumference, elevated fasting glucose, reduced high-density lipoprotein cholesterol, and elevated triglycerides, is common. One large study found that 33% of PCOS patients have metabolic syndrome (ACOG Practice Bulletin No. 194 2018) and another study demonstrated its incidence to range from 33 to 47%. Metabolic syndrome is further associated with a fivefold higher risk for type 2 diabetes and twofold higher risk for cardiovascular disease (Anagnostis et al. 2018). Diet and lifestyle changes should be implemented first line in women at risk for type 2 diabetes or metabolic syndrome. In women with frank diabetes or in those with impaired glucose tolerance who do not respond adequately to lifestyle modifications, treatment with metformin should be initiated (ACOG Practice Bulletin No. 194 2018; Fauser et al. 2012). Insulinsensitizing agents such as thiazolidinediones and glucagon-like peptide-1 analogs should be used with caution in women of reproductive age (Fauser et al. 2012). These drugs are classified as FDA pregnancy category C, and their use may result in resumption of ovulation, increasing the risk of pregnancy. Women with PCOS are three times more likely to have the classic cardiovascular disease risk markers (impaired glucose tolerance, metabolic syndrome, type 2 diabetes, dyslipidemia) than women without PCOS. This is exaggerated in obese patients. Patients should undergo periodic cardiovascular risk assessment, including measurement of body mass index, psychosocial stress screening, blood pressure, glucose, lipid profile, waist circumference, physical activity, nutrition counseling, and smoking assessment (ACOG Practice Bulletin No. 194 2018; Fauser et al. 2012).

Cancer Risk Women with PCOS may have an increased risk of endometrial, ovarian, and breast cancer, although there are limited data to support these conclusions. Disruption of the normal reproductive physiology increases the risk. The most documented

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association is an increased risk of endometrial cancer, for which there appears to be a two- to sevenfold increased risk in PCOS patients (Fauser et al. 2012; Dumesic and Lobo 2013). Endometrial cancer in this population usually has a good prognosis. At this time, there is no widely accepted modality to screen for endometrial cancer, and the decision to assess should be based on clinical factors. Suspicion should be raised in the setting of abnormal uterine bleeding or endometrial hyperplasia, on imaging and correlated with the patient’s age (Fauser et al. 2012). Endometrial protection can be provided using low-dose combined hormonal contraceptives. Alternative therapies include intermittent or continuous progestin therapy or a progestin-releasing intrauterine device (ACOG Practice Bulletin No. 194 2018; Barbieri and Ehrmann 2015b).

Conclusion PCOS typically presents in adolescence and is characterized by various combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. PCOS affects approximately 6–15% of women of reproductive age in the United States. Populations at increased risk include women with anovulatory cycles, obesity, insulin resistance, diabetes mellitus, premature adrenarche, an affected first-degree relative, and antiepileptic drug use. PCOS arises from both heritable and nonheritable factors. Epigenetic factors such as obesity and insulin resistance have been implicated in the pathogenesis for some patients. The 2012 NIH workshop recommends utilizing the Rotterdam criteria for diagnosis. Diagnosis under these criteria requires the presence of any two of the three PCOS characteristics, hyperandrogenism, oligomenorrhea, or amenorrhea, and polycystic ovaries. Evaluation of the PCOS patients should include careful history and physical exam, documentation of hyperandrogenism, and exclusion of other differential diagnoses. Patients should also be screened for cardiovascular and metabolic sequelae and other

A. Regens et al.

comorbid conditions. Treatment of PCOS is largely symptomatic, but lifestyle changes through diet modification and exercise should take a central role.

References American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Gynecology. ACOG practice bulletin no. 194: polycystic ovary syndrome. Obstet Gynecol. 2018;131(6):e157–71. Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): long-term metabolic consequences. Metabolism. 2018;86:33–43. Azziz R. Epidemiology and pathogenesis of the polycystic ovary syndrome in adults. In: UpToDate, Crowley WF, editors. Waltham: UpToDate; 2015 Accessed 7 Aug 2015. Azziz R. Polycystic ovary syndrome. Obstet Gynecol. 2018;132(2):321–36. Azziz R, Dumesic DA, Goodarzi MO. Polycystic ovary syndrome: an ancient disorder? Fertil Steril. 2011;95 (5):1544–8. Barbieri RL. Steroid hormone metabolism in polycystic ovary syndrome. In: UpToDate, Synder PJ, Crowley WF, editors. Waltham: UpToDate; 2015. Accessed 7 Aug 2015. Barbieri RL, Ehrmann DA. Diagnosis of polycystic ovary syndrome in adults. In: UpToDate, Crowley WF, editors. Waltham: UpToDate; 2015a. Accessed 7 Aug 2015. Barbieri RL, Ehrmann DA. Treatment of polycystic ovary syndrome in adults. In: UpToDate, Crowley WF, editors. Waltham: UpToDate; 2015b. Accessed 7 Aug 2015. Bednarska S, Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: what’s new? Adv Clin Exp Med. 2017;26(2):359–67. Donesky BW. Laparoscopic surgery for ovulation induction in polycystic ovary syndrome. In: UpToDate, Falcone T, editors. Waltham: UpToDate; 2015 Accessed 7 Aug 2015. Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids. 2013;78(8):782–5. Fauser BC, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus workshop group. Fertil Steril. 2012;97(1):28–38.e25. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018;24(5(5)):CD010287. Gnanadass S, Divakar Prabhu Y, Valsala Gopalakrishnan A. Association of metabolic and inflammatory markers with polycystic ovarian syndrome (PCOS): an update. Arch Gynecol Obstet. 2021;303(3):631–43.

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Hussain A, et al. Prevalence of psychiatric disorders in patients with a diagnosis of polycystic ovary syndrome in kashmir. Indian J Psychol Med. 2015;37(1):66–70. Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2(6):56. Johnson TRB, Kaplan LK, Ouyang P, Rizza RA. Evidencebased methodology workshop on polycystic ovary syndrome, Executive summary; 2012 Available at: http:// prevention.nih.gov/workshops/2012/pcos/docs/ FinalReport.pdf. Accessed 7 Aug 2015. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H. NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–29. Lentscher JA, Slocum B, Torrealday S. Polycystic ovarian syndrome and fertility. Clin Obstet Gynecol. 2021;64 (1):65–75.

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Mendoza N, Simoncini T, Genazzani AD. Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies. Gynecol Endocrinol. 2014;30(12):1–11. Rosenfield RL. Definition, clinical features and differential diagnosis of polycystic ovary syndrome in adolescents. In: UpToDate, Middleman AB, Geffner M, editors. Waltham: UpToDate; 2015. Accessed 7 Aug 2015. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89(3):505–22. Vitek W, Sun F, Hoeger KM, Santoro N, Diamond MP, Zhang H, Legro RS, Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network. Short-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction. Fertil Steril. 2020;114(5):1032–9.

Management of Recurrent Pregnancy Loss

37

Sana N. Khan

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 Causes and Management of Recurrent Pregnancy Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . Karyotypic Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Genetic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunologic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polycystic Ovarian Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infectious/Microbial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unexplained . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

540 540 540 541 541 541 542 542 542 543

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

Abstract

Recurrent pregnancy loss (RPL) defined as two pregnancies diagnosed on ultrasound or histopathologic examination or any three consecutive pregnancy losses. Approximately 2% of reproductive aged women experience RPL in contrast to the 15% of women who experience sporadic losses. Etiologies are varied and research continues to further understanding of the unknown. Management of recurrent pregnancy loss depends largely on the etiology, keeping in mind that

S. N. Khan (*) Wayne State University, Detroit, MI, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_39

approximately 50% of cases will be unexplained. Improved outcomes are achieved when this condition is managed by a specialist, who can provide psychological support throughout diagnosis and management. Briefly, when karyotype abnormalities are encountered, the couple will need genetic counseling and may be offered prenatal genetic screening or even assisted reproductive techniques to largely ensure a euploid fetus. Anatomic abnormalities of the uterus are often managed surgically. When antiphospholipid antibody syndrome is encountered, treatment with aspirin and heparin has been shown to improve outcomes. Treatment of overt thyroid disease, diabetes mellitus, or hyperprolactinemia is warranted to normalize 539

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hormone values. Anticoagulation may be warranted for inherited conditions; however testing and treatment of acquired conditions are not advised. Given that a large percentage of cases are unexplained, treatment options for this subset have also been proposed including lifestyle modifications, or as last resort oocyte donation or gestational surrogacy. Keywords

Recurrent pregnancy loss · Recurrent miscarriage · Habitual aborter · Unexplained pregnancy loss · Idiopathic pregnancy loss

Introduction Recurrent pregnancy loss (RPL) can be a challenging and complicated problem, defined as two or more failed clinical pregnancies diagnosed ultrasonographically or histopathologically or any three consecutive pregnancy losses. This problem is encountered by approximately 2% of reproductive aged women, in contrast to 15% of reproductive aged women who experience sporadic miscarriage. RPL is complex because of the fact that an etiology is often not encountered, in approximately 50% of cases, and because of the fact that the problem is psychologically very taxing for couples (Li et al. 2002). RPL, defined as three or more miscarriages, is thought to affect 1% of reproductive aged couples (Stirrat 1990; Salat-Baroux 1988). This condition is further complicated by the lack of randomized clinical data, and most recommendations are based on meta-analysis, observational studies, and expert opinions (Practice Committee of the American Society for Reproductive Medicine 2012). However, patients can be reassured that live birth rates after normal and abnormal diagnostic testing are 71% and 77%, respectively (Harger et al. 1983). It has been reported that patients have improved outcomes when managed by a specialist with experience in the treatment of RPL.

S. N. Khan

Causes and Management of Recurrent Pregnancy Loss Karyotypic Abnormalities When chromosomal abnormalities are discovered in one or both parents, it is essential that comprehensive genetic counseling be offered to the patient. The reasons for this are twofold, one to understand the abnormalities and the rates of abnormal gametes and risk for future loss events as well as to understand the rate of transmission to future generations (Laurino et al. 2005). Unfortunately, when products of conception are evaluated, the majority have sporadic chromosomal abnormalities. Balanced reciprocal translocations in one or both parents make up approximately 2–5% of RPL cases, and genetic counseling is strongly encouraged to identify breakpoints, which can help couples determine their future risks and chances for success. This data, as well as the fact that RPL is approximately six times higher in first cousins, supports the suggestion that RPL may be associated with nonrandom genetic errors (Christiansen et al. 1990). One option for these couples as well as those with RPL is embryo evaluation with preimplantation genetic screening (PGS); however, some couples opt for gamete or embryo donation. This information may be of particular importance considering that fetal chromosomal abnormalities are found in >70% of products of conception in women greater than 35 years of age (Marquard et al. 2010).

Other Genetic Causes A variety of other genetic causes including single or multiple gene defects or polymorphisms have also been associated with RPL. These include methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (Chen et al. 2016). Other etiologies include skewed X chromosome inactivation and Y chromosome microdeletion in the male partner (Agarwal et al. 2015).

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Uterine Abnormalities When uterine abnormalities are encountered, which can include congenital or mullerian abnormalities, adhesive disease, or submucosal myomata, these are surgically resected with improved pregnancy rates (Mollo et al. 2009; Tomazevic et al. 2010). Various techniques have been employed to restore normal anatomy including hysteroscopy, laparoscopic and open depending on the lesion encountered. The use of prophylactic cerclage is controversial in patients receiving uterine reconstruction for a mullerian anomaly.

Immunologic Factors Some preliminary data suggests that in addition to immunologic disease entities, paternal antigens in the embryo may trigger a rejection response. Others postulate that abnormal expressions of normal signaling mediators such as cytokines or integrins may play a role (Saito et al. 2016).

Antiphospholipid Syndrome Testing for antiphospholipid antibody syndrome (APAS) includes laboratory detection of high levels of anticardiolipin, lupus anticoagulant, or anti-β-2 glycoprotein-1 antibodies on two separate occasions in addition to the clinical criteria of vascular thrombosis of a deep vessel or unexplained death of a morphologically normal fetus >10 weeks, or premature delivery 0.85 is congruent with central/truncal obesity and is significantly related to insulin insensitivity (Barbieri 2013). However, although an elevated BMI is not necessarily related to insulin insensitivity, 50% of women with PCOS do have a BMI within the obese range [1, 13]. In the event of moderate to high androgen excess, symptoms of virilization are often present such as severe acne, deepening of the voice, clitoromegaly, frontal balding, and increased muscle mass (Barbieri and Ehrmann 2013a). A pelvic examination should also be conducted to rule out mass lesions indicative of an androgen-secreting tumor (Barbieri and Ehrmann 2013a).

Diagnostic Studies After a thorough history and physical examination has been conducted and hirsutism is clinically evident, finding the source of hirsutism is the next most important step. Serum androgens: Both the ovaries and the zona reticularis portion of the adrenal cortex produce serum androgens that can lead to hirsutism. The ovaries and adrenals both produce testosterone, and the androgen specific to the adrenal glands is dehydroepiandrosterone sulfate (DHEA-S) (Barbieri 2013). • Testosterone (T ): Both unbound (free) and total testosterone. • Total T values above 200 ng/dL or free T values >2.2 pg/mL require further evaluation. Levels above this are suspicious for an androgen-producing ovarian tumor, and a pelvic ultrasound should be performed (Lebovic et al. 2013b). • Percentage of free T of the total T is 3% in normal men, 1% in normal women, and 2% in hirsute women. • Some guidelines recommend a 24-h mean value of T levels as androgen secretion is pulsatile and cannot be appropriately evaluated with a single isolated value. Obtaining an

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isolated total T level can differ by 38% from a 24-h mean value (Lebovic et al. 2013b; Phipps 2001). • Measuring total T by equilibrium dialysis or calculating using total T and sex hormonebinding globulin (SHBG) results has been traditionally used, but measuring total testosterone itself readily identifies patients adequately enough, and traditional methods are not necessarily needed to detect androgen-secreting tumors (Miller et al. 2004). • Most PCOS patients have testosterone concentrations below 200 ng/dL and sometimes in the normal range (19–60 ng/dL). However, a higher androgen level indicates an increased cardiovascular risk even if it does not correlate with the degree of hirsutism (Wild et al. 2010). • Dehydroepiandrosterone sulfate (DHEA-S): An adrenal androgen that, if found >700 mcg/dL, is concerning for an androgenproducing tumor or carcinoma of the adrenal gland. An adrenal CT should be performed with this lab finding (Lebovic et al. 2013b). – These patients typically present with Cushing’s syndrome alone (45%), or a mixed Cushing’s syndrome and virilization (25%), or virilization alone (800 are abnormal. Intermediate results between 200 and 800 ng/dL during the morning follicular phase of the menstrual cycle need further screening. Levels >1500 ng/dL in response to a cosyntropin (ACTH) stimulation test confirm CAH (Barbieri and Ehrmann 2013a). • Dexamethasone 0.5 mg PO every 6 h  2 days can be administered, and DHEA-S and 17-OHP are measured before and after the steroid course. – If levels do not decrease or are unchanged, Cushing’s syndrome is the likely diagnosis.

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– If the levels decrease, the suspected diagnosis is nonclassical congenital adrenal hyperplasia versus PCOS. Decreased overall cortisol is the normal response to a dexamethasone suppression test in a patient without Cushing’s syndrome. • 17-OHP is drawn during the early follicular phase as it is normally elevated in the luteal phase of the menstrual cycle. • Progesterone (P4) can be drawn with 17-OHP to ensure the patient is not in the luteal phase of the menstrual cycle, when 17-OHP is normally elevated. It should be 2:1 None of the above results are necessary for the diagnosis Normal androgen levels 17-OHP: >800 ng/dL or > 1500 after ACTH stimulation test Androstenedione: Increased 17-OHP: >800 ng/dL or > 1500 after ACTH stimulation test Androstenedione: Increased Total T level: >200 ng/dL Ovarian tumor on transvaginal ultrasound DHEA-S: >700 mcg/dL Adrenal tumor on CT abdomen 24-h urine cortisol: 3 x’s upper limit of normal (at least 150 mcg/24 h) Other screening tools include midnight salivary cortisol and the overnight dexamethasone suppression test Abnormal toxicology screen

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555

Patient complains of hirsutism/acne

Obtain history and physical

Excessive hair growth in androgen-independent areas

Hirsutism Virilization?

(-)

(+) Hypertrichosis DHEAS,17-OHP, Free/unbound T, androstenedione elevated?

Menstrual history

Local treatment. Discontinue offending medication. Evaluate for anorexia, hypothyroidism, dermatomyositis, porphyria.

Transvaginal US, abdominal CT to evaluate ovarian or adrenal tumor Normal

Total T or Free T

17-OHP Anovulation

FSH and Estradiol

Anovulation algorighm, obesity present? > 200 ng/dL or > 2.2 pg/mL Pelvic exam and Pelvic NCAH/21 – US/Adrenal CT hydroxylase > 1500 deficiency ng/dL *ACTH Heterozygote 21> 200 ng/dL morning stimulation hydroxylase < 1500 follicular phase test deficiency ng/dL < 200 ng/dL morning CAH /NCAH Anovulation algorighm, obesity follicular phase excluded present? < 200 ng/dL or < 2.2 pg/mL

Thyroid labs

Prolactin

Elevated Decreased

Hypogonadotropic hypogonadism

17-OHP, serum T (free and total), DHEAS, DHEA, 24 hour cortisol

Normal

Decreased estradiol, increased FSH

Brain MRI, TSH

Normal Consider PCOS or CAH

Premature ovarian failure NCAH or PCOS Cushing’s syndrome

Fig. 3 Hyperandrogenism evaluation algorithm. *Elevated 17-OHP levels can be evaluated by a dexamethasone suppression test and/or an ACTH (cosyntropin) stimulation test. **A lower dexamethasone dose should normally

Abnormal Treat as Elevated appropriate. Prolactin if TSH increased CT adrenals w/ contrast, pelvicUS Decreased cortisol **Decreased /normal cortisol

*Elevated 17-OHP

Dexamethasone suppression test

elicit a decreased overall cortisol. In Cushing’s syndrome, a low-dose dexamethasone results in no change in cortisol levels, and a higher dose of dexamethasone results in suppression of cortisol (Schorge and Williams 2008a)

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Weight Reduction

Oral Contraceptives (OCPs)

Restoration of normal cyclic menses and therefore fertility can be achieved in up to 75% of women who only lose as little as 5–7% of their overall body weight. Weight reduction will also improve insulin sensitivity and subsequently reduce hyperandrogenism. To help put things into perspective, a 200-lb patient seeking treatment for hirsutism and fertility will only need to lose 10–15 lb. to improve her symptoms. This can easily be achieved over the course of a few short months with a low-calorie diet (1000–1500 kcal/day) and exercise and can also be supplemented with metformin to aid in insulin sensitivity (Lebovic et al. 2013c).

OCPs are the first-line drug treatment of choice for treatment against acne, but severe hirsutism will usually require the addition of an antiandrogen to the treatment regimen (Lebovic et al. 2013c). Between 60% and 100% of hyperandrogenic women treated with OCPs experienced a significant reduction in hair growth (Barbieri 2013). Although most data is derived from studies utilizing OCPs, transdermal and vaginal estrogenprogestin formulations are considered to be effective as well (Barbieri 2013). OCPs treat hyperandrogenism by increasing hepatic production of SHBG levels (increased estrogen!increased SHBG!decreased levels of unbound free T from both the ovaries and adrenal glands), suppressing LH via negative feedback (usually suppressed to normal levels), and inhibiting 5-alpha-reductase and androgen receptor binding. For women with PCOS, OCPs have the additional benefit of decreasing the risk for endometrial hyperplasia. Typically, OCPs containing 30–35 micrograms of ethinyl estradiol are used, and switching to the lower dose of 20 micrograms in women over 40 years of age reduces the risk of endometrial malignancies and deep venous thrombosis risk (Barbieri 2013). Progestins such as levonorgestrel should be avoided when prescribing OCPs as this progestin has androgenic properties. However, progestins should be considered every 2–3 months to prevent endometrial hyperplasia, a known risk factor of patients with chronic anovulation (Lebovic et al. 2013c). Carr et al. conducted a study to determine whether or not a gonadotropin-releasing hormone agonist plus add-back therapy would be better treatment than OCPs alone and concluded that this treatment was no better than OCPs alone (Carr et al. 1995).

Hair Removal Treatments In order to receive optimum suppression of hirsutism symptoms, nonpharmacological treatment methods such as hair removal should be supplemented with antiandrogens in order to prevent regrowth (to be discussed later) (Barbieri 2013). The most cost-effective approaches include shaving, plucking, waxing, and bleaching. However, there are permanent hair reduction methods that can be utilized including electrolysis and laser-assisted hair removal (photoepilation) (Barbieri 2013). Electrolysis is a relatively expensive method that is also somewhat painful and time-consuming. It involves placement of a needle within hair follicles and initiates an electric current that destroys the hair follicle. The most effective method involves a blend of galvanic electrolysis and thermolysis (Lebovic et al. 2013c). Laser-assisted hair removal (photoepilation) usually involves four to six treatments utilizing thermal destruction to follicular melanin and has most optimum results if the patient waxes prior to the procedure. This method works best in patients who have light skin with dark hair and may cause pigment changes: hypopigmentation or hyperpigmentation. This method should also be avoided in patients who have a tendency to form keloids or hypertrophic scars (Lebovic et al. 2013c).

Antiandrogens Antiandrogens are often given OCPs if the patient has severe imperative to keep women on other form of contraception

in addition to hirsutism. It is OCPs or some while taking

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antiandrogens as incomplete virilization of a male fetus may occur (Lebovic et al. 2013c). These women must be counseled on the importance of contraception compliance while taking antiandrogens as most antiandrogens are category  in pregnancy. • Spironolactone (Aldactone) of 50– 200 mg/day in addition to taking OCPs is a common regimen used for treatment of severe hirsutism. Spironolactone works by inhibition of aldosterone, inhibition of steroidogenic enzymes, and binding to androgen receptors located on the hair follicle. This medicine is relatively inexpensive, comes in a generic form, and is commonly prescribed. Additionally, irregular uterine bleeding, hyperkalemia, and gastrointestinal discomfort are common side effect of spironolactone (Lebovic et al. 2013c). The oral contraceptive pill containing ethinyl estradiol and and progestin derivative of spironolactone drospirenone is useful in suppressing hirsutism and controlling uterine bleeding. Generally, it should not be used with spironolactone. • Finasteride is an excellent and safe antiandrogen that is a type 2 5-alpha-reductase inhibitor, although its use for hirsutism is considered “off-label.” It prevents the conversion of T to DHT. Administering a low dose of 2.5–5 mg/day every 3 days has proven effective. Failure to take contraception while on finasteride can increase the risk of hypospadias and other genital abnormalities in male fetuses (Lebovic et al. 2013c). • Cyproterone acetate (Androcur) is a derivative of 17-hydroxyprogesterone that decreases 5-alpha-reductase activity and acts as an androgen receptor antagonist. It also competes with DHT binding sites on androgen receptors and reduces serum LH levels/ovarian androgen concentrations. Although this medication is used extensively in Europe and Israel, its use is not FDA approved in the United States as studies have reported liver tumors in beagles that have taken Androcur (Lebovic et al. 2013c).

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• Flutamide is similar to Androcur in that it is an androgen receptor antagonist. Flutamide is nonsteroidal and is used primarily in the treatment of prostate cancer. However, it has been used as an off-label medication to treat hirsutism and is not FDA recommended as its use is associated with hepatotoxicity. A recommended treatment regimen is 250–750 mg/day (Barbieri 2013). • Eflornithine: Ornithine decarboxylase (ODC) is an enzyme required to synthesize follicle polyamines necessary for hair growth. Eflornithine irreversibly inhibits ODC, and reduction in hirsutism is seen over 4–8 weeks. If the medicine is discontinued, hirsutism will return. This medication is also available as an eflornithine hydrochloride 13.9% cream for the use of unwanted facial hair (Barbieri 2013). The main disclaimers pertaining to this medication are that it may cause skin irritation in a small percentage of patients and that it is also a category C drug (Lebovic et al. 2013c).

Insulin-Sensitizing Agents Metformin has been used to restore ovulatory cycles and lower insulin resistance in patients with PCOS, but it is not recommended for routine treatment of hirsutism and acne (Barbieri 2013). Metformin is a biguanide oral hypoglycemic agent that inhibits hepatic glucose production and increases peripheral insulin sensitivity. As circulating insulin levels are decreased from its use, LH levels as well as free testosterone and plasminogen activator inhibitor-1 levels are also decreased (Lebovic et al. 2013c). Although there is evidence revealing possible efficacy in hirsutism treatment and one would presume from its mechanism of action that it would reduce hyperandrogenism, multiple studies reveal no statistically significant reduction in Ferriman-Gallwey scores when using metformin compared to placebo use (Cosma et al. 2008).

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Other Treatment Modalities

Postmenopausal Women

Although it is not routinely recommended per the 2008 Endocrine Society guidelines, it is relatively expensive, and there are other more effective hirsutism treatment modalities available, the use of a GnRH agonist with supplementation of add-back therapy can be used in women who have hypertension as a comorbidity. Add-back therapy typically entails a combination OCP or a low-dose progesterone. Progesterone therapy is important to reduce bone mineralization loss, and OCP add-back therapy reduces the adverse effects of estrogen deficiency without altering the GnRH agonist treatment properties (Barbieri 2013). Additionally, the routine use of glucocorticoids is not recommended for treatment of hirsutism per the 2008 Endocrine Society guidelines. They have been used in the past with women who have classic 21-hydroxylase (CYP21A2) deficiency and women with the nonclassic CYP21A2 deficiency but only with minimal effectiveness (Barbieri 2013). One exception would be a patient with nonclassical congenital adrenal hyperplasia who does not respond to or does not respond well to the use of OCPs and antiandrogen therapies. In theory, glucocorticoid administration will suppress hypothalamic corticotrophin-releasing hormone (CRH), which in turn will decrease ACTH and subsequently adrenal androgen production. Although these medications do effectively suppress serum DHEA and DHEA-S, they are less effective than OCPs at decreasing hirsutism scores (Barbieri 2013).

Prior to initiating treatment, an androgensecreting tumor must be ruled out in postmenopausal women with the sudden onset of hirsutism. Treatment options typically entail an antiandrogen in addition to a low-dose estrogen. If a postmenopausal woman has hyperthecosis, hyperandrogenism, and severe hirsutism, a bilateral oophorectomy should be considered (Barbieri 2013).

Treatment of Acne Although treatment of the underlying hyperandrogenism will eventually treat the patient’s acne, there are various treatment regimens for acne treatment including oral treatments, topical treatments, and a combination of the two (Table 2). Typically, acne is treated based on the severity of the presentation. This spectrum includes comedonal (or noninflammatory) acne, mild papulopustular and mixed (comedonal and papulopustular) acne, moderate papulopustular and mixed acne, moderate nodular acne, and severe nodular/conglobate acne (Grabber 2015). It is mandatory that patients take birth control when taking any oral acne medication, and most topical acne medications are category C and should be used sparingly. Of the oral antibiotics, trimethoprim-sulfamethoxazole, tetracycline, and minocycline are contraindications to pregnancy and should only be given when the patient is using contraception. Some dermatologists will

Table 2 Treatment of acne

Comedonal (noninflammatory) Topical retinoid (azelaic acid or salicylic acid)

a

Mild papulopustular and mixed acne Topical retinoid þ topical antimicrobial (i.e., benzoyl peroxide) +/ topical antibiotic (erythromycin and clindamycin, sulfacetamide, or dapsone)

Moderate papulopustular and mixed acne Topical retinoid þ oral antibiotica þ topical benzoyl peroxide

Moderate nodular acne Topical retinoid þ oral antibiotic þ topical benzoyl peroxide

Severe nodular/ conglobate acne Oral isotretinoin

Oral antibiotics include tetracycline, doxycycline, minocycline, erythromycin, trimethoprim-sulfamethoxazole, clindamycin, and azithromycin (Grabber 2015)

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not prescribe an oral isotretinoin unless the patient is on two forms of contraception. Following is a brief and general approach to the treatment of acne (Grabber 2015).

Conclusion In conclusion, hyperandrogenism (with PCOS being the most common culprit) is an extremely common pathology among women. Aside from hirsutism causing psychological distress and insecurities of a woman’s physical appearance, hirsutism is commonly affiliated with particular comorbidities including endometrial hyperplasia, hyperlipidemia, infertility, diabetes mellitus, CAH, and adnexal/adrenal masses. A full workup is warranted in order to initiate appropriate treatment to alleviate the etiology of the hyperandrogenism and subsequently alleviate hirsutism and acne. Not only will a full workup identify the etiology of the hyperandrogenism, but comorbidities such as hyperlipidemia and diabetes mellitus requiring long-term monitoring and treatment can be identified as well.

Cross-References ▶ Gynecologic History and Examination of the Patient ▶ Impact of Obesity on Gynecological Diseases

References Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J. 1986;293(6543):355–9. Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. Endocr Rev. 2000;21(4):347–62. Barbieri RL. Treatment of hirsutism. Wolters Kluwer Health; 2013. Available from: Web 2 Mar 2015. http://www.uptodate.com/contents/treatment-of-hirsut ism?source¼search_result&search¼treatment%2Bof %2Bhirsutism&selectedTitle¼1~128 Barbieri RL, Ehrmann DA. Evaluation of premenopausal women with hirsutism. Wolters Kluwer Health; 2013a. Web 24 Nov 2014. http://www.uptodate.com/contents/ evaluation-of-premenopausal-women-with-hirsutism

559 Barbieri RL, Ehrmann DA. Pathogenesis and causes of hirsutism. Wolters Kluwer Health; 2013b. Available from: Web 27 Feb 2015. http://www.uptodate.com/ contents/pathogenesis-and-causes-of-hirsutism Carr B, Breslau N, et al. Oral contraceptive pill, GnRH agonist, or use in combination for treatment of hirsutism. J Clin Endocrinol Metab. 1995;60(4):1169. Cosma M, Swiglo BA, Flynn DN, et al. Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab. 2008;93: 1135. Demidov VN, Lipatenkova J, Vikhareva O, Van Holsbeke C, Timmerman D, Valentin L. Imaging of gynecological disease (2): clinical and ultrasound characteristics of Sertoli cell tumors, Sertoli-Leydig cell tumors and Leydig cell tumors. Ultrasound Obstet Gynecol. 2008;31(1):85–91. Dorn C, Mouillet JF, Yan X, Ou Q, Sadovsky Y. Insulin enhances the transcription of luteinizing hormone-beta gene. Am J Obstet Gynecol. 2004;191(1):132–7. Goljan EF, Sloka KI. Endocrine disorders rapid review laboratory testing in clinical medicine. Philadelphia: Mosby Elsevier; 2007. p. 365–70. Grabber E. Treatment of acne vulgaris. Wolters Kluwer Health; 2015. Available from: Web 27 Mar 2015. http://www.uptodate.com/contents/treatment-of-acnevulgaris?source¼search_result&search¼treatment% 2Bof%2Bacne&selectedTitle¼1~150#H1 Lebovic DI, Gordon JD, Taylor RN. Polycystic ovarian syndrome. In: Reproductive endocrinology and infertility: handbook for clinicians. Arlington: Scrub Hill; 2013a. p. 194–6. Lebovic DI, Gordon JD, Taylor RN. Polycystic ovarian syndrome. In: Reproductive endocrinology and infertility: handbook for clinicians. Arlington: Scrub Hill; 2013b. p. 186–9. Lebovic DI, Gordon JD, Taylor RN. Polycystic ovarian syndrome. In: Reproductive endocrinology and infertility: handbook for clinicians. Arlington: Scrub Hill; 2013c. p. 197–9. Miller KK, Rosner W, Lee H, et al. Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods. J Clin Endocrinol Metab. 2004;89(2):525–33. Phipps WR. Polycystic ovary syndrome and ovulation induction. Obstet Gynecol Clin North Am. 2001;28(1): 165. Rotterdam EA-SPcwg. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–7. Schorge JO, Williams JW. Polycystic ovarian syndrome and hyperandrogenism: introduction. In: Williams gynecology. New York: McGraw-Hill Medical; 2008a. p. 779–91. Schorge JO, Williams JW. Polycystic ovarian syndrome and hyperandrogenism: introduction. In: Williams

560 gynecology. New York: McGraw-Hill Medical; 2008b. p. 785. Speiser PW. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinol Metab Clin North Am. 2001;30(1):31–59. vi Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of

M. B. Evans and M. Hill cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95(5):2038–49.

Hyperprolactinemia, Galactorrhea, and Pituitary Adenomas

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Kate C. Arnold and Caroline J. Flint

Contents Introduction to the Pituitary and Pituitary Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 Prolactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 Galactorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 Signs and Symptoms of Prolactinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 Diagnosis of Hyperprolactinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 Diagnosing the Cause of Hyperprolactinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 Management of Hyperprolactinemia Due to Medications . . . . . . . . . . . . . . . . . . . . . . . . . . 566 Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

Abstract

Pituitary adenomas, hyperprolactinemia, and galactorrhea are disorders which can occur concomitantly or independently. In the following chapter, we will discuss the differential, signs and symptoms, and diagnosis of these diseases.

K. C. Arnold (*) · C. J. Flint Department of OBGYN, University of Oklahoma Health and Science Center, Oklahoma City, OK, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_41

Pituitary adenomas are classified by their size with less than 1 cm being a microadenoma and equal to or greater than 1 cm being a macroadenoma. They can be additionally delineated as functioning versus nonfunctioning based on their hormone production status. Prolactin is synthesized in the pituitary and is primarily controlled by suppression with dopamine. Elevations may be due to many causes including prolactinomas, stalk compression, medications, or hypothyroidism. Galactorrhea may be due to prolactin elevations or may be unrelated. The chapter includes a discussion of both medical 561

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and surgical therapy options as well as a discussion regarding management during pregnancy. Generally, medical therapy involves treatment with dopamine agonists to suppress prolactin, although hormonal therapy with combined oral contraceptives or cyclic progestin is a reasonable alternative. In patients that are resistant to first time medications at their maximum dose, surgical management should be considered. Keywords

Hyperprolactinemia · Adenoma · Pituitary · Galactorrhea · Prolactinoma · Amenorrhea · Dopamine

Introduction to the Pituitary and Pituitary Adenomas In patients who present who problems relating to nipple discharge and/or changes in their menstrual cycle, a diagnosis of hyperprolactinemia should be considered. Understanding hyperprolactinemia and its clinical correlates can aid significantly in correctly diagnosing this disorder. Doing so can be difficult because it requires an understanding of the anatomy, neurology, physiology, and endocrinology of the pituitary and its receptor organs. Given that it may have been years since sitting in a classroom, we will review the basics at this time. An adenoma is a benign growth formed from glandular structures in epithelial tissue. Adenomas are classified by size; a macroadenoma is 1 cm or greater in diameter and a microadenoma is less than 1 cm. They are further organized by either being functioning, meaning that they secrete hormones, or nonfunctioning (Samarasinghe et al. 2014). The differential diagnosis for a pituitary mass includes a multitude of disorders including pituitary hyperplasia, lymphocytic hypophysitis, granulomatous hypophysitis, sarcoidosis, pituitary abscess, craniopharyngioma, Rathke’s cleft cyst, pars intermedia cyst, colloid cyst, arachnoid cyst, empty sella, germ cell tumors, hamartoma, astrocytoma, aneurysm, histiocytosis, chordoma, and metastatic carcinoma (Samarasinghe et al. 2014). Despite this extensive differential diagnosis, the

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most common cause by far is the adenoma. Also common is pituitary hyperplasia, which is generally due to the physiologic changes associated with pregnancy, leading to lactotroph hyperplasia (Samarasinghe et al. 2014). In the case of pituitary apoplexy, acute symptoms can develop including changes in vision, nausea, or sudden onset of severe headache. Pituitary apoplexy occurs when an existing adenoma has outgrown its own blood supply which results in pituitary hemorrhage. Alternatively, this can occur when the growing adenoma compresses the stalk, which subsequently slows the flow of venous blood return. Treatment of this acute phenomenon typically requires immediate corticosteroids administration as death can occur due to adrenal insufficiency. The steroids have an added benefit of decreasing associated inflammation and help prevent the occurrence of mass effect (Samarasinghe et al. 2014). Nonfunctioning adenomas may be asymptomatic or may cause significant dysfunction, as stated, due to mass effect or via hormone alterations. If a macroadenoma is present, the resulting side effects will be directly related to the speed by which the mass grew, the size, and the location of the adenoma (Samarasinghe et al. 2014). When a pituitary adenoma is incidentally found, a workup is indicated. Necessary testing includes prolactin, IGF-1 to screen for acromegaly, cortisol levels to screen for Cushing’s disease, and visual field testing. Approximately 10% of microadenomas and 24% of macroadenomas will progress in size. Conservative management can be undertaken if no changes in hormone levels are noted and there are no mass symptoms present. This includes surveillance with repeat imaging to monitor for change in size (Samarasinghe et al. 2014).

Prolactin Prolactin is synthesized by the pituitary lactotrophs (Melmed et al. 2011) in the anterior pituitary in both physiologic situations, as well as pathologic states (Romijin 2014). Prolactin synthesis is suppressed by dopamine, which acts on the D2 receptors in the anterior pituitary (Melmed et al. 2011). Dopamine is synthesized in the hypothalamus and delivered to the

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anterior pituitary via the pituitary stalk (Romijin 2014). Prolactin production is increased by estrogen, thyrotropin-releasing hormone (TRH), epidermal growth factor, and dopamine receptor antagonists (Melmed et al. 2011). The production of prolactin is uniquely regulated in comparison to other hormones of the anterior pituitary in that it is modulated by suppression, rather than stimulation (Samarasinghe et al. 2014). Additionally dopamine not only inhibits the release of prolactin, but it also inhibits prolactin gene expression and lactotroph proliferation (Samarasinghe et al. 2014). Prolactin induces and maintains female breast lactation (Melmed et al. 2011). During pregnancy, prolactin increases and stimulates the alveoli in the mammary glands to generate milk (Romijin 2014). Hyperprolactinemia outside of pregnancy can be caused by prolactinomas, adenomas, and changes in dopamine regulation or can be idiopathic (Melmed et al. 2011). Prolactinomas account for up to 40% of pituitary tumors (Melmed et al. 2011). Pituitary tumors and parasellar masses can indirectly result in increased prolactin levels by means of stalk compression which prevents the delivery of dopamine. As mentioned, dopamine inhibits the secretion of prolactin, so if this is blocked then a rise in prolactin will be observed (Melmed et al. 2011). A prolactin cutoff of 94 μg/l has been proposed to distinguish between a prolactinoma and a nonfunctioning adenoma. This distinction is important as it dictates treatment modalities. In patients with nonfunctioning adenomas that are indirectly increasing prolactin levels by means of compression, dopamine agonist can be used to treat symptoms of hyperprolactinemia; however, this will not treat the actual mass. In patients with prolactinomas, dopamine agonists will both treat the tumor and reduce its size (Melmed et al. 2011).

Galactorrhea Galactorrhea is defined as nonphysiologic mammary secretion of milky fluid, meaning that it occurs outside of the peripartum period. Generally, this is persistent, and colors of expressed

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fluid range from clear white to even yellow or green. Secretions associated with hormonal causes are from multiple ducts, as opposed to pathologic causes, which are from single ducts. Any bloody secretions should raise the suspicion for cancer (Fritz and Speroff 2011). Elevated prolactin levels inhibit the release of gonadotropinreleasing hormone (GnRH) and therefore affect the secretion of luteinizing hormone (LH). Effects in luteinizing hormone (LH) production can lead to changes in menstrual cycle regularity and fertility (Romijin 2014). Idiopathic galactorrhea should be suspected in women with galactorrhea in the presence of normal menstrual cycles that is not associated with pregnancy. This usually indicates a normal prolactin level (Romijin 2014). Approximately only one-third of women with hyperprolactinemia will also have galactorrhea. This is due to the fact that estrogen plays an important role in galactorrhea and hyperprolactinemia generally causes a decrease in estrogen (Fritz and Speroff 2011). A broad differential is important in considering the cause of galactorrhea. Although prolactin elevation is a common cause, other causes include drugs, hypothyroidism, excessive estrogen, prolonged suckling or nipple piercing, stress, and renal disease (Fritz and Speroff 2011). If galactorrhea is due to hyperprolactinemia, it generally resolves with treatment of the hyperprolactinemia (Melmed et al. 2011).

Signs and Symptoms of Prolactinomas Masses arising in the pituitary can become symptomatic by two different mechanisms: mass effect and endocrine changes. The pituitary is located within the sella turcica behind and above the sphenoid sinus. It weighs less than one gram and is composed of an anterior and posterior compartment. When a pituitary tumor becomes too large for the sella turcica, it begins to compress on the optic chiasm and can subsequently cause vision changes (Samarasinghe et al. 2014). Generally only macroadenomas cause mass symptoms. Most often, the vision changes are

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gradual, so a patient may not be aware of their deficiency until they are given formal visual field testing. The most common deficit in vision noted is termed bitemporal hemianopsia, which is defined as the loss of vision in the temporal fields due to direct compression of the optic chiasm (Samarasinghe et al. 2014). If the mass extends laterally, it can lead to cranial nerve palsies, primarily of cranial nerve 3, 4, 5, and 6. Symptoms with cranial nerve 3 are the most commonly experienced and result in a patient having difficulty moving their eye muscles normally. Changes in cranial nerve 5 are generally due to apoplexy (Samarasinghe et al. 2014). Headaches are incredibly common in patients with macroadenomas and even microadenomas. The cause of this is not known. Generally, symptoms improve after surgical or medical treatment (Samarasinghe et al. 2014). Clinical effects of hyperprolactinemia may include hypogonadism, infertility, and galactorrhea, or it may be asymptomatic (Melmed et al. 2011). Decreased levels of gonadotropin-releasing hormone (GnRH) cause decreased folliclestimulating hormone (FSH) and luteinizing hormone (LH), which leads to these downstream effects. The decrease in GnRH can also lead to bone loss due to sex steroid attenuation. In some cases, spine bone density can decrease up to 25% and may not be restored despite adequate treatment (Melmed et al. 2011). Women with hyperprolactinemia specifically may experience menstrual disorders including primary amenorrhea (menstruation never starting) or secondary amenorrhea (cessation of menstrual cycles). Generally, with high levels of prolactin, the patient is more likely to be amenorrheic, whereas with levels less than 100, the patient will likely experience oligomenorrhea or infrequent menses (Fritz and Speroff 2011). Hyperprolactinemia may also lead to delayed menarche and infertility (Romijin 2014). Because of decreased ovulation, hirsutism is a common complaint as well (Fritz and Speroff 2011). Women may complain of decreased libido and pain with intercourse (2, 3). In adolescence, girls can present with disturbances in menses or galactorrhea. In boys, it may present with delayed

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puberty and hypogonadism. Treatment does not differ in these two groups (Melmed et al. 2011).

Diagnosis of Hyperprolactinemia Diagnosing hyperprolactinemia is simple and only requires a single lab test revealing an elevated serum prolactin. The World Health Organization (WHO) defines hyperprolactinemia as a prolactin level above 25 μg/l. If serum prolactin is found to be elevated, a repeat or confirmatory testing is not recommended to establish the diagnosis of hyperprolactinemia. The test may be performed at any time of the day. If the prolactin level is found to be within normal limits, but one has high clinical suspicion, then a repeat test can be performed as variations can be seen due to pulsatility of hormone production (Melmed et al. 2011). The prevalence of clinically relevant hyperprolactinemia ranges from 6 to 50/100,000 people (Melmed et al. 2011). Macroprolactin is a large, polymeric form of prolactin that may be associated with autoantibodies. It is recommended that patients be screened for the presence of macroprolactin if hyperprolactinemia is found in an asymptomatic patient. These large forms of prolactin are often less biologically active (Melmed et al. 2011). A thorough physical examination is important in patients who are found to have hyperprolactinemia, as it may be a symptom of another disorder. For example, over half of patients with a growth hormone-secreting tumor, which leads to acromegaly, will also have elevated prolactin levels (Melmed et al. 2011). Acromegaly causes clinical features related to the overgrowth of many tissues. Physical exam findings consist of enlargement of the nose and frontal bones, enlarged tongue, coarse facial features, and swollen hands and feet (Fritz and Speroff 2011). If a patient is found to have a large pituitary tumor but a relatively low prolactin level, serial dilution of the serum samples should be performed to test for the hook effect. The hook effect occurs when the concentration of the sample is so high that it saturates the antibodies in the assay, which results in the signaling antibody in

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the sample resulting as falsely low. Diluting the sample will overcome this effect, as will a washout to eliminate the unbound prolactin. If the sample is diluted, it will distinguish between a large prolactinoma, which will have a high prolactin, and a large nonfunctioning adenoma (Melmed et al. 2011). In prolactinomas, the prolactin level is generally correlated with the size of the tumor, and, as mentioned, most patients with a level above 250 μg/l will have a prolactinoma (Melmed et al. 2011).

Imaging The treatment of an adenoma may depend on the size and location of the lesion and its resulting symptoms caused by mass effect. Given this, obtaining detailed imaging of the lesion is very important. An optimal report should describe the displacement of adjacent structures the size shape, and location of the mass and the density of the mass. MRI is the ideal modality and should be focused on the sellar region. Without this specification, the cuts obtained generally do not provide the necessary detail. If done well, the pituitary stalk, pituitary, optic tracts, and sinuses can all be visualized as distinct entities (Samarasinghe et al. 2014).

Diagnosing the Cause of Hyperprolactinemia There are various physiologic, pathologic, and pharmacologic causes of hyperprolactinemia. Physiologic causes include nipple stimulation, pregnancy, and stress. Pathologic causes include diseases of the pituitary and hypothalamus as well as decreased clearance of prolactin. Pharmacologic causes generally include drugs that serve as dopamine antagonists, which indirectly elevated levels of prolactin as discussed earlier (Romijin 2014). A macroprolactinoma is suspected when a prolactin level is found to be greater than 500 μg/l. Levels around 200 μg/l generally indicate a

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prolactinoma; however, this can also be seen with the use of antipsychotic drugs like risperidone and metoclopramide (Melmed et al. 2011). Other studies suggest that a cutoff of 94–100 μg/l detects the presence of a prolactinoma as opposed to a nonfunctioning mass. Below this cutoff, the elevation in prolactin is likely due to stalk compression. In patients with symptomatic nonphysiological hyperprolactinemia who do not have a tumor, medication use, renal failure, and hypothyroidism should all be considered in the differential diagnosis (Samarasinghe et al. 2014). Renal insufficiency can cause moderate elevations in prolactin due to slowed clearance of serum prolactin. Production can also be increased in these patients. Dialysis does not decrease serum levels; however, levels are noted to normalize following renal transplants. In patients with hyperprolactinemia due to renal disease who have hypogonadal symptoms, bromocriptine therapy can lead to resumption of menses (Melmed et al. 2011). Hypothyroidism that is chronic or not adequately treated can cause pituitary hyperplasia, which may lead to hyperprolactinemia. This can be reversed when the hypothyroidism is adequately treated with levothyroxine. Thus, close attention must be paid to the thyroid exam as part of a workup for hyperprolactinemia (Melmed et al. 2011). In patients with idiopathic hyperprolactinemia, spontaneous return to normal levels of prolactin occurs in one-third of patients (Melmed et al. 2011). Typical prolactin levels associated with medication use are approximately 25 micrograms to 100 micrograms; however, metoclopramide, risperidone, and phenothiazines can lead to more elevated levels, as these antipsychotic drugs serve as dopamine antagonists (Melmed et al. 2011). The calcium channel blocker verapamil can also lead to hyperprolactinemia in 8.5% of patients. Other drugs that may cause mild elevations in prolactin include opiates or estrogen-containing drugs such as oral contraceptives. It is recommended that asymptomatic hyperprolactinemia due to medications not be treated (Melmed et al. 2011).

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Management of Hyperprolactinemia Due to Medications If the physician suspects that a patient’s hyperprolactinemia is due to a medication, there are two options. One is to stop the medication for 3 days and redraw the serum prolactin. If normalized, no further work-up is needed. If it is not possible to stop the medication, or the timing of the medication does not correlate with the hyperprolactinemia, an MRI of the head should be obtained to rule out a pituitary or hypothalamic mass (Melmed et al. 2011). In patients without a tumor, medications are the most common cause of hyperprolactinemia (Melmed et al. 2011). In the case of antipsychotics causing hyperprolactinemia, the patient and physician must consider the risks and benefits of stopping the drug versus continuing it. This discussion must include available alternatives such as atypical antipsychotics (Melmed et al. 2011). Treatment is not recommended for patients with asymptomatic medication-induced hyperprolactinemia (Melmed et al. 2011), although estrogen or testosterone may be given in patients with hypogonadal symptoms (Melmed et al. 2011). As stated above, the most common medications are typical antipsychotics. Hyperprolactinemia is found in 40–90% of patients taking typical antipsychotics and in 50–100% of patients taking risperidone (Melmed et al. 2011). Patients may remain asymptomatic. Other times, women develop galactorrhea and amenorrhea, and men develop low libido and erectile dysfunction (Melmed et al. 2011).

Medical Management Medical treatment is not necessary in women with a microadenoma and normal menses. Adequate treatment with a dopamine agonist can normalize prolactin levels, decrease galactorrhea, restore menses, and decrease tumor size. Options include bromocriptine, cabergoline, and quinagolide (Samarasinghe et al. 2014). First line treatment is cabergoline because it has a high affinity for the D2 lactotroph receptor

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and is associated with fewer side effects than bromocriptine (Samarasinghe et al. 2014). Decreases in tumor size and decrease in visual field deficits can be seen after several weeks of therapy (Samarasinghe et al. 2014) with normalization in prolactin in 85% of patients (Romijin 2014). Bromocriptine must be taken two to three times per day in doses of 2.5–15 mg, while cabergoline, which has a half-life of 65 h, can be dosed once to twice weekly (Romijin 2014). In counseling patients regarding possible side effects, it is important to include gastrointestinal symptoms and orthostatic hypotension, both of which can be reduced by using dose titration (Samarasinghe et al. 2014). When initiating patients on dopamine agonists for prolactinomas, prolactin should be measured 1 month after starting treatment (Melmed et al. 2011). Visual field testing should also be performed as well as assessment of comorbidities such as galactorrhea and bone loss (Melmed et al. 2011). Medication should be tapered at 2 years if prolactin is normal and no visible tumor is noted on MRI (Melmed et al. 2011). Alternative managements from the gynecologic perspective include hormonal therapy either in the form of cyclic progestin or combined oral contraceptives. These treatments can decrease the effects of unopposed estrogen. Previous concerns that this may exacerbate hyperprolactinemia have not come to fruition in clinical studies. Treatment with progesterone or combined hormonal therapy protects the patient from the dangers of unopposed estrogen such as endometrial hyperplasia, atypia, and endometrial cancer. Unlike the dopamine agonists, these treatments can be used in patients with medication-induced hyperprolactinemia (Fritz and Speroff 2011). Prior to consideration of surgery, doses of the dopamine agonist should be titrated to the maximum tolerable dose. There are reports of valvular abnormalities in patients on dopamine agonists at high doses for prolonged periods of time; hence, echocardiograms in these patients may be reasonable. If bromocriptine has failed, cabergoline should be attempted prior to referral as well (Melmed et al. 2011).

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Hyperprolactinemia, Galactorrhea, and Pituitary Adenomas

Surgical Management Surgical management is indicated if there is mass effect with visual compromise, the mass is resistant to medical therapy, apoplexy has occurred, or a histological diagnosis is needed. Remission rates after surgery are reportedly 90% in active pituitary adenomas (Samarasinghe et al. 2014). The approach for surgery is generally transsphenoidal. This is favored as it is minimally invasive with a low mortality of 0.2–1%. If the mass is too large/invasive for this approach, a transcranial approach may be necessary (Samarasinghe et al. 2014). Complications of the surgery include anterior pituitary insufficiency, diabetes insipidus, sinus disease, CSF leak, intracranial hemorrhage, septal perforation, and epistaxis (Samarasinghe et al. 2014). If surgical treatment fails and the tumor is resistant or malignant, radiotherapy is a reasonable treatment. Malignant is defined as metastatic spread within or outside the central nervous system. These are very rare with only 50 ever having been described (Melmed et al. 2011).

Pregnancy Patients with prolactinomas should stop dopamine agonist prior to pregnancy or upon a positive pregnancy test; however, in patients with macroadenomas, it may be reasonable to continue dopamine agonist treatment. Bromocriptine does cross the placenta; however, the incidence of congenital malformations and abortions are not increased. There is less data regarding cabergoline during pregnancy; but, it does not appear to be harmful (Melmed et al. 2011). Quinagolide, which is not used in the United States, is known to have a high incidence of adverse outcomes during pregnancy and should not be used (Romijin 2014). Serial measurements of prolactin during pregnancy should not be performed, as these can be difficult to interpret. Imaging should not be performed on patients with microadenomas unless there is suspicion for growth based on a change in visual field testing. If patients do experience systematic growth of a prolactinoma, bromocriptine should be initiated during pregnancy. If visual field

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is changed or headaches occur, MRI without gadolinium is reasonable (Melmed et al. 2011). If a patient with hyperprolactinemia is unable to achieve pregnancy, treatment with dopamine agonists can restore fertility in 90% of patients with cabergoline being the most effective (Romijin 2014). If a dopamine agonist has been used to induce pregnancy, the decision of when to stop the medication is more complex. Generally, patients with macroadenomas are advised to continue their agonist and patients with microadenomas are advised to stop their medication once a pregnancy is achieved. Preference is for bromocriptine as noted above as there is more experience with it in pregnancy. If medications are stopped, monthly evaluations must be done regarding visual field testing or must be counseled regarding seeking care for headaches and vision changes (Romijin 2014).

Conclusion Pituitary adenomas, hyperprolactinemia, and galactorrhea may occur as part of a unified disorder or may be due to a wide differential. In diagnosing the cause for symptoms associated with adenomas and hyperprolactinemia, a good history and physical is always the first step. This may reveal the cause for the symptoms and dictate management decisions. A thorough understanding of how each cause can present with slightly altered symptomatology is also key in managing these patients.

References Fritz MA, Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed. Lippinicott: Williams & Wilkins; 2011. Melmed S, et al. Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(Romijin 2014):273–88. Romijin JA. Hyperprolactinemia and prolactinoma, Chapter 13. In: Handbook of clinical neurology, 3rd series, vol. 124; 2014. Samarasinghe S, Emanuele MA, Mazhari A. Neurology of the pituitary, Chapter 47. In: Neurologic aspects of systemic disease part II, Handbook of clinical neurology, vol. 123; 2014.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Age and Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Fecundity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Definition of Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Causes of Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Female Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovulatory Causes of Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Causes of Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unexplained Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

571 571 571 571 572 572

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History and Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serum Progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Tests for Tubal Patency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chromotubation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysterosalpingogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysteroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tests for Ovarian Reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Tests for Evaluation of Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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B. A. Gibson (*) University of Oklahoma Health Science Center, Oklahoma City, OK, USA e-mail: [email protected] J. Wilkerson (*) Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OK, USA © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_42

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B. A. Gibson and J. Wilkerson Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optimizing the Window of Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment for Ovulation Dysfunction: Ovulation Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment for Decreased Ovarian Reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment for Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment for Unexplained Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intrauterine Insemination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assisted Reproductive Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

580 580 580 582 582 583 583 583 584

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585

Abstract

In this chapter, the basic management of infertility will be reviewed. An overview of pertinent definitions, evaluation and diagnosis of infertility, and relevant components of history and the physical exam will be discussed. Most importantly, the causes of infertility will be reviewed along with treatments for the specific causes of infertility. Keywords

Primary infertility · Secondary infertility · Fecundity · Hysterosalpingogram · Chromotubation · Sonohystogram · Assisted reproductive technology · In vitro fertilization

Introduction Infertility is the inability to procreate and a source of anxiety for couples affected. Infertility is a disease that must be investigated in a comprehensive manner. Determining the underlying etiology of infertility specific to the couple, allows for individualized treatments that will increase the chances of conception.

remain unclear, but there are many proposed theories. There has been an increase in sexually transmitted infections over time which plays a role in the increasing infertility rates due to tubal occlusion caused by these infections. Over the last several decades, there is increased public knowledge of the medical treatments available for infertility which in turn has increased the rates of those seeking medical attention. Lastly, it is well known that age effects fertility, and with more women delaying child bearing until a later age, this may be a contributing factor to more women seeking medical assistance for infertility (Lobo 2007).

Age and Infertility Women are born with a complete and final set of eggs. By puberty, only about 500,000 eggs remain and the supply continues to decrease by atresia throughout the women’s life. As there is a limited supply of eggs, along with other hormonal factors, fertility decreases gradually with increasing age. At age 32, there is a significant decrease in the rate of conception and an even greater decrease at the age of 37. Along with decreasing fertility, there is an increase in miscarriage and aneuploidy with increasing age (Practice Committee of American Society for Reproductive Medicine 2014a).

Epidemiology In the United States, approximately 12% of women have had an appointment for an infertility related concern (Christianson and Wallach 2011). There has been a steady increase in the number of women seeking medical care for infertility over the last several decades. The reasons for the increase

Fecundity Fecundity refers to the probability of conception in one menstrual cycle. The probability of conception in one menstrual cycle is about 20%. This percentage increases over time and is cumulative

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in nature. The vast majority, or about 70% of women, will have conceived by 6 months and 93% will have conceived by 2 years. For any couple trying to conceive, it is important to discuss the probability of conception over time and present realistic expectations. Time in months 1 3 6 12 24

Percent pregnant 20 57 72 85 93

Guttmacher (1956)

Definition of Infertility Infertility, as defined by the American Society for Reproductive Medicine, is a disease that results in failure to achieve a successful pregnancy by 12 months of timed unprotected intercourse or therapeutic donor insemination (Committee Opinion: Definitions of Infertility and Recurrent Pregnancy Loss 2013a). Primary infertility refers to infertility in a woman that has never been pregnant while secondary infertility refers to infertility in a woman that has previously been pregnant.

Causes of Infertility There are several recognized causes of infertility. Understanding and identifying the cause helps the practitioner manage and treat the patient or couple. Several causes are discussed below. It is important to remember when reviewing common causes of infertility that there may be more than one cause and in up to 30% of couples, a cause cannot be identified (Fritz and Speroff 2011).

Male Infertility Male factor infertility can account for as high as 30% of infertility. Evaluation of male infertility is determined by a semen analysis with the goal to

identify conditions that can be treated. Unfortunately, not all identified conditions that lead to male infertility can be treated and up to 50% of males will have an idiopathic cause. Other causes of male infertility involve sperm transport (i.e., congenital absents of the vas in cystic fibrosis), gonadal disorders (i.e., cryptorchidism, Klinefelter syndrome, varicoceles, and genetic deletions or mutations), and hypothalamicpituitary disorders. Infertility in the male can result from infections including gonorrhea, chlamydia, HIV, tuberculosis, leprosy, and mumps causing orchitis. Drugs that may cause male infertility include alkylating agents, antiandrogens, and anabolic steroids. More commonly used medications like ketoconazole and cimetidine are also linked with male infertility. Heavy use of drugs and alcohol, in particular marijuana and cocaine, will cause infertility. Other environmental exposures like febrile illness, exposure to pesticides or organic solvents, and smoking have also been associated with infertility. Additionally, chronic diseases are not uncommon in men with infertility such as cirrhosis, chronic renal insufficiency, and sickle cell disease (Fritz and Speroff 2011).

Female Infertility The two most common causes of female factor infertility are ovulatory dysfunction, accounting for 20–40%, and tubal or peritoneal disease, accounting for 30–40%. These causes along with other less common causes of female infertility are discussed in further detail below (Fritz and Speroff 2011).

Ovulatory Causes of Infertility Ovulation is a necessary means for conception. Even oligoovulation or infrequent or irregular ovulation can delay conception. Confirmatory tests for ovulation are discussed in detail below, but a menstrual history will often be enough information to determine if the patient is ovulatory. Women that are ovulatory have predictable

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periods at regular intervals and will often have a set of moliminal symptoms (i.e., breast tenderness) that accompanies their cycle. The most common cause of anovulation is Polycystic Ovarian Syndrome or PCOS. PCOS is a condition characterized by an increased number of cysts on the ovaries, hyperandrogenism often characterized by acne and hirsutism, and oligo or anovulation.

Structural Causes of Infertility Tubal Tubal patency is necessary for conception as fertilization of the egg and sperm occurs in the fallopian tube. The two main causes of tubal occlusion are the result of a prior infection and endometriosis. Infectious causes of tubal occlusion include pelvic inflammatory disease (PID) and a prior infection with gonorrhea and/or chlamydia. Infertility increases with each occurrence of acute pelvic inflammatory disease and those with a history of three episodes of acute PID can have and infertility rate up to 75%. Other causes of tubal occlusion include abdominal adhesive disease and prior ectopic pregnancy (Fritz and Speroff 2011). Uterine Uterine abnormalities are an infrequent cause of infertility, but should still be considered in an infertility evaluation. The most common uterine causes of infertility include fibroids, polyps, adhesions, and developmental anomalies. All of these conditions interfere with implantation and may increase the risk of miscarriage as well. Fibroids are monoclonal growths that occur commonly in women. Up to 40% of women have uterine fibroids. Infertility is dependent on location of the fibroids in the uterus with submucosal having the greatest effect on infertility, especially those distorting the endometrial cavity, followed by intramural fibroids. Uterine polyps are benign pedunculated growths in the uterine cavity that often cause irregular or heavy bleeding. Uterine adhesions, or Asherman’s syndrome, are the result of damage to the endometrium usually by instrumentation such as a curettage following a missed

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abortion or retained products of conception. Uterine developmental anomalies are exceedingly rare. The most common anomaly is a uterine septum. Others include a bicornuate uterus, a unicornuate uterus, and uterine didelphis.

Cervical Infertility related to a cervical cause is rare but should be considered in women with prior treatments for cervical dysplasia. These treatments can result in cervical stenosis, and ultimately the inability of the sperm to reach the egg. Cervical stenosis can be evaluated in the office by simply passing a uterine sound. In the past, a postcoital test was performed as this was thought to evaluate the interaction between the cervical mucus and sperm but this test has fallen out of favor as information obtained from the results of the test did not change pregnancy outcomes and the test was largely inconvenient and embarrassing for patients. Endometriosis Endometriosis is a chronic disease in which there is uterine tissue outside the uterus, predominately in the pelvis. This tissue acts as normal endometrial tissues and responds to the hormonal changes of the cycle. As a result, endometriosis can cause pain and infertility. Around 25–50% of infertile women have endometriosis and 30–50% of women with endometriosis have issues with infertility. Caucasian women are more likely to have endometriosis and risk factors include smoking, alcohol use, and a low body mass index. Although endometriosis affects fertility, the mechanism in which it does so is unclear. Several mechanisms have been proposed but none have been proven indefinitely. Some mechanisms include a distorted pelvic anatomy, systemic and local inflammation, and decreased uterotubal transport capacity (Committee Opinion: Endometriosis and Infertility 2012a).

Unexplained Infertility Unexplained infertility is a diagnosis of exclusion and accounts for up to 30% of cases of infertility.

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All other explanations of infertility must first be ruled out prior to making this diagnosis. This includes proof of ovulation, proof of a normal uterine cavity and patent fallopian tubes, and a normal semen analysis. It is difficult to say if the cause of decreased fecundity in couples with unexplained infertility is due to a cause we have not identified or if the cause is one of the known explanations for infertility and it is just not picked up by the diagnostic tests performed. Unexplained infertility is more common in women >35 years old suggesting that age plays a role. Prognosis for a couple with unexplained infertility is poor without treatment. Without treatment, the conception rate for a couple with unexplained infertility is only about 20% after 5 years (Fritz and Speroff 2011).

Diagnosis The diagnosis of infertility is made when a couple has failed to achieve a successful pregnancy by 12 months of timed unprotected intercourse or therapeutic donor insemination. There are certain circumstances that warrant earlier evaluation. The American Society for Reproductive Medicine recommends evaluation of infertility for women 35 after 6 months of attempted conception and immediately for women 40 (Committee Opinion No. 589 2014a).

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Have you had any surgeries? (Previous laparoscopy for endometriosis for females, any testicular surgery for males) Are you taking any medications? (Chemotherapy, antiandrogens, birth control, ketoconazole, cimetidine) Do you smoke, drink alcohol, or use illicit drugs? Do you have any family history of birth defects or mental retardation? (May indicate genetic causes of infertility) Have you been pregnant before/have you fathered a child before? (Determine gravity and parity, and determine primary or secondary infertility, and male or female infertility). How long have you been trying to conceive? How often are you having intercourse? Have you had any previous infertility work up? Have you had infertility issues in a previous relationship? Do you have any history of sexually transmitted infections? (PID, gonorrhea, chlamydia)

A large proportion of the etiology of infertility can be determined from the couple’s history. The interview with the infertile couple generally takes place with both the male and female present for the interview. Below are questions that may be of benefit to determine the cause of infertility.

QUESTIONS SPECIFIC TO THE FEMALE At what age did you start your periods? How long are your cycles? Are they regular? (May indicate ovulatory dysfunction, regular cycle is 21–35 days). Do you have painful periods? (Dysmenorrhea many suggest endometriosis). Do you have pain with intercourse? (Dyspareunia may suggest endometriosis). Have you had any abnormal pap smears? What was the treatment? (May indicate cervical stenosis if prior excisional procedure or cryoablation). Do you know when you will menstruate? (Moliminal symptoms suggest ovulation). Have you had any miscarriages? Do you have a family history of early menopause? What have you used for birth control in the past? (Depo Provera has a longer time to conception after discontinuation)

QUESTIONS FOR BOTH MALE AND FEMALE Do you have any medical problems? (Endometriosis, polycystic ovarian syndrome, thyroid disease for females, cystic fibrosis, Klinefelter syndrome for males)

QUESTIONS SPECIFIC TO THE MALE Have you had a semen analysis before? What do you do for work? (Environmental exposures: pesticides or organic solvents, truck driving may cause infertility) Ever had mumps? Prior pregnancy in partner?

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Physical Exam The physical exam should include vitals, a body mass index, a thyroid exam, a breast exam with evaluation for galactorrhea, evaluation of excess androgens (hirsutism and acne), and a pelvic exam. The pelvic exam should include evaluation of cervical abnormalities and cervical or vaginal discharge, uterine contour, size and mobility, adnexal tenderness or fullness, and an evaluation of the cul-de-sac. Findings on exam that may point to endometriosis may include a fixed uterus, an adnexal mass (endometrioma), nodularity of the uterosacral ligaments, and overall tenderness on exam.

Diagnostic Tests Diagnostic evaluation should be cost efficient and timely. Tests that are both minimally invasive and high yield should be performed first. Diagnostic tests should also focus on the most likely cause of infertility based on the couple’s interview. Below is a discussion on diagnostic tests that are used to evaluate the most common causes of infertility.

Diagnostic Test for Ovulation Confirmation Although a good menstrual history is a good evaluation tool for ovulation, there are several tests to confirm ovulation. Ovulation Prediction Kits Ovulation predictor kits are available over the counter and can be purchased at most drug stores. These kits detect the luteinizing hormone (LH) surge as LH is excreted in urine. Patients are instructed to urinate on the test sticks, similar to a pregnancy test, in the afternoon or evening as the LH surge typically starts in the morning and cannot be detected by the test until a threshold has been reached. As the LH surge proceeds ovulation by 1–2 days, the test is useful in determining the time of greatest fertility in the cycle which is usually the day of the LH surge and the following day. The patient is instructed to have intercourse

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based on the positive result. Ovulation predictor kits not only confirm ovulation but have many other benefits. Ovulation predictor kits allow for women to be involved in their treatment and care, it is a relatively quick and easy test, and it allows for timed intercourse for couples who have infrequent intercourse. There are drawbacks to ovulation predictor kits as well. They can be expensive for some patients; depending on the brand, they can be difficult for the patient to interpret, and there is a chance of false positive and false negative test results (Committee Opinion: Diagnostic Evaluation of the Infertile Female 2015a). Basal Body Temperature Charts Basal body temperature (BBT) record is an inexpensive way to determine when ovulation occurs. The patient is instructed to take her temperature every morning prior to getting out of bed and document the result on graph paper. With the rise in progesterone following ovulation, the BBT will increase about 0.4–0.8 Fahrenheit and this can be appreciated on the chart. Ovulation usually occurs 4–5 days prior to the temperature change. Unfortunately the patient will not be aware that ovulation has occurred until a full cycle of temperatures are obtained. For this reason, the BBT charts are best used when data can be reviewed over several months. Patients should be instructed to have every other day intercourse for 7 days prior to the change in body temperature based cycle trends. Although this method is inexpensive for patients, it is tedious and takes time. For this reason, the American Society of Reproductive Medicine no longer recommends this evaluation as the best or preferred method to evaluate ovulatory function (Fritz and Speroff 2011 and Committee Opinion: Diagnostic Evaluation of the Infertile Female 2015a) (Fig. 1).

Serum Progesterone Serum progesterone levels have proven to be a reliable evaluation of ovulation. In the past, this level was typically drawn on cycle day 21. As cycle lengths vary greatly among women, this

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may be accurate for women with 28 day cycles, but will not be useful for women with shorter or longer cycles. For this reason, The American Society of Reproductive Medicine recommends that serum progesterone be drawn 1 week prior to the day of anticipated menses. A serum value >3 indicates ovulation has occurred. As a review, serum progesterone is low in the follicular phase and increases steadily after ovulation and again is low during menses. A serum progesterone level is the most commonly used test for confirmation of ovulation as it is easy and a reliable test (Fig. 2). Fig. 1 Basal body temperature chart

Diagnostic Tests for Tubal Patency Hysterosalpingogram A hysterosalpingogram or HSG is a procedure performed in the radiology department in which contrast is pushed into the uterine cavity. Fluoroscopic images are taken to determine if the dye introduced was able to exit the tubes which by confirming tubal patency. This procedure does not require any anesthesia or sedation and can be performed by either a trained radiologist or gynecologist. An acorn manipulator or a small tube is

Basal Body Temperature Chart 99.5 99 98.5 98 97.5 97 96.5 96

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Fig. 2 Progesterone in the menstrual cycle

Estrogen and Progesterone in the Menstrual Cycle Estrogen Progesterone

Follicular Phase

Ovulation

Luteal Phase

Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

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passed though the cervix to the internal os. Approximately 10 cc of contrast is all that is needed to obtain images. As the contrast is introduced, the patient may have mild discomfort but overall this procedure is tolerated quite well. Typically three images are obtained and there is minimal radiation exposure. An image is obtained when the dye fills the uterine cavity to document the shape and filling of the cavity. Additional pictures are taken as the dye fills the tubes and when the dye spills into the peritoneal cavity. When the dye enters the peritoneal cavity, it disperses creating a cloud like image on fluoroscopy, see below. If one or both of the tubes are occluded, this image will not be visualized. Either hydrosalpinx, or a dilation of the tube, and salpingitis isthmica nodosa, or thickening of the tube, can be appreciated on HSG. Both of these conditions are associated with infertility. Occasionally, one or both tubes can spasm during the procedure preventing the dye from passing though the tubes and giving the impression that one or both tubes are occluded. To prevent spasm, it is best to introduce the dye slowly. Atropine can also be given prior to the procedure for prevention. Nonsteroidal anti-inflammatory medications are frequently given prior to, or just following the procedure. The American Congress of Obstetricians and Gynecologists or ACOG recommends giving a 5 day course of doxycycline 100 mg BID if dilated tubes are seen on HSG or this course can be completed before the procedure in patients with a history of PID to prevent post procedure PID. If a patient has not had a history of PID, the procedure can be completed without the use of antibiotics (Practice Bulletin No. 1042009) (Fig. 3).

Chromotubation Chromotubation is similar to an HSG but is done at the time of surgery, most commonly at the time of a diagnostic laparoscopy. An acorn manipulator is placed though the cervix during an open or laparoscopic case. A blue dye, usually indigo carmine, is pushed into the uterine cavity through the acorn manipulator. The surgeon then watches

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Fig. 3 HSG picture showing hydrosalpinx

the fimbriae of the fallopian tubes for spillage of the blue dye, confirming patency. If no leaking of blue dye is observed, then the tube is occluded. Antibiotic recommendations by ACOG are the same for chromotubation as for HSG. Although chromotubation requires general anesthesia, it does have some benefits over HSG. Chromotubation is a more accurate test for tubal patency and as it is more invasive, lends itself to correction of identifiable problems. For example, tubal adhesions and tubal phimosis, an occlusion near the fimbriae, can be corrected at the time of surgery (Fig. 4).

Diagnostic Tests to Evaluate the Uterine Cavity Both a transvaginal ultrasound and HSG are common first line diagnostic tests to evaluate the uterine cavity. The diagnostic test of choice for evaluation of the endometrial cavity can be tailored to the patient’s history. If the patient has a history of fibroids, menorrhagia, or a family history of fibroids, a transvaginal ultrasound may be the most useful. If a patient has menorrhagia or intermenstrual bleeding suggesting a polyp, a sonohystogram would be the preferred method of evaluation. Below is a discussion of the different modalities available to evaluate the uterine cavity.

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Fig. 4 LSC image of chromotubation demonstrating tubal spillage

Transvaginal Ultrasound Transvaginal ultrasound (TVUS) is a quick and easy way to evaluate the uterus. It can easily identify uterine fibroids and can detect some uterine anomalies but MRI or 3-D ultrasound is usually best for detecting complex anomalies. Transvaginal ultrasound also has the benefit of evaluating the ovaries and can be done in the office. Although it will likely identify fibroids impinging on the uterine cavity, it is a poor detector of uterine polyps. As the uterine cavity is not expanded during a TVUS, polyps and adhesions can easily be missed. TVUS may also be helpful in distinguishing between a septate uterus and a bicornuate uterus by examining the shape of the fundus as a septate uterus will have a normal fundus and a bicornuate uterus will have a heart shaped fundus (Fig. 5).

Fig. 5 Vaginal ultrasound picture of septate uterus with normal fundus

Hysterosalpingogram Hysterosalpingogram or HSG can also be used to evaluate the uterine cavity. The procedure is described above, but the filling of the uterine cavity with contrast allows for evaluation of the uterine shape. An HSG can identify polyps, fibroids that protrude into the endometrial cavity, and uterine adhesions (Asherman’s syndrome). An HSG can also be helpful in diagnosing uterine anomalies, if the usual triangle shape of the uterine cavity is misshapen. If a bicornuate or septate uterus is suspected on HSG, again, a TVUS will be needed to determine the shape of the uterine fundus. Although an HSG can identify polyps and

Fig. 6 HSG demonstrating uterine anomaly

fibroids, it has a relatively low sensitivity and positive predictive value, 50% and 30%, respectively (Committee Opinion: Diagnostic Evaluation of the Infertile Female 2015a) (Fig. 6).

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Fig. 7 Sonohystogram demonstrating endometrial polyps

B. A. Gibson and J. Wilkerson

Fig. 8 Image of normal endometrial cavity

Sonohystogram A sonohystogram is an in-office procedure to evaluate the endometrial cavity. Similar to an HSG, the cervix is cannulated and saline is introduced into the endometrial cavity. A simultaneous TVUS is performed. The saline distends the normally compressed endometrial cavity and the saline appears dark, or anechoic, allowing the physician to see any abnormalities in the cavity including polyps, fibroids, and adhesions. Compared to an HSG and a TVUS, a sonohystogram is a better test for evaluating the endometrial cavity with a positive predictive value of >90%. It is also useful in identifying uterine anomalies, but once again other imaging like an MRI or 3-D TVUS may be needed. ACOG does not recommend routine antibiotic prophylaxis for this procedure but does recommend considering treatment based on the patient’s personal history of PID (Practice Bulletin No. 104 2009) (Fig. 7).

hysteroscopy over the other methods is that it allows for correction of the abnormality. Fibroids, polyps, and adhesions can be removed at that the time of the procedure. As a hysteroscopy is an invasive procedure, generally, an HSG, TVUS, or sonohystogram is performed first followed by a hysteroscopy to correct the findings on the preliminary diagnostic tests. In the recent past, hysteroscopy has become a common in-office procedure. As there is no need for general anesthesia or even sedation, this has become an increasingly popular trend. In-office hysteroscopy may become a more common first-line evaluation of the endometrial cavity in the infertile patient in years to come. As the postprocedure PID rate is low with hysteroscopy, ACOG does not recommend prophylactic antibiotic but antibiotics may certainly be considered based on the patient’s history of PID (Practice Bulletin No. 104 2009) (Figs. 8 and 9).

Hysteroscopy

Tests for Ovarian Reserve

Hysteroscopy is the most definite way to evaluate abnormalities in the endometrial cavity. It is a minor surgical procedure requiring general anesthesia in which the cervix is dilated and a camera is introduced through the cervix into the endometrial cavity and a survey of the cavity is performed. Fibroids, polyps, and adhesions are easily seen by the surgeon. The benefit of

As discussed previously, ovarian function, and therefore the fecundity rate decreases with increasing age. There are several indications to investigate ovarian reserve. These include age  35, a family history of early menopause, any history of ovarian surgery, a history of chemotherapy or pelvic radiation, a history of a unilateral oophorectomy, unexplained infertility, or

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aging. Estradiol is not useful alone and even when used with FSH is a poor prognostic tool for conception (Committee Opinion: Testing and Interpreting Measures of Ovarian Reserve 2015c).

Fig. 9 Image of polyp on hysteroscopy

plans to initiate artificial reproductive technology (Committee Opinion: Diagnostic Evaluation of the Infertile Female). The following tests are not diagnostic in nature, they simply give a prognosis. An important point to discuss with patients is that just because a lab in abnormal does not definitively mean that conception is impossible. These tests are also useful in determining appropriate treatments and success rates with artificial reproductive therapies.

Serum Follicle Stimulating Hormone Serum follicle stimulating hormone (FSH) and estradiol (E2) can be obtained on cycle day 2–4. An elevated FSH is one of the first signs of decreased ovarian reserve. Although different assays may have different cut-off values, a result >10 IU/L is generally considered elevated. As there is some fluctuation in FSH between cycles so this test can be repeated. Consistently elevated FSH levels often confer a poor prognosis for conception. Serum estradiol is drawn at the same time as the FSH and levels are only useful to interpret the result of the FSH level. With reproductive aging, estradiol levels increase earlier in the cycle. An elevated estradiol level, >60–80 pg/mL, may suggest that the patient is in the beginnings of ovarian

Antral Follicle Count The antral follicle count or AFC is a count of ovarian follicles by TVUS measured in the follicular phase. It is a total count of follicles measuring anywhere from 2 to 10 mm in mean diameter from both ovaries. Follicles with a mean diameter of one or less are not counted in the AFC. A value of less than 3–6 is considered low. It is important to note that polycystic ovarian syndrome or PCOS will increase the AFC and combined oral contraceptive pills can decrease the AFC (Committee Opinion: Testing and Interpreting Measures of Ovarian Reserve 2015c). Antimullerian Hormone Antimullerian hormone or AMH is produced by the granulosa cells in the antral follicles. The level of AMH produced by the granulosa cells decreases overtime until it ceases at menopause. It is a measure of the pool of remaining follicles; therefore, a low AMH is concerning for a decreased ovarian reserve. Unlike FSH, serum AMH can be drawn anytime during the cycle. AMH can be affected by exogenous estrogens including OCPs and even obesity. Women with PCOS have an elevated AMH, up to a threefold increase from the normal population. Generally, values less than one confer a poor prognosis for conception (Committee Opinion: Diagnostic Evaluation of the Infertile Female 2015a).

Other Laboratory Tests Thyroid stimulating hormone or TSH and a prolactin should be ordered in women with oligo or amenorrhea as this may be a contributing factor to the patient’s infertility. Both thyroid disorders and hyperprolactinemia are treatable conditions. If the patient has hirsutism along with anovulation, a testosterone, DHEA-S, and a 17-hydroxyprogesterone should also be ordered.

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Diagnostic Tests for Evaluation of Male Infertility Semen Analysis The semen analysis is the most important evaluation for male infertility. The specimen can be collected at home or in the office but if the specimen is collected at home, it needs to not only be kept at room temperature but also be evaluated within 1 h of ejaculation. The patient is also instructed to abstain for 2–5 days prior to collection. The volume, pH, concentration, total sperm number, motility, and morphology are then analyzed. The table below has normal reference ranges. Azoospermia is the absence of sperm, oligospermia is a concentration of 65 years of age increased the risks of coronary heart disease events, pulmonary embolism, and stroke (Rossouw et al. 2002). While hormone therapy

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should not be used for the primary or secondary prevention of cardiovascular disease, studies have not demonstrated mortality differences in women who do and do not take hormone therapy (Santoro et al. 2021). Estrogen replacement therapy is contraindicated in women with a history of breast cancer, liver disease, abnormal uterine or vaginal bleeding, estrogen-dependent cancer, history of deep venous thromboembolism, or pulmonary embolism. Women with a uterus taking systemic estrogen must take a progestin or uterine-level estrogen receptor antagonist to decrease the risk of endometrial hyperplasia and cancer. Estrogen preparations are available in transdermal, oral, vaginal, and topical emulsions/sprays. Additionally, hormone therapy is available in bioidentical, chemical preparations (i.e., 17β-estradiol) that mimic the action of the endogenous hormone, and conjugated forms (conjugated equine estrogen). Approved estrogen formulations for the treatment of vasomotor symptoms are listed in Table 1. Bazedoxifene is a selective estrogen receptor modulator (SERM) combined with conjugated estrogen (CE) approved by the FDA to treat vasomotor symptoms in women with an intact uterus. This combination of SERM and CE is termed tissue-selective estrogen complex (TSEC) and is designed to provide better treatment than either drug independently. BZA has agonist properties that promote bone growth and diminish hot flushes and antagonistic properties that inhibit uterine and breast tissue proliferation. The SMART-1 trial studied the effects of BZA/CE on vasomotor symptoms and demonstrated a 51–87% decrease in daily hot flush symptoms compared with a 0–17% decrease in the placebo arm (Lobo et al. 2009). BZA/CE demonstrated a similar adverse event profile compared with placebo. Bijuva is the first FDA-approved fixed-dose combination of bioidentical 1 mg 17β-estradiol and 100 mg progesterone in a single capsule. In the REPLENISH study, 1835 women were randomized to placebo or combination estradiol/progesterone capsule and found that 50–63% of women reported improvement in symptoms by week 4 of treatment compared with 33% for placebo. By week 12 of treatment, 73–82% of women had much improved vasomotor symptoms

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Table 1 Therapies for vasomotor symptoms Estrogen formulations Oral CEE (conjugated equine estrogens) Oral 17β-estradiol Oral synthetic estrogen Oral synthetic CEE Oral esterified estrogen Oral ethinyl estradiol 17β-Estradiol transdermal patch 17β-Estradiol transdermal gel 17β-Estradiol transdermal spray Combined formulations Oral cyclic CEE + MPA Oral 17β-estradiol + progesterone Oral 17β-estradiol + norgestimate Oral 17β-estradiol + drospirenone Oral continuous CEE + MPA Oral continuous 17β-estradiol + norethindrone acetate Oral ethinyl estradiol + norethindrone acetate 17β-Estradiol + progestina transdermal patch Oral CE + bazedoxifene Nonhormonal formulations Paroxetineb Serotonin-norepinephrine reuptake inhibitors Gabapentin Clonidine Neurokinin B (NK3) receptor antagonistc

Brand name(s)

Dosing

Premarin

0.3–1.25 mg/d

Estrace Enjuvia Cenestin Menest Estinyl Alora, Climara, Estraderm, Menostar, Vivelle-dot EstroGel, Estrasorb, Divigel, Elestrin Evamist

0.5–2 mg/d 0.3–1.25 mg/d 0.3–1.25 mg/d 0.3–1.25 mg/d 0.2–0.05 mg up to 3 times daily 0.014–0.1 mg/d 1–2x/wk 0.25–1 mg/d 1.53 mg/spray

Bijuva

0.625 mg/d CEE  14d then 0.625 mg/d CEE/5.0 mg/d MPA  14d or 2.5–5 mg daily 1 mg/100 mg daily

Ortho Prefest

1 mg  3d then 1 mg/0.09 mg  3d

Angelique

1 mg/0.5 mg daily

Prempro Activella

0.3–0.625 mg/d CEE and 1.5–5 mg/d MPA 0.5 mg/0.1 mg daily

FemHRT

5 mcg/1 mg daily

CombiPatch, Climara pro Duavee

0.05 mg E + 0.14 mg P 2x/wk 0.045 mg E + 0.014 mg P 1x/wk 0.45 mg/day + 20 mg/day

Paxil, Brisdelle Venlafaxine, Desvenlafaxine

7.5 mg/day 37.5–150 mg/day

Neurontin Catapres MLE4901, Fezolinetant

900 mg nightly 0.1–0.4 mg/day 40 mg twice daily 90 mg twice daily

Premphase, Prempro

CEE conjugated equine estrogen, mg/d milligrams per day, x/wk times per week, MPA medroxyprogesterone acetate, E 17β-estradiol, P progestin, CE conjugated estrogen a CombiPatch – progestin is norethindrone acetate, Climara Pro – progestin is levonorgestrel b Only FDA-approved nonhormonal therapy for vasomotor symptoms c Completed phase 2 clinical trials with significant improvement in vasomotor symptoms

with the combination pill compared with 53% taking placebo (Constantine et al. 2020). Progesterone therapy alone is not recommended for the treatment of bothersome vasomotor symptoms, though it may improve vasomotor symptoms when combined with estrogen, and alone has

shown suppression of hot flashes in add-back studies for women receiving Lupron for suppression of endometriosis. The duration of the recommended use of estrogen therapies is not concrete, and discontinuation of HRT results in return of vasomotor symptoms in up to half of

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Management of Menopausal Symptoms

women. Whereas patients were previously counseled not to continue treatment past age 65, the American College of Obstetricians and Gynecologists (ACOG) recommends that treatment duration be determined on a case-by-case basis, with the goal of treating for the shortest duration possible while taking into account a woman’s clinical picture and risk–benefit of continuing hormone therapy.

Nonhormonal Therapies The only nonhormonal FDA-approved medication for the treatment of vasomotor symptoms is paroxetine mesylate. Paroxetine reduces hot flushes in women without depression by nearly 30% (Simon et al. 2013). Selective serotonin reuptake inhibitors (SSRIs) generally improve symptoms after 8 weeks of treatment. While SSRIs are inferior to HRT in reducing vasomotor symptoms, these medications are a reliable alternative for women in whom hormonal therapy is contraindicated. Risk factors of SSRIs include a black box warning for possible suicidal ideation, along with other common side effects such as dry mouth, dizziness, and sexual dysfunction. Other nonhormonal therapies, including serotonin-norepinephrine reuptake inhibitors (SNRIs) clonidine and gabapentin, have demonstrated therapeutic benefits for vasomotor symptoms. Desvenlafaxine, an SNRI, decreased the number of hot flushes by 62% compared with 38% in the placebo arm of a randomized controlled trial and maintained a treatment effect for a year (Pinkerton et al. 2013). Trials evaluating clonidine have demonstrated a modest reduction of hot flush frequency ranging from 24% to 44% (Nelson et al. 2006). Women receiving gabapentin dose of 900 mg/day experienced a decreased number of vasomotor symptoms by roughly 45% in two trials (Guttuso et al. 2003). These therapies, however, have not demonstrated superiority to estrogen therapies and are currently not approved by the FDA for treatment. NK3R antagonists (fezolinetant, MLE4901) are currently in development with promising results for the treatment of vasomotor symptoms. Phase 2a trials of fezolinetant found that it

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significantly reduced the total vasomotor symptoms experienced by women from 39.0 episodes per week with placebo to 5.7 episodes per week with treatment (Depypere et al. 2021), and a phase 2b trial similarly showed a significant reduction in vasomotor episodes and improvement in qualityof-life measures (Santoro et al. 2020). The most common treatment-related side effects reported were mild gastrointestinal disorders. Studies of MLE4901 found vasomotor symptom frequency to be reduced by 72% compared with baseline (Prague et al. 2017). These compounds, if approved by the FDA, could provide a promising treatment option for women in whom hormone treatment is contraindicated.

Nonmedication Therapies Phytoestrogens, a group of plant-derived estrogen-like supplements found in soy and red clover, have not been demonstrated to effectively reduce hot flushes, and many studies have demonstrated a large placebo effect. The potential benefits of acupuncture have thus far not demonstrated a significant reduction in hot flushes compared with placebo in a randomized controlled trial. Herbal treatments of menopause include Chinese medicines dong quai and dang gui bu. xue tang, black cohosh, St. John’s wort, and ginkgo biloba. There are benefits of combining traditional Chinese medicine with acupuncture in treating vasomotor symptoms, and preliminary trials are attempting to demonstrate that these modalities are as effective as hormone therapy for decreasing hot flushes. However, some trials have suggested no benefits, and there are not enough data to demonstrate the efficacy and safety to support the routine use of these therapies. No study has convincingly demonstrated that exercise confers benefit to decrease vasomotor symptoms in menopause; however, it may improve the quality of life and mood. Other changes women can make to their daily lives to possibly improve symptoms include dressing in layers, drinking cold beverages, keeping a cooler living temperature, and avoiding possible triggers such as alcohol and caffeine.

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Genitourinary Syndrome of Menopause Genitourinary syndrome of menopause (GSM) encompasses the signs and symptoms related to changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and/or bladder that occur in menopausal women (Portman and Gass 2014). GSM is a highly variable but common condition, with prevalence estimates ranging from 27% to 85% of postmenopausal patients though women often do not discuss these bothersome symptoms with their healthcare provider (Kingsberg et al. 2017). GSM is caused, in part, by decreased estrogen receptor stimulation of the female reproductive tract as a result of menopause. This subsequently leads to architectural changes in the urogenital tract, including a loss of vaginal surface epithelium with a decrease in superficial cells and increased parabasal cells, decreased vaginal wall blood flow and, thus, decreased vaginal connective tissue hydration, soft-tissue atrophy of the vulva, and, eventually, vestibular narrowing. There is also a decrease in sebaceous gland secretions and an increase in vaginal pH, causing alterations in the vaginal flora and microbiome. Together, these changes lead to the constellation of common symptoms seen in GSM, including vulvar and/or vaginal dryness, burning, itching, dyspareunia, and/or uterine prolapse. Additionally, the lack of lubrication places women at higher risk of vaginal irritation and urinary symptoms, including urinary

incontinence and urinary tract infections (Levine et al. 2008). Hormonal Therapies: Estrogen therapy, both systemic and local, may help improve GSM. Low-dose systemic estrogen is approved for the treatment of persistent GSM; however, for women in whom vaginal dryness is the predominant complaint, local therapy is preferred (see Table 2). FDA-approved vaginal estrogen therapies include an estradiol ring, estradiol vaginal tablet/insert, estradiol cream, or conjugated estrogen cream (Table 2). Vaginal creams or tablets are used daily for 1–2 weeks and then once or twice a week thereafter, while rings are replaced once every 3 months. Overall, the estrogen therapy in ring form may provide the most patient satisfaction compared with creams and tablets, while tablets may be preferred to creams. Although there is a possible risk of endometrial hyperplasia or endometrial cancer due to systemic absorption of local estrogen therapy, all studies to date have been reassuring and the current data do not support a need for additional surveillance for endometrial cancer or routine use of progestin therapy for women utilizing vaginal estrogens. However, women with a history of breast cancer are not recommended to utilize vaginal estrogens as first-line therapy and should only try short-term and low-dose vaginal estrogen treatment for refractory symptoms and only after consultation with their oncologists. Nonhormonal Therapies: While not FDA-approved, typical first-line treatments for

Table 2 Local therapies for vaginal atrophy Estrogen formulations 17β-Estradiol ring 17β-Estradiol inserts 17β-Estradiol cream CEE cream SERM Ospemifene Other Dehydroepiandrosterone

Brand name

Dosing

E-string Vagifem Imvexxy Estrace cream Premarin cream

2 mg for 3 months 10–25 μg/d for 2 wk, then 2/wk 4–10 μg/d for 2 wk, then 2/wk 2 g/d for 2 wk, then 2/wk 0.5–2 g/d for 2 wk, then 2/wk

Osphena

60 mg/d

Intrarosa

6.5 mg/d

mg milligrams, μg micrograms, d day, wk week, g grams, CEE conjugated equine estrogen, SERM selective estrogenreceptor modulator

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GSM include vaginal moisturizers and lubricants. Lubricants and moisturizers come in water-based or silicone-based preparations and may alleviate vaginal dryness symptoms. Lubricants can be applied to the vulva, vagina, or partner’s penis prior to intercourse to decrease friction and irritation. Vaginal moisturizers are utilized to reduce itching, irritation, and dyspareunia, and can be applied from three times weekly to daily and help retain lubrication of the vaginal mucosa. Moisturizers do not need to be applied prior to intercourse, though they can help alleviate painful sex. The combination of a moisturizer with pre-intercourse application of lubrication may be beneficial for some women. Moisturizers are sold over the counter; hence, cost can be prohibitive for some patients. Additionally, the various lubricants and moisturizers available on the market may have a wide variation of ingredients with some adding preservatives and other additives to their products. SERMs have also demonstrated efficacy in the treatment of GSM by acting as agonists on the vaginal mucosa and increasing the number of superficial and intermediate cells. In the SMART-1 study, patients treated with BZA/CE reported improved dyspareunia compared with placebo treatment (Lobo et al. 2009). However, the only SERM approved by the FDA for the treatment of GSM is ospemifene. Studies have compared ospemifene with placebo and demonstrated improvement of vaginal atrophy with 30 and 60 mg daily compared with placebo and a reduction in dyspareunia with 60 mg/day (Bachmann and Komi 2010). The most common side effects noted with ospemifene are vasomotor symptoms, and though not common, there is a possible risk of endometrial proliferation. An additional nonhormonal option that has been FDA-approved for the treatment of moderate-tosevere dyspareunia and vaginal dryness in GSM is vaginal dehydroepiandrosterone (DHEA). DHEA is a corticosteroid hormone precursor that is metabolized to estradiol and testosterone by vaginal mucosal cells. It has been shown in several randomized controlled trials to improve symptomatic vaginal dryness and dyspareunia in menopausal women with GSM in addition to an improvement in vaginal epithelial surface

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thickness, epithelial integrity, and vaginal pH compared with placebo (Labrie et al. 2016). Additional treatment options that require more research include laser or radiofrequency devices, oral vitamins D and E, and vaginal probiotics. Dietary and compounded phytoestrogens, black cohosh, and herbal remedies have not demonstrated significant benefits in improving GSM.

Bone Strength Bone resorption increases with the decreasing estrogen levels that accompany the transition to menopause and leads to decreased bone mass, which, in turn, can lead to osteoporosis and increased fracture risk. Estrogen, calcium, and vitamin D play pivotal roles in maintaining bone health. Estrogen inhibits osteoblast production of RANKL, a ligand that binds RANK receptors on osteoclasts to stimulate activation and bone resorption. Estrogen also increases osteoblast production of osteoprotegerin (OPG), which inhibits RANKL. Thus, the decreasing estrogen levels of the menopause promote osteoclast resorption of bone. Adequate intake of calcium inhibits parathyroid hormone (PTH) breakdown of bone. However, aging leads to a decrease in calcium intestinal absorption and subsequently rising PTH hormone activates osteoclast activity to increase serum calcium and promote vitamin D production. Decreased estrogen also increases bone sensitivity to PTH. Vitamin D increases intestinal absorption of calcium and promotes renal calcium reabsorption. Thus, adequate vitamin D and calcium intake promote healthy bone mass density. Bone mass typically declines 2–5% per year during the first 10 years after menopause and then 1% yearly thereafter. The United States Preventative Services Task Force (USPSTF) and ACOG both recommend bone mineral density screening via dual x-ray absorptiometry (DEXA) scan in women >65 years or post /perimenopausal women with risk factors for osteoporosis. Risk factors for osteoporosis include early menopause (3 months), prior fragility fracture, high-fall risk, family history of osteoporotic fracture, and

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primary hyperparathyroidism. White race confers a higher risk of osteoporosis. The DEXA scan result of importance is the T score, which is the standard deviation from the peak BMD of an average, healthy, white female. The fracture risk assessment tool (FRAX) is another tool available to screen women for osteoporotic fracture risk. Medical therapy for osteoporosis is recommended for postmenopausal women who have had a vertebral or hip fracture, with a DEXA T score less than 2.5 or who have a T score between 1.0 and 2.5 and a 10 year FRAX major fracture risk of at least 20% or 3% hip fracture risk. Hormonal Therapies: Systemic estrogen treatment with or without progesterone promotes bone formation, decreases fractures, and is currently approved for the prevention of osteoporosis. Initiation of hormonal therapy for the prevention of osteoporosis is an added benefit for those

initiating hormone therapy for other menopause symptoms such as vaginal atrophy or hot flushes, though therapeutic benefits and risks can be compared with other pharmaceutical options. Estrogen therapy, with or without progesterone, is available in oral or transdermal patch forms and is approved for the prevention of osteoporosis (see Table 3). The Postmenopausal Estrogen/Progestin Interventions trial (PEPI) and the WHI study both demonstrated significantly increased spine and hip BMD with HRT (Cauley et al. 2003; Greendale et al. 1996). Combined estrogen/progestin formulations confer more than a 25% reduction in fracture risk. CE formulations are available in oral forms between 0.3 and 1.25 mg/ day and 17B-estradiol in patch forms between 0.025 and 0.14 mg/day. Combinations with progesterone include oral continuous cyclic or continuous combined (see Table 1). The TSEC

Table 3 Therapies for osteoporosis Brand name(s)

Dosing

Oral risedronate

Fosamax, Fosamax plus Da Actonel, Atelvia

Oral ibandronate

Boniva

IV ibandronate IV zoledronic acid

Boniva IV Reclast

Preventative: 5 mg/d or 35 mg/wk Treatment: 10 mg/d or 70 mg/wk (pill or solution) Preventative: 5 mg/d, 35 mg/wk Treatment: 35 mg/wk. DR, 75 mg/mo on two consecutive days, 150 mg/mo Preventative: 150 mg/mo Treatment: 150 mg/mo 3 mg every 3 months Preventative: 5 mg once every 2 years or 5 mg as single (one-time) dose Treatment: 5 mg/y

Bisphosphonates Oral alendronate

Hormonal formulations Systemic estrogens alone or with progestin CE + bazedoxifene SERM Raloxifene Monoclonal antibody SC denosumab Recombinant hPTH SC teriparatide Calcitonin Intranasal calcitonin SC or IM calcitonin

See Table 1 See Table 1 Evista

60 mg/d

Prolia

60 mg every 6 months

Forteo

20 μg/d

Fortical Miacalcin

200 IU/d 100 IU/d

mg/d milligrams per day, mg/wk milligrams per week, mg/mo milligrams per month, μ/d micrograms per day, SC subcutaneous, hPTH human parathyroid hormone, IM intramuscular a Contains vitamin D3 2800 IU/wk

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CE/bazedoxifene is approved for the prevention of osteoporosis and simultaneously treats vasomotor symptoms (0.045 CE + 20 mg). After discontinuation of estrogen therapy, bone mineral density begins to decrease within the first 1–2 years, often to levels similar to that of untreated patients by 5 years after discontinuation, and women may need to be placed on an alternate treatment method (Karim et al. 2011). The North American Menopause Society (NAMS) recommends utilizing the lowest effective dose for the desired treatment result. While there is no clearly delineated time when estrogen therapy should be initiated, commencing treatment earlier in menopause is encouraged. Nonhormonal Therapies: Bisphosphonates inhibit bone resorption by osteoclasts, decrease fracture risk, and were the first medications approved for both treatment and prevention of osteoporosis. Therapy with bisphosphonates in women with osteoporosis has demonstrated a 40–70% reduction in vertebral fracture risk and roughly 50% hip fracture risk reduction (McClung 2003). Bisphosphonates are the first-line therapy for the treatment of osteoporosis in postmenopausal women. Alendronate, risedronate, ibandronate, and zoledronic acid are the bisphosphonates approved by the FDA. Alendronate is available in oral solution or pill form in both treatment and preventative doses. Bisphosphonates have a favorable safety profile, with the main side effect being gastrointestinal upset, but also possible osteonecrosis of the jaw. Discontinuation of bisphosphonates after therapy of at least 5 years has a continued effect on BMD for an additional 5 years. Therapy duration with bisphosphonates is indeterminate. Contraindications to bisphosphonates include chronic kidney disease and esophageal disorders and should be avoided after Roux-en-Y gastric bypass surgeries. The SERM, raloxifene, is approved for the treatment and prevention of osteoporosis. In the MORE trial, 60 mg a day decreased vertebral fracture risk by 39% over 4 years (Delmas et al. 2002). Raloxifene may also confer a reduction in breast cancer risk, particularly in those with a family history of breast cancer. Raloxifene is best suited for younger women as it may increase venous clot and stroke risk.

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Denosumab, a monoclonal antibody against RANK-L that inhibits osteoclast activation and proliferation, is approved for the treatment of osteoporosis. The FREEDOM trial demonstrated that 60 mg of subcutaneous denosumab administered once every 6 months significantly decreased hip and nonvertebral fracture risk by 40% and 20%, respectively (Cummings et al. 2009). Common adverse reactions include eczema and cellulitis at the site of injection. Recombinant human parathyroid hormone 1–34, teriparatide, is approved for the treatment of women at high risk of osteoporosis. Teriparatide promotes bone growth via anabolic effects by recruiting osteoblasts and decreasing osteoblast death. This therapy demonstrated more than a 60% decrease in vertebral and nonvertebral fracture risk (Neer 2001). Therapy duration, however, is limited to 2 years as there is a risk of bone malignancy and osteosarcoma, and alternate therapy is typically swiftly indicated as BMD quickly decreases after cessation of teriparatide. Calcitonin inhibits calcium reabsorption from bone by osteoclasts and decreases the risk of vertebral fractures. It is a protein, and thus at risk of degradation in the stomach; hence, pharmaceutically it is available in nasal, intramuscular, or subcutaneous preparations. This therapy is indicated for the treatment of osteoporosis in women greater than 5 years from their last menstrual period. Calcitonin is not considered a first-line drug by the NAMS as it is less efficacious than alternative therapies. Calcitonin is derived from salmon, and at available doses 200 IU/day intranasally, or 100 units SC or IM every other day. It also has an analgesic effect on osteoporotic fractures. Typical side effects include local site reactions. Calcium, vitamin D, exercise, and a balanced diet are recommended for the prevention of osteoporosis in postmenopausal women. The WHI demonstrated that women who reliably took daily calcium 1000 mg and 400 IU vitamin D had a significantly reduced risk of hip fracture (Jackson et al. 2006). Calcium supplementation, however, may increase the risk of cardiovascular disease by depositing in vessels and increasing plaque thickness and is associated with other

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side effects, including gastrointestinal upset and kidney stones. Studies evaluating the risk of MI, stroke, and sudden death with calcium supplementation are ongoing. Currently, as per the Institute of Medicine (IOM), the recommended calcium intake is 1200 mg/day for women 51 years of age or older and for vitamin D is 600 IU/day up to age 70. After the age of 70, women should increase their uptake to 800 IU daily. The total intake of calcium should not exceed 2000 mg/day due to the risk of nephrolithiasis, cardiovascular disease, dyspepsia, and constipation. Examples of calcium-rich foods include milk, low-fat plain yogurt, orange juice, salmon, baked beans, and so on. Vitamin-D rich foods include egg yolks, saltwater fish, liver, and fortified milk. Regular exercise may improve BMD, not simply due to weight-bearing on specific bone areas but also due to the improvement in balance, flexibility, and muscle tone.

Libido A decrease in female sexual activity and desire is associated with increasing age and the menopausal transition, Important determinants of sexual well-being in the elderly include the availability of a satisfactory partner and adequate physical health. A major contributor to sexual dysfunction in postmenopausal women is vulvovaginal dryness and irritation, affecting >50% of postmenopausal women who complain of impaired sexual function (Levine et al. 2008). Additionally, the decreased levels of estradiol, as well as testosterone seen with age, are also thought to contribute to declining sexual function. Other risk factors for dyspareunia include chronic pelvic pain, pelvic organ prolapse, arthritis, fibromyalgia, and prior gynecological surgery as it can shorten the vagina. A number of social factors may also contribute to decreased libido in postmenopausal women, including increased stress, smoking, and alcohol use. Hormonal Therapies: Both estrogen and testosterone replacement may improve sexual function and mood in postmenopausal women. Testosterone therapy, typically administered transdermally at a

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dose of 300 mcg/day, with or without concurrent estrogen replacement has shown modest benefits on sexual desire and satisfaction. The APHRODITE study, a double-blind placebo-controlled trial, highlighted that testosterone therapy increased enjoyable sexual experiences by 13% compared with placebo (Davis et al. 2008). However, testosterone replacement therapy is not currently FDA-approved for the treatment of libido in postmenopausal women due to the lack of longterm safety data. Nonhormonal Therapies: As noted above, daily vaginal DHEA use has been FDA-approved for the treatment of moderate-to-severe dyspareunia in menopausal women with GSM. The mechanism of action remains unknown, though this may act by promoting local metabolism to androgens and estrogens. Additionally, although only currently FDA-approved for the treatment of hypoactive sexual desire disorder in premenopausal women, the two new pharmaceutical agents bremelanotide (Vyleesi) and flibanserin (Addyi) may also help treat low libido in postmenopausal women, though more data are needed. Bremelanotide is a melanocortin receptor agonist that acts on receptors in the central nervous system, and flibanserin is a 5-HT1A receptor agonist and 5-HT2A antagonist. Additionally, cognitive behavior therapy (CBT) and/or couple’s counseling may elevate libido and sexual drive by identifying the possible underlying physical or psychological barriers to fulfilling sexual encounters. Lifestyle changes, including healthy diet modifications, reduced alcohol intake, cessation of smoking, and relaxation exercises, may improve sexual functioning as well.

Neuropsychological Changes Social, cultural, and hormonal factors have been associated with mood and cognitive changes that accompany the menopause transition. Women who have higher estradiol level spikes during the transition to menopause may be at higher risk of depression. There are many changes that accompany menopause, one being that women can no longer conceive, which in itself may trigger mental anxiety and depression. A longitudinal

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analysis of the Massachusetts Women’s Health Study suggests that a history of depression is the most common risk factor for future depression. They also demonstrated that a lengthier transition to menopause (27 months or greater) was associated with depression but likely due to an increase in menopausal symptoms (Avis et al. 2001). A large US population-based study found that vasomotor symptoms of menopause can cause a substantial burden on women’s lives, interfering with work, social activities, leisure activities, sexual activity, sleep, mood, concentration, total energy level, and overall quality of life (Williams et al. 2009). Older premenopausal women are more likely to become depressed if they are nulliparous, smokers, or are no longer with a spouse. Different cultures harbor their unique attitudes toward menopause, which may influence how women feel as physiological changes occur. Cognitive changes such as impaired function and memory are associated with age but may also be due to hormonal changes. Impaired sleep may also accompany menopause and result in poor cognition, irritability, and depressed symptoms. Sleep difficulties related to menopause are often due to hot vasomotor symptoms but can also be related to age-related physical changes such as pharyngeal narrowing, lighter sleeping, chronic health conditions, and restless sleep partners.

Hormonal Therapies Some studies suggest that the treatment of vasomotor symptoms alleviates disruption of sleep and elevates mood, thus making systemic estrogen therapies and TSECs possible therapies to improve the quality of life in postmenopausal women. It was previously thought that women’s higher risk of dementia was due to lower postmenopausal estrogen levels and loss of estrogen’s protective effects on the brain. Thus, it was previously hypothesized that hormone therapy could potentially enhance cognition and mood if administered at menopause. This was evaluated by the WHIMS study, which investigated the effect of combined estrogen and progestin on the incidence of dementia and cognition. They found that

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combined hormone therapy actually doubled the risk for probable dementia and did not prevent cognitive impairment (Schumaker et al. 2003). However, the KEEPS-Cog study evaluated the cognitive and mood effects of 4 years of hormone treatment and found that menopausal hormone treatment was neither harmful nor beneficial for cognition. In addition, they found that treatment with oral CEEs did improve depression and anxiety symptoms, demonstrating that estrogens positively influence serotonergic neurotransmitters involved in mood regulation (Gleason et al. 2015). While some women may present with disruption of sleep or depression and presenting symptoms, underlying vasomotor symptoms may be the culprit and treatment with therapies as described above may subsequently resolve sleep and psychological disturbances. As noted above, treatment with hormonal therapies should be individualized for the shortest needed time of treatment for symptomatic relief.

Nonhormonal Therapies Sleep aids may help improve insomnia and quality of life. Sleep aids, aside from improving sleep in peri- and early postmenopausal women, can enhance mood, menopause-related symptoms, and quality of life. Antidepressant medications, along with therapy and counseling, may improve symptoms of depression in postmenopausal females. Women not on estrogen therapy who suffer from depression can benefit from SSRIs or SNRIs for treatment.

Conclusion Menopause is a period marked by estrogen depletion that can lead to deleterious side effects that affect women physically and emotionally. There are many different therapies, both hormonal and nonhormonal, available to treat symptoms of menopause. Choosing the appropriate therapy for a patient should be based on the patient’s individual symptoms, medical history, and goals

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of care. A general rule for treating vasomotor spasms and vulvovaginal complaints, the most common bothersome symptoms of menopause, is that the lowest dose of therapy results in the lowest risk of side effects such as bleeding problems. Estrogen and progestin therapies benefit bone health and are FDA-approved for the prevention of bone loss and osteoporosis. Women should be asked about the symptoms related to menopause by their providers at each visit to evaluate the need for management initiation, change of dose, and for a discussion of the benefits and risks of continued use of HRT.

References Avis N, et al. Longitudinal study of hormone levels and depression among women transitioning through menopause. Climacteric. 2001;4(3):243–9. Bachmann G, Komi J. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Ospemifene Study Group. Menopause. 2010;17:480–6. Barnabei V, et al. For the Women’s Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol. 2005;105:1063–73. Cauley J., For the Women’s Health Initiative Investigators, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729– 1738. Constantine G, Simon J, Kaunitz A, Pickar J, Revicki D, Graham S, Bernick B, Mirkin S. TX-001HR is associated with a clinically meaningful effect on severity of moderate to severe vasomotor symptoms in the REPLENISH trial. Menopause. 2020;27(11):1236–41. Cummings S, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65. Davis S, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008;359:2005–17. Delmas P, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year rsults from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87(8):3609–17. Depypere H, Lademacher C, Siddiqui E, Fraser GL. Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs. 2021;30(7):681–94. Feldman S, et al. Two-year follow-up of 263 patients with post/perimenopausal vaginal bleeding and negative initial biopsy. Gynecol Oncol. 1994;55:56–9.

M. Conklin et al. Gleason C, Dowling N, Wharton W, Manson J, Miller V, Atwood C, Brinton E, Cedars M, Lobo R, Merriam G, Neal-Perry G, Santoro N, Taylor H, Black D, Budoff M, Hodis H, Naftolin F, Harman S, Asthana S. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS–cognitive and affective study. PLoS Med. 2015;12(6):e1001833. Greendale G, et al. For the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) Investigators. Sexual functioning in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. J Women’s Health. 1996;5:445–58. Guttuso T, et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337–45. Jackson R., For the Women’s Health Initiative Investigators, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669–683. Karim R, et al. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause. 2011;18:1172–7. Kingsberg SA, Krychman M, Graham S, et al. The women’s EMPOWER survey: identifying women’s perceptions on vulvar and vaginal atrophy and its treatment. J Sex Med. 2017;14(3):413–24. Labrie F, Archer DF, Kolton W, et al. VVA Prasterone Research Group, Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and the genitourinary syndrome of menopause. Menopause. 2016;23:243–56. Levine K, et al. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. N Engl J Med. 2008;359(19):2005–17. Lobo R, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–38. McClung M. Bisphosphonates. Endocrinol Metab Clin N Am. 2003;32:253–71. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, McMullen NT, Rance NE. Role for kisspeptin/ neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci U S A. 2012;109(48): 19846–51. Neer R. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434– 41. Nelson H, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–71. Pinkerton J, et al. Maintenance of the efficacy of desvenlafaxine in menopausal vasomotor symptoms:

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a 1-year randomized controlled trial. Menopause. 2013;20:38–46. Portman DJ, Gass ML. Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Maturitas. 2014;79(3):349–54. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10081): 1809–20. Rapkin A. Vasomotor symptoms in menopause: physiologic condition and central nercous system approaches to treatment. Am J Obstet Gynecol. 2007;192(2):97– 106. Rossouw J, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33. Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser G, Lademacher C, Skillern L, Young J, Ramael S. Effect of the neurokinin 3 receptor antagonist fezolinetant on

613 patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020;2:1350–6. Santoro N, Roeca C, Peters B, Neal-Perry G. The menopause transition: signs, symptoms, and management options. J Clin Endocrinol Metabol. 2021;106(1):1–15. Shumaker S, Legault C, Rapp S. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative memory study: a randomized clinical trial. JAMA. 2003;289(20):2651–62. Simon J, et al. Low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013;20:1027– 35. Slopien R, et al. Relationship between climacteric symptoms and serum serotonin levels in postmenopausal women. Climacteric. 2003;6(1):53–7. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009;62(2): 153–9.

Diagnosis and Management of Postmenopausal Bleeding

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Trevin C. Lau, Tina O’Shea, and Lisa B. Spiryda

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Risk Factors for Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 Diagnostic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History and Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Pap Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621

Abstract

T. C. Lau Massachusetts General Hospital, Boston, MA, USA e-mail: [email protected] T. O’Shea Obstetrics and Gynecology, University of Florida, College of Medicine, Gainesville, FL, USA e-mail: t.oshea@ufl.edu L. B. Spiryda (*) Obstetrics and Gynecology, Phelps Hospital-Northwell Health; Zucker School of Medicine at Hofstra/Northwell, New York, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_46

Postmenopausal bleeding refers to any uterine bleeding that occurs after a woman reaches menopause and accounts for up to 5% of gynecological office visits. Excluding an endometrial malignancy is the key component to the workup. Ultimately, the management of these patients is dictated by the diagnosis. The differential diagnosis ranges from gynecological causes to nongynecological causes, including urological and gastrointestinal etiologies.

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Presentation

Keywords

Postmenopausal bleeding · Endometrial hyperplasia · Endometrial cancer · Endometrial polyp · Urogenital atrophy · Endometrial biopsy · Transvaginal ultrasound · Endometrial thickness

Introduction Postmenopausal bleeding is a common gynecological complaint occurring in 5–10% of postmenopausal women. The differential diagnosis includes urogenital atrophy, genital tract lesions, endometrial polyps, endometrial hyperplasia or malignancy, medications, as well as nongynecological sources of bleeding (Table 1). Evaluation should focus on excluding uterine malignancy, which accounts for about 10% of postmenopausal bleeding cases and may be lethal if not identified and treated at an early stage. Management depends on the underlying cause. This chapter offers guidance on the diagnostic evaluation and management of postmenopausal bleeding.

Table 1 Differential diagnosis of postmenopausal bleeding Gynecological

Urological

Gastrointestinal

Medications Others

Endometrial polyp Urogenital atrophy Endometrial hyperplasia Uterine cancer Endometritis Uterine fibroid Endocervical polyp Cervicitis Cervical cancer Estrogen-secreting ovarian cancer Urinary tract infection Urethral caruncle/polyp Urological cancer Hemorrhoids Diverticulitis Inflammatory bowel disease Gastrointestinal cancer Hormone therapy Anticoagulation therapy Trauma Foreign body

Postmenopausal bleeding (PMB) refers to bleeding from the genital tract in a menopausal woman. Patients present with “vaginal” bleeding that varies in quantity, quality, and duration. Patients may complain of one episode of brownish spotting, recurrent red staining, or several days of heavy bleeding resembling a menses. Bleeding may arise from the vulva, vagina, cervix, endometrium of the uterus, and fallopian tubes. Bleeding from the urinary tract or gastrointestinal tract may be confused for vaginal bleeding, and a detailed history and physical exam are necessary to discern the source of bleeding. PMB may also be occult in women with cervical stenosis; these patients may present with pelvic pain and are found to have hematometra on imaging.

Epidemiology About 10% of women experience PMB, and the chance of occurrence is highest within the first year after menopause (Astrup and Olivarius 2004). This complaint accounts for 5% of gynecology visits. The overall incidence of endometrial cancer in women with PMB is approximately 5–10% (Moodley and Roberts 2004; Burbos et al. 2010, 2012) and can be as high as 25% in patients with pertinent risk factors and increasing age.

Risk Factors for Endometrial Cancer Age, excess estrogen exposure, hypertension, diabetes, family history, and certain genetic syndromes are well-described risk factors for the development of endometrial cancer (Table 2). The incidence of endometrial cancer is low before age 50 and peaks in the 60s. Excess estrogen exposure may be endogenous (early menarche, late menopause, nulliparity, obesity, chronic anovulation) or exogenous (unopposed estrogen therapy, tamoxifen). Hypertension and diabetes have been shown to

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Table 2 Risk factors for endometrial cancer Risk factor Older age Hypertension Diabetes Estrogen exposure endogenous Early menarche Late menopause Nulliparity Obesity Chronic anovulation Estrogen-secreting tumor Estrogen exposure exogenous Unopposed estrogen therapy Tamoxifen Family history Lynch syndrome

Estimated relative risk 2–3 1.3–3 1.3–3

1.5–2 2–3 3 2–5 1.5 >5 10–20 2–3 1.3 6–20

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uterine cancer, hormone therapy, and endometritis. Leiomyomas (uterine fibroids) could cause PMB; however, this is a less likely cause given that leiomyomas generally become quiescent after menopause. Although the vast majority of leiomyomas are benign, a malignant leiomyosarcoma should be suspected when a patient presents with PMB and a rapidly enlarging fibroid. Cervical polyps, cervicitis, cervical cancer, and the rare estrogen-secreting ovarian cancer may also cause PMB. Trauma or the presence of a foreign body in the lower genital tract could also be a source of bleeding. Nongynecological causes include urethral caruncle or polyp, urinary tract infection, urological malignancy, diverticulitis, inflammatory bowel disease, gastrointestinal malignancies, and current use of anticoagulation.

Adapted from ACOG Practice Bulletin Number 149

Diagnostic Evaluation be risk factors independent of their association with obesity. Family history of endometrial cancer appears to confer a slightly higher risk compared with the general population. Lynch (formerly HNPCC) syndrome, an autosomal-dominant condition caused by a mutation in a mismatch repair (MMR) gene, is associated with a 40–60% lifetime risk of endometrial cancer (American Society of Clinical Oncology 2020). In contrast, the use of hormonal contraceptives – including combined oral contraceptive pills, depot medroxyprogesterone acetate (Depo-Provera ®), and levonorgestrel intrauterine device (Mirena ®) – decreases the risk of endometrial cancer.

Etiology The causes of PMB can be categorized into gynecological and nongynecological (Table 1). The most common gynecological cause is urogenital atrophy, which can account for upward of 50% of cases, but this is the diagnosis of exclusion. Other causes include endometrial polyps, followed by endometrial hyperplasia (with or without atypia),

Evaluation of PMB should focus on determining the cause and excluding endometrial hyperplasia or malignancy. An outpatient workup includes obtaining a history, physical examination, and endometrial evaluation. A diagnostic Pap test should be included in the initial workup because cervical cancer also may present with PMB.

History and Physical Examination A thorough history narrows the differential diagnosis and should cover • Onset, quantity, quality, duration, and pattern of bleeding • Presence of associated symptoms such as weight changes, fevers, abdominal pain, pelvic pressure, and urinary or bowel function disturbances • Precipitating factors such as trauma • Use of foreign bodies such as pessaries • Medical history and medical comorbidities • Medications (e.g., hormone therapy, selective estrogen receptor modulators, anticoagulants) • Family history of endometrial, colon, and breast cancer

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A focused examination may localize the source of the bleeding to the lower genital tract and should include inspection of the external genitalia, urethral meatus, vagina and cervix for atrophy, inflammation, lesions, trauma, and foreign body. Bimanual palpation of the upper genital tract should assess the size and contour of the uterus, presence of adnexal masses, and presence of uterine or adnexal tenderness. Additionally, a rectovaginal exam should be considered to assess for rectal masses if the history indicates this. Urinalysis, cystoscopy, and colonoscopy may help differentiate if the source of the vaginal bleeding is nongynecological.

Endometrial Evaluation Assessment for endometrial malignancy is paramount to the evaluation of PMB and is the main diagnostic goal. There are two strategies supported by the American College of Obstetrics and Gynecology (Practice Bulletin 2015; ACOG

2018) for the initial evaluation of the endometrium endometrial biopsy and/or transvaginal ultrasound (Fig. 1). Outpatient endometrial biopsy is a minimally invasive method of obtaining a histopathological sample of endometrial tissue. This office procedure is generally well tolerated and requires little or no anesthesia; thus, it has largely replaced the more expensive, operating room-based dilation and curettage (D&C) procedure. While several endometrial suction devices for endometrial sampling exist, the Pipelle® low-pressure endometrial suction curette has been shown in a meta-analysis to have the highest sensitivity of 99.6% in detecting endometrial cancer and 82% in detecting endometrial hyperplasia with atypia (Dijkhuizen et al. 2000) with a low complication rate. Endometrial biopsies are not sensitive for diagnosing structural abnormalities such as endometrial polyps and leiomyomas. The alternative in the initial evaluation is a transvaginal ultrasound (TVUS). TVUS is a noninvasive test that measures the maximal thickness of the endometrial lining from one basalis layer to

Postmenopausal bleeding (PMB) start with 1 test

Transvaginal ultrasound (TVUS)

Endometrial biopsy (EMB)

EMB negative

EMB positive

EMB insufficient

Expectantly manage / treat underlying cause

Treat hyperplasia/cancer

Perform TVUS

Persistent PMB

Endometrial thickness ≤4mm

Endometrial thickness >4mm, heterogeneity or focal thickening

Perform TVUS, consider hysteroscopy D&C

Expectantly manage / treat underlying cause

Perform hysteroscopy D&C

Persistent PMB

Fig. 1 Endometrial evaluation in postmenopausal bleeding

Endometrial thickness ≤4mm

Expectantly manage / treat underlying cause

Persistent PMB

Endometrial thickness >4mm, heterogeneity, or focal thickening

Perform EMB

EMB negative

EMB positive

Expectantly manage / treat underlying cause

Treat hyperplasia/cancer

Persistent PMB

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the opposing layer in the anteroposterior dimension with a sagittal view of the uterus. Fluid within the uterine cavity is excluded from the endometrial thickness measurement. Studies have shown that an endometrial thickness of 4 mm in symptomatic patients has a sensitivity and specificity of about 95% and 50% in detecting endometrial cancer and a negative predictive value of >99% in excluding endometrial cancer (Hanegem et al. 2011). Limitations do exist for this method, including prior uterine surgery, obesity, adenomyosis, and leiomyoma, that may all obscure the endometrial canal. When initial evaluation with TVUS recognizes an endometrial thickness of 4 mm, a follow-up endometrial biopsy is not necessary given the low risk of malignancy, unless otherwise clinically indicated. An endometrial thickness >4 mm does not diagnose endometrial cancer but cannot be used to exclude malignancy. Additionally, the finding of any focal thickening or heterogeneity in the endometrial lining should warrant further evaluation. Saline infusion sonography can be used as an adjuvant to TVUS (Smith et al. 2014). The American College of Obstetricians and Gynecologists supports the use of either TVUS or endometrial biopsy for initial endometrial evaluation. TVUS is better tolerated in nulliparous women, women with severe vaginal atrophy, or those with cervical stenosis (ACOG 2015, 2018). Both tests do not need to be performed together as the initial diagnostic approach. However, if an initial TVUS shows an endometrial thickness of >4 mm, heterogeneity, or focal thickening, then a follow-up endometrial biopsy is indicated. Likewise, if an initial endometrial biopsy is insufficient for diagnosis, then a follow-up TVUS is indicated. TVUS cannot be reliably used to identify type II endometrial cancers (uterine sarcomas, adenocarcinoma); in these cases, the endometrial echo complex can be thin and homogenous (Wang et al. 2006). Importantly, if an initial TVUS shows the endometrial thickness as 4 mm but the patient has persistent PMB, an endometrial biopsy should be performed. When the findings from both TVUS and endometrial biopsy are insufficient to exclude

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malignancy, a biopsy cannot be performed secondary to cervical stenosis or patient intolerance, or when the patient has recurrent bleeding (even in the setting of a negative endometrial biopsy and reassuring TVUS), the endometrium should be further evaluated with hysteroscopy and D&C. Hysteroscopy directly visualizes the endometrial cavity for focal lesions and allows for lesionspecific biopsy or excision. D&C allows for a more complete and systematic sampling of the endometrial cavity, which cannot be accomplished with a Pipelle aspirator. These procedures may be done concomitantly in the office or in the operating room, depending on provider and patient preference, availability of resources, and anesthesia requirement. Hysteroscopy has the theoretical risk of dissemination of malignant cells by flushing endometrial tissue through the fallopian tubes into the peritoneal cavity during uterine cavity distention, but studies to date have not validated this theoretical concern. Prognosis and survival for women with endometrial cancer who have undergone hysteroscopy prior to their cancer treatment (Ben-Arie et al. 2008; Takac and Zegura 2007) are not worsened. Hysteroscopy remains an important diagnostic tool in women with PMB when indicated.

Diagnostic Pap Test All women with PMB should have a diagnostic Pap test with concurrent HPV testing performed to assess for cervical cancer, if one has not been performed in the past year, or if there are any concerning findings on physical exam. Abnormal Pap test cytology and subsequent pathology from the colposcopy-directed biopsies (and endocervical curettage) should be managed according to the current American Society for Colposcopy and Cervical Pathology guidelines. Any gross lesions or masses identified should be directly biopsied even if cervical cytology is normal. The evaluation of the cervix should not preclude or eliminate the evaluation of the endometrial cavity outlined above to exclude endometrial cancer.

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Management Management of postmenopausal bleeding ultimately depends on the suspected cause (Table 3). Diagnosis of endometrial cancer warrants prompt referral to a gynecological oncologist for a total hysterectomy (bilateral salpingo-oophorectomy and possible lymph node dissection). The approach of the hysterectomy (laparoscopic or open) depends on multiple factors, including prior surgical history, uterine size, comorbidities, extent of disease, and surgeon preference. Endometrial intraepithelial neoplasia diagnosed on endometrial biopsy warrants further evaluation with a hysteroscopy and D&C, given the high risk of concurrent endometrial adenocarcinoma (up to 40%) (ACOG Committee Opinion 631) (Trimble 2006). Treatment of endometrial intraepithelial neoplasia once malignancy is excluded should involve a total hysterectomy with consideration of bilateral salpingo-oophorectomy since it is considered a precancerous lesion and carries a high risk of Table 3 Treatment of postmenopausal bleeding based on diagnosis Diagnosis Endometrial cancer

Endometrial intraepithelial neoplasia

Benign endometrial hyperplasia Leiomyosarcoma suspected Endometrial or cervical polyp Urogenital atrophy Symptomatic

Asymptomatic Endometritis Nongynecological causes a

Treatment Hysterectomy with BSO +/ lymph node dissection Referral to gynecology oncology Consider referral to gynecology oncology Hysterectomy with BSOa Progestin therapy (poor surgical candidates) Progestin therapy Hysterectomy with BSO Referral to gynecology oncology Hysteroscopy with polypectomy Vaginal moisturizers or lubricants Vaginal estrogen therapy Expectant management Doxycycline Appropriate referral

BSO bilateral salpingo-oophorectomy

progression to endometrial cancer (Kurman et al. 1985). Alternatively, patients who are poor surgical candidates, or desire future fertility, can consider management with either systemic or localized (levonorgestrel intrauterine device) progesterone therapy with surveillance endometrial sampling. Progression to endometrial cancer without treatment is 25–30%. Conservative management of EIN should be done in consultation with a gynecological oncologist. Benign endometrial hyperplasia is generally treated with either systemic or localized progesterone therapy. Progression to cancer for benign endometrial hyperplasia is 1–3%. Diagnosis of endometrial hyperplasia (benign or endometrial intraepithelial hyperplasia) with no source of exogenous or endogenous estrogen excess warrants evaluation for an estrogen-producing tumor (ovary, adrenal gland), given that menopause is an estrogen-depleted state. When leiomyosarcoma is suspected in the setting of PMB and a rapidly enlarging fibroid, a total hysterectomy with bilateral salpingooophorectomy is recommended. The diagnosis of a uterine sarcoma can only be made on histopathology; no imaging test can reliably exclude a leiomyosarcoma. A negative endometrial biopsy is insufficient for excluding a uterine sarcoma as this type of malignancy is most often found deep in the endometrial lining. Once hyperplasia and malignancy have been excluded, many cases of PMB tend to be selflimited and may be expectantly managed. Women with PMB secondary to endometrial or endocervical polyp(s) should be counseled for the removal of the polyps. The vast majority of endometrial and endocervical polyps are benign, but malignancy within a polyp is found in approximately 5% of symptomatic, postmenopausal women. A hysteroscopy with polypectomy can be done in either an office setting under local anesthesia or as an outpatient in the operating room, depending on surgeon and patient preference and the extent of polyps. Women diagnosed with endometritis on endometrial biopsy should be treated with a course of doxycycline 100 mg BID  7 days.

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Diagnosis and Management of Postmenopausal Bleeding

Women with symptomatic urogenital atrophy tend to have vaginal irritation or dyspareunia in addition to light bleeding. Treatment strategies include vaginal moisturizers and lubricants and topical estrogen therapy (vaginal suppositories, rings, creams). Additionally, these patients may benefit from pelvic physical therapy. Patients should be counseled that any persistent or recurrent bleeding should be reported to their physician for further evaluation, even if the initial evaluation was benign. All tests for endometrial evaluation have false-negative rates; therefore, further assessment of the endometrium is warranted with a hysteroscopy for direct visualization of the endometrial cavity, directed biopsies, and a thorough curettage of the entire cavity. Moreover, both nonendometrial and nongynecological sources of the bleeding should be carefully explored.

Conclusion Postmenopausal bleeding is a common gynecological complaint that warrants a thorough workup to exclude an endometrial (and cervical) malignancy. Once cancer has been excluded, treatment should be tailored to the specific etiology, ranging from expectant management to topical vaginal estrogen therapy for urogenital atrophy and surgical management for endometrial polyps and endometrial hyperplasia with atypia. Recurrent and persistent bleeding should be managed aggressively.

Cross-References ▶ Endometrial Hyperplasia

References American College of Obstetricians and Gynecologists. Endometrial intraepithelial neoplasia. ACOG Committee opinion no. 631. Obstet Gynecol. 2015;125:1272– 8. Reaffirmed 2020

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American College of Obstetricians and Gynecologists. The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. ACOG Committee opinion no. 734. Obstet Gynecol. 2018;131(5):e124–9. Reaffirmed 2020 American College of Obstetrics and Gynecologists. Endometrial cancer. Practice bulletin no. 149. Obstet Gynecol. 2015;124(4):1006–26. Reaffirmed 2021 American Society of Clinical Oncology. Lynch syndrome. Approved 01/2020. Available from http://www.cancer. net/cancer-types/lynch-syndrome Astrup K, Olivarius NF. Frequency of spontaneously occurring postmenopausal bleeding in the general population. Acta Obstet Gynecol Scand. 2004;83(2):203. Ben-Arie A, et al. Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer? Int J Gynecol Cancer. 2008;18:813–9. Burbos N, et al. Age-related differential diagnosis of vaginal bleeding in postmenopausal women: a series of 3047 symptomatic postmenopausal women. Menopause Int. 2010;16(1):5–8. Burbos N, et al. Outcome of investigations for postmenopausal vaginal bleeding in women under the age of 50 years. Gynecol Oncol. 2012;125(1):120–3. Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer. 2000;89(8):1765. Hanegem N, et al. Diagnostic evaluation of the endometrium in postmenopausal bleeding: an evidence-based approach. Maturitas. 2011;68(2):155–64. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer. 1985;56(2):403. Moodley M, Roberts C. Clinical pathway for the evaluation of postmenopausal bleeding with an emphasis on endometrial cancer detection. J Obstet Gynaecol. 2004;24(7):736. Smith PP, O’Connor S, Gupta J, Clark TJ. Recurrent postmenopausal bleeding: a prospective cohort study. J Minim Invasive Gynecol. 2014;21(5):799–803. Takac I, Zegura B. Office hysteroscopy and the risk of microscopic extrauterine spread in endometrial cancer. Gynecol Oncol. 2007;107(1):94–8. Trimble CL, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006;106(4):812–9. Wang J, Wieslander C, Hansen G, Cass I, Vasilev S, Holschneider CH. Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers. Gynecol Oncol. 2006;101(1):120–5.

Management of Risks Factors for Older Women: Osteoporosis and Cardiovascular Disease (CVD)

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Philipp Quaas, Katrina Wade, and Alexander M. Quaas

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Cardiovascular Disease (CVD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630 Risk Factors Unique to Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polycystic Ovary Syndrome (PCOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636

Abstract

Osteoporosis and cardiovascular disease (CVD) are common conditions in older women, with a high prevalence and associated morbidity and mortality after the menopausal

P. Quaas (*) Department of Obstetrics and Gynecology, University Hospital Basel, Basel, Switzerland e-mail: [email protected] K. Wade Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Ochsner Medical Center, New Orleans, LA, USA e-mail: [email protected] A. M. Quaas Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology and Infertility, University Hospital Basel, Basel, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_47

transition. Osteoporosis is more common in women than in men, occurring primarily after menopause when estrogen levels drop. Fractures are the most concerning complication of osteoporosis in women, with the hip, vertebrae, and forearm as the most common sites of fracture. Risk factors and nonpharmacological prevention, diagnosis, and pharmacological management are reviewed in this chapter. New attitudes toward the use of hormone replacement therapy (HRT) are also addressed. CVD is the leading cause of death for women in the United States. The risk factors for CVD are discussed in this chapter, specifically those unique to women such as polycystic ovary syndrome (PCOS), menopause, and certain complications of pregnancy.

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Keywords

Menopause · Osteoporosis · Cardiovascular disease (CVD) · Disease prevention · Screening · Hormone replacement therapy (HRT) · Bisphosphonates · Risk factors · Bone density Abbreviations

AAA ABI ACC ACE ACOG

Abdominal aortic aneurysm Ankle-brachial index American College of Cardiology Angiotensin-converting enzyme American College of Obstetrics and Gynecology AHA American Heart Association AI Aromatase inhibitor ARB Angiotensin receptor blocker ASCVD Atherosclerotic cardiovascular disease BHOF Bone Health and Osteoporosis Foundation BMD Bone mineral density BMI Body mass index BP Blood pressure CAC Coronary artery calcification CHD Coronary heart disease CRP C-reactive protein CVD Cardiovascular disease DBP Diastolic blood pressure DM2 Type 2 diabetes mellitus EBCT Electron-beam computed tomography GnRH Gonadotropin-releasing hormone HRT Hormone replacement therapy IGT Impaired glucose tolerance IMT Intima-media thickness IR Insulin resistance LDL Low-density lipoprotein PCOS Polycystic ovary syndrome PPI Proton-pump inhibitor PTH Parathyroid hormone RANKL Receptor Activator of NF-κB Ligand RCT Randomized controlled trial SBP Systolic blood pressure

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SERM SSRI WHI WHO

Selective estrogen receptor modulator Selective serotonin reuptake inhibitor Women’s Health Initiative World Health Organization

Introduction As life expectancy continues to increase, management of chronic conditions associated with aging in women becomes even more important. Especially after the menopausal transition, women face the risk of the serious and disabling conditions of osteoporosis and cardiovascular disease (CVD). Awareness of risk factors and strategies for primary and secondary prevention are essential for clinicians caring for older women, given the massive public health burden of osteoporosis and CVD on society. Osteoporosis-related fractures and cardiovascular events are the major causes of morbidity and premature mortality in aging women. Modifiable and nonmodifiable risk factors have been identified for both conditions, some of which are specific to the female gender.

Osteoporosis Epidemiology Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility (Consensus development conference 1991). Of the more than ten million people in the United States who have osteoporosis, 80% are estimated to be women, most of which are over the age of 50. In fact, the risk of having an osteoporosis-related hip fracture is greater than the risk of developing breast, ovarian, and uterine cancer combined (Home – Bone Health & Osteoporosis Foundation 2022). For menopausal women over the age of 65, 38% have osteopenia and an additional 20% have osteoporosis. By age 85, only 15% of women still have normal bone density.

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Management of Risks Factors for Older Women: Osteoporosis and Cardiovascular Disease (CVD)

One in two women over the age of 50 are estimated to have an osteoporosis-related fracture during their lifetime (Home – Bone Health & Osteoporosis Foundation 2022).

Table 1 Risk factors for osteoporosis: nonmodifiable and potentially modifiable Nonmodifiable Female sex Advancing age

Chronic bone loss in the spine results in gradual collapse/fracture of the thoracic vertebrae and excessive curvature [kyphosis]. White women have a one-in-six lifetime risk of having a hip fracture (International Osteoporosis Foundation| IOF 2022). Osteoporosis is most commonly seen in Caucasian women or those of Asian descent. About 15% of Caucasian women and 90% of AsianAmerican women are lactose-intolerant, making it more difficult to obtain enough calcium in the diet. Caucasian women are estimated to lose on average one-third of the bone density in their hip between 20 and 80 years of age. Most bone density is lost following menopause when estrogen levels drop. Many African-American and Latina women over the age of 50 also have osteoporosis but to a lesser extent, 5% and 10%, respectively (Home – Bone Health & Osteoporosis Foundation 2022). Fractures are the most concerning complication of osteoporosis in women. The most common types of fractures include those of the hip, vertebrae, and forearm. These fractures often occur after falls in elderly women (Prevention and management of osteoporosis: report of a WHO scientific group 2022). The main underlying cause of osteoporosis in postmenopausal women is a result of an imbalance between bone resorption and bone formation. After loss of estrogen in the menopause, excessive bone resorption results in a 1–8% loss of bone density per year. Many women may enter the menopause with osteopenia due to risk factors (Table 1). Bone health counseling begins in adolescence during peak bone building (Osteoporosis Prevention, Screening, and Diagnosis|ACOG 2022) and continues for a lifetime. Women’s healthcare providers should counsel their patients about lifestyle factors, including smoking, poor nutrition, weight-bearing exercises, and excessive weight loss.

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European or Asian race Family history of fracture or osteoporosis Previous fracture Early menopause/ hysterectomy/ oophorectomy Small stature, slender Medical disorders: Turner’s syndrome, hypothalamic amenorrhea, Cushing’s syndrome, hyperthyroidism, malabsorption, diabetes, liver disease, inflammatory bowel disease

Potentially modifiable Vitamin D deficiency, calcium deficiency Excessive alcohol consumption [3 or more/ day] Tobacco smoking Malnutrition Inactive Heavy metals: aluminum, cadmium, and lead intake High phosphoric acid intake [soft drinks] Many medicines: protonpump inhibitors (PPIs), antiestrogens, steroids, chemotherapy, antiepileptics, excess thyroid, anticoagulants, thiazolidinediones, lithium, GnRH agonists, aromatase inhibitors (AI)

As perimenopausal patients enter the menopause, evaluation of lifelong risk factors, correction of potentially modifiable factors, consideration of a bone density study in high-risk patients, and having a risk–benefit discussion regarding estrogen replacement therapy are important to reduce potential fracture risk.

Diagnosis It is recommended that women should begin screening for osteoporosis at age 65. Postmenopausal women younger than 65 should be screened if they have risk factors or history of adult fracture (Osteoporosis Prevention, Screening, and Diagnosis|ACOG 2022). Screening tests for bone mineral density (BMD) are most commonly done using dual-energy X-ray

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absorptiometry (DXA). The results of this test are reported as a T-score, which compares the current bone density with that of a healthy young woman (NIH). T-scores between 1.0 and 2.5 are considered osteopenia, and T-scores less than 2.5 are indicative of osteoporosis. Osteoporosis can also be a valid diagnosis even if the patient has a normal T-score if they have a history of frequent bone fractures (Home – Bone Health & Osteoporosis Foundation 2022). DXA has been shown to have a high specificity but low sensitivity, meaning that the risk of fracture is high with a low BMD but should still not be ignored with normal BMD (Prevention and management of osteoporosis: report of a WHO scientific group 2022). DXA also often underestimates BMD in small, thin women with T-scores indicating osteoporosis when BMD is actually normal for their body size (Cosman et al. 2014). Postmenopausal women make the largest population of individuals with osteoporosis in the United States. This is largely due to the significant reduction in the production of estrogen. Estrogen is an important hormone for inhibiting bone resorption. It functions by binding to receptors on osteoblasts to inhibit synthesis of interleukin6 (IL-6), a potent stimulator of bone resorption. Estrogen also stimulates apoptosis of osteoclasts, the bone cells responsible for bone resorption. Decreased estrogen levels lead to an increase in IL-6 production and increased life span of osteoclasts. Both these factors lead to increased bone breakdown and risk of osteoporosis (Prevention and management of osteoporosis: report of a WHO scientific group 2022).

Pharmacological Management Prevention of Osteoporosis and Bone Loss Estrogen–progestin therapy was previously considered optimal for preventing postmenopausal osteoporosis. However, the impact of the Women’s Health Initiative (WHI) in 2002 led to a reduction in its use due to concerns regarding breast cancer and heart disease (Prevention and management of osteoporosis: report of a WHO scientific group 2022; Rossouw et al. 2002; Anderson et al. 2004). The more recent identification of significant side effects associated with

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prolonged bisphosphonate treatment, along with better clarification of the WHI studies, has resulted in new recommendations for the use of estrogen for the prevention of bone loss. ACOG recommends that the clinician must work closely with the patient to determine what is in her best interest because the risk of HRT is smallest in the younger postmenopausal woman and increases with age (Osteoporosis Prevention, Screening, and Diagnosis|ACOG 2022). • HRT has a beneficial effect on bone health (Osteoporosis Prevention, Screening, and Diagnosis|ACOG 2022). – WHI provided a randomized controlled trial (RCT) that reported a statistically significant 33–36% reduction in hip and vertebral fractures in a “normal” non-osteoporotic population of postmenopausal women (Rossouw et al. 2002). – The Danish Osteoporosis Prevention Study (prospective controlled comprehensive cohort of 2016 women) reported that the use of HRT for 5 years in recently postmenopausal women statistically reduced the number of forearm fractures (Mosekilde et al. 2000). • HRT is FDA-approved for the prevention of osteoporosis in women at increased risk of osteoporosis and fracture. The last three large RCTs reported no increase in breast cancer and were associated with reductions in CVD if initiated within early menopause. These studies are consistent with the multiple prospective cohort studies in 1980 that indicated HRT was associated with a nearly 50% lower risk of coronary heart disease in postmenopausal women (Keaney and Solomon 2016). • WHI 2002 and WHI 2004 reported that there was no increased risk of breast cancer or heart disease (adjusted relative risk confidence intervals used) (Rossouw et al. 2002; Anderson et al. 2004). – Follow-up studies reported significant reductions in CVD if started in early menopause (Manson et al. 2007; Hodis et al. 2016).

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• 1006 recently postmenopausal women randomized for a 10 year trial but followed for 16 years. Women using HRT had a significantly lower risk of mortality, heart failure, or myocardial infarction, without any apparent increase in the risk of any cancer, venous thromboembolism, or stroke (Schierbeck et al. 2012). – Several bisphosphonates are approved for prevention but are currently often reserved for patients with established osteoporosis [due to a widely accepted 3–5 year limitation of use except in specific patients]. • Drug therapy may also be beneficial for women with osteopenia indicated by a T-score between 1.0 and 2.5 and a 10 year >20% estimated risk of osteoporosis-related fracture or >3% estimated risk of hip fracture according to the Fracture Risk Assessment Tool (FRAX) calculator created by the World Health Organization (WHO) (Home – Bone Health & Osteoporosis Foundation 2022). Treatment for Established Osteoporosis The most common treatment for osteoporosis are bisphosphonates. Bisphosphonates bind hydroxyapatite crystals on the bone surface and inhibit bone resorption by osteoclasts (Srivastava and Deal 2002). Alendronate, risedronate, and ibandronate are the bisphosphonates currently approved by the FDA. Alendronate and risedronate have been shown to reduce the occurrence of hip and vertebral fractures, while ibandronate has only been shown to reduce the risk of vertebral fracture. The Bone Health and Osteoporosis Foundation (BHOF) recommends the use of bisphosphonates in postmenopausal women with a history of fracture or T-score less than 2.5. Bisphosphonates are available as pills and taken once per day, week, or month depending on the medication. Oral options include the following: • Alendronate sodium is available as a daily tablet of 5 mg or weekly tablet of 35 mg. There are also 10 mg daily tablets and 70 mg weekly tablets combined with 2800–5600 international units (IU) of vitamin D for

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prevention in women with previous fractures. A special form of alendronate must be dissolved in 4 oz of water and taken on an empty stomach (Cosman et al. 2014). • Risedronate is available as a 5 mg daily tablet, 35 mg weekly tablet with 500 mg calcium carbonate, 75 mg twice-monthly tablet, and 150 mg monthly tablet. • Ibandronate sodium is available as a 150 mg monthly tablet. – It is recommended that patients take these medications first thing in the morning on an empty stomach with 8 oz of plain water. Patients should wait 60 min before eating, drinking, or taking any other medication. Delayed-release risedronate should be taken immediately after eating breakfast, and they should wait 30 min before eating, drinking, or taking any other medication. It is also recommended to stay upright for an hour in each case (Cosman et al. 2014). Bisphosphonates can cause gastrointestinal distress; hence, it is important to follow these guidelines (Prevention and management of osteoporosis: report of a WHO scientific group 2022). “Estrogen-like” drugs such as tamoxifen and raloxifene have been shown to decrease postmenopausal bone loss but to a lesser extent than bisphosphonates and estrogen. They are described as selective estrogen receptor modulators (SERMs). Tamoxifen is also used in patients with previous breast cancer in order to reduce the risk of recurrence. Studies have shown that raloxifene increases BMD of the lumbar vertebrae, hip, and femur. It has also been shown to decrease the risk of fracture by 50% in women without a prior fracture and 30% in women with a prior fracture. However, raloxifene has been associated with an increased risk of thromboembolism, similar to that seen in treatment with estrogen (Srivastava and Deal 2002). Injectable or IV options include the following: • Ibandronate is also available as a 3 mg injection administered every 3 months.

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• Zoledronic acid is another bisphosphonate available as a yearly injection of 5 mg in 100 mL. It is offered as an alternative for women who cannot tolerate oral bisphosphonates or would rather receive a once-yearly regimen. It has been shown to decrease the risk of hip and vertebral fractures and reduce the risk of recurrent fractures in women with a recent hip fracture. Injection with zoledronic acid has been shown to cause an acute-phase reaction of arthralgia, headache, myalgia, and fever in 32%, 7%, and 3% of patients upon first, second, and third injection, respectively. Pretreatment with acetaminophen should decrease these symptoms (Cosman et al. 2014; Lyles et al. 2007). • Denosumab is another available treatment for patients who cannot tolerate or do not respond to bisphosphonate therapy. This antibody acts against the factor “Receptor Activator of NF-κB Ligand” (RANKL), which is involved in the development of osteoclasts. It has been shown to improve BMD and reduce fracture risks in postmenopausal women. Patients taking denosumab sometimes present with decreased blood calcium levels. Therefore, it is contraindicated in patients with kidney disease or a prior reduction in blood calcium levels. Low blood calcium levels can, however, be corrected by increasing calcium and vitamin D intake. Denosumab is administered through a 60 mg subcutaneous injection every 6 months by a healthcare professional. There is a small risk of cellulitis and eczema following administration (Cosman et al. 2014). Calcitonin and parathyroid hormone (PTH) are also offered for the treatment of postmenopausal osteoporosis. PTH works directly by stimulating bone formation unlike the other drug therapies that only prevent bone resorption. PTH is available as a preparation called teriparatide, which is administered as a 20 μg daily subcutaneous injection in patients with severe osteoporosis for 2 years. It is effective in increasing vertebral bone density and is more effective than any other treatment in reducing the risk of vertebral fracture.

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However, this drug is very expensive and therefore only offered for patients with severe osteoporosis and a history of hip or vertebral fracture (Prevention and management of osteoporosis: report of a WHO scientific group 2022). On the other hand, calcitonin works with PTH to regulate calcium levels in the body. It has not been shown to improve BMD anywhere besides the vertebrae, but it is often used immediately following vertebral fractures due to its analgesic properties. It is administered as either a nasal spray or an injection. Treatment usually only lasts until pain symptoms have subsided when patients are switched to more effective long-term therapy (Cosman et al. 2014).

Risk Factors and Nonpharmacological Prevention Prevention is the key when it comes to osteoporosis. Adolescent girls reach their peak bone mass at the conclusion of skeletal maturation, which is usually at the end of puberty. Studies have shown that a 10% increase in peak bone mass reduces the risk of hip fracture by 30%. Therefore, it is of much interest to find ways to increase peak bone mass in adolescent girls to prevent osteoporosis later in life (Prevention and management of osteoporosis: report of a WHO scientific group 2022). The American College of Obstetrics and Gynecology (ACOG) recommends that bone health counseling should already begin in adolescents. Peak bone mass is influenced by a variety of factors, including heredity, sex, diet, exercise, and exposures (Table 1). Twin studies indicate that genetics account for up to 50% of the variation in BMD in the population. Heritability of peak bone mass is likely polygenic, and the effects of these genes vary depending on the skeletal site. Women also tend to have a lower peak bone mass than men, which is attributed to a decrease in the period of bone maturation following puberty in women compared with men (Prevention and management of osteoporosis: report of a WHO scientific group 2022). Environmental factors, including diet, exercise, and exposure to risk factors, also greatly affect peak bone mass, as well as the rate of

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decline in BMD during one’s lifetime (Table 1). Deficiencies in calcium, vitamin D, and protein have been associated with decreased bone grown and accelerated bone loss. Deficiencies in these nutritional components are common in elderly women due to a reduction in dairy consumption, a decreased absorptive capacity of the intestinal epithelium, and an impairment of the kidneys to resorb calcium and respond to PTH. Elderly individuals are also not able to produce as much vitamin D and often reduce their sun exposure. All these factors contribute to a decrease in BMD, putting this population at a higher risk for developing osteoporosis (Srivastava and Deal 2002). Protein deficiency has also been associated with decreased BMD and increased risk of fracture. This is likely also due to a decrease in muscle mass, resulting in impaired coordination and balance, which increases the risk of having a fall. Other nutritional components, including vitamin K, phosphates, magnesium, and other trace elements, have also been shown to be important in decreasing bone loss (Prevention and management of osteoporosis: report of a WHO scientific group 2022). It is recommended that premenopausal women consume 1000 mg of calcium per day, and postmenopausal women should consume 1200–1500 mg per day. Calcium supplements are often suggested for postmenopausal women. Experts also recommend that postmenopausal women consume 800 IUs of vitamin D per day. This also often requires supplementation. Premenopausal women should consume 600 IUs of vitamin D per day. Furthermore, protein supplements may also be recommended in postmenopausal women with a history of a fracture (Bilezikian et al. 1994). Exercise is another major component in increasing bone density and decreasing bone loss. Exercise not only increases bone strength but also improves muscle strength and coordination, which reduces the risk of falling. Weightbearing exercises have been shown to be the most effective at increasing bone mass and preventing age-related bone loss (Srivastava and Deal 2002). Women should be encouraged to

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engage in 30 min of weight-bearing exercise three times per week (Cosman et al. 2014). Exercise has also been shown to help decrease pain and improve functional capacity in women with a previous fracture. It also decreases the risk of future fractures. However, women with vertebral fractures should use caution when performing some exercises, especially those involving spinal flexion, so that they do not develop new fractures (Srivastava and Deal 2002). Other risk factors for osteoporosis include tobacco use and excessive alcohol consumption. Studies have linked tobacco use with a decrease in bone density, bone healing, and bone formation (Table 1). In postmenopausal women, tobacco is thought to increase estrogen metabolism, resulting in a longer life for osteoclasts, which function to break down bone. Studies have also suggested that tobacco users typically have lower body weights, nutritional deficiencies, and decreased physical activity, which contribute to the increased risk of osteoporosis. Postmenopausal women who use tobacco have been shown to lose cortical bone 50% faster than postmenopausal women who do not use tobacco. Excessive alcohol consumption (>3 drinks/day) has also been associated with an increased risk of osteoporosis. Although the exact mechanism of action of alcohol on the bone is poorly understood, excessive alcohol consumption is thought to have the greatest effect on bone formation. Therefore, alcoholism earlier in life is likely to have adverse consequences for older women. Excessive alcohol consumption will decrease the peak bone mass, making even smaller amounts of bone loss more detrimental. Excessive alcohol consumption in elderly women has also been shown to increase bone loss. Like tobacco use, excessive alcohol use is often associated with nutritional deficiencies, decreased calcium absorption, and physical inactivity, which likely contribute to such bone loss. Intoxication also causes a loss in coordination and balance, which increases the risk of falling and have a fracture. On the other hand, light to moderate alcohol consumption has not been associated with an increased risk of osteoporosis (Alcohol and

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Other Factors Affecting Osteoporosis Risk in Women 2022). Some medications can also increase bone loss. The most widely known are glucocorticoids (or steroids), which are used to reduce inflammation in conditions such as rheumatoid arthritis, Crohn’s disease, lupus, and asthma (Table 1). Taking steroid pills at a 5 mg dosage for longer than 3 months greatly increases the risk of developing osteoporosis. Therefore, healthcare providers should use steroids only when necessary and should use the lowest dose possible for the shortest time. Patients should also ensure they consume adequate amounts of calcium and vitamin D, as well as exercise regularly and refrain from smoking while taking steroids. Other medications associated with bone loss include aluminum-containing antacids, antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, primidone), aromatase inhibitors (AI), chemotherapeutic drugs, gonadotropin-releasing hormone (GnRH), cyclosporine, heparin, lithium, medroxyprogesterone acetate, methotrexate, proton-pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs), thiazolidinediones, tamoxifen (premenopausal use), and thyroid hormones in excess. Similar precautions should be taken when using these medications (Home – Bone Health & Osteoporosis Foundation 2022).

Cardiovascular Disease (CVD) Background Cardiovascular disease (CVD) is the leading cause of death for women in the United States, killing approximately 290,000 women annually or one in every four female deaths. Although CVD is sometimes thought of as a “man’s disease,” around the same number of women and men die each year of heart disease in the United States. Despite increases in awareness over the past decade, only 54% of women recognize that CVD is their number 1 killer. CVD and stroke are the most frequent causes of death in women. Knowledge among women themselves has

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improved (from 30% to 56% from 1997 to 2012), but this still leaves roughly half of women unaware that they are at the highest risk of dying from heart disease or stroke as opposed to other causes, such as cancer (Table 2). Almost two-thirds (64%) of women who die suddenly of coronary heart disease have no previous symptoms. Women tend to present with chest pain evaluation in the emergency room at a greater rate compared with men (4.0 million visits for women vs. 2.4 million visits for men). However, women tend to present with less typical symptoms, such as fatigue sleep disturbance and shortness of breath, back pain, indigestion, weakness, and nausea/vomiting. Thus, women are frequently a clinical challenge for the cardiologist, and their symptom misinterpretation may lead to the wrong diagnosis and treatment with potentially unfavorable consequences. Intensive preventative efforts across a woman’s life span and appropriate diagnostic efforts later in life are essential to minimize the current high rates of morbidity and mortality of CVD in women. Direct and indirect costs of heart disease total more than $320.1 billion, including health expenditures and lost productivity. This highlights CVD as an important public health challenge. Table 2 Causes of death in women

Heart disease + stroke Heart disease Cancer Stroke Chronic lower respiratory disease Alzheimer’s disease Unintentional injuries Diabetes Suicide Influenza and pneumonia Kidney disease Septicemia

Women (%) 29.7 23.5 22.1 6.2 5.9 4.7 3.6 2.7 0.7 2.1 2.1 1.5

Men (%) 29.1 24.9 24.4 4.2 5.3 2.1 6.2 2.9 2.5 1.9 2.0 1.3

From the Centers for Disease Control. Deaths, percent of total deaths, and death rates for the 15 leading causes of death in selected age groups, by race and sex: United States, 2011 (Center for Health Statistics N 2011)

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Management of Risks Factors for Older Women: Osteoporosis and Cardiovascular Disease (CVD)

Risk Factors: Prevention and Interventions Traditional and nontraditional risk factors (Table 3) contribute to the development of CVD in both women and men, but some risk factors are more exclusive to women (e.g., pregnancy-related complications) or selectively disadvantage women (e.g., depression). Clinicians have traditionally relied on the Framingham Risk Score to assess CVD risk; however, this risk assessment underestimates the risk in women and classifies 90% of women as low risk. The 2013 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on the assessment of CVD recommend estimating 10 year or lifetime CVD risk from a pooled cohort of equations that take into account such factors as race and sex (Goff et al. 2014). Table 3 Risk factors of CVD Traditional Hypertension Hyperlipidemia Tobacco use Diabetes Peripheral arterial disease Chronic kidney disease Physical inactivity Obesity Metabolic syndrome Genetic, family history Age Psychological factors High stress Acute mental illness Depression Anxiety anger/stress Marital status Socioeconomic status Other Elevated C-reactive protein/systemic autoimmune disorders/anemia Menopause/oophorectomy Polycystic ovary syndrome (PCOS) Gestational diabetes/hypertension/preeclampsia Obstructive sleep apnea Radiation/chemotherapy Excessive alcohol consumption [>1 drink/day women, >2 drinks/day men]

631

Hypertension Underdiagnosed and undertreated hypertension remains a major risk factor for CHD in women. The prevalence of hypertension in women and men continues to increase, and it is estimated that the lifetime risk of developing hypertension is approximately 90%. Hypertension significantly increases the risk of myocardial infarction, heart failure, atrial fibrillation, stroke, and renal failure. Premenopausal women are at a higher risk of hypertensive end-organ damage than age-matched men, including microalbuminuria and left ventricular hypertrophy. Blood pressure (BP) increases during the menopausal transition may be related to the decline in estrogen levels, which leads to upregulation of the renin–angiotensin system, production of vasoconstrictive factors such as endothelin, and increased salt sensitivity. Over the age of 65 years, hypertension prevalence is higher in women than men, but less than half receive adequate treatment. Lifestyle modifications can prevent hypertension. Control of hypertension decreases both the risk of stroke and that of fatal and nonfatal coronary events and heart failure. Table 4 outlines the recommendations for the management of hypertension from the panel members appointed to the Eighth Joint National Committee (JNC 8) (Armstrong 2014). Cholesterol Elevated cholesterol, specifically low-density lipoprotein (LDL), is a major cause of heart disease. In addition to heart-healthy lifestyle modifications, the primary pharmacological therapy is a statin. Traditionally clinicians have treated patients with statin therapy to a certain target, an LDL goal of below 100 mg/dL in those at a high cardiovascular risk and a goal of 70 mg/dL or lower for patients at very high risk. In November 2013, the ACC and AHA released updated clinical practice guidelines on reducing cardiovascular risk, which emphasized a move away from specific cholesterol treatment targets and focused on the intensity of statin therapy for four “major statin benefit groups”(Neil Stone et al. 2014).

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Table 4 Recommendation for the management of hypertension Recommendation 1. The guideline recommends the initiation of drug therapy in order to lower a systolic blood pressure (SBP) of 150 mmHg or a diastolic blood pressure (DBP) of 90 mmHg for the general population at 60 years of age or older (Grade A). A corollary recommendation is that patients whose achieved SBP on pharmacological therapy is lower than the new guideline recommendation can be continued at that level of therapy, if well tolerated. [Grade E] Recommendation 2. The target DBP to start pharmacological therapy for subjects younger than 60 years of age is 90 mmHg. Based on available evidence, the recommendation for patients aged 30–59 years is strong (Grade A). For those between the ages of 18 and 29, the recommendation is on the basis of expert opinion. [Grade E] Recommendation 3. The target SBP to start pharmacological therapy for subjects younger than 60 years of age is 140 mmHg. [Grade E] Recommendation 4. In the population aged 18 years or older with chronic kidney disease, initiate pharmacological treatment to lower BP at SBP 140 mmHg or DBP 90 mmHg and treat to a goal of SBP 1.6 million patient visits predicted for the year 2030 (Kirby et al. 2013). Two common musculoskeletal causes of pelvic pain are myofascial pain syndrome and pelvic floor tension myalgia. These two conditions are often unrecognized and misdiagnosed. The pathophysiological mechanism is not fully understood, but there are multiple risk factors that must be evaluated. Studies have revealed a high prevalence of primary or secondary musculoskeletal abnormalities in women with chronic pelvic pain. Visceral pain, orthopedic pathology, direct trauma, and psychosocial stressors may trigger discomfort in the abdominal wall and pelvic floor. Physical examination can help to differentiate the pain sources. Carnett’s test is a useful exercise to assess the abdominal myofascial involvement. Briefly, Carnett’s sign is a finding on clinical examination in which (acute) abdominal pain remains unchanged or increases when the muscles of the abdominal wall are tensed. For this part of the abdominal examination, the patient can be asked to lift the head and shoulders from the examination table to tense the abdominal muscles. Alternatively, ask the patient to raise both legs with straight knees (Fig. 2). Pelvic organ prolapse and injury to the levator ani have also been described as the cause of pain. Pelvic organ prolapse may present as herniation of the pelvic organs against the vaginal walls and often through the vaginal introitus. This is related to a defect in support of vaginal anatomy that is supported and held in place by connective tissues and the pelvic musculature.

Advancing age, obesity, connective tissue disorder, and parity beyond one pregnancy are risk factors for pelvic organ prolapse. A spasm of the pelvic floor muscles has also been described as a cause of pain associated with this condition that can be reduced by the botulinum toxin injection. Musculoskeletal treatment approaches are based on their underlying cause. Using injections (e.g., lidocaine, bupivacaine, and botulinum toxin

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Fig. 2 Carnett’s test

A) have demonstrated an improvement in pain management. For the pelvic organ prolapse, patients may choose to receive conservative treatment, physical therapy, surgical repair, pessaries, or observation. For surgical correction, patients should be referred to a subspecialty practice such as urogynecology or to a gynecologist experienced in the surgical management of prolapse.

Pelvic Congestion Syndrome (PCS) Pelvic congestion syndrome (PCS) is a common cause of disabling chronic pelvic pain in women of childbearing age and occurs when varicose veins develop around the ovaries in a CPP setting. It has been estimated that as many as one-third of women with CPP have congested pelvic veins as a comorbid condition. The underlying cause is pelvic venous insufficiency (PVI), which is defined as the incompetence of the ovarian vein or internal iliac vein, or both. Asymptomatic women have also been found to have pelvic varicosities, making PCS a challenging disorder to diagnose. There are nonspecific associated symptoms, including depression, headache, lower backache, rectal discomfort, and bloating. Pregnancy and previous pelvic surgery are known to act as associated risk factors (Khilnani et al. 2019). Pelvic pain is thought to result from engorged ovarian and pelvic veins. A popular theory is that the hormonal changes, weight gain, and anatomic changes during pregnancy cause an increase in pressure in the ovarian veins. This pressure may damage or weaken the vessel wall, leading to dilation and incomplete valve closure. This can result

in a backward flow of blood and pooling of blood within the pelvis, leading to pelvic varicose veins and symptoms of pain and heaviness. The activation of selective pain receptors of the venous walls and diffusion through the viscera. Symptoms of PCS may include 1. Aching, dull, dragging pain in the pelvis or lower back that gets worse during menses or standing. 2. Deep dyspareunia. 3. Irritable bladder symptoms: urgency. 4. Irritable bowel symptoms: recurrent abdominal pain, diarrhea, constipation. 5. Vaginal or vulvar varicose [bulging] veins. Imaging techniques can confirm the pattern of the varicosities in the setting of pelvic symptoms. A CT scan and MRI can identify the pathology. Venography has been considered the “gold standard” assessment of pelvic vein congestion and provides an option of performing interventional treatment if needed (Rossi et al. 2020). PCS treatment is a two-step process involving selective embolization of the ovarian vein(s) and balloon occlusion sclerotherapy of the internal iliac veins. Ovarian vein embolization is feasible by advancing the catheter to close proximity to the associated para-uterine varicosities. Embolization materials, including vascular occlusion devices and liquid or foamed sclerosants, can be used via a popular technique called “sandwich” to occlude the varicose vein. Briefly, sandwich technique is the mechanical occlusion of the proximal and distal ends of the ovarian vein (Phillips et al. 2014).

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Management of Pelvic Pain in Older Women

681

Pain After Surgery

Adhesions

Patients with a chronic pain condition are more likely to develop postoperative pain. This is at least in part due to the fact that many women with CPP have a history of previous surgeries, thus increasing their risk of complications. Pain control studies after gynecological surgery are limited, and those pertaining directly to urogynecological procedures are desperately sparse. Poor postoperative pain control during the postoperative period may cause heightened sympathetic discharge that can increase the risk for myocardial infarction and stroke. Postoperative pain also leads to decreased ambulation with a resultant increased risk for thromboembolism, poor inspiratory effort, and increased risk for postoperative pneumonia. Lastly, poor acute postoperative pain control can lead to central sensitization with resultant chronic pain sequelae. Multimodal analgesic approaches should be considered for all procedures because they have been shown to improve postoperative pain relief as well as reduce opioid requirements and opioidrelated adverse effects. Perioperative paracetamol, NSAIDs, dexamethasone, and local anesthetic techniques have been shown to improve postoperative pain relief. In patients with vaginal surgery for prolapse or incontinence, infiltration of local anesthetic into the posterior vagina and perineum reduces postoperative pain. Pudendal blockade may also be considered for improved early postoperative pain control. Postoperative pain management of patients with abdominal urogynecological procedures includes bilateral transversus abdominis plane (TAP) block. The TAP blocks may not be necessary for laparoscopic procedures because the pain from the port-site incisions may be adequately managed by wound infiltration. Although opioid analgesic medications have always been the mainstay of postoperative pain management, this review reveals that many other pain control strategies are effective after gynecological surgery. Augmenting the current pool of resources for controlling pain after urogynecological surgery may significantly improve the patient surgical experience for pelvic floor disorders (Collins et al. 2014).

Adhesions are a common occurrence in women with and without pelvic pain. These may be caused by earlier infections such as appendicitis or pelvic inflammatory disease, endometriosis, or previous surgery. Not all adhesions cause pain; however, two distinct cases where adhesions have been suspected to cause pain are ovarian remnant syndrome and trapped ovary syndrome. Vascular adhesions also have also been linked to CPP, particularly when the ovarian tissue is involved. But the association between the adhesions and pain is still unclear, and there is no evidence to support the division of fine adhesions in women with chronic pelvic pain and relief pain, except in women who have dense, vascular adhesions involving the bowel. In case of ovarian entrapment, the GnRH analog or ovarian tissue removal may be beneficial. Overall, there is no conclusive evidence to support the division of fine adhesions in women with CPP (Hindocha et al. 2015).

Endometriosis Endometriosis is traditionally the most common cause of chronic pelvic pain and is usually cyclical. It happens in women in their reproductive age; however, in older women in premenopausal period, there can be a remote chance of endometriosis contributing to patients’ pain. In severe cases, the pain may involve the bladder and bowel. The pain is not always cyclical and is often in the lower back. Endometriosis is the presence of ectopic endometrial tissue in extrauterine sites; however, the precise pathogenesis of endometriosis is unknown. Retrograde menstruation, altered immunity, metaplasia of the germinal epithelium, stem cell, and genetic origins are reported as the pathogenesis behind the disease. Abdominopelvic pain is reported in 58% of women with endometriosis. Diagnostic laparoscopy is known as the definitive diagnosis of endometriosis. Transvaginal ultrasonography has been shown to reliably identify endometriomas. For cases with subperitoneal endometriotic deposits, MRI is a better diagnostic tool.

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Medical and surgical interventions are treatment recommendations dependent on the patient’s symptoms, severity, medical history, age, and reproductive age. Medical therapies aim to reduce pain and disease activity by ovarian and implant suppression include hormonal releasing IUDs, progestin dominant combination oral contraceptives, medroxyprogesterone acetate, cyproterone acetate, or dienogest only pill [not available in the United States], for pain associated with endometriosis. Although the androgenic steroid danazol was previously the most prescribed drug for endometriosis, their androgenic side effects outweigh the benefits. Gonadotropin-releasing hormones such as GnRH agonists are considered the second-line therapy. NSAIDs and the combined oral contraceptive pill (COCP) and hormonal IUDs have been shown to be effective in relieving pain in primary dysmenorrhea. Surgical treatment of endometriosis aims to remove all areas of ovarian and deep infiltrating endometriosis, particularly when the disease affects the bowel and other organs as there might be associated morbidity. Advancements in surgical tools help in a better excision of the diseased area rather than just ablation. Laparoscopic treatment results in improved pain outcomes. Studies showed that in cases with endometriosis greater than 3 cm in diameter, excisional surgery leads to a better outcome than ablation considering the recurrence of pain and endometrioma (Kim and Han 2018).

Physical Therapy Intervention Pelvic floor stretching and biofeedback try to reestablish the resting tonus of the pelvic floor muscles and improve their function. When pelvic floor dysfunction (PFD) progresses to a myofascial pain syndrome, directed physical therapy is advised to reestablish coordinated dynamic and resting behavior. Myofascial pain syndrome is the end result of long-standing stress, with a high tone on a specific muscle group resulting in shortened myofibrils. The American Physical Therapy Association (APTA) stated that the physical therapy interventionists’ goal is to restore normal function of pelvic

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floor while working to reduce any negative psychological impact associated with the disease, pain, or dysfunction being addressed (Hartmann and Sarton 2014). In this setting, physical therapists bring a broad approach to the management of chronic vulvar and pelvic pain. They utilize a variety of manual therapy techniques to treat comorbid conditions of pelvic floor dysfunction (PFD), including biofeedback (Anderson et al. 2016). Therapy methods and tools used by physical therapists vary according to the symptoms and clinical findings of each patient. They include external and internal tissue mobilization and myofascial release, manipulation of visceral, urogenital, and joint structures; electrical stimulation; active pelvic floor retraining; biofeedback; bladder and bowel retraining; and pelvic floor muscle stretching. Women’s health physical therapists are equipped to address emotional issues associated with chronic pain, including sexual dysfunction. It will be much less successful if the treating therapist is unable or unwilling to discuss sexual function as she goes through her chosen treatment protocol. Intervention is driven by organ system dysfunction and physical findings. Through the assessment process, abnormal physical findings need to be examined for full pelvic health recovery. To address physical findings, manual therapy, including modalities like soft-tissue mobilization, myofascial release, joint manipulation, visceral mobilization, therapeutic exercise, and neural mobilization, can be used to correct musculoskeletal dysfunction throughout the body as well as within the pelvic cavity. Physical therapies always include an exercise prescription with home exercise program designed to improve core stability and correction of any gait or postural imbalances as indicated. Optimally, women are given the expectation of a commitment of approximately 20 minutes of home exercise nightly to optimize their physical therapy experience.

Conclusion In conclusion, pelvic pain is a common symptom in women that is challenging to manage. In many cases, CPP is not caused by a particular cause. Patients, clinicians, and researchers are faced with

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this challenge. Most physicians view CPP within the context of their own specialization, but it is best managed by taking a holistic multidisciplinary view in close partnership with the woman. To gain a deeper understanding of CPP’s burden on the population and the individual, further study of its epidemiological characteristics is required. The average gynecologist will encounter many women with this condition over the course of their career. CPP is a difficult condition for patients and clinicians alike: insufficient understanding of the problem’s precise etiology and sometimes multifactorial nature leads to complex treatment strategies. A precise assessment of CPP prevalence and its associated risk factors is necessary. Developing and evaluating effective management strategies requires an understanding of the factors that influence how women are affected by CPP. The assessment process should allow enough time for the woman to be able to tell her story. This may be therapeutic in itself. Because pain is subjective, a pain diary may be helpful in tracking symptoms or activities associated with the pain. Identifying the primary cause of the pain, it is clearly important that the secondary consequences (be they musculoskeletal, psychological, gastrointestinal, sexual, etc.) must also be managed, and this is best done within a multidisciplinary setting. It is important to consider psychological and social factors as well as physical causes of pain.

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683 Chapron C, Querleu D, Bruhat MA, Madelenat P, Fernandez H, Pierre F, et al. Surgical complications of diagnostic and operative gynaecological laparoscopy: a series of 29,966 cases. Hum Reprod. 1998;13(4):867–72. Chronic Pelvic Pain. ACOG practice bulletin, number 218. Obstet Gynecol. 2020;135(3):e98–e109. Collins SA, Joshi G, Quiroz LH, Steinberg AC, Nihira MA. Pain management strategies for urogynecologic surgery: a review. Female Pelvic Med Reconstr Surg. 2014;20(6):310–5. Hartmann D, Sarton J. Chronic pelvic floor dysfunction. Best Pract Res Clin Obstet Gynaecol. 2014;28(7):977–90. Hindocha A, Beere L, Dias S, Watson A, Ahmad G. Adhesion prevention agents for gynaecological surgery: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2015;1:CD011254. Khilnani NM, Meissner MH, Learman LA, Gibson KD, Daniels JP, Winokur RS, et al. Research priorities in pelvic venous disorders in women: recommendations from a multidisciplinary research consensus panel. J Vasc Interv Radiol. 2019;30(6):781–9. Kim JH, Han E. Endometriosis and female pelvic pain. Semin Reprod Med. 2018;36(2):143–51. Kirby AC, Luber KM, Menefee SA. An update on the current and future demand for care of pelvic floor disorders in the United States. Am J Obstet Gynecol. 2013;209(6):584:e1–5. Levy G, Dehaene A, Laurent N, Lernout M, Collinet P, Lucot JP, et al. An update on adenomyosis. Diagn Interv Imaging. 2013;94(1):3–25. Loving S, Thomsen T, Jaszczak P, Nordling J. Female chronic pelvic pain is highly prevalent in Denmark. A cross-sectional population-based study with randomly selected participants. Scand J Pain. 2014;5(2):93–101. Mathias S, Kuppermann M, Liberman R, Lipschutz R, Steege J. Chronic pelvic pain: prevalence, healthrelated quality of life, and economic correlates. Obstet Gynecol. 1996;87:321–7. Meister MR, Sutcliffe S, Ghetti C, Chu CM, Spitznagle T, Warren DK, et al. Development of a standardized, reproducible screening examination for assessment of pelvic floor myofascial pain. Am J Obstet Gynecol. 2019;220(3):255.e1–9. Mitchell C, Prabhu M. Pelvic inflammatory disease: current concepts in pathogenesis, diagnosis and treatment. Infect Dis Clin N Am. 2013;27(4):793–809. Nickel JC, Shoskes D, Irvine-Bird K. Clinical phenotyping of women with interstitial cystitis/painful bladder syndrome: a key to classification and potentially improved management. J Urol. 2009;182(1):155–60. Pape J, Falconi G, De Mattos Lourenco TR, Doumouchtsis SK, Betschart C. Variations in bladder pain syndrome/ interstitial cystitis (IC) definitions, pathogenesis, diagnostics and treatment: a systematic review and evaluation of national and international guidelines. Int Urogynecol J. 2019;30(11):1795–805. Phillips D, Deipolyi AR, Hesketh RL, Midia M, Oklu R. Pelvic congestion syndrome: etiology of pain, diagnosis, and clinical management. J Vasc Interv Radiol. 2014;25(5):725–33.

684 Rossi FH, Rodrigues TO, Izukawa NM, Kambara AM. Best practices in diagnosis and treatment of chronic iliac vein obstruction. J Vasc Brasileiro. 2020;19:e20190134. Rourke W, Khan SA, Ahmed K, Masood S, Dasgupta P, Khan MS. Painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management. Archivio italiano di urologia, andrologia: organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2014;86(2):126–31. Sharma D, Dahiya K, Duhan N, Bansal R. Diagnostic laparoscopy in chronic pelvic pain. Arch Gynecol Obstet. 2011;283(2):295–7. Shobeiri SA, White D, Quiroz LH, Nihira MA. Anterior and posterior compartment 3D endovaginal ultrasound anatomy based on direct histologic comparison. Int Urogynecol J. 2012;23(8):1047–53. Speer LM, Mushkbar S, Erbele T. Chronic pelvic pain in women. Am Fam Physician. 2016;93(5):380–7. Springer KW, Sheridan J, Kuo D, Carnes M. The long-term health outcomes of childhood abuse. An overview and a call to action. J Gen Intern Med. 2003;18(10):864–70.

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Management of Sexual Dysfunctions

49

Luwam Ghidei, Pardis Hosseinzadeh, and Terri L. Woodard

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686 Definition and Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Partner Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694 Advanced Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Educating Patients on Sexual Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assess the Patient’s Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optimizing General Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use a Team Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Make a Treatment Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of Female Sexual Interest/Arousal Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of Female Orgasmic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genito-Pelvic Pain/Penetration Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

694 694 694 695 695 695 695 697 697

L. Ghidei (*) · P. Hosseinzadeh Baylor College of Medicine, Houston, TX, USA e-mail: [email protected] T. L. Woodard (*) Baylor College of Medicine, Houston, TX, USA The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] © This is a U.S. Government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_52

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L. Ghidei et al. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698

Abstract

Female sexual disorders are common. Despite their prevalence, clinicians often feel they are inadequately prepared to address the needs of women with sexual complaints. The aim of this chapter is to highlight and review the diagnosis and management of sexual dysfunction in women, including how to take a thorough history, perform a targeted physical examination, and order appropriate laboratory testing to help determine etiology. Diagnostic algorithms and treatment options are reviewed. Keywords

Female sexual dysfunction · Women · Female sexual interest/arousal disorder · Female orgasmic disorder · Genito-pelvic pain/ penetration disorder

Introduction Millions of women in the United States experience sexual problems at some point in their lives. However, only one-third of women suffering from seriously distressing sexual problems seek professional help for their concerns. Of those, the majority bring their complaints to primary care physicians and gynecologists. Thus, it is important for providers to be familiar with the varying presentations of female sexual dysfunction and attain the necessary skills to screen patients, make an accurate diagnosis, and initiate appropriate treatment. Providers should also be prepared to refer refractory or complex cases to sexual medicine specialists.

intercourse) that causes significant distress in a woman’s daily life and relationships. The definition and classification of female sexual dysfunction disorders continue to evolve. Currently, three major classification systems exist: the World Health Organization’s International Classification of Disease (ICD-10), the classification proposed by the American Foundation of Urologic Disease (AFUD), and the classification defined by the American Psychiatric Association’s Diagnosis and Statistical Manual of Mental Disorders, which was recently updated as the DSM-V (Chen et al. 2013). Prior to the DSM-V, the DSM-IV-TR was used to define and diagnose sexual dysfunction in women and included disorders of sexual desire [hypoactive sexual desire disorder (HSDD) and sexual aversion disorder], sexual arousal [female sexual arousal disorder (FSAD)]), orgasm (female orgasmic disorder), and sexual pain (dyspareunia and vaginismus). These disorders were primarily based on the traditional concept of a linear sexual response. However, research has shown that the sexual response of women is not always a linear, uniform process and that distinction between certain phases of sexual response (e.g., desire and arousal) may not be valid; the new DSM-V criteria were proposed to reflect this shift in thinking. DSM-V aims to improve the precision of female sexual dysfunction diagnoses by adding a minimum requirement of 6-month duration for the symptoms to avoid overdiagnosis. In this chapter, we will refer to the DSM-V criteria because this is the most current classification system in use. On the basis of DSM-V diagnostic criteria, female sexual dysfunction (FSD), which is not caused by an organic disorder or disease, may be divided into the following categories (van Lankveld 2018; ACOG 2019).

Definition and Classifications Female sexual dysfunction (FSD) is defined as any problem or disturbance during any stage of the sexual response cycle (desire, arousal, orgasm, and

1. Female sexual interest/arousal disorder (FSIAD) The new DSM-V criteria merged sexual desire and sexual arousal disorders into one

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category, now called female sexual interest/ arousal disorder (FSIAD), which is defined as the presence of three of the following six criteria for a minimum duration of approximately 6 months: • Persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts • Absent/reduced interest in sexual activity • No/reduced initiation of sexual activity and typically unreceptive to a partner’s attempts to initiate • Absent/reduced sexual excitement/pleasure during sexual activity in almost all or all (approximately 75–100%) sexual encounters (in identified situational contexts or, if generalized, in all contexts) • Absent/reduced sexual interest/arousal in response to any internal or external sexual/ erotic cues (e.g., written, verbal, visual) • Absent/reduced genital or nongenital sensations during sexual activity in almost all or all (approximately 75–100%) sexual encounters (in identified situational contexts or, if generalized, in all contexts) To be classified as FSIAD, the symptoms should cause clinically significant distress in a woman’s life and cannot be attributed to a nonsexual mental disorder, relationship distress (e.g., partner violence), or other significant stressors. In addition, it cannot be attributable to the effects of a substance/medication or another medical condition. FSIAD can be further specified according to the duration of the onset, frequency, and severity of symptoms: • Lifelong: The disturbance has been present since the individual became sexually active. Or • Acquired: The disturbance began after a period of relatively normal sexual function. And • Generalized: Not limited to certain types of stimulation, situations, or partners. Or • Situational: Only occurs with certain types of stimulation, situations, or partners. And

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• Mild, moderate, or severe: Based on evidence of mild, moderate, or severe distress in response to the symptoms. 2. Female orgasmic disorder (FOD) Female orgasmic disorder (FOD) is defined by the presence of one of the following: • Inability to reach orgasm after adequate sexual arousal and stimulation • Infrequent or delayed orgasm • Reduced intensity of orgasmic sensation These symptoms should be present for at least 6 months on all or almost all (approximately 75–100%) occasions of sexual activity and cause significant individual distress. Orgasmic disorder can be further specified as acquired or lifelong, generalized or situational, and mild, moderate, or severe. 3. Genito-pelvic pain/penetration disorder Genito-pelvic pain/penetration disorder (GPPD) represents the merging of the prior DSM-IV sexual pain disorder (vaginismus, recurrent involuntary spasm of the musculature of the outer third of the vagina, and dyspareunia, genital pain associated with intercourse) categories. GPPD is the presence of at least one of the following: • Difficulty in vaginal penetration • Marked vulvovaginal or pelvic pain during vaginal intercourse or attempt at penetration • Marked fear or anxiety about pain in anticipation of, during, or after penetration And/or • Marked tightening or tensing of pelvic floor muscles during attempted penetration These symptoms must cause significant distress for at least 6 months and should not be a result of another nonsexual mental disorder or the consequence of a severe relationship distress (e.g., partner violence) or other significant stressors and should not be attributable to the effects of a substance/medication or another medical condition. GPPD can also be categorized as acquired or lifelong, generalized or situational, and mild, moderate, or severe.

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Prevalence As the largest US survey on women’s sexual problems, the PRESIDE study (Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking) queried 30,000 women using validated questionnaires. In this study, the prevalence of low desire, low arousal, and difficulties with orgasm showed that the prevalence of any of these three sexual problems (with or without distress) was 43%; 22% reported sexually related personal distress and 12% attributed distress to a specific type of sexual problem (e.g., desire) (Shifren et al. 2008). Lack of desire was the most commonly reported sexual problem in women. While reported by 39% of women, it was sufficiently severe to cause distress in 10–14%. Low arousal (26%) and difficulties with orgasm (21%) were slightly less prevalent and were associated with distress in 5% of the cases. Five percent of women reported both low desire and another sexual problem; 2% reported all three problems (Shifren et al. 2008).

Etiology Female sexual disorders, like many other medical problems, often do not have a single cause. They are likely associated with a combination of factors under biological, psychological, and social influences. 1. Biological Age has been shown to be correlated with the likelihood of FSD. The prevalence of all classes of FSD (except GPPD) increases substantially with age. Although aging is known to cause physical and hormonal changes, the sexual behavior of midlife and older women is highly dependent on several factors such as general physical and mental well-being, quality and duration of relationships, and life situation. Sex hormones, particularly low levels of estradiol, can contribute to the lack of sexual interest and to the presence of vaginal

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dryness and atrophy in naturally menopausal women. In addition to hormonal alterations, psychosocial and interpersonal factors, medication use, and associated illnesses are factors that may intensify the effects of aging on sexual function in women. However, sexuality and sexual function remain important aspects of life for many older women. In women aged 50–60 years, 65% reported sexual desire and almost 48% had at least three episodes of sexual intercourse per month (Safarinejad 2006). In addition to aging, chronic illnesses such as diabetes, hypertension, rheumatological disorders, or presence of other serious medical conditions (such as cancer) may impair a woman’s sexual function because of psychosocial changes associated with the condition as well as the condition itself (Buster 2013). Furthermore, some other physical problems make sexual activity uncomfortable, including endometriosis or atrophic vaginitis. Chronic pelvic pain, uterine fibroids, interstitial cystitis, and pelvic inflammatory disease can cause deep dyspareunia. Superficial dyspareunia, on the other hand, is usually related to vestibulodynia and vulvodynia. Localized vulvodynia or vestibulodynia is pain that is caused by touching a localized area of the vulva, commonly occurring in the region of the vestibular glands. It can also occur at the clitoris, clitorodynia, or on one side of the vulva. The pain is often described as a feeling of burning, stinging, tearing, throbbing, or being cut by razor blades or glass. Women with vaginismus may demonstrate high pelvic floor muscle tension and/or experience genital pain and/or report fearing vaginal penetration or pain that makes vaginal penetration impossible. Some women, however, may not feel pain. For some, vaginismus is limited to sexual activity. Vaginismus is frequently associated with female sexual interest/arousal disorder and sexual aversion. In other cases, vaginismus is linked with gynecologic disorders, such as vestibulitis or endometriosis, chronic medical conditions, or

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drugs and responds to treatment for those problems. 2. Psychological Psychiatric problems, including mood disorders such as depression and/or anxiety, can be associated with impaired sexual function. Many psychotropic medications used to treat these conditions can also exacerbate sexual problems. Trauma, such as a history of prior physical or sexual abuse, can also contribute to sexual dysfunction. 3. Social Fatigue, stress, lack of privacy, and conflict within an intimate relationship can impair sexual functioning. Factors such as lower educational levels, financial dependence, and poor health have all been shown to be correlated with a significant increase in the risk of FSD.

Screening

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History The evaluation of sexual dysfunction in women begins with a comprehensive medical history. The clinician should ask about the duration of symptoms as well as their severity and the setting in which the symptoms most frequently occur. Initial questions should be open-ended questions, such as, “Many people have concerns about sex and sexual health; do you have any questions or concerns that you would like to discuss?” Openended questions should be followed by silences that encourage the patient to speak and then by directed questions that should be asked (American Psychiatric Association 2013b). As sexual problems may be difficult for some women to discuss, it is important to use words and body language that put the patient at ease. Maintaining an open, nondefensive body posture can help facilitate communication. The clinician should sit down and maintain eye contact and choose language that is appropriate to the age, ethnicity, and culture of the patient. A complete medical and medication history is elicited in order to identify organic, psychological, and medication or substance-related issues that may affect sexuality (e.g., depression, diabetes, use of selective serotonin reuptake inhibitors). Any suspicion of an undiagnosed medical or mental illness should be followed by further evaluation or referral.

Ideally, women should be queried about sexual health concerns at regular intervals. Practices can adopt intake forms that include questions about sexual function as part of their review of systems. There are several validated questionnaires that can be used as screening tools, including the Female Sexual Function Index (FSFI). The FSFI is a brief, 19-item questionnaire that assesses multiple dimensions of female sexual function, including sexual satisfaction. Typically, a general routine health encounter (a) Gynecologic History A gynecologic history and review of sysdoes not provide adequate time for a thorough tems should include symptoms and conditions evaluation of sexual concerns. To ensure that that might affect sexual activity or signal the they are appropriately addressed, a follow-up need for further evaluation; this includes visit should be scheduled to provide dedicated information about menopausal status (natural, time to focus on these issues. surgical, or post-chemotherapy); pregnancy A diagnostic algorithm based on the recently and childbirth history and history of pelvic released DSM-5 classification system and the latinjury, cancer, or surgery; vulvovaginal or pelest recommendations of the International Consenvic pain and vulvovaginal pruritus, dryness, or sus of Sexual Medicine is presented to assist with discharge; abnormal genital tract bleeding; evaluation of patients with sexual complaints and urinary or fecal incontinence (Latif and (Fig. 1; Latif and Diamond 2013). This tool conDiamond 2013). tains various questions practitioners can ask to Multiple gynecologic factors have been assist with the diagnosis of a particular sexual found to be associated with sexual function. disorder.

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Establishing a Diagnosis of Female Sexual Dysfunction Is there a persistent lack of interest in sex or sexual fantasizing?

Is there a persistent difficulty becoming sexually aroused?

No

No

Is there lack of, diminished, or delay in ability to achieve orgasm?

Is there pain or discomfort associated with sexual encounters? No

No Sexual Dysfunction

No

Yes

Yes

Yes

Yes Is there a lack of spontaneous or innate sexual desire?

Is there a lack of sexual desire in response to sexual stimuli?

Is there difficulty maintaining subjective sexual excitement?

Is there difficulty becoming lubricated?

Is there adequate stimulation?

Is intercourse painful?

Is there genital pain associated with sexual stimulation or arousal?

Is there pain or tightness associated with vaginal entry?

Dyspareunia May be normal

Sexual Desire / Interest Disorder

Genital Sexual Arousal Disorder

Subjective Arousal Disorder

Women’s Orgasmic Disorder

Is there difficulty with both subjective and physical arousal? Female Sexual Interest / Arousal Disorder

Combined Genital and Subjective Arousal Disorder

Vaginismus Noncoital pain disorder

Genitopelvic pain / penetration disorder

For any Disorder: Global vs. Situational? Primary vs. Secondary? Level of distress? Contributing medical problems or medications? Partner factors?

Establishing a diagnosis of female sexual dysfunction. Latif. Diagnosing female sexual dysfuntion. Fertil Steril 2013.

Fig. 1 Evaluation of patients with sexual dysfunction. (Originally published in Latif and Diamond (2013); with kind permission of © Elsevier ® 2013; all rights reserved)

Low sexual desire and/or dyspareunia is a common finding in postpartum women. There is no evidence of long-term differences among women with vaginal vs. cesarean delivery, and tissue trauma, such as that experienced from forcep delivery, cesarean section, episiotomy, and lacerations, has been associated with postpartum FSIAD or GPPD (ACOG 2019; Macleod et al. 2013; McDonald et al. 2015a, b). Greater parity does not appear to be related to low sexual desire or sexual satisfaction (Rosen and Simon 2014). Aside from factors related to delivery, increased prevalence of intimate partner violence, and changes to maternal sleep/stress/ roles with a newborn can also be associated with postpartum sexual dysfunction (ACOG 2019; McDonald 2015a; DeJudicibus and McCabe 2002).

Coital pain is more prevalent in young women than in older women, perhaps because of the presence of higher-tone pelvic floor musculature, which can result in pain during sexual activity. Weak pelvic floor muscles are associated with urinary incontinence and pelvic organ prolapse. Sexual dysfunction is reported in 20–40% of women with urinary incontinence. In women with pelvic organ prolapse, the rate of sexual complaints appears to be higher than in others with no prolapse. Since muscular dysfunction may be directly responsible for the symptoms related to sexual function, health professionals who treat symptoms related to pelvic floor dysfunction should also screen for sexual dysfunction, which enables them to offer the most comprehensive treatment options (Serati et al. 2009).

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Menopause is associated with declining levels of circulating estrogen whether natural, surgically induced, or medically induced. Up to 50% of menopausal women may develop genitourinary syndrome of menopause, which is characterized by vulvovaginal atrophy, vaginal dryness, burning, and irritation; decreased lubrication and pain with intercourse; urinary symptoms of urgency, and dysuria, and recurrent urinary tract infections (ACOG 2019; Santoro and Komi 2009; Nappi and KokotKierepa 2012). (b) Sexual History Additionally, detailed questions regarding the onset of the current symptoms as well as changes in frequency and severity should be addressed. The patient’s sexual and gender identify, number of partners, types of sexual practices, and past sexual history with the current or previous partners should be discussed. History of rape, domestic violence, and childhood sexual abuse can have significant effects on one’s sexual health, and patients are most often uncomfortable to disclose. Providers should deliberately address these traumatic life events. (c) Medical History Chronic underlying medical illnesses can be associated with female sexual dysfunction. For instance, thyroid problems are associated with distressing desire problems in younger patients (Nusbaum et al. 2004). In addition to thyroid disorders, other endocrinological and nonendocrinological disorders (such as diabetes, hypopituitarism, Cushing disease, hypertension, arthritis, and inflammatory or irritable bowel disease) are associated with an increased risk for sexual problems. Some of the more common medical conditions associated with FSD are discussed below: 1. Diabetes: The effect of diabetes on female sexual functioning is uncertain. Hyperglycemia, which is a main determinant of vascular and microvascular diabetic complications, could potentially explain the pathogenic mechanisms that could cause sexual dysfunction in diabetes. Poorer

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levels of sexual functioning may be seen in diabetic women with peripheral neuropathy. While one study found reduced genital sensation in women with diabetes, studies comparing sexual dysfunction in women with and without diabetes have yielded inconsistent results (Maiorino et al. 2014). In addition, people with diabetes often present with multiple medical comorbidities, including hypertension, obesity, metabolic syndrome, tobacco use, and atherogenic dyslipidemia, which are themselves risk factors for sexual dysfunction. 2. Hypertension: Sexual dysfunction is common in hypertensive patients. Available data indicate that sexual dysfunction is more frequent in treated than in untreated patients, generating the hypothesis that antihypertensive therapy might be associated with sexual dysfunction. Hypertension-related atherosclerosis, endothelial disorder, and antihypertensive drugs are important risk factors for female sexual dysfunction. The negative effects of beta-blockers on male sexual function are well known; some data suggest that betablockers also have a detrimental effect on female sexual function. Studies have reported that the risk of sexual dysfunction was greater in hypertensive women treated with beta-blockers than in those treated with other agents (Duncan et al. 2000). 3. Neurological Conditions: Neurological conditions and their treatments have been shown to be associated with sexual dysfunction. Specifically, spinal cord injury, the use of antiepileptic drugs in epileptic patients, multiple sclerosis, and Parkinson’s disease are all associated with sexual dysfunction. 4. Cancer: The sexual consequences of multiple types of cancer and their treatments have been documented. Fatigue associated with treatment, reactive depression, anxiety, and changes in body image following surgery on the breasts or pelvic organs may contribute to sexual dysfunction in women with cancer (Falk and Dizon 2013). Breast

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cancer is the most common cancer in (e) Psychiatric History Sexual dysfunction is increased among women in the United States. Sexual dyspatients with psychiatric disorders and may function following breast cancer is prevabe related to both psychiatric condition and lent, with multiple issues contributing to its medical treatment. A significant associathe problem. In addition to changes in tion has been reported between psychiatric body image, hormonal therapy such as the problems and all aspects of FSD. Psychiatric use of aromatase inhibitors can have vast diseases may increase the risk of SD, and SD implications for sexual functioning by conmay further exacerbate psychiatric problems, tributing to vulvar and vaginal atrophic suggesting a bidirectional relationship. The changes. persistence of sexual problems can have a (d) Surgical History significant negative impact on a patient’s satHysterectomy can be a risk factor for FSD isfaction, adherence to the treatment, quality (ACOG 2019). It is estimated that 10–20% of of life, and partnership. women experience deteriorated sexual function Depression and its associated drug therapy such as dyspareunia or FOD after hysterectomy. are some of the most common psychiatric While hysterectomy performed for malignant factors that inhibit sexual function. Depresindications is associated with FSD, hysterecsion is present in 17–26% of women who tomy performed for symptom relief and somatic complain of low sexual desire. SD may be conditions (such as bleeding from fibroids and aggravated by antidepressants, especially dyspareunia from endometriosis) can improve selective serotonin reuptake inhibitors sexual function and quality of life. The removal (SSRIs). Selective serotonin receptor inhibiof the cervix at the time of hysterectomy does tors (SSRIs) can cause low desire and diffinot appear to be a factor associated with FSD culty with orgasm in women. (Lonnée-Hoffmann and Pinas 2014). PreoperaThe negative symptoms of schizophrenia tive sexual dysfunction and depression are two limit the capability for interpersonal and sexual risk factors for postoperative FSD (Flory et al. relationships (Zajecka 2001). First-generation 2005). Additionally, women who hold uterine/ (typical) antipsychotic medications may lead cervical contractions as important parts of to sexual dysfunction by affecting dopamine orgasm may also be a group at risk for postopand prolactin levels. Dopamine serves as a cenerative dysfunction. The true association tral neuromodulator of sexual function and acts between hysterectomy and FSD is difficult to as the only inhibitor of prolactin release from ascertain given the heterogeneity of patient the anterior pituitary. First-generation (typical) populations, bias within study designs, and the antipsychotic medications block dopamine inherent multifactorial complexity and etiology receptors and may give rise to hyperof FSD. Hysterectomy with concomitant bilatprolactinemia. High levels of serum eral oophorectomy is associated with negative prolactin lead to gonadal suppression. Secondeffects on long-term health and sexual function, generation (atypical) antipsychotic medications especially for premenopausal women (LonnéeHoffmann and Pinas 2014). (e.g., aripiprazole) raise prolactin levels to a Tubal sterilization has been associated with lesser degree than first-generation antipsypostoperative FSD in some studies, but a large chotics (e.g., olanzapine or risperidone) and prospective multicenter cohort of 4576 patients thus may have less impact on sexual function found that most women reported no positive (Reichenpfader et al. 2014). changes after the surgery (Costello et al. 2002). (f) Medication History Similarly, most studies report improved sexual Many over-the-counter and prescription function after surgery for urinary incontinence. drugs may affect sexual function in women. However, studies assessing the impact of pelvic Thus, a thorough review of a patient’s current organ prolapse surgery on sexual function are and recent medication use is necessary. less reassuring (Pauls 2010). Table 1 demonstrates some of the most

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Table 1 Drugs associated with sexual dysfunction: medications that cause sexual dysfunction. (Originally published in Conaglen and Conaglen (2013); with kind Drug class Antidepressants

Decreased desire Amitriptyline Clomipramine Fluoxetine Imipramine Paroxetine Phenelzine Sertraline

Decreased arousal Amitriptyline Citalopram Clomipramine Doxepin Fluoxetine Imipramine Nortriptyline Paroxetine Phenelzine Sertraline Tranylcypromine

Other psychotropic drugs

Alprazolam Chlorpromazine Fluphenazine Haloperidol Lithium Risperidone Clonidine Digoxin Hydrochlorothiazide Methyldopa Spironolactone

Chlorpromazine Fluphenazine Lithium Risperidone

Cardiovascular drugs

Other drugs

a

permission of © Australian Prescriber 2013. All rights reserved (Conaglen and Conaglen 2013))

Cimetidine

Beta-blockers Clonidine Digoxin Hydrochlorothiazide Methyldopa Perhexiline Spironolactone Antihistamines Cimetidine Cyproterone Disulfiram Gonadotrophin-releasing hormone Agonists Propantheline Pseudoephedrine

Orgasm or ejaculatory difficulties Citalopram Clomipramine Doxepin Escitalopram Fluoxetinea Fluvoxamine Imipramine Nortriptyline Paroxetinea Sertralinea Tranylcypromine Venlafaxine Alprazolam Fluphenazine Haloperidol Risperidone

Naproxen

Common cause of orgasmic difficulty

common medications that may cause sexual dysfunction (Table 1).

Partner Assessment Since relationship factors are a principal determinant of sexual satisfaction for women, women with partners should be asked about the status and quality of their intimate and sexual relationships. A patient should also be asked about whether her partner has sexual issues (e.g., lack of desire or erectile dysfunction). Studies of sexual function in older women have revealed that a common

reason for sexual inactivity was not having a partner or having a male partner with sexual problems. As erectile dysfunction in men increases with aging, and women typically live longer than men, the “partner gap” becomes a major cause of sexual dissatisfaction for older women.

Physical Examination A complete physical examination, which includes a pelvic examination, is important to identify any pathology and determining potential causes of sexual dysfunction. The clinician should search

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for evidence of vaginal atrophy, dryness, and pain-triggering spots. Women may benefit from ability to view and contribute to the examination with a mirror. This would also serve as an excellent opportunity to educate the patient regarding genital anatomy. A pelvic examination is indicated to confirm a normal pelvic anatomy, evaluate for genital or pelvic tenderness or lesions, assess for pelvic organ prolapse or vaginal atrophy, and follow up on concerns raised by the medical history (e.g., vaginal discharge or abnormal genital bleeding). The clinician should refer the patient to other health professionals if she/he does not have the time or expertise required to perform a proper evaluation.

Laboratory Evaluation Laboratory testing should be performed if indicated by history and/or examination and may include cervical cultures for gonorrhea and chlamydia, complete blood count, thyroid stimulation hormone (TSH), and measurement of prolactin levels. Androgen levels should not be used to determine the cause of a sexual problem, as serum androgen concentrations do not appear to be an independent predictor of sexual function in women (Rivera-Woll et al. 2004). There is not a known lower limit of androgens or androgen precursors that is diagnostic of decreased female sexual function (ACOG 2019). An endocrine evaluation in appropriately selected patients may include measurement of the serum early follicular follicle-stimulating hormone, luteinizing hormone, and serum estradiol, in addition to serum dehydroepiandrosterone, total testosterone, free testosterone, and prolactin levels.

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specialized clinics and research settings to study and help diagnose sexual dysfunction and monitor treatment efficacy. Other advanced sexual health evaluations performed by sexual medicine specialists may include vulvoscopy, vaginal photoplethysmography (measurement of vaginal vasocongestion), biothesiometry, and perineometry (assessment of pelvic floor musculature).

Treatment Treatment of female sexual dysfunction can be challenging. FSD is usually multifactorial, and physicians have limited expertise in the treatment of female sexual dysfunction. Treatment should be tailored to address causal factors (Latif and Diamond 2013).

Educating Patients on Sexual Health Educating the patient and her partner about “normal” sexual response and anatomy is often necessary, especially as it relates to major life events such as childbirth and menopause. Addressing a patient’s fears or concerns about sexual dysfunction and educating her about sexual health can help improve the patient’s receptiveness to treatment and increase her overall knowledge. It is important to discuss any obvious reversible causes of FSD and encourage adoption of lifestyle changes that may be beneficial to sexual functioning, such as stopping smoking, eating a healthy diet, exercising regularly, and reducing stress. Efforts should also be made to improve communication and intimacy in relationships.

Assess the Patient’s Goals

Advanced Testing In certain cases, a pelvic or transvaginal ultrasound may be necessary to assess pelvic anatomy and rule out underlying structural pathology. Measures of genital blood flow, vaginal wall compliance, and genital vibratory sensation thresholds are experimental procedures that may be used in

After the cause or causes of the patient’s sexual dysfunction have been identified, it is important to determine what the patient is expecting to accomplish with treatment and use her goals to evaluate progress. This gives the clinician the opportunity to set realistic goals, clarify any misconceptions about treatment, and allow for progress to be more

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Management of Sexual Dysfunctions

accurately measured. While some women may desire modest improvements in their sexual life, others may expect that treatment will allow them to achieve an ideal based on past experience or cultural images of sexuality.

Optimizing General Health Some patients experiencing sexual dysfunction have other underlying medical issues such as depression, substance abuse, or drug side effects. Many physical and psychological conditions are associated with sexual dysfunction. Often, treating these underlying conditions or adjusting medication and dosing may lead to improvements in sexual function. For example, women with depression who are experiencing sexual side effects when taking a selective serotonin reuptake inhibitor (SSRI) can sometimes be treated with a different class of antidepressant. Identification and treatment of substance abuse, as well as the underlying factors that precipitated it, often result in improved sexuality and overall quality of life.

Use a Team Approach Sexual disorders can be complex and their treatment can be time intensive and require special expertise. Despite this complexity, gynecologists can offer initial treatment that improves sexual function. Other experts may sometimes be needed to address underlying physical and psychological factors; referral to psychotherapists, sex therapists, or pelvic physical therapists may be warranted. With the patient’s consent, communication and management decisions should be shared between the patient’s clinician and other healthcare providers who treat the patient (e.g., cardiologist, psychiatrist, etc.). This communication is important when trying to find a treatment strategy that works best for the patient. It can also be useful to involve the patient’s partner in the treatment, especially if relationship therapy is needed or the partner’s sexual dysfunction is contributing to that of the patient.

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Make a Treatment Plan The ultimate goal of therapy is to utilize interventions that address and optimize the biological, psychological, and social factors that contribute to sexual satisfaction. Treatment options range from sexual health counseling to pharmacologic interventions and surgery.

Treatment of Female Sexual Interest/ Arousal Disorder Treatment of female sexual interest/arousal disorder should be based on its identifying causes. Both pharmacological and nonpharmacological options are available.

Nonpharmacological Counseling may help patients deal with underlying psychological or relationship issues. Couple’s therapy and/or sex therapy may improve communication and decrease conflict within the relationship that contributes to sexual dysfunction. Given the efficacy and high degree of safety of sex therapy, it is reasonable to refer women with no obvious biological pathology to a sex therapist prior to initiating a trial of pharmacological therapy. Group-based or couples-based cognitivebehavioral therapy to identify and change dysfunctional beliefs can help certain patients, especially those who associate guilt and shame with sexual activity and masturbation. Mindfulnessbased therapy focused on stress reduction has also been proven effective for FSAID and FOD (ACOG 2019; Brotto et al. 2016; Fruhauf et al. 2013; Faubion and Rullo 2015; Gunzler and Berner 2012; Brotto et al. 2008). Pharmacological Sexual desire and arousal are facilitated by neural, vascular, and hormonal phenomenon. Women’s arousal is associated with increased blood flow to the vagina and clitoris that results in clitoral erection, vaginal engorgement, changes in vaginal luminal diameter, and vaginal lubrication. Phosphodiesterase type 5 (PDE5) inhibitors have been

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widely used for the treatment of erectile dysfunction; although the physiological effects of PDE5 inhibitors are similar in males and females, results in women have been conflicting (Schoen and Bachmann 2009). Clinical trials have not demonstrated efficacy for women with FSAID (ACOG 2019; Basson et al. 2002; Berman et al. 2003; Caruso et al. 2001). However, there is evidence that phosphodiesterase type 5 inhibitors can reverse inadequate lubrication and delayed orgasm induced by SSRI (Larson 2016). Side effects include headache, flushing, dyspepsia, nasal congestion, and visual disturbances (Basson et al. 2002). Sex steroids (estrogens, progestogens, and androgens) play a crucial role in modulating neuroendocrine and neurovascular responses to sexual stimuli (Basson 2014). Female sexual interest/ arousal disorder is seen in patients who have undergone bilateral oophorectomy or have premature ovarian failure, panhypopituitarism, or adrenal insufficiency as all of these conditions are associated with decreased androgen production. Many older women report decreased interest or arousal, but also have underlying dyspareunia. In older women, estrogen depletion may improve sexual desire indirectly through reduction of genital secretions and pelvic muscle elasticity. Hormone therapy can potentially improve sexual function in postmenopausal women, but results have been conflicting (Martins et al. 2014). Low-dose vaginal estrogen therapy alone is highly effective in treating atrophic changes and dyspareunia related to a hypoestrogenic state, and may lead to improvement in sexual interest, arousal, and satisfaction with sexual activity. Vaginal tablets, gels, creams, and rings appear to be equally effective therapy (Lethaby et al. 2016; Mitchell et al. 2018). Ospemifene, a selective estrogen receptor modulator, can serve as an alternative to vaginal estrogen for low estrogenic states. Low-dose systemic estrogen therapy with or without progestin can be used to treat dyspareunia, but is less preferred than vaginal therapy given higher systemic absorption. Treatment with androgen replacement (such as testosterone gels, implants, patches, etc.) can induce sexual desire in women. Transdermal

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testosterone (IntrInsa, Watson Pharmaceuticals/ Theratech and Procter & Gamble) in physiological to slightly super-physiological doses (300 microgram/day) has been shown to result in increased sexual activity and pleasure for postmenopausal women (Basson et al. 2000; Rosen and Simon 2014). Potential side effects of the use of testosterone include acne, hirsutism, and virilization (including clitoral enlargement and voice deepening), and increased risk of cardiovascular disease, which limits long-term use. The long-term risks of breast cancer and other disease remain unknown (Buster et al. 2005; Braunstein et al. 2005).While this product was previously approved for use in Europe, it failed to gain FDA approval in the United States. Still, shortterm use of transdermal testosterone is a reasonable treatment option for appropriately counseled postmenopausal women with FSAID (Achilli et al. 2017; Wierman et al. 2014). ACOG recommends a short trial with monitoring of serum testosterone at baseline and at 3–6 weeks to ensure it remains normal for reproductive-age women. Women who respond should be frequently monitored for clinical signs of hyperandrogenism. Of note, there is no strong evidence for transdermal testosterone use in premenopausal women. Systemic dehydroepiandrosterone (DHEA) is not effective for sexual interest and arousal disorders. Nonhormonal treatments are available and may be effective in some patients. Bremelanotide (Palatin) is a melanocortin receptor (MC3R and MC4R) agonist that is in phase 3 trials for the treatment of FSIAD. Preliminary studies have demonstrated efficacy in the treatment of this disorder. In June 2015, the FDA advisory committee approved flibanserin for the treatment of hypoactive desire disorder in premenopausal women, making flibanserin the first FDA-approved drug for the treatment of hypoactive desire disorder (now FSIAD). Flibanserin is a 5-HT 1A receptor agonist and 5-HT 2A receptor antagonist. It is postulated to work by improving the balance between the excitatory effect of dopamine and inhibitory effect of serotonin in the neurotransmitter systems (Allers et al. 2010). Three major clinical trials have reported statistically significant improvement in “satisfying sexual events” (SSE)

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over placebo after 24 weeks of treatment with a single dose of 100 mg per day. The rate of serious adverse effects has been reported to be 6–12 months, and women with postmenopausal bleeding. In addition to identifying neoplasia or malignancy, an endometrial biopsy can provide useful information regarding ovulatory status when secretory endometrium is identified or in diagnosing chronic endometritis. For persistent bleeding, adjunctive testing may be indicated (Table 3). Ordering of adjunctive testing depends on the age of patient, length of time and heaviness of abnormal bleeding, gynecologic history, prior imaging results, medical conditions, contraceptive or hormonal use, other medications, size of the uterus, the presence of androgen, or steroid excess. Acute heavy bleeding may need acute surgical intervention or transfusion. • For perimenopausal or postmenopausal women, it is important to get a full evaluation of the endometrium as cancer of the endometrium is the most common type of gynecologic cancer in the United States. Clinical risk factors for endometrial cancer include type 2 diabetes Table 3 Adjunctive testing: evaluation of abnormal bleeding (when indicated) Transvaginal and transabdominal pelvic ultrasound (MRI, CT), hydrosonogram Pap smear, gonorrhea, and Chlamydia screening Hormone labs: pregnancy test, androgens, 17-hydroxyprogesterone, prolactin, progesterone, FSH, LH, estradiol Other labs: CBC, liver function tests, thyroid function tests, renal function tests, ferritin glucose tolerance test, HgA1c, 24-h urinary free cortisol, coagulation testing Office or hospital hysteroscopy

D. Shoupe

mellitus, atypical glandular cells on screening cervical cytology, family history of gynecologic malignancy, history of polycystic ovary syndrome, history of many months of abnormal, irregular premenopausal bleeding, use of unopposed estrogen, and age (ACOG, May 2019). – Endometrial sampling is a first approach to evaluation of postmenopausal bleeding. If a blind sampling does not reveal endometrial hyperplasia or malignancy and the woman continues to bleed, further testing is advised. Repeat endometrial biopsy, hysteroscopy with dilation and curettage, and transvaginal ultrasound are advised. • For insufficient tissue on endometrial biopsy, transvaginal ultrasonography is useful for further triage. – Alternatively, use of transvaginal ultrasonography can reasonably be used for the initial evaluation of abnormal bleeding. If the endometrial thickness is 4 mm or less, it has a 99% negative predictive value for endometrial cancer. • Failure to adequately identify a distinct, thin endometrial echo complex in a postmenopausal woman with bleeding should trigger endometrial sampling, sonohysterography, or office hysteroscopy. – If an endometrial thickness of >4 mm is incidentally discovered in a postmenopausal patient without bleeding, assessment of the patient for risk factors is advised (ACOG, May 2019).

Contraindications The presence of a viable and desired pregnancy is the only absolute contraindication to endometrial biopsy. Caution should be used when considering a biopsy in women with bleeding abnormalities, severe liver disease, use of anticoagulation medications, acute cervical or pelvic infection, obstructing lesion, or cervical cancer. A low-suction Pipelle device can generally be used safely in the presence of an intrauterine device.

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Sampling Technique An in-office endometrial biopsy is a relatively easy procedure, especially in young, parous women. An endometrial biopsy can be done with a variety of instruments, including disposable low-pressure devices (Pipelle catheters), or high-pressure device machine vacuums such as a vacuum aspirating biopsy retrieval apparatus (VABRA) or Karman cannula, or reusable low-pressure devices (metal pipette, Randall curette, Novak curette). These methods collect strips or sections of the endometrium by suction and/or scraping of the endometrial surface. The Pipelle is one of the most popular methods used. The outer diameter of a Pipelle sheath is about 3 mm with a 2.1–2.4 mm opening at the distal end for collection of the sample. The sheath is made of flexible polypropylene and contains a firm plastic internal plunger that slides up and down. The Pipelle samples only a small section of the endometrial surface, 4.5–15% (Eddowes 1990; Rodriguez et al. 1993; Guido et al. 1995). However, the Pipelle is relatively easy to use, causes less pain, and is less expensive than the other methods that collect a larger proportion of the endometrial surface (Stovall et al. 1991; Silver et al. 1991). Importantly, the combined technique of using endometrial scraping or curettage, with a corkscrew twisting motion, is reported to result in a 95% success rate for obtaining adequate tissue for diagnosis (Sierecki et al. 2008). The recommendation is that even if an adequate sample was obtained, if bleeding persists, further evaluation is needed (Meniru and Hopkins 2006). Further evaluation may be necessary such as repeat Pipelle sampling, ultrasound evaluation, VABRA, hysteroscopy, or dilation and curettage depending on clinical presentation and risk factors. There is a 4–10% risk that cervical stenosis may interfere with getting the catheter through the cervical canal (Guido et al. 1995). In these cases, the use of either a disposable plastic dilatros (Os Finder) or nondisposable dilators from 1 to 5 mm diameter can be used to dilate the cervix in the office. Pretreatment with vaginal or buccal

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misoprostol and/or NSAIDs may be helpful in patients with stenosis. In some cases, a paracervical block as described above can ease pain in the cervix and usually throughout the lower uterine segment. The steps for an endometrial biopsy using a pipette are listed in Table 4. Rare complications include 0.1–0.2% perforation (Kaunitz et al. 1998; McElin et al. 1974; Leclair 2002), bleeding, vasovagal reaction (from paracervical block), severe cramping during or after procedure, and infection. Desired pregnancy is a contraindication to endometrial biopsy. Relative contraindications include coagulation disorder, use of anticoagulation medication, and coagulopathy from other causes such as liver failure and endometritis. The use of prophylaxis antibiotics to prevent bacterial endocarditis is not required (Dajani et al. 1997) (Table 4). There is also a disposable endometrial brush that is available. It is like the brush used for endocervical sampling. The use of the brush, in addition to the endometrial low-pressure suction device, was reported to result in a 100% specificity and diagnosis rate for hyperplasia or cancer (Del Priore et al. 2001). Serial endometrial biopsies can be considered in high-risk patients, those with recurrent bleeding or refractory to treatment.

Treatment Options For younger women with anovulatory bleeding, treatment with the levonorgestrel-releasing IUD, combination of birth control pills or vaginal ring, depo-medroxyprogesterone, or progestins can regulate and generally decrease menstrual flow. Younger women with hyperplasia without atypia can be appropriately treated with cyclic or continuous progestins. Pre- or postmenopausal women with hyperplasia with atypia should be referred to a gynecologist or gynecologic oncologist. Younger women with ovulatory bleeding should first be treated by addressing any clear structural or medical causes. After these problems are addressed, management may also include the levonorgestrelreleasing IUD; combination of oral contraceptive

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Table 4 Steps for performing an endometrial biopsy Consent signed and questions answered (consider vaginal or buccal Cytotec to soften the cervix the night before and morning of and/or 1 h prior to procedure oral NSAID) Bimanual exam to establish size and position of the uterus Evaluation of the vulva and vagina and cervix for lesion; Betadine solution to clean the cervix Evaluate the cervical ostium and take note of possible stenosis, parous versus non-parous, amount of bleeding, and the absence of infection If there is stenosis of the cervix that prevents introduction of the biopsy catheter, dilation of the cervix may be necessary. The use of a tenaculum or paracervical block may facilitate this procedure (see below) There are multiple disposable as well as nondisposable dilators. A popular disposable dilator is the Os Finder. Having several dilation options available is helpful as the amount of beveling, diameter, and degree of flexibility of the dilator may play an important role in determining whether dilation is possible. A very stenotic os requires a firm, tapered dilator to initiate the dilation, while canals that are very tortuous may need the more flexible and less pointed dilators When dilation is necessary or high-suction device is used, consider: 1. Paracervical block (prepackaged kits that include a needle guide and plastic needle spacer that control the depth of needle penetration 2. Or 21–22 gauge (15 cm) extended length spinal needle 10 ml syringe with a large 18–20 gauge needle to draw up 10 ml lidocaine, with or without epinephrine 1% or with vasopressin 3–5 units; prior to injection of lidocaine, reverse pressure on the plunger to insure no backflow of blood (to avoid direct injection into the vessel). Typical injection sites are at 2, 6, and 10 o’clock, although up to six sites on ectocervix can be used, depth 3–7 mm Topical anesthetic cervical gels or creams can be used prior to injection Consider: Single-toothed tenaculum applied to upper cervix to stabilize the cervix and in some cases straighten out the cervix for easier insertion. After removal, insure hemostasis at sites of cervical perforation. Cotton tip swab can be pressed against any bleeding area with or without Monsel’s solution. The use of a tenaculum and sound is standard when using a VABRA or high-suction device Insertion of uterine sound is not always necessary but can be used to establish a tract and measure the length of the uterus (generally 6–8 cm) and always used when using high-suction device Endometrial sampler is gently introduced into the uterine cavity; several passes are usually performed unless the patient is too uncomfortable to continue. The combined technique of endometrial curetting with a corkscrew twisting motion while withdrawing suction device is recommended The sample is placed into specimen container and sent to pathology lab The presence of hemostasis ensured Procedure note and orders entered into the chart Patient allowed to rest supine on the exam table for about 1–10 min after the procedure generally until moderate to severe cramping resolves. The patient should be then allowed to sit on the exam table, making sure she has no lightheadedness for 1–2 min before she stands up She should be counseled that, although unlikely to happen, she should to return to clinic and seek medical help if she has fever, chills, continued cramping past 24–48 h, or abnormally heavy continuous bleeding. The use of nonsteroidal antiinflammatory drugs can be used during the day and before bedtime for moderate to severe cramping Patient should be given peri-pad and advised to have nothing enter the vagina for at least 72 h up to 2 weeks

pills, ring, or patch; tranexamic acid; or nonsteroidal anti-inflammatory drugs (Sweet et al. 2012). Treatment for postmenopausal bleeding is also directed at the underlying cause, including removal of polyps or full evaluation of endometrial lesions by hysteroscopy, dilatation and curettage, or hysterectomy. Treatment options also include vaginal estrogen for vaginal atrophy, correction of systemic illness, or adjustment of hormone replacement therapy.

Complications and Side Effects Cramping generally resolves within a few minutes of the procedure. The high-suction devices are associated with more cramping than the low-suction devices. After the procedure, patients should be encouraged to stay supine for a few minutes to avoid a vasovagal reaction. Rare complications include perforation, excessive bleeding, and infection. Unless prolonged dilation is

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needed, a paracervical block is generally not needed. A paracervical block interrupts the sensory fibers of the cervix, upper vagina, and lower uterus. Intravascular injection or absorption of the anesthetic agent may cause headache, syncope, excessive sedation, or rarely generalized convulsions.

Evaluation: Cervical Biopsy Evaluation of the cervix is an integral part of the standard pelvic exam and includes both a visual and manual inspection as well as timely cervical cytology. Visual inspection of the cervix includes clear visualization of the cervical ostium noting color changes, signs of infection, raised lesions, the presence of endocervical polyp or mass, trauma, foreign body, or discharge. The nonpregnant cervix is generally 2.5–3 cm in diameter and 3–5 cm in length. It is usually angled slightly backward and downward. The external cervical ostium in nonparous women is usually small and round, while in parous women there is often a transverse slit. The canal is approximately 8 mm wide and has longitudinal ridges. A cervical biopsy can either be a visually directed biopsy on the surface of the cervix using a cervical biopsy instrument or a blind scraping of the endocervical canal using an endocervical curette (endocervical curettage). There are other types of cervical biopsies that are not covered in this chapter as they are often done in the operating room as an outpatient surgery. The loop electrosurgical excision procedure (LEEP) and various forms of cone biopsy procedures remove large, cone-shaped pieces of tissue from the cervix.

Differential Diagnosis While most cervical biopsies are done as part of colposcopy for abnormal Pap smear-positive HPV testing, visual inspection of the cervix by itself may reveal abnormal lesions that may warrant biopsy. The following are clinically significant cervical findings:

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• Cervical or endocervical polyps are generally red, smooth, fingerlike growths often arising from within the cervical canal. The etiology of cervical polyps is not well understood, but they are likely due to estrogen stimulation of endocervical cells. Other possible etiologies include chronic infection or congestion of blood vessels. Cervical polyps are often asymptomatic but may cause bleeding or vaginal discharge. They can be very small, pea-sized, or large, several centimeters. While they are usually single, multiple cervical polyps can form. Removal of most cervical polyps is relatively simple and can be done in office using a ring forceps. Polyps with a thick diameter that originate deep within the cervical canal can be difficult to remove in office. Endometrial polyps can also extrude from the cervical os and are not easily distinguished from cervical polyps. • There are a variety of histologic patterns that can occur: (1) typical endocervical polyp (mucosal), (2) granulation tissue, and (3) vascular, fibrous, pseudodecidual, endometrial or mixed endometrial and endocervical, and malignant area on part of polyp. The removal technique is described in Table 5. • Microglandular hyperplasia is a polypoid growth measuring 1–2 cm occurring most often in women on oral contraceptives or depot medroxyprogesterone acetate. It can also occur in pregnant or postpartum women. It is thought to be due to progesterone activity. Removal is the same as a typical cervical polyp (Table 5) (Nichols and Fidler 1971). • Nabothian cysts are mucus-filled, firm cysts that appear on the surface of the cervix. They are thought to be caused when stratified squamous epithelium of the ectocervix grow over and cover the columnar epithelium of the endocervix. The result is that cervical crypts (usually 2–10 mm in diameter) are formed by trapped cervical mucus inside the crypts. Nabothian cysts, clearly seen as cysts filled with mucus, are benign and do not need to be biopsied. • Currently, there are more than 40 HPV serotypes that can infect mucosal surfaces. Exophytic warts, from HPV 6 or 11, can occur on the vulva, vagina, and cervix, while flat warts on

710 Table 5 Steps in removing a cervical/endocervical polyp After informed consent, removal can usually be done by grasping the polyp with a ring forceps The ring forceps are then twisted. The thicker the stalk, the slower the twisting needed to allow hemostasis at the base of the polyp. Polyps with a very thick stalk may require surgical removal After removal of the polyp, the cervical ostium or base of polyp if visible should be checked for bleeding If there is bleeding after the removal, a small cotton-tip applicator dipped in Monsel’s solution can be placed into the cervical canal to the level of the base of the polyp. Good hemostasis should be ensured Specimen sent to pathology. Procedure note and pathology orders entered into the chart Although many of these removals are associated with minimal pain, patients with moderate to severe pain should be encouraged to stay in a supine position for a few minutes to avoid a vasovagal reaction

•

•

•

•

the cervix, from 16, 18, 31, 33, and 35, are associated with CIN. Pap testing now includes identification of the serotype of HPV present on the cervix. HPV is therefore associated with both flat and warty-like lesions on the cervix. The flat lesions are better visualized when treated with 3–5% acetic acid, which causes cellular dehydration and increased nuclear density and acetowhite appearance in dysplastic lesions. Lesions suggestive of HPV should be biopsied under colposcopic guidance for confirmation. Cancer generally will often appear as a friable ulcer or cauliflower-like growth. Biopsy of any raised or suspicious lesion on the cervix should be carefully considered. The technique for cervical biopsy is shown in Table 6. Squamous papilloma is a benign, small, solid, cervical lesion that commonly arises from inflammation or trauma. They are generally 2–5 mm in diameter. Treatment is removal (Table 6). Leiomyomas (smooth muscle tumors) may originate in the cervix accounting for about 8% of all uterine myomas. They are similar to lesions in the fundus but usually are small 5–10 mm in diameter. Removal can be performed with ring forceps if pedunculated (Table 5). Mesonephric duct remnants are usually located at the 3 or 9 o’clock position deep within the

D. Shoupe Table 6 Techniques for cervical biopsy Consents signed; questions answered Area cleaned with Betadine or equivalent Consider use of a tenaculum for stabilization of the cervix if needed Consider use of a local anesthetic injection (not typically done for in-office procedures) Paracervical block (see above for technique) or local injection under lesion Cervical biopsy forceps used to remove lesion (under direct vision or using colposcopy). Specimen placed in formalin and sent to pathology Ensure hemostasis following procedure using a long cotton-tipped applicator (8 inches long), if necessary pressure for 30 s to 2 min or longer Addition of Monsel’s solution applied to cotton-tipped applicator and placed directly on bleeding area with pressure at site of biopsy when necessary Removal of tenaculum (if used) and careful to insure hemostasis at site of tenaculum puncture sites. Use of cotton-tipped applicators (pressure to area for 30 s to longer) with or without Monsel’s solution when necessary Postprocedure patient counseling to avoid sex or anything in the vagina for at least 3 days (some clinics ask for 2 weeks). Report to clinic if heavy persistent bleeding, fever, or pain

cervical stoma. These are remnants of the mesonephric or Wolffian ducts. They are usually only a few millimeters in diameter and usually incidental findings on 15–20% of sectioned cervices (Ferry and Scully 1990). • Endometriosis is usually an incidental finding but may appear as a mass or cause abnormal or typically postcoital bleeding. It often appears as a bluish-black or bluish-red lesion 1–3 mm in diameter. Diagnosis is made by biopsy, often colposcopy-directed biopsy (Phadins et al. 2005). • Papillary adenofibroma is an uncommon neoplasm that appears as a polypoid structure. Similar growths may appear in the fallopian tubes or endometrium. Hemangiomas are also rare and similar to those found in the rest of the body. They can cause vaginal bleeding or pain. The differential diagnosis included cervical cancer and treatment if surgical removal (Gupta et al. 2006; Gusdon 1965).

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Contraindications and Complications There are a very limited number of relative contraindications for cervical biopsy, and they are mainly various etiologies of active cervicitis. Although control of postprocedure bleeding with ferric subsulfate, Monsel’s solution, silver nitrate, or pressure is very effective for most patients, a careful risk–benefit analysis is important in evaluating patients with known bleeding disorders, liver failure, or other coagulopathies. Generally, if colposcopy is done in a pregnant patient, biopsies, particularly endocervical curettage, are avoided until after pregnancy is over. Bleeding at the site of biopsy is the most common complication. Other complications include failure to biopsy the correct site or, rarely, postprocedure infection.

Follow-Up Care Patients should avoid coitus, use, of tampons, or any another intravaginal item for at least 3–14 days after the biopsy to allow healing based on the extent of the biopsy. The patient should be instructed to return to the clinic or seek medical care if she experiences heavy prolonged bleeding, moderate to severe (worsening) pain over the next few days, or persistent fever.

Evaluation and Procedure: Vulvar Biopsy Symptoms related to vulvar lesions are common, often chronic, and can have a significant effect on a woman’s sexual function, self-esteem, and quality of life. Inquiring about specific complaints as well as onset, duration, location, prior treatments, and any possible aggravating or precipitating factors is important in determining the etiology. Important past history includes childbirth, overthe-counter treatments, cryotherapy, prior treatment for condyloma, vulvar laser, or prior vulvar biopsy or surgery. The examination should begin with a thorough examination with good lighting. Adding

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colposcopic examination can often be helpful. Color changes, changes in texture, vaginal discharge, swelling, edema, visible lesions, raised lesion, tenderness, changes in architecture, fissures, and vascular lesions should be noted. These findings as well as size, nature of the border, contour, raised areas, and the presence of ulcerated areas should be accurately recorded. Biopsy of lesions showing hyperpigmentation, raised exophytic areas, changes in vascular patterns, or those that remain unresolved after treatment should be performed to rule out carcinoma and aid in diagnosis. White or hypopigmented lesions or those with pebbling, skin thickening, or thinning may represent skin conditions where biopsy is particularly useful for diagnosis and directing treatment. • Dermatitis is a common finding, reportedly occurring in half of patients complaining of chronic vulvar “itchy rash.” It is often called contact dermatitis as it is often due to vulvar irritants, including chronic vaginal discharge, semen, spermicides, soaps, propylene glycol found in many medicines, and allergic reactions. – A comprehensive interview regarding hygiene practices (cleaning and drying the vulva and introitus), the presence of chronic vaginal discharge, and vulvar product use is very important. The skin lesions are sometimes poorly demarcated, erythematous, scaly, cracked, or lichenified with thin “cigarette-paper” skin often with gray or white color. – Chronic cases may benefit from a biopsy. Emphasis on cleaning and drying techniques is recommended. Avoiding chronic “wetness” in the vulva and discontinuing any contributing irritants are important counseling points. The use of protective emollient, topical antibiotics (A&D ointment), and topical steroids are treatment options (Schlosser 2010). – Acute or chronic vulvovaginitis candidiasis is often associated with vulvar burning and itching, erythema and edema of the introitus, labia, vestibule, and proximal

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vulva due to creamy gray, off-white, or yellow vaginal discharge. – Chronic conditions may show lichenification of the vulva and may be associated with pain and dyspareunia (Krapf 2016). Treatment with local or systemic antifungal and antibacterial products plus local drying hygiene techniques is indicated. Additional treatment for concomitant bacterial infection may need to be added if clinically indicated. • Atrophic vaginitis often plays a role in this condition, and it may positively respond to local or systemic estrogen therapy. Normal vaginal epithelial and cervical discharge is an alkaline transudate with a pH ranging from 3.8 to 4.5. Lactobacillus produces acetic acid and helps maintain a low vaginal pH. Lack of estrogen results in a higher vaginal pH and resultant change in vaginal flora. • Lichen sclerosus is a chronic skin condition whose definite cause is not currently known but likely associated with chronic dermatitis as discussed above. Lichen sclerosus is strongly associated with low endogenous estrogen levels, autoimmune diseases, and genetic factors (Higgins and Cruickshank 2012). Estimates are that between 1 in 70 and 1 in 1000 women have vulvar lichen sclerosus, a rate that is tenfold higher than men. On examination, typical lesions are shiny, flat, blanched white plaques with “crinkled tissue paper” affecting the vulva. There can be associated narrowing of the introitus, thinning, fusion of labia, phimosis of the clitoral hood, and fissures surrounded by purple or red borders (Eva 2012). In particular in chronic, large, nonresponsive lesions, or those with complex surface, a biopsy is recommended to confirm the diagnosis and rule out cancer. – First-line treatment is high-dose topical steroid, clobetasol propionate, nightly for 4 weeks, then every other night for 4 weeks, and then twice weekly for maintenance (Chi et al. 2012; Thorstensen and Birenbaum 2012). Fissures, ecchymoses, hyperkeratosis, and erosions are expected

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to heal, but pigmentation changes may remain (Thorstensen and Birenbaum 2012). Avoiding chronic vulvar moisture is an important counseling point. Treatment options include the use of short-term highdose topical corticosteroids, protective emollients, topical antibiotics, A&D ointment, and other topical hormones. Followup is critically important. • Vulvar HPV lesions and VIN. There are at least 40 HPV subtypes that infect the anogenital region. HPV infections in the vulva often appear as bumps or growths. The most common strains of HPV that cause anogenital warts are 6 and 11 HPV (Pennycook and McCready 2021). They can be asymptomatic or cause itching, burning, bleeding, or pain. They can range in appearance from flat-topped papules, keratotic warts, or dome-shaped, flesh-colored papules. Extensive condyloma acuminata may have a cauliflower-like appearance (Boardman and Cooper 2007). Differentiating genital warts from a vulvar neoplasia from appearance alone can be difficult. Generally, indurated, fixed, hyperpigmented, or ulcerative lesions or lesions that are chronic or do not respond to treatment should be biopsied. – Treatment options include cryotherapy, podophyllotoxin solutions and creams, imiquimod cream, sinecatechins ointment (herbal), trichloroacetic acid solution, and laser or surgical approaches. Multiple treatments are often needed (Pennycook and McCready 2021). • VIN can be white, red, dark, eroded, or raised. If the biopsy returns VIN, the patient should generally be referral to gynecologic oncology (Boardman and Cooper 2007). • Paget’s disease of the vulva is a rare type of skin disease that is most often found in postmenopausal women. The most common complaint is itching or pruritus. It is very slow in spreading, but in some cases an invasive cancer of the vulva is found below the affected area (Shaco-Levy et al. 2010). The appearance of Paget’s disease is sharply demarcated

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patches of red and white scaly skin, like the appearance of eczema. Biopsy confirms the diagnosis and rules out the underlying risk of cancer. Referral to gynecologic oncology is recommended as wide resection and further evaluations are the mainstay of treatment (Edey et al. 2013). • Squamous cell carcinomas are the most common vulvar malignancy, but other pathologies include basal cell, melanoma, Bartholin’s gland cancer, and nonsquamous cell malignancy. These lesions present as a nodule or exophytic mass, asymptomatic lump, or flat or raised lesion with ulceration or excoriation. Melanomas are usually brown to bluish black, but they may be nonpigmented. Lesions with these findings or any lesion that the patient reports have changed in size and shape should be biopsied. • An acrochordon or skin tag may first present as a tiny soft bump on the skin. With time it may grow into a flesh-colored or darker lesion that is attached to the skin below often on a small stalk. A skin tag is generally painless, but it can become irritated if rubbed or moved often. Biopsy is not necessary unless there are suspicious features or symptoms.

Biopsy Techniques The Threshold for Performing a Vulvar Biopsy Should Be Low Chronic, recently changing, or exophytic lesions require a biopsy. Other indications are listed below. Techniques for three types of vulvar biopsies are detailed in Table 7.

Indications Indications for performing a vulvar biopsy include the following: • • • •

Possible malignancy Chronic, changing, or exophytic lesion Visible lesion and no definitive diagnosis Visible lesion, particularly white lesion not responding to usual therapy • Lesions with atypical vascular patterns

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• Benign-appearing lesions requiring definitive diagnosis • Symptomatic lesions

Contraindications There are no absolute contraindications for vulvar biopsy. Relative contraindications include • Gross infection at site • Coagulopathy, liver disease, and anticoagulation medication use • Allergy to local anesthetic • Avoid biopsies on the clitoris or urethra

Approach Considerations • Small, superficial lesions can be biopsied/ removed using a shave biopsy. A shave biopsy samples the epidermis, and it may or may not include a section of the underlying dermis. Therefore, a shave biopsy may not provide information of the subcutaneous tissue. The lesion can be covered with a bandage. • Punch biopsies can be used when the lesion is small enough for complete excision. Punch biopsies from 2 to 10 mm are available. Commonly punch biopsies from 3 to 5 mm are used. • Large lesions, suspected inflammatory lesions, lesion suspicious for neoplasia, and ulcerated or pigmented lesions are often sampled using a punch biopsy. The punch biopsy can be used to either remove the entire specimen or take a small biopsy for diagnosis. In the latter case, the biopsy should include the edges of the lesion to get the best tissue for definitive diagnosis. Multiple punch biopsies may be necessary for larger lesion where areas appear to be different. Each biopsy should be placed in a separate container and labeled correctly. • Larger lesions where complete excision with clear margins is desired may need excisional biopsy with suture repair. Dressing • The vulva is a difficult area to keep a dressing in place. A small spot bandage or regular bandage can be used to cover many vulvar biopsies. For other cases, a small gauze tissue over the lesion plus a pad or panty liner is adequate.

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Table 7 Techniques for three types of vulvar biopsies Initial steps for all three techniques Consent patient and discuss risks and benefits

Risks may include infection, bleeding, inadequate sample, scarring, pain, or allergic reaction

Generally, eye protection should be used. Sterile gloves may be used

Marking area of concern is often helpful. Betadine and local anesthetic can blur boundaries

Punch biopsy After initial steps as shown in first column In general, the smallest punch biopsy (1–3 mm) that will adequately sample the lesion is used. For larger lesions, 4–5 mm biopsies are used. Multiple biopsies can be used

Local resection After initial steps as shown in first column Larger lesions may need excisional biopsy with scalpel (i.e., 15 blade)

Punch biopsy instrument is firmly placed against the skin, encompassing the entire lesion when possible and then rotated with a constant firm pressure both clockwise and counterclockwise until penetration through the skin to the base of the lesion. There is a change in tension as the punch biopsy enters the subcutaneous layer The punch biopsy instrument is then removed, and the specimen is grasped using forceps. Small scissors (curved Isis scissors are a good choice) are used to cut the base of the biopsied tissue Immediate assessment is done as to the amount of bleeding noted. Pressure to the area using gauze is often all that is needed

The lesion is grasped with forceps for stabilization or elevation. The scalpel is used to cut entirely around the lesion, generally including a margin around the entire lesion including the base. The incision is extended down to the base of the lesion. The specimen is held firmly with the forceps and removed using either the scalpel or Iris scissors Immediate assessment of amount of bleeding, Hemostasis done with sterile gauze

Clean area with Betadine or equivalent; sterile drapes can be used

Punch biopsies generally heal without suturing, but sutures may be considered for hemostasis

Topical anesthetic agent may be applied prior to injecting a standard local anesthetic agent

Monel’s solution or silver nitrate can be used if hemostasis is a problem (both may cause increased skin pigmentation and

Suture closure is often used. A needle driver and suture, such as 4–0 monofilament or polyglactin, are used. Re-approximation of skin edges and lower tissue planes with one or more through-and-through stitches is done Monsel’s solution or silver nitrate can be used [both may cause increased skin pigmentation and silver nitrate may cause scarring (Boardman and Cooper 2007) Bandage of sterile gauze coverage of site

Shave biopsy After initial steps as shown in first column Elevate the lesion with a forceps, and then using either a scalpel, i.e., 15 blade, or curved scissors, use a single sweeping stroke to remove the lesion (or cut lesion with scissors with curved tips pointed upward) Achieve hemostasis by pressure. Use of Monsel’s solution or stitches is rarely indicated

Bandage coverage of site

Specimen to pathology. Orders done

Procedure note written

Aftercare discussed. Pressure to lesion if bleeding occurs, keep dressing, or bandage on for 24 h. Following that, (continued)

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Table 7 (continued) Initial steps for all three techniques

Using a large needle, 1–5 mL of 1–2% local anesthetic, such as lidocaine (preferably with epi). The skin injection is done using a small needle (e.g., 25–30 gauge) to minimize pain (Eddowes 1990) After inserting the needle, the plunger is withdrawn to minimize risk of injecting into a vessel The anesthetic agent is slowly injected into the base and underneath the lesion, injecting enough to create a wheal and making sure to also anesthetize the base of the lesion

Punch biopsy After initial steps as shown in first column silver nitrate may cause scarring) (Boardman and Cooper 2007) Bandage coverage of site

Local resection After initial steps as shown in first column

gentle cleaning, and drying techniques okay Specimen to pathology. Orders done

Specimen to pathology. Orders done

Procedure note written

Procedure note written Aftercare discussed. Pressure to lesion if bleeding occurs, keep dressing, or bandage on for 24 h. Following that, gentle cleaning, and drying techniques okay

Aftercare discussed. Pressure to lesion if bleeding occurs, keep dressing, or bandage on for 24 h. Following that, gentle cleaning, and drying techniques okay. Return appointment for suture removal

Aftercare • Generally, patients should be told to avoid the area of biopsy for 24 h. After that, gradually increasing care is appropriate. If bleeding occurs, it can generally be stopped by direct pressure from the patient. • The patient should attempt to keep the area clean and dry. If in the lower perineal area, cleaning after bowel movements is important as the biopsy site may be potentially contaminated with stool. • 24 hours after biopsy with suture placements, showers are permitted, but hot tub baths should be avoided until healing is complete (usually about 5 days). Area should be kept clean and dry and washed once to twice daily. • Patients with suture placement are usually scheduled for suture removal about 7 days

Shave biopsy After initial steps as shown in first column

after the procedure even if delayed absorbable is used.

Conclusions In-office gynecologic procedures are common office procedures that are now a mainstay of women’s healthcare. Endometrial, cervical, and vulvar biopsies can be safely done in the office while allowing a woman to quickly resume her normal activities. Many of these biopsies are done primarily to exclude the diagnosis of cancer, but additionally they are often helpful in establishing the correct diagnosis and treatment options. Most importantly, they alleviate symptoms for many and lessen the emotional and physical burden of an abnormal genital lesion.

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D. Shoupe Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA. 1997;277:22. Del Priore G, Williams R, Harbatkin CB, Wan LS, Mittal K, Yang GC. Endometrial brush biopsy for the diagnosis of endometrial cancer. J Reprod Med. 2001;46(5):439. Eddowes HA. Pipelle: a more acceptable technique for outpatient endometrial biopsy. Br J Obstet Gynecol. 1990;97:961–2. Edey KA, Murdoch AE, Cooper S, Bryant A. Interventions for the treatment of Paget’s disease of the vulva. Chchrane Database Ss Rev. 2013;10:CD009245. Elmaogullan S, Aycan Z. Abnormal Uteirne bleeding in adolescents. J Clin Res Pediatr Endocrinol. 2018;10(3): 1910197. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6083466/#ref5 Esen İ, Oğuz B, Serin HM. Menstrual characteristics of pubertal girls: a questionnaire-based study in Turkey. J Clin Res Pediatr Endocrinol. 2016;8(2):192–6. Eva LJ. Screening and follow up of vulval skin disorders. Best Pract Res Clin Obstet Gynaecol. 2012;26(2): 175–88. Ferry JA, Scully RE. Mesonephric remnants, hyperplasia, and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol. 1990;14(12):1100–11. Finer LB, Philbin JM. Trends in ages at key reproductive transitions in the United States, 1951–2010. Womens Health Issues. 2014;24:271–9. Flug D, Largo RH, Prader A. Menstrual patterns in adolescent Swiss girls: a longitudinal study. Ann Hum Biol. 1984;11:495–508. Guido RS, Ranbour-Shakir A, Rulin MC, et al. Pipelle endometrial sampling: sensitivity in the detection of endometrial lesions. Cancer J Reprod Med. 1995;40:553–5. Gupta R, Singh S, Nigam S, Khurana N. Benign vascular tumors of the female genital tract. Int J Gynecol Cancer. 2006;16:1195–2000. Gusdon JP. Hemangioma of the cervix: four new cases and a review. Am J Obstet Gynecol. 1965;91:204–9. Hickey M, Balen A. Menstrual disorders in adolescence: investigation and management. Hum Reprod Update. 2003;9:493–504. Higgins CA, Cruickshank ME. A population-based casecontrol study of aetiological factors associated with vulvar lichen sclerosus. J Obstet Gynaecol. 2012;32(3):271–5. Kaunitz AM, Masciello A, Ostrowski M. Comparison of endometrial biopsy with the endometrial Pipelle and Vabra aspirator. J Reprod Med. 1998;33:427. Krapf JM, chief editor Isaacs C. Vulvovaginitis. 2016. Medscape. http://emedicine.medscape.com/article/ 2188931-overview. Assessed 27 Feb 2016. Leclair C. Anesthesia for in office endometrial procedures: a review of the literature. Curr Womens Health Rep. 2002;2(6):429–33. McElin TW, Bird CC, Reeves BD, et al. Diagnostic dilation and curettage. Obstet Gynecol. 1974;17:205.

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Meniru G, Hopkins M. Abnormal uterine bleeding. In: Curtis M, Overholt S, Hopkins M, editors. Glass’ office gynecology. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 190. Nichols TM, Fidler HK. Microglandular hyperplasia in cervical cone biopsies taken for suspicious and positive cytology. Am J Clin Pathol. 1971;56(4):424–9. Pennycook KB, McCready TA. Condyloma Acuminata. StatPearls [Internet] August 9, 2021. Condyloma Acuminata – Stat Pearls – NCBI Bookshelf NCBI. nim.nih.gov Phadins SV, Doshi JS, Ogunnalke O, Coady A, Padwick M, Sanusi FA. Cervical endometriosis: a diagnostic and management dilemma. Arch Gynecol Obstet. 2005;272:289–93. Rodriguez GC, Yaqub N, King ME. A comparison of the Pipelle device and the Vabra aspirator as measured by endometrial denudation in hysterectomy specimens: the Pipelle device samples significantly less of the endometrial surface than the Vabra aspirator. Am J Obstet Gynecol. 1993;168:55–9. Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin. 2010;28(4):697–706. Shaco-Levy R, Bean SM, Vollmer RT, Jewell E, Jones EL, Valdes CL, et al. Paget disease of the vulva: a study of

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56 cases. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):86–91. Sierecki AR, Gudipudi DK, Montemarano N, Del Priore G. Comparison of endometrial aspiration techniques: specimen adequacy. J Reprod Med. 2008;53(10):760. Silver MM, Miles P, Rosa C. Comparison of Novak and Pipelle endometrial biopsy instruments. Obstet Gynecol. 1991;79:828–30. Stovall TG, Ling FW, Morgan PL. A prospective, randomized comparison of the Pipelle endometrial sampling device with the Novak curette. Am J Obstet Gynecol. 1991;165:1287–9. Sweet MG, Schmidt-Dalton TA, Weiss PM. Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012;85(1): 35–43. Thorstensen KA, Birenbaum DL. Recognition and management of vulvar dermatologic conditions: lichen sclerosus, lichen planus, and lichen simplex chronicus. J Midwifery Womens Health. 2012;57(3): 260–75. Widholm O, Kantero RL. A statistical analysis of the menstrual patterns of 8,000 Finnish girls and their mothers. Acta Obstet Gynecol Scand Suppl. 1971;14 (Suppl 14):1–36.

Operative Hysteroscopy

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Paul P. Smith and T. Justin Clark

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721 Patient Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722 Prevention of Cervical Trauma and Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722 Distension Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722 Hysteroscopic Treatment of Fibroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Submucous Fibroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysteroscopic Equipment for Removal of Fibroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

723 723 724 724 725

Hysteroscopic Polypectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hysteroscopic Equipment for Removal of Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

726 726 727 727

Endometrial Destruction for Abnormal Uterine Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial Destruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique of Transcervical Resection of the Endometrium and Endometrial Electrocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique for Second-Generation Endometrial Ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

730 730 731 732

Hysteroscopic Treatment of Acquired Uterine Abnormalities . . . . . . . . . . . . . . . . . . . . . Intrauterine Adhesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retained Products of Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

733 733 733 734 734

P. P. Smith · T. J. Clark (*) Birmingham Women’s NHS Foundation Trust, Edgbaston, UK e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_53

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P. P. Smith and T. J. Clark Hysteroscopic Treatment of Congenital Uterine Anomalies . . . . . . . . . . . . . . . . . . . . . . . . 734 Uterine Septum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Hysteroscopic Sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Hysteroscopic Tubal Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736 Technique for Tubal Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736 Outpatient Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737 Equipment and Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737 Safety of Operative Hysteroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737 Case Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738 Teaching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739 Clinical Governance and Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740 Future Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

Abstract

In this chapter, we aim to describe contemporary operative hysteroscopy. A further aim is to provide an outline for safe and effective practice when performing such procedures by summarizing the best available evidence supplemented by the authors’ own experience. More specifically, this chapter covers the available equipment, technologies, and techniques necessary to perform a variety of hysteroscopic procedures, namely, removal of fibroids and polyps, endometrial ablation, treatment of acquired and congenital uterine abnormalities, removal of placental remnants, and sterilization. The role of teaching, clinical governance, and audit in improving operative hysteroscopic services is also discussed. Keywords

Hysteroscopy · Vaginoscopy · Operative hysteroscopy · Outpatient hysteroscopy · Ambulatory hysteroscopy · Office hysteroscopy · Resectoscopy

Introduction In 1869, the first successful diagnostic and operative hysteroscopy was performed when Pantaleoni used a cystoscope and candlelight to treat an endometrial polyp causing postmenopausal bleeding. Then in 1907, Charles David was the first to describe a lens system that allowed uterine cavity visualization. Yet, it was not until 1943 that Forestiere’s cold light source and Hopkin’s rod lens were combined to form the endoscopes that have become the basis for today’s hysteroscopy. With advances in technology and techniques, hysteroscopy has taken over from dilatation and curettage to become the gold-standard procedure for investigation and treatment of pathologies in the uterine cavity. It has the advantage of being able to visualize the uterine cavity directly and can sometimes allow simultaneous treatment to be performed. A large number of procedures can now be performed hysteroscopically. These include fibroid resection, polyp removal, sterilization, removal of chronically retained products of conception (RPOC), adhesiolysis, septoplasty,

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and endometrial ablation. Hysteroscopic surgery is minimally invasive, avoiding surgical incisions and the need for prolonged inpatient hospital stay. Furthermore, proficient operative hysteroscopy is both quick and safe. Increasingly procedures are being performed in a more convenient ambulatory or “office” setting avoiding the need for hospital admission or general anesthesia. Indeed, the concept of office-based “seeand-treat” hysteroscopy has been propagated over the last decade with simultaneous treatments being undertaken conditional upon the prior diagnostic hysteroscopy. Although complication rates for operative hysteroscopy are low, some complications can be life-threatening. It is therefore imperative that appropriate training programs are combined with an understanding of the equipment and techniques to make operative hysteroscopy a safe and efficient tool. Fig. 1 Components of operative hysteroscope

Fig. 2 Endoscopic viewing angles (hysteroscopes have a 0
, 12
, 25
, or 30
)

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Equipment Most operative hysteroscopes consist of an inflow channel for distension media, an outflow channel for distension media, an operating channel with a sheath to allow instrumentation, a light lead, and telescope with fiber-optic cables and a camera head (Fig. 1). Some hysteroscopes use an angled optic that allows better visualization of the cavity. It is important to realize that when inserting the hysteroscope through the cervix, the endocervical canal is positioned at 6 o’clock if the optic is upward and 12 o’clock if the optic is downward (Fig. 2). For most hysteroscopes, the position of the light lead is the same as the location of the endocervical canal. Light leads are fiber-optic cables that act as conduits for light between the generator and the telescope. Fiber-optic cables are prone to damage

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and are normally the cause of low light generated by the telescope. Looking for dark spots at the end of the cable can assess this.

Patient Preparation An important part of patient preparation is adequate counseling about the rationale for the procedure and what it involves. The patient experience is important to describe especially for those women undergoing office-based procedures without general anesthesia. Potential complications and the expected clinical outcomes need to be discussed in a frank manner. Patient information leaflets are an essential component in preoperative counseling because they support verbal information given to further ensure that patients are adequately informed and prepared for their hysteroscopic procedure. The Royal College of Obstetricians and Gynaecologists (RCOG), in conjunction with the British Society for Gynaecological Endoscopy (BSGE), has developed a generic outpatient hysteroscopy patient information leaflet available at https:// www.rcog.org.uk/en/patients/patient-leaflets/outpa tient-hysteroscopy.

Technique Although not always practical, hysteroscopy should be performed in the first half of the menstrual cycle when the endometrium is at its thinnest. Pregnancy should be ruled out before all cases begin. When positioning a patient for hysteroscopic procedures, the patient should be in the lithotomy position with the buttocks slightly over the edge of the operating table.

Prevention of Cervical Trauma and Perforation There is evidence to suggest that the hysteroscopic procedures under direct vision are more accurate than dilatation and curettage (Loffer et al. 2000; Valle 1981). Not only should procedures under direct vision be done in preference to

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blind procedures for the purpose of accuracy but also for safety reasons. As further advances are made resulting in miniaturization of equipment, the need for blind dilatation, which risks uterine trauma, will also be reduced. Cervical trauma and patient discomfort can be reduced by using the thinnest hysteroscopic equipment available and the “no touch” or vaginoscopic technique (Smith et al. 2019). The vaginoscopic technique is achieved by guiding the hysteroscope into the uterus under direct vision without using any potentially painful instrumentation. The easiest way to do this is to enter the vagina, allowing the distension media to fill the cavity and follow the posterior wall of the vagina down into the posterior fornix. The hysteroscope is then maneuvered into the cervix above and pushed through the cervical canal into the uterus. The vaginoscopic technique can only be used for hysteroscopes less than 6 millimeters in diameter. The administration of oral or vaginal prostaglandins such as misoprostol prior to operative procedures has been researched and has shown that spontaneous cervical dilatation is increased but with no decrease in complications (Cooper et al. 2011a). There are inconsistent results on the benefits of osmotic dilatators such as laminaria prior to operative procedures.

Distension Media The technique of hysteroscopy requires a distension medium to be instilled into the uterine cavity to allow visualization of the uterine cavity enabling both diagnosis and surgical treatment of intrauterine pathology. A variety of distension media can be used, including liquids such as glycine, dextran, sorbitol, water, and normal saline, and gases such as carbon dioxide. Comparisons of normal saline to carbon dioxide as distension media have shown no difference in pain or visualization, although procedures done with normal saline were found to be significantly faster (Cooper et al. 2011b). However, carbon dioxide is infrequently used nowadays because special insufflation equipment is needed and its use is

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restricted to simple diagnosis. The plethora of new therapeutic hysteroscopic systems requires fluid distension media to continuously irrigate the uterine cavity removing blood and tissue debris, thereby providing a clear operative picture. The use of isotonic fluid normal or “physiological” saline is the preferred fluid media for operative hysteroscopic procedures because inadvertent fluid overload does not lead to severe osmotic imbalance (hypervolemic hyponatremia) (Berg et al. 2009). Mechanical technologies such as tissue removal systems can be used in normal saline. When it comes to operative procedures using electrical energy, the type of distension media is dictated by whether monopolar or bipolar electrical circuits are being used. Bipolar electrodes require conductive, electrolytic solutions such as normal saline (285 mOsm/L) or Ringer’s lactate (279 mOsm/L), while procedures using monopolar electrodes need nonconductive, hypo-osmolar, nonionic solutions such as glycine 1.5% (200 mOsm/L) or sorbitol 3% (165 mOsm/L). The new generation of bipolar electrodes is generally safer than monopolar electrodes because they do not affect serum osmolality or sodium levels. However, all solutions can cause complications from intravascular absorption of large volumes of fluid into the circulatory system. Excessive fluid absorption is most likely with prolonged hysteroscopic procedures using larger diameter endoscopes with continuous irrigation of fluid or where blood vessels within the myometrium are opened. Thus, particular care is required with resection of the endometrium [transcervical resection of the endometrium (TCRE)] and hysteroscopic myomectomy [transcervical resection of fibroids (TCRF)]. Serious complications arising from expansion of the extracellular fluid volume with the potential to generate fluid overload, pulmonary edema, include acute pulmonary edema, cerebral edema, and cardiac failure. Therefore, it is important to accurately measure the input and output of fluid during operative hysteroscopy so that significant fluid deficits can be recognized and managed promptly. While delivery of the distension medium can be safely and effectively achieved using simple gravity or pressure bags, automated pressure delivery

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systems facilitate the creation of a constant intrauterine pressure and accurate fluid deficit surveillance. The American Association of Gynecologic Laparoscopy (AAGL) guidelines recommend that when fluid deficits with a nonelectrolyte solution reach 1500 or 2500 mL with normal saline, the procedure should be brought to a halt (Loffer et al. 2000).

Hysteroscopic Treatment of Fibroids Submucous Fibroids Fibroids or leiomyomas are benign overgrowths of the smooth muscle layer of the uterus. They remain the most common indication for hysterectomy. Submucous fibroids are those that protrude into the uterine cavity. They account for 5% of all fibroids. Submucous fibroids are associated with pain, bleeding, infertility, and recurrent miscarriage. The most established classification system for submucous fibroids was developed by Wamsteker and the European Society of Gynecologic Endoscopy (ESGE) and accepted by the International Federation for Obstetrics and Gynecology (FIGO) (Munro et al. 2011). This nomenclature states that if the submucous fibroid is entirely intracavitary, that is, attached to the uterine cavity sidewall by only a small stalk, they are classified as type 0; if a portion of the fibroid is intramural, then they are type 1 if less than 50% is intramural and type 2 if more than 50% is intramural. Submucosal fibroids can be selectively removed hysteroscopically, which is particularly useful in women who want to preserve their fertility and avoid the complications of laparoscopic or laparotomic surgery. Types 0 and 1 are suitable for hysteroscopic resection. Removal of type 2 fibroids is more challenging because the risks of perioperative bleeding, incomplete removal, and uterine trauma are significantly greater. Furthermore, the need for repeated hysteroscopic or other surgical interventions is greater to treat ongoing abnormal bleeding symptoms compared with type 0 and 1 fibroids (Vercellini et al. 1999). Another classification system has been developed to

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describe additional prognostic features related to submucous fibroids; in addition to depth of myometrial penetration, the STEPW classification records the size, topography (location), and extension of the base in relation to the uterine wall (Lasmar et al. 2012). Hysteroscopic removal is mostly done with resectoscopy, that is, electrosurgical resection using a modified urological resecting loop. More recently, hysteroscopic morcellators, now termed tissue removal systems, have been introduced offering simultaneous mechanical cutting and tissue aspiration, and these technologies appear to be gaining increasing popularity (van Dongen et al. 2008). Some surgeons did use laser hysteroscopic myomectomy in the past, but the laser units are associated with high capital and running costs and have largely been abandoned now.

Endometrial Preparation It is common practice to give medication to suppress the endometrium and shrink fibroids prior to surgery. It is thought that this improves visualization by thinning the endometrium and helps ensure complete removal of the fibroid. The use of gonadotropin-releasing hormone analogs (GnRHa) 3–4 months prior to surgery does reduce fibroid size and corrects anemia prior to surgery (Lethaby et al. 2001). However, data supporting the benefits of endometrial downregulation prior to operative hysteroscopy are conflicting, and currently there are no randomized controlled studies showing surgical removal, and clinical outcomes are improved by this practice (Kamath et al. 2014). Initial work on the selective progesterone receptor modulator, ulipristal acetate, showed it to be an effective alternative to GnRHa for reducing fibroid size and inducing amenorrhea prior to Fig. 3 Resectoscope

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fibroid surgery with fewer menopausal symptoms (Donnez et al. 2012a, b). However, as with GnRHa, data supporting improved outcomes with hysteroscopic myomectomy are lacking and concerns about the risk of serious liver injury and liver failure have restricted the use of ulipristal acetate; the original indication for controlling symptoms of uterine fibroids while awaiting surgical treatment has been revoked by the EMA’s Human Medicines Committee. It is important to assess the size and the degree of intramural involvement before embarking on medication to shrink the fibroids, to effectively counsel the patient and plan appropriate surgery. Transvaginal ultrasound is now common in the evaluation of women with gynecological problems, but on its own, it is not accurate enough to adequately describe protrusion of the fibroids into the endometrial cavity. The advent of the 3D ultrasound and saline infusion sonography has been shown to improve accuracy (de Kroon et al. 2003; Lee et al. 2006). Ultrasound is useful to describe the distance between the intramural component and the serosa, which can help the surgeon prevent perforation of the uterus during hysteroscopic treatment. Hysteroscopy provides the best method for assessing the degree of protrusion into the endometrial cavity and the suitability for surgery. With the advent of outpatient hysteroscopy, this can be done without subjecting the patient to general anesthesia.

Hysteroscopic Equipment for Removal of Fibroids Hysteroscopic resectoscopes are versatile tools that consist of a movable cauterization electrode usually in the form of a loop (Fig. 3). Originally, the resectoscopes used a monopolar electrode, but

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advances in technologies have led to the development of equally effective bipolar resectoscopes that have the increased safety advantage of using isotonic distension media with reduced risk of serious complications arising from fluid overload and hypervolemic hyponatremia.

Technique The first step is to identify all the uterine cavity landmarks, and these should continue to be visualized throughout the procedure. The surgeon should be familiar with their equipment and technology, especially the angle of the offset lens, energy modality, and distension media management. The amount of fluid deficit considered reasonable, which will depend upon its nature and the patients’ medical comorbidities, should be discussed between the surgical team and the anesthetist prior to commencing the procedure.

Electrosurgical Resection For electrosurgical resection, the loop electrode should be extended beyond the fibroid. The activated electrode is then drawn toward the surgeon by either moving the entire hysteroscope or closing the electrode or a combination of these two movements. Usually, a blended or pure cut current set at 120 W cutting is adequate. The activated electrode should never be pushed away from the surgeon as this can cause perforation. Cutting into the myometrium should be avoided, particularly near the cornua and cervix where it is at its thinnest and bleeding or uterine perforation may occur. The degree of magnification and extension of the loop from the distal lens should be adjusted according to the location of the fibroid or area being resected, for example, a higher degree of magnification (proximity of the distal lens) is needed when resecting fibroid tissue near the fundus or cornua. One of the main disadvantages of electrosurgical resection of submucous fibroids is that as the fibroid is progressively debulked, “chips” of fibroid tissue are generated, which compromise visualization and impede the free movement of

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the loop electrode. One strategy to combat the impact of these fibroid chips is to push them toward the fundus to keep the view clear until enough are generated to obscure the visual field. A variety of techniques are then used to remove the chips, which include using curette and polyp forceps or closing the inactivated resectoscope loop, thus catching the chips. Also, the resectoscope can be removed from its outer sheath, allowing the chips to traverse the cervical canal through the sheath. The fibroid should be resected until it is level with the endometrium. Spontaneous uterine contractions as well as fluctuations in intrauterine pressure, for example, increasing and decreasing the distension media pressure, can help push some of the intra-myometrial component of a grade 1/2 fibroid into the uterine cavity, allowing safer resection under direct vision. Mechanical undermining of the intramural fibroid component with the passive inactivated electrode or with a firmer specially designed hook can achieve the same thing. This latter surgical approach has been described as adopting a “cold knife” technique (Mazzon et al. 2016). As the intramural extension of the capsule is reached, the myometrial sinuses are exposed, which can lead to bleeding and increased and sometimes rapid intravascular absorption of fluid. The production of fibroid chips can be avoided if grade 0 fibroids are removed en bloc by cutting through the basal attachment to the uterine side wall with miniature bipolar electrodes such as Versapoint ® bipolar electrosurgical system (Gynecare™; Ethicon Inc., NJ, USA). These electrodes can be passed down the operating channel of a standard continuous flow operating hysteroscope, and detachment of the grade 0 fibroid can be rapidly achieved. However, given the shape and small size of the electrode, they are not generally suitable for fundally located lesions. Moreover, blind removal of the fibrous specimen from the uterine cavity is not always possible. In these cases, the fibroid will often be left in situ and subsequently degenerate and pass. Another alternative to reduce the production of fibroid chips is the vaporization electrode. The

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first vaporizing electrode developed by CIRCON ACMI was the VaporTrode ® Grooved Bar. Using the Grooved VaporTrode ® and higher wattage, the device is able to vaporize tissue in contact with the electrode (Brooks 1995).

Shaver (IBS). More recently, the SYMPHION™ (Boston Scientific, Natick, MA, USA) has been produced, which combines a tissue removal system with bipolar radiofrequency energy.

Tissue Removal Systems Hysteroscopic tissue removal systems appear to have overcome the most frustrating problem with resectoscopes by avoiding the generation of tissue chips. This makes fibroid removal easier to learn than traditional electrosurgical resections (van Dongen et al. 2008). Tissue removal systems use a simultaneous mechanical cutting and tissue retrieval setup that maintains better views while operating. The tissue removal systems consist of a bespoke operating 0
hysteroscope with an operating channel through which a disposable cutting handpiece comprising two rotating hollow metal tubes with a small aperture distally. This is attached to an external suction tubing. A generator provides the electrical energy to rotate the mechanical tissue removal system. Before the device is inserted, it is important to make sure the window lock is closed when it is not activated. Once the fibroid requiring removal is identified, the window should be aimed toward the top of the fibroid, and the tissue will be sucked inside the window and shaved. As with electrosurgical resectoscopes, the strategy for fibroid removal using these systems is to start on the periphery and move closer to the myometrium. The technique is to position the opening near the pathology, which is then sucked into the opening. Rotation of the inner metal tube then shaves away the pathology. Afterward, the pathology is sucked through the device and trapped in a tissue collector. Gentle pressure is applied with minimal movement of the hysteroscope to ensure the base of the fibroid is removed. To prevent blood and debris obscuring the visual field, it is important to keep the device activated to ensure these products will be sucked into the window. The first of these systems was the TRUCLEAR™ (Medtronic™, Minneapolis, MN, USA), which has been followed by a similar product by Hologic (Bedford, MA, USA) called Myosure™ and Karl Storz (Tuttlingen, USA) called Integrated Bigatti

Hysteroscopic Polypectomy Endometrial Polyps Endometrial polyps are benign overgrowths of endometrium that project into the uterine cavity. Generally, they are pedunculated and are attached to the uterus by an elongated pedicle, but sometimes they are sessile and have a large flat base (Fig. 4). They can be distinguished from submucous fibroids because they are soft and can be indented by the hysteroscope, and they move with the distension media. They often have a pink-red appearance similar to endometrium, but less vascular polyps can appear pale gray. The specific hysteroscopic appearance of polyps will vary according to the relative makeup of stroma, glands, and blood vessels. Endometrial polyps are common with a prevalence of around 10% in women undergoing a diagnostic hysteroscopy (Clark and Gupta 2005). Most gynecologists recommend the removal of endometrial polyps because of their association with malignant and premalignant conditions (van Dijk et al. 2012;

Fig. 4 Endometrial polyp as seen at hysteroscopy

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Timmermans et al. 2008; van Hanegem et al. 2017). The incidence of polyps and risk of malignancy increases with age. Hysteroscopic visualization allows a subjective assessment of the nature of polyps, but it can also be used to direct biopsies to increase diagnostic accuracy (Birinyi et al. 2004). Indeed, hysteroscopy has the added advantage of allowing simultaneous treatment of detected endometrial polyps. Depending on the local resources and expertise that is available, polypectomy can invariably be performed in the office setting without general anesthesia (Cooper et al. 2015). Hysteroscopic techniques utilizing both miniature mechanical and electrosurgical technologies allow polyp removal under direct vision, reducing the risk of incomplete removal and uterine trauma. This represents a shift in management because until recently polyps were often removed blindly using dilation and curettage (D&C) or using largediameter electrosurgical resecting loops under general anesthesia.

Hysteroscopic Equipment for Removal of Polyps Hysteroscopic polypectomy began with a range of mechanical instruments that could be passed down the operating channel of the hysteroscope, including graspers, biopsy cups, and scissors (Bettocchi et al. 2004; Nathani and Clark 2006; Timmermans and Veersema 2005). However, these instruments are flimsy, making it difficult to remove large pathology, and there have been some studies showing problems with bleeding (Clark and Gupta 2005; Garuti et al. 2008). The resectoscope was the first electrosurgical instrument described for removing endometrial polyps, but these are large-diameter instruments necessitating the use of general anesthesia and potentially traumatic, blind cervical dilatation. It is well recognized that polyps are softer than fibroids such that newer miniature electrosurgical instrumentation such as bipolar electrodes [e.g., Versapoint™ bipolar electrosurgical system (Gynecare, Ethicon, Somerville, NJ, USA)] and monopolar snares have been developed that obviate the need

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for large-diameter hysteroscopes and blind cervical dilatation. The bipolar electrodes have been demonstrated in observational series to be feasible and safe (Clark et al. 2002a; Kung et al. 1999; Vilos 1999) and have snares. The latter technology is less widely used (Timmermans and Veersema 2005). The previously mentioned hysteroscopic morcellator devices or tissue removal systems, TRUCLEAR™ (Medtronic™, Minneapolis, MN, USA) and Myosure™ (Hologic™, Marlborough, MA, USA), are utilized for polypectomy as well as myomectomy. Randomized trials have shown that when compared to electrosurgical devices, tissue removal systems that allow simultaneous tissue cutting and retrieval are quicker to learn, less painful, more acceptable, faster, and more likely to completely remove polyps (van Dongen et al. 2008; Smith et al. 2014a).

Technique Electrosurgery Resecting Loops The main drawback to the use of large-diameter resectoscopes is the need for cervical dilatation and regional or general anesthesia. As with resecting submucous fibroids, the loop is extended beyond the focal lesion and then is activated and drawn toward the operator by closing the loop using the trigger or moving the whole resectoscope or a combination of both methods. The softer, less vascular nature of endometrial polyps in comparison to submucous fibroids makes them much easier to remove. They are rapidly resected either in pieces after a few passes off the resecting loop or en bloc with a sweep of the resecting loop at the polyp base where it is attached to the uterine side wall. Occasionally, the inactivated loop can be deployed as a simple snare, closing the extended loop to mechanically detach the polyp from its attachment. Retrieval from the already dilated cervical canal of compressible, glandular polyps is usually achieved under vision by trapping the tissue within the withdrawn loop and end of the hysteroscope and removing the whole unit along the cervical canal.

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Bipolar Electrical Resection with Miniature Electrodes The cutting point of the bipolar electrode works by vaporization. High-temperature Ohmic heating in the immediate vicinity of the active electrode boils the saline to create a vapor pocket. This has the advantage of minimizing bleeding by cauterization of blood vessels. The initial bipolar miniature electrodes were the Versapoint™ electrodes (Fig. 5) that were designed to be used with a bespoke small-diameter operating hysteroscope. This “Versascope™,” subsequently modified and renamed “Alphascope™,” is a small-diameter 0
semirigid hysteroscope incorporating a rotating cuff to manipulate the orientation of the bipolar electrodes and other ancillary instruments that have been passed down the expandable disposable outer sheath. The bipolar electrodes can, however, fit down any standard continuous flow operating 30
hysteroscope incorporating a 1.6 mm operating channel, making them highly versatile instruments. In contrast to the formal resectoscopes, use of smaller-diameter electrosurgical operating set ups minimizes the need for traumatic cervical dilatation. Indeed, the development of the Versapoint™ electrode as a more effective cutting tool compared with flimsy mechanical graspers and scissors was one of the main technologies to shift polypectomy to an office setting. Once a polyp has been diagnosed, the bipolar electrode is passed down the operating channel of a standard rigid operating hysteroscope. However, if using the Alphascope with its expandable plastic working channel, it is advisable to insert it into the uterine cavity without the electrode in the operating channel. This is because the Alphascope is narrower without the electrode

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and the operating channel also acts as the outflow; hence, it is harder to clear the turbid fluid at the beginning of the procedure unless it is empty. However, for selected cases such as fundal polyps, it may be beneficial to insert the electrode at the beginning so that the twizzle tip can be bent across the camera lens to create a cutting hook and then allow entry into the uterine cavity. The main drawback of the miniature electrodes is the ability to manipulate them as the cutting surface is small and fixed in contrast to electrosurgical loops. When cutting a polyp using an Alphascope, there are three techniques that can be used. The first is to fix the electrode and hysteroscope but swivel the sheath using the rotating cuff creating an arc, which is particularly effective at cutting sidewall polyps. The second is to fix the sheath and hysteroscope and move the electrode in and out. The last technique is to fix the electrode and sheath and then move the hysteroscope and electrode as one instrument. If using the bipolar electrode down a rigid operating 30
hysteroscope, the orientation of the electrode can be altered by moving the light cable and hence the position of the distal offset lens. It is important that with all the techniques, the electrode is not activated when it is going toward the direction of the fundus as this could lead to perforation and damage. The activated electrode should be withdrawn toward the operator, and when approaching attachments at the fundus and especially the thinner cornual aspects of the uterine side wall, higher magnification is required by ensuring the electrode is close to the distal lens. The exact technique chosen to cut the polyp will depend on the operator preference, size, and position of the polyp. In the author’s opinion, as polyps are compressible and feasible for removal

Fig. 5 Alphascope™ and Versapoint™ bipolar electrodes: (a) twizzle electrode; (b) spring electrode

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in an office setting, the most efficient technique is to remove the polyp en bloc by cutting its basal attachment to the uterine side wall. This is easiest if the polyps are nonfundal and located on the anterior, posterior, or lateral sidewalls. Sometimes, it may be necessary to bisect the polyps if they are large and located fundally so as to access the base. Other operators prefer to cut the polyp into segments, but this is time-consuming and either creates chips of tissue, which may obscure visualization within the cavity or repeated insertions and withdrawal of the hysteroscope. Removing the polyp in one piece avoids these problems, but the larger tissue specimen is harder to remove along the narrow cervical canal. A variety of biopsy cups, grasping forceps, and snares are available that can be passed down the operating channel to remove the polyp fragments from the cavity. Leaving a small attachment between the polyp and the sidewall will make it easier to grab and stop it from swirling around from the inflow of saline. If the polyp is completely detached, then turning off the fluid inflow and gently pushing the polyp using the opened forceps to pin it against the fundus can be used to then take a substantial “bite” of tissue. Others prefer to use inactivated snares to grasp the specimen. To give the greatest chance of traversing the cervical canal without the polyp becoming detached, a good degree of purchase on the polyp by having it firmly grasped should be ensured, and the largest part of the polyp should be brought proximally over the distal lens and then the whole unit moved slowly move backward down the endocervical canal. If this does not work because the polyps are large and fibrous or the cervical canal is narrow, then it may be necessary to break the polyp up under vision, although this is rarely possible given its mobility within the cavity. More often the cervix will need to be dilated up to H6–8 and the hysteroscope and graspers inserted again. Blind retrieval using large polyp forceps should be avoided where possible.

Mechanical Scissors and Grasping Forceps Cold scissor resection can be performed using similar equipment as above to detach endometrial

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polyps. Scissors have the advantage of not producing bubbles that can impede the visual field, and they are also reusable. However, they are fragile, become blunt over time, and are difficult to manipulate. In contrast to the bipolar electrodes, they create bleeding and cannot cut through more fibrous polyps. Tissue Removal Systems The TRUCLEAR™ and Myosure™ tissue removal systems have been described in the preceding section on submucous fibroids (Figs. 6 and 7). These technologies can be used for removing uterine polyps. However, in contrast to submucous fibroids, the softer tissue constituting polyps makes them amenable to morcellation using systems with less cutting power (Myosure REACH, LITE & CLASSIC). In the case of TRUCLEAR, a much smaller-diameter system is available, the OD TRUCLEAR system with a 2.9 mm rotary cutting blade. The outer diameter is 5.6 mm, and it is a continuous flow system aiding visualization even in the presence of significant tissue debris and bleeding. If the outflow sheath is removed, outflow is then provided by the negative pressure, which draws saline through the aperture and along the hollow activated device. The outer diameter is then reduced to 5 mm, which is advantageous in the office setting, and vaginoscopy is more feasible.

Fig. 6 TRUCLEAR ® hysteroscopic tissue retrieval system

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Fig. 7 Myosure ® hysteroscopic tissue retrieval system

The technique for morcellation is similar to removing fibroids. The distal aperture incorporating the cutting edges of the rotating inner and outer hollow tubes should be embedded in the polyp tissue and not visible. As polyps are mobile in a fluid distension media, they will be seen to move when the device is in contact with the tissue, simultaneously cutting and aspirating material. Movement of the device should be kept to a minimum. Small rotations of the handpiece to redirect the cutting window are all that is generally required. As the polyp base is reached, more exaggerated vertical or horizontal movements of the handpiece will lever the cutting window up against the uterine side wall. The ease of use of these systems and short learning curve compared to traditional resectoscopy was highlighted in a recent randomized control trial (RCT) (van Dongen et al. 2008). A recent RCT showed that the TRUCLEAR™ tissue removal system was quicker, less painful, and more acceptable and successful compared with Versapoint™ electrosurgery for the office removal of endometrial polyps (Smith et al. 2014b).

Endometrial Destruction for Abnormal Uterine Bleeding Endometrial Destruction Heavy menstrual bleeding is one of the most common reasons patients consult with their gynecologist. There is an increasing range of medical

therapies, but most have a hormonal basis for action. Some women do not like taking hormones long term, while others suffer from side effects, and these problems can limit the application of medical therapies. Traditionally, after medical therapies had failed, definitive treatment with hysterectomy was used, but this has the morbidity and mortality associated with a major surgery. Moreover, patient preference studies have shown that women put a high value avoiding hysterectomy and retaining their uterus. Endometrial destruction techniques, that is, ablation and resection of the endometrium, provide a cheaper, safer alternative to hysterectomy. The first-generation hysteroscopic techniques include laser ablation, rollerball ablation, and transcervical resection of the endometrium (TCRE). The costs of laser equipment were prohibitive so that electrosurgical resection with cutting loops and/or rollerball ablation using rollerball electrodes became the preeminent technique. When comparing TCRE with rollerball ablation, there is no evidence of difference in rates of complication or reintervention (Lethaby et al. 2005). The second-generation techniques were then developed. These semiautomated technologies utilized the principle of controlled, global thermal destruction of the endometrium but without the requirement for enhanced operative hysteroscopic skills. They also aimed to reduce complications, particularly those of uterine trauma and fluid overload. While evidence supports their enhanced feasibility and safety, they are generally less flexible being restricted to use in regular-shaped cavities without submucous fibroids or congenital

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anomalies. There have been many different devices that have come to market with some no longer in use. The most prevalent devices are based upon the application to the endometrial surface of impedance-controlled radiofrequency energy (NovaSure™ Fig. 8) or conducted heat from fluid within a pressurized balloon [Thermachoice™ (Gynecare™; Ethicon™ Inc., NJ, USA); Cavaterm™ (Wallsten Medical SA, Lausanne, Switzerland); Thermablate™ (Gynecare™, NJ, USA)]. The Genesys HTA™ (Boston Scientific) is a hydrothermal ablation method that uses heated saline and allows for visualization of the endometrial cavity during the ablation procedure. It allows for ablation of larger and irregularly shaped endometrial cavities. The main drawback of uterine-sparing endometrial ablation in comparison to hysterectomy is that it cannot guarantee amenorrhea. Around 10% of patients who have endometrial ablation will go on to have a further intervention usually in the form of a hysterectomy (Peeters et al. 2013; Smith et al. 2014a). Research looking at prognostic factors has found that large uterine cavities (>9 cm), preoperative dysmenorrhea, and younger age (50 procedures. This may be because the more experienced surgeons are doing the most difficult cases, but it also emphasizes the importance of audit and careful consideration before procedures are performed (Jansen et al. 2000). Not only is it important to consider the complexity of the case but also pain relief and embarrassment with procedures done in the ambulatory setting without anesthesia. Various strategies can be employed to reduce pain, but some patients will find these procedures very embarrassing or painful, and they can be difficult to predict. Important clues can be gained by how the patient has

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tolerated other uterine procedures such as endometrial biopsies or diagnostic hysteroscopy. If dilation of the cervix is needed, local anesthetic should be used. Analgesia and antiemetics can also be given prior to the procedure. It is important to have a low threshold for stopping the procedure in the ambulatory setting.

Teaching National training bodies, such as the Royal College of Obstetricians and Gynaecologists (RCOG) and the American Association of Gynecologic Laparoscopists (AAGL), are providing structured training and accreditation packages for hysteroscopic training. The European Academy of Gynaecolgoical Surgery, in conjunction with the European Society for Gynaecological Endoscopy (ESGE), has developed a hysteroscopy and laparoscopy program called the Gynaecological Endoscopic Surgical Education and Assessment (GESEA) that is gaining worldwide popularity. The hysteroscopy modules focus on assessing psychomotor skills. Table 3 provides a list of procedures stratified by complexity and therefore risk. Training should target skills appropriate for the level of practice of the individual. As the procedures become more complex, not only does the risk increase, but the opportunities to perform them regularly decrease. It will therefore not be

Table 3 Classification of operative hysteroscopy levels Level 1

Level 2

Level 3

Diagnostic hysteroscopy with target biopsy Removal of simple polyps Removal of intrauterine contraceptive device Proximal fallopian tube cannulation Minor Asherman’s syndrome Removal of pedunculated fibroid (type 0) or large polyp Endometrial ablation Division/resection of uterine septum Major Asherman’s syndrome Endometrial resection Resection of submucous fibroid (type 1 or type 2) Repeat endometrial ablation or resection

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appropriate for everyone to perform all levels of hysteroscopic procedure. Operative hysteroscopy skills are difficult to learn, and structured training and mentorship is required for competencies to be achieved. The rapid increase in the number of procedures done while patients are awake along with decreased training hours has led to legal and ethical concerns about training on real patients. Many minimally invasive training programs around the world have tried to tackle this by incorporating training outside the operating room. There are models and computerized simulators that are now available to help performance. However, the application of hysteroscopic models appears to have lagged behind the use of their laparoscopic counterparts. Despite this, a wide variety of models have been used, although few of them have been validated. Animal tissues such as pig bladders have been used as “wet” models. Pig bladders can be used to simulate endometrial ablation, and by using stitches, they can also be used to simulate polyp and septum resection (Hiemstra et al. 2008). Animal hearts have also been used to simulate endometrial ablation and resection. Training on vegetables offers a cheaper and more readily available method. Reports of peppers and squash being used to practice biopsy and tissue removal have been stated (Hiemstra et al. 2008; Kingston et al. 2004). Training using plastic models or box trainers has been shown to improve resident performance (Burchard et al. 2007). Tactile skills can be improved by performing abstract tasks such as removal of pin from the sidewall of plastic uterus, or models with fake pathology for resection have been made (Burchard et al. 2007). Virtual reality simulators create a safe and controlled environment, but more importantly, they create standardized environments that allow the objective performance of the trainee. The VirtaMed HystSim™ (Hysteroscopic Surgery Simulator System) (Zurich, Switzerland) is the only hysteroscopic simulator available, and it has a large number of stored cases and pathologies with different levels of difficulty. The disadvantage of the simulator is the high cost and the lack of haptic feedback.

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Clinical Governance and Audit An important part of clinical governance is risk management. Periodic assessment of infection control, staff training, equipment condition, patient information leaflets, and local protocols should be performed. Audit is an essential tool to improve and maintain standards especially when setting up new services. Areas suggested for audit include • Complications of hysteroscopic surgery (e.g., uterine perforation, fluid overload, infection, vasovagal reactions, heavy bleeding, and cervical trauma). • Failure rates of operative hysteroscopy. • Standards of documentation. • Use of perioperative and postoperative analgesia. • Patient satisfaction in terms of pain experienced, acceptability, and quality of services.

Future Developments In the past, new developments in operative hysteroscopy have been dominated by miniaturization of equipment. With an increasing number of procedures being performed in the office setting, it is likely that future developments will also focus on miniaturization. Essential to the miniaturization of equipment are improvements in optics and enhanced image quality with the introduction of high-definition (HD) cameras. Portability is also becoming increasingly important such that hysteroscopy can be performed in a variety of community settings. The Endosee ® (CooperSurgical, Trumbull, CT, USA) office hysteroscopy system incorporates a disposable inflow cannula light lead and camera and a reusable lightweight handset incorporating a tiny touch LCD screen. The LiNA OperaScope™ (LiNA Medical ApS, Glostrup, Denmark) is a single-use battery-operated hysteroscope that also has an operating channel than can use 5 Fr instruments. Other similar and totally disposable systems are likely to be developed or ones compatible with smart devices to provide imaging and data recoding.

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One of the biggest challenges in hysteroscopy is to improve pain relief and acceptability of procedures in the outpatient setting. Not only is research needed to improve the technology, but also research is needed to optimize technique and patient selection. Further refinement of tissue removal systems and evaluations of how they compare with bipolar electrosurgery for polyps and fibroids will be forthcoming. The Symphion™ system (Boston Scientific) is a new, tissue removal system utilizing radiofrequency energy and direct intrauterine fluid pressure monitoring. For endometrial ablation, future developments will focus on improvements to existing technologies, such as miniaturization, portability, disposability, and shortened treatment times, and the development of new technologies utilizing a variety of previously tried and new energies such as cryotherapy, microwave energy, and steam. The Librata™ endometrial ablation system (LiNA Medical, Glostrup, Denmark) is another example of a disposable, handheld, battery-operated device that has recently become available. Now that the Essure ® device has been withdrawn from market due to commercial reasons and concerns about long-term complications, it is not clear whether there is an appetite for hysteroscopic sterilization. The AltaSeal ® device is an alternative that is under development that might be able to take advantage of the benefits of avoiding an abdominal approach to sterilization. As well as the patient experience, research is still needed to clarify the role of operative hysteroscopy in the treatment of submucosal fibroids for heavy menstrual bleeding and reproductive outcomes. Research is also needed when new technologies are introduced to ensure they do not get embedded in practice before rigorous scientific evaluation.

Conclusion Operative hysteroscopy has an increasing role in the management of uterine problems causing abnormal uterine bleeding and reproductive failure. Treatments have shown to be safe, effective,

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and an acceptable replacement for more invasive surgery such as hysterectomy, and this is increasingly the case with the development of new operative hysteroscopic technologies such as tissue removal systems and bipolar electrosurgery. There has been an increasing movement, driven by the miniaturization, feasibility, and portability of new endoscopic technologies, as well as patient expectations, toward performing procedures, while patients are awake in an office setting. This helps reduce cost and complications of general anesthesia. Surgeons undertaking operative hysteroscopic procedures should ensure they have a sufficient caseload to maintain their skills and audit performance and outcome. Best practice guidelines should help inform practice. In addition, valid and structured training and accreditation packages for hysteroscopic training need to be implemented and keep pace with contemporary technologies and the evolving evidence.

Cross-References ▶ Basic Management of Infertility ▶ Diagnosis and Management of the Cancer of the Uterus ▶ Laparoscopic Hysterectomy ▶ Laparoscopic Myomectomy ▶ Management of Abnormal Uterine Bleeding: Later Reproductive Years ▶ Management of Fibroids ▶ Management of Pelvic Pain, Dyspareunia, and Endometriosis ▶ Management of Recurrent Pregnancy Loss ▶ Pathology of the Uterine Corpus ▶ Treatment of Gynecological Congenital Anomalies

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741 1.5% with two different types of bipolar electrodes (TCRis, Versapoint) using saline, in hysteroscopic surgery. Fertil Steril. 2009;91:1273–8. Bettocchi S, Ceci O, Nappi L, Di Venere R, Masciopinto V, Pansini V, Pinto L, Santoro A, Cormio G. Operative office hysteroscopy without anesthesia: analysis of 4863 cases performed with mechanical instruments. J Am Assoc Gynecol Laparosc. 2004;11:59–61. Birinyi L, Daragó P, Török P, Csiszár P, Major T, Borsos A, Bacskó G. Predictive value of hysteroscopic examination in intrauterine abnormalities. Eur J Obstet Gynecol Reprod Biol. 2004;115:75–9. Brooks PG. Resectoscopic myoma vaporizer. J Reprod Med. 1995;40:791–5. Brun J-L, Raynal J, Burlet G, Galand B, Quéreux C, Bernard P. Cavaterm thermal balloon endometrial ablation versus hysteroscopic endometrial resection to treat menorrhagia: the French, multicenter, randomized study. J Minim Invasive Gynecol. 2006;13:424–30. Burchard ER, Lockrow EG, Zahn CM, Dunlow SG, Satin AJ. Simulation training improves resident performance in operative hysteroscopic resection techniques. Am J Obstet Gynecol. 2007;197:542.e1–4. Clark TJ, Gupta JK. Handbook of outpatient hysteroscopy: a complete guide to diagnosis and therapy. London: CRC Press; 2005. Clark TJ, Godwin J, Khan KS, Gupta JK. Ambulatory endoscopic treatment of symptomatic benign endometrial polyps: feasibility study. Gynaecol Endosc. 2002a;11:91–7. Clark TJ, Bakour SH, Gupta JK, Khan KS. Evaluation of outpatient hysteroscopy and ultrasonography in the diagnosis of endometrial disease. Obstet Gynecol. 2002b;99:1001–7. Clark TJ, Cooper NAM, Kremer C. Best practice in outpatient hysteroscopy, Best practice in outpatient hysteroscopy: green top guideline 59. RCOG/ BSGE joint green top guideline. RCOG; 2011. https://www.rcog.org.uk/ globalassets/documents/guidelines/gtg59hysteros copy.pdf Cohen SB, Kalter-Ferber A, Weisz BS. Hysteroscopy may be the method of choice for management of residual trophoblastic tissue. J Am Assoc Gynecol Laparosc. 2001;8:199–202. Cooper NAM, Smith P, Khan KS, Clark TJ. Does cervical preparation before outpatient hysteroscopy reduce women’s pain experience? A systematic review. BJOG Int J Obstet Gynaecol. 2011a;118:1292–301. Cooper NAM, Smith P, Khan KS, Clark TJ. A systematic review of the effect of the distension medium on pain during outpatient hysteroscopy. Fertil Steril. 2011b;95: 264–71. Cooper NAM, Barton PM, Breijer MC, Caffrey O, Opmeer BC, Timmermans A, Mol BWJ, Khan KS, Clark TJ. NIHR HTA Project: 09/63/01 – cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): model based economic evaluation. Health Technol Assess. 2014;18:1–201.

742 https://www.journalslibrary.nihr.ac.uk/hta/hta18240#/ abstract Cooper NAM, Clark TJ, Middleton L, Diwakar L, Smith P, Denny E, Roberts T, Stobert L, Jowett S, Daniels J, et al. Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study. BMJ. 2015;350:h1398. Corson SL. A multicenter evaluation of endometrial ablation by Hydro ThermAblator and rollerball for treatment of menorrhagia. J Am Assoc Gynecol Laparosc. 2001;8:359–67. Daniels JP, Middleton LJ, Champaneria R, Khan KS, Cooper K, Mol BWJ, Bhattacharya S, International Heavy Menstrual Bleeding IPD Meta-analysis Collaborative Group. Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis. BMJ. 2012;344:e2564. de Kroon CD, de Bock GH, Dieben SWM, Jansen FW. Saline contrast hysterosonography in abnormal uterine bleeding: a systematic review and metaanalysis. BJOG Int J Obstet Gynaecol. 2003;110: 938–47. Di Spiezio SA, Florio P, Nazzaro G, Spinelli M, Paladini D, Di Carlo C, Nappi C. Hysteroscopic outpatient metroplasty to expand dysmorphic uteri (HOME-DU technique): a pilot study. Reprod Biomed Online. 2015;30:166–74. Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, Ugocsai G, Mara M, Jilla MP, Bestel E, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012a;366:409–20. Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Baró F, Nouri K, Selvaggi L, Sodowski K, Bestel E, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012b;366:421–32. El-Nashar SA, Hopkins MR, Creedon DJ, St Sauver JL, Weaver AL, McGree ME, Cliby WA, Famuyide AO. Prediction of treatment outcomes after global endometrial ablation. Obstet Gynecol. 2009;113: 97–106. Fortin C. Performance and effectiveness of the LiNA librata endometrial ablation system. Journal of Minimally Invasive Gynecology. 2018 Nov 1;25(7):S63. Garuti G, Centinaio G, Luerti M. Outpatient hysteroscopic polypectomy in postmenopausal women: a comparison between mechanical and electrosurgical resection. J Minim Invasive Gynecol. 2008;15:595–600. Hamerlynck TWO, Blikkendaal MD, Schoot BC, Hanstede MMF, Jansen FW. An alternative approach for removal of placental remnants: hysteroscopic morcellation. J Minim Invasive Gynecol. 2013;20: 796–802. Hawe J, Abbott J, Hunter D, Phillips G, Garry R. A randomised controlled trial comparing the Cavaterm endometrial ablation system with the Nd:YAG laser for the treatment of dysfunctional uterine bleeding. BJOG Int J Obstet Gynaecol. 2003;110:350–7.

P. P. Smith and T. J. Clark Hiemstra E, Kolkman W, Jansen FW. Skills training in minimally invasive surgery in Dutch obstetrics and gynecology residency curriculum. Gynecol Surg. 2008;5:321–5. Jansen FW, Vredevoogd CB, van Ulzen K, Hermans J, Trimbos JB, Trimbos-Kemper TC. Complications of hysteroscopy: a prospective, multicenter study. Obstet Gynecol. 2000;96:266–70. Kamath MS, Kalampokas EE, Kalampokas TE. Use of GnRH analogues pre-operatively for hysteroscopic resection of submucous fibroids: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;177:11–8. Kingston A, Abbott J, Lenart M, Vancaillie T. Hysteroscopic training: the butternut pumpkin model. J Am Assoc Gynecol Laparosc. 2004;11:256–61. Kleijn JH, Engels R, Bourdrez P, Mol BWJ, Bongers MY. Five-year follow up of a randomised controlled trial comparing NovaSure and ThermaChoice endometrial ablation. BJOG Int J Obstet Gynaecol. 2008;115: 193–8. Kremer C, Duffy S, Moroney M. Patient satisfaction with outpatient hysteroscopy versus day case hysteroscopy: randomised controlled trial. BMJ. 2000;320:279–82. Kung RC, Vilos GA, Thomas B, Penkin P, Zaltz AP, Stabinsky SA. A new bipolar system for performing operative hysteroscopy in normal saline. J Am Assoc Gynecol Laparosc. 1999;6:331–6. Lasmar RB, Lasmar BP, Celeste RK, da Rosa DB, Depes DB, Lopes RGC. A new system to classify submucous myomas: a Brazilian multicenter study. J Minim Invasive Gynecol. 2012;19:575–80. Lee C, Salim R, Ofili-Yebovi D, Yazbek J, Davies A, Jurkovic D. Reproducibility of the measurement of submucous fibroid protrusion into the uterine cavity using three-dimensional saline contrast sonohysterography. Ultrasound Obstet Gynecol. 2006;28:837–41. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;2:CD000547. Lethaby A, Hickey M, Garry R. Endometrial destruction techniques for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;4:CD001501. Loffer FD, Bradley LD, Brill AI, Brooks PG, Cooper JM. Hysteroscopic fluid monitoring guidelines. The ad hoc committee on hysteroscopic training guidelines of the American Association of Gynecologic Laparoscopists. J Am Assoc Gynecol Laparosc. 2000;7:167–8. Mao J, Pfeifer S, Schlegel P, Sedrakyan A. Safety and efficacy of hysteroscopic sterilization compared with laparoscopic sterilization: an observational cohort study. BMJ. 2015;351:h5162. Mazzon I, Bettocchi S, Fascilla F, De Palma D, Palma F, Zizolfi B, Di Spiezio Sardo A. Resectoscopic myomectomy. Minerva Ginecol. 2016;68:334–44. Moawad NS, Santamaria E, Johnson M, Shuster J. Costeffectiveness of office hysteroscopy for abnormal uterine bleeding. JSLS. 2014;18(3):pii: e2014.00393. https://doi.

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org/10.4293/JSLS.2014.00393. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC4154435/pdf/e2014.00393.pdf Munro MG, Critchley HOD, Fraser IS. FIGO menstrual disorders working group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011;95:2204–2208.e1–e3. Nathani F, Clark TJ. Uterine polypectomy in the management of abnormal uterine bleeding: a systematic review. J Minim Invasive Gynecol. 2006;13:260–8. Peeters JAH, Penninx JPM, Mol BW, Bongers MY. Prognostic factors for the success of endometrial ablation in the treatment of menorrhagia with special reference to previous cesarean section. Eur J Obstet Gynecol Reprod Biol. 2013;167:100–3. Penninx JPM, Herman MC, Mol BW, Bongers MY. Fiveyear follow-up after comparing bipolar endometrial ablation with hydrothermablation for menorrhagia. Obstet Gynecol. 2011;118:1287–92. Penninx JPM, Herman MC, Kruitwagen RFPM, Haar AJFT, Mol BW, Bongers MY. Bipolar versus balloon endometrial ablation in the office: a randomized controlled trial. Eur J Obstet Gynecol Reprod Biol. 2016;196:52–6. Rikken JFW, Kowalik CR, Emanuel MH, et al. Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial. Hum Reprod. 2021;36(5): 1260–7. Robinson LLL, Cooper NAM, Clark TJ. The role of ambulatory hysteroscopy in reproduction. J Fam Plann Reprod Health Care. 2013;39:127–35. Smith PP, Malick S, Clark TJ. Bipolar radiofrequency compared with thermal balloon ablation in the office: a randomized controlled trial. Obstet Gynecol. 2014a;124:219–25. Smith PP, Middleton LJ, Connor M, Clark TJ. Hysteroscopic morcellation compared with electrical resection of endometrial polyps: a randomized controlled trial. Obstet Gynecol. 2014b;123:745–51. Smith PP, Kolhe S, O’Conor S, Clark TJ. Vaginoscopy Against Standard Treatment (VAST): a randomized controlled trial. BJOG. 2019;126:891–9. Smorgick N, Barel O, Fuchs N, Ben-Ami I, Pansky M, Vaknin Z. Hysteroscopic management of retained products of conception: meta-analysis and literature review. Eur J Obstet Gynecol Reprod Biol. 2014;173: 19–22.

743 Tas B. Five-year experience of Mintouch endometrial outpatient ablation performed in an office stting without anaesthesia by a solo operator. J Minim Invasive Gynecol. 2017;24:S120. Thinkhamrop J, Laopaiboon M, Lumbiganon P. Prophylactic antibiotics for transcervical intrauterine procedures. Cochrane Database Syst Rev. 2007;3:CD005637. Timmermans A, Veersema S. Ambulatory transcervical resection of polyps with the Duckbill polyp snare: a modality for treatment of endometrial polyps. J Minim Invasive Gynecol. 2005;12:37–9. Timmermans A, van Dongen H, Mol BW, Veersema S, Jansen FW. Hysteroscopy and removal of endometrial polyps: a Dutch survey. Eur J Obstet Gynecol Reprod Biol. 2008;138:76–9. Valle RF. Hysteroscopic evaluation of patients with abnormal uterine bleeding. Surg Gynecol Obstet. 1981;153: 521–6. Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol. 1988;158:1459–70. van Dijk LJEW, Breijer MC, Veersema S, Mol BWJ, Timmermans A. Current practice in the removal of benign endometrial polyps: a Dutch survey. Gynecol Surg. 2012;9:163–8. van Dongen H, Emanuel MH, Wolterbeek R, Trimbos J, Jansen FW. Hysteroscopic morcellator for removal of intrauterine polyps and myomas: a randomized controlled pilot study among residents in training. J Minim Invasive Gynecol. 2008;15:466–71. Van Eyk N, van Schalkwyk J, Infectious Diseases Committee. Antibiotic prophylaxis in gynaecologic procedures. J Obstet Gynaecol Can. 2012;34:382–91. Van Hanegem N, Breiger MC, Slockers SA, et al. Diagnostic workup for postmenopausal bleeding: a ranodmised controlled trial. BJOG. 2017;124:231–40. Vercellini P, Zàina B, Yaylayan L, Pisacreta A, De Giorgi O, Crosignani PG. Hysteroscopic myomectomy: long-term effects on menstrual pattern and fertility. Obstet Gynecol. 1999;94:341–7. Vilos GA. Intrauterine surgery using a new coaxial bipolar electrode in normal saline solution (Versapoint): a pilot study. Fertil Steril. 1999;72:740–3. Yang J-H, Chen C-D, Chen S-U, Yang Y-S, Chen M-J. The influence of the location and extent of intrauterine adhesions on recurrence after hysteroscopic adhesiolysis. BJOG Int J Obstet Gynaecol. 2016;123:618–23.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovarian Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benign Cystic Ovarian Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

746 746 747 747

Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 Serum Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Observation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aspiration of Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laparoscopic Ovarian Cystectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Standard Closed Entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contraindications to Laparoscopic Ovarian Cystectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oophorectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

749 749 750 750 750 750 751 753 754

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754

Abstract

Laparoscopy has enabled the laparoscopic gynecologic surgeon to manage many gynecologic surgical challenges in a minimally invasive manner. The laparoscopic approach has become the gold standard in the surgical management of ovarian cysts due to innovative

C. S. Reinsch (*) Kaiser Permanente Southern California, San Diego, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_54

changes in surgical instrumentation and the development of new surgical techniques. Benign ovarian cysts such as persistent and symptomatic functional ovarian cysts, corpus luteum cysts, and cystic ovarian neoplasms such as endometriomas or mature cystic teratomas are now managed as an outpatient procedure decreasing cost and recovery time to the patient. Pelvic ultrasound is the most useful imaging tool in the evaluation of an ovarian cyst. Complex ovarian cysts should be considered for removal in the symptomatic premenopausal woman and in all postmenopausal 745

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women. The decision to intervene surgically may be complicated and should be individualized for each patient. Aspiration of ovarian cysts is associated with a high rate of recurrence; therefore, cystectomy is the procedure of choice. Ovarian conservation is preferred in the premenopausal woman if at all feasible, and laparoscopic salpingo-oophorectomy is usually the procedure of choice for the postmenopausal woman. Laparoscopic entry into the abdomen requires a detailed understanding of the vasculature of the anterior abdominal wall. Techniques may need to be altered depending on a patient’s BMI (body mass index), past history of abdominal surgeries, and history of bowel obstruction or hernias. Laparoscopic removal of the ovarian cyst should facilitate intact removal and avoid intraoperative spillage. Keywords

Laparoscopic · Ovarian · Cystectomy · Functional cyst · Endometrioma · Dermoid · Complex cyst · Simple cyst · Port placement

Introduction Laparoscopy has become a standard surgical approach for many gynecologic procedures in the last 40 years. It has now become the standard treatment of choice for surgical management of ectopic pregnancies and persistent and/or symptomatic adnexal masses and diagnosis and surgical treatment of endometriosis. The laparoscopic surgical approach has also enabled surgeons to offer minimally invasive hysterectomies. When laparoscopy was initially utilized in gynecologic surgery, it was limited to diagnostic procedures and tubal ligations. The repertoire of the laparoscopic approach has evolved in the last 20 years as a result of the development of new innovations involving more advanced equipment, improved imaging with new camera systems, and improved expertise in surgical technique. In recent years, newer surgical approaches have developed. In particular, robotic-assisted

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laparoscopy and, very recently, single-port laparoscopy are gaining more popularity with laparoscopic surgeons. As with the development of any new procedures, the actual roles of these procedures in gynecologic surgery are controversial, and their role remains to be well defined. Scientific data has consistently supported the laparoscopic approach to the adnexal mass as the preferred treatment. It has been estimated that approximately 10% of women in the United States will undergo a surgical procedure for an adnexal mass in their lifetime (Hilger et al. 2006). Laparoscopy has also been consistently shown to be associated with decreased postoperative complications such as fever, infection, postoperative pain, and blood loss. Decreased length of hospitalization and overall cost offer additional advantages compared to laparotomy (Yuen et al. 1997; Fanfani et al. 2004; Medeiros et al. 2008). Despite the abovementioned advantages, laparoscopy should be considered to involve similar surgical risks to laparotomy such as anesthesia risks, infection, injury to intra-abdominal and pelvic organs, and bleeding. Unique risks are also associated with the laparoscopic approach. These risks include the risk of damage to organs and vasculature with laparoscopic port placement and intravascular carbon dioxide gas insufflation with use of pneumoperitoneum to perform surgery. The use of cautery or ultrasonic energy sources also introduces another element of risk to damage to intra-abdominal structures.

Ovarian Cysts Ovarian cysts can occur at any stage in life from fetal life through menopause. They can be symptomatic or asymptomatic and found incidentally on clinical exam or on imaging. The most common types of benign ovarian cysts that the gynecologist encounters include functional cysts (follicular, hemorrhagic, and corpus luteum cysts), mature cystic teratomas (dermoids), endometriomas, and serous and mucinous cystadenomas (Table 1).

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Table 1 Classification and characteristics of benign ovarian cysts Functional ovarian cysts Follicular cyst Common in reproductive age women Corpus luteum Common in reproductive age cyst women; forms when the corpus luteum fails to regress, may be hemorrhagic Benign cystic ovarian neoplasms Epithelial cell Derived from mesothelial cells lining tumors the peritoneal cavity and ovary Examples: serous cystadenoma, mucinous cystadenoma, endometrioma Germ cell Derived from germ cells: may tumors contain ectoderm, mesoderm, or endoderm Cystic mature teratoma dermoid cyst Sex cordDerived from sex cords and stroma of stromal tumors developing gonad; may cause feminizing/virilizing effects Examples: granulosa-theca cell tumor, Sertoli-Leydig cell tumor (Beckmann et al. 2006; Nelson and Gambone 2010)

Functional Cysts Most ovarian cysts develop as a result of faulty ovulation where the follicle fails to release an oocyte. Gradually, a cyst forms because the follicular cells continue to secrete fluid and the fluid accumulates. The cysts are referred to as follicular cysts, and they often resolve spontaneously and do not require surgical intervention (Nelson and Gambone 2010). Another type of functional cyst is a corpus luteum cyst. The actual mechanism of how the cyst forms is not well understood. This cyst can become quite large and cause symptoms, may be associated with a delay of menses, and is more apt to undergo torsion due to the increased size when compared to the follicular cyst.

Benign Cystic Ovarian Neoplasms These cysts are usually categorized due to the cell type of origin such as surface epithelium, germ cell, or sex cord-stromal cells. The majority of these cysts are benign. At least 30% of ovarian

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masses in women over the age of 50 are malignant (Kinkel et al. 2005). The risk of malignancy significantly increases in the postmenopausal woman with a cystic neoplasm (Beckmann et al. 2006). Epithelial cell tumors are thought to develop from mesothelial cells that line the ovary and peritoneal cavity. Cystic epithelial tumors account for approximately 60% of all true ovarian neoplasms. The endometrioma, serous cystadenoma, and mucinous cystadenoma fall into this category. Serous and mucinous cystadenomas are typically thin walled, unilocular, or multilocular and can range widely in size. Mucinous cystadenomas tend to be multilocular and much larger than serous cystadenomas. The peak incidence of serous and mucinous cystadenomas is in the fourth to fifth decade. One-third of all ovarian tumors are serous and two-thirds of those are benign. Mucinous epithelial tumors account for 10–15% of all epithelial neoplasms and 75% are benign (Goldberg 2015). Serous tumors are bilateral 25% of the time, whereas mucinous tumors have a much lower incidence of bilaterality ranging 2–3% (ACOG 2007). The incidence of bilaterality should be taken into consideration and discussed with the patient at the time of evaluation, particularly if surgical management is required. The origin of the endometrioma is controversial. Several investigators favor the theory that the endometrioma originates as invaginated endometrial glands on the surface of the ovary (Hughesdon 1957; Pe 1957; Nezhat et al. 1992; Brosens et al. 1994). The endometrioma tends to develop very slowly over time and tends to be moderate in size averaging 5–6 cm in size. Endometriomas are hormonally active with the menstrual cycle. This often translates into exacerbation of symptoms just prior to and during menses for the patient. The endometrioma can also present a challenge in removal of the capsule to the surgeon. The capsules tend to be very adherent to adjacent ovarian tissue and often are only able to be partially removed which may increase risk of recurrence if ovarian conservation is desired. Mature cystic teratomas (dermoid cysts) are also common benign cystic ovarian neoplasms. Dermoid cysts account for 10–20% of ovarian neoplasms and

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have an incidence of bilaterality of 8–14%. They are also the most common benign ovarian tumor in the second and third decade of life (Killackey and Neuwirth 1988). They are commonly composed of multiple cell types derived from one or more of the three germ cell layers (Hamilton 2015). They are almost always benign but can undergo malignant transformation in 0.2–2% of cases (Comerci et al. 1994; Hamilton 2015). Historically, laparoscopic management of mature cystic teratomas was not pursued due to concerns regarding the risk of chemical peritonitis in the event of intraoperative spillage of the cyst’s sebaceous contents. Recent evidence has not supported this concern. Nezhat et al. noted an incidence of 0.2% of chemical peritonitis with review of 10 years of experience (Nezhat et al. 1999) It is now very feasible to remove a dermoid cyst via laparoscopic cystectomy. Simple ovarian cysts up to 10 cm are likely to be benign at all ages with the incidence of malignancy 5–10 cm in size should be considered for surgical removal. Complex ovarian cysts should be considered for surgical removal in the symptomatic premenopausal female. With the exception of simple ovarian cysts on a transvaginal ultrasound finding, most pelvic masses in postmenopausal women will require surgical intervention. The decision to intervene surgically may be complicated and involve many factors and should be individualized based on the clinical scenario and associated findings.

Laparoscopy The use of laparoscopy is constantly expanding in gynecologic surgery. It has become the preferred surgical approach for the management of symptomatic or persistent benign ovarian cysts, depending on the experience and skill of the surgeon. This includes suspected endometriomas, hemorrhagic cysts, dermoids, functional cysts, or cystadenomas that have not resolved with expectant management or are symptomatic. Typically, endometriomas, dermoid cysts, or cystadenomas do not resolve spontaneously. Quite often, the diagnosis of a serous or mucinous cystadenoma is not made until laparoscopic evaluation and subsequent removal via cystectomy or oophorectomy.

Aspiration of Cyst Aspiration of an ovarian cyst at the time of laparoscopy is generally not recommended unless it is used to facilitate a laparoscopic ovarian cystectomy. Even in the situation of cystectomy, this should only be carried out in an endoscopic

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bag to avoid spillage in the event of an unsuspected malignancy. If aspiration is solely used to manage an ovarian cyst, there is a high recurrence rate of the cyst approaching up to 65% (Mesogitis et al. 2005). In addition, there is no tissue for pathologic evaluation and malignancy cannot be ruled out. It has also not been proven more effective than expectant management (Zanetta et al. 1996). Aspiration of ovarian cysts is contraindicated in postmenopausal women due to concerns regarding the increased potential for malignancy. Evidence shows that there is demonstrated decrease survival of stage 1 ovarian cancer patients if spillage occurs intraoperatively compared to patients with tumors removed intact (Cuesta et al. 1994; Mizuno et al. 2003).

Laparoscopic Ovarian Cystectomy The optimal surgical goal is to remove the entire cyst intact. The cyst should be removed inside a laparoscopic bag so that inadvertent spillage into the peritoneal cavity may be avoided. If an oophorectomy is performed, the ovary with the intact cyst should be removed contained within an endoscopic bag. Very large benign-appearing ovarian cysts are now being managed more commonly via the laparoscopic approach. In this approach, the ovary is usually placed in an endoscopic bag and drained of excess fluid and then removed within the bag through a small incision (Eltabbakh et al. 2008). This approach obviously avoids a large laparotomy incision and facilitates a faster recovery with decreased morbidity and cost for the patient. Ovarian conservation is generally the goal in a premenopausal woman with a benign ovarian cyst requiring surgical excision. The advantage is preservation of viable ovarian tissue and thus fertility and hormone production. Oophorectomy and possibly bilateral salpingo-oophorectomy may be elected in surgical management of a postmenopausal woman with a benign cyst. Oophorectomy may also be considered for premenopausal women who are considered for increased genetic risk for ovarian cancer.

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Entry into the abdomen may be performed with several techniques. In a Cochrane review of 46 randomized controlled trials comparing various techniques, there was no advantage of using any single technique in preventing vascular or visceral complications. There is insufficient evidence to recommend on laparoscopic entry technique over another (Ahmad et al. 2008). An understanding of the anterior abdominal wall vessels is of paramount importance to avoid injury to these vessels. There are two sets of bilateral vessels, the superficial and inferior epigastric vessels. The vessels are located an average of 5.5 cm from the midline. The lateral ports should be placed approximately 8 cm from the midline to avoid vascular injury. Transillumination of the anterior abdominal wall with the laparoscope to visualize the superficial vessels is recommended during placement of lateral ports. It is also optimal to try and visualize the inferior vessels intra-abdominally with visualization of the laparoscope whenever possible. In patients with a history of prior abdominal surgery, there is a risk of 20% of adhesions to the anterior abdominal wall involving the omentum or bowel (Vilos et al. 2007). As a result, surgeons may elect to gain entry with any of the three following techniques: the closed entry with the Veress needle, open laparoscopy, or left upper quadrant placement at Palmer’s site.

Standard Closed Entry The Veress needle may be used to create a pneumoperitoneum prior to laparoscopic port placement. The needle is advanced into the peritoneal cavity usually through a 5 mm incision at the umbilicus. During placement of the Veress needle, the abdominal wall is elevated by using two perforating towel clamps placed just lateral to the umbilicus and lifting up during insertion or manually grasping and lifting the abdominal wall superior to the suprapubic area during insertion. The abdominal wall is elevated to maximize the distance between the abdominal wall and retroperitoneal vessels. Entry into the peritoneal cavity may be confirmed with the saline drop test and

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observation for pressure less than 8 mmHg during insufflation. The CO2 gas is then insufflated into the needle to create a pneumoperitoneum. Maximum insufflation pressure is usually set at 15 mm but can be increased to 20 mm if needed and tolerated by the patient. Once this pressure is obtained, then an adequate pneumoperitoneum is obtained, and the surgeon can now proceed with umbilical primary port placement. Hurd et al. (1991) characterized the difference in abdominal wall thickness and how it can influence laparoscopic port entry. In women with ideal body weight (body mass index, [BMI] 30 kg/m2), a more vertical approach, approximately 70–80 , is necessary to enter the peritoneal cavity because of increased thickness of the abdominal wall (Fig. 1c). Open laparoscopy may also be performed to gain entry into the abdominal cavity. There is no evidence to support that overall open entry is superior or safer than the other entry techniques (Ahmad et al. 2015). Surgeons may elect to gain entry via the left upper quadrant in the event that periumbilical adhesions are suspected, patient has a history of umbilical hernia, or there are failed attempts at entry via the umbilicus. With this technique, the Veress needle is advanced through a 5 mm incision at Palmer’s point, which is at the midclavicular line just beneath the lower rib margin and pneumoperitoneum created with insufflation of CO2 gas. A 5 mm laparoscopic port is then advanced into the peritoneal cavity and confirmed with visualization with the laparoscope. Direct laparoscopic port placement is considered safe without a pneumoperitoneum when done with disposable blunt trocars. It is also faster than the Veress needle technique and is not associated with insufflation-related injuries because proper placement is confirmed with visualization with the laparoscope prior to insufflation. This is performed while elevating the abdominal wall

752

C. S. Reinsch

a

b

Ideal weight

c

Overweight

Obese

11 cm (median)

4 ± 2 cm

3 ± 2 cm 1 ± 2 cm 13 ± 4 cm 10 ± 2 cm 6 ± 3 cm

Fig. 1 Differences in umbilical trocar placement in patients with different BMIs (body mass index). (Adapted from Hurd et al. 1991)

with perforating towel clamps or manually grasping the abdominal wall and elevating it. Elevation of the abdominal wall during trocar insertion maximizes the distance between the umbilicus and the retroperitoneal vessels. Elevation of the abdominal wall during trocar or Veress needle placement, however, does not necessarily guarantee visceral or blood vessel injury. The initial laparoscopic port is usually placed at the umbilicus with a 5–12 mm port. The pelvis is carefully surveyed, and the ovarian cyst is examined for any signs that may be suggestive of malignancy such as ascites, excrescences on the surface of the ovary, and implants noted on peritoneal, liver, or diaphragm surfaces. Five millimeter ports are then placed laterally. The surgeon may opt to obtain cell washings at this time for cytology. If the cyst appears benign, then cystectomy is performed. Cystectomy is then performed by incising the capsule of the ovary with endoshears or the

surgeon’s preferred laparoscopic power source. The cyst is then enucleated carefully with traction and countertraction and dissection as needed. If intraoperative rupture occurs, particularly with a dermoid cyst, the peritoneal cavity should liberally be rinsed with normal saline or Ringer’s lactate that has been shown to be safe (Nezhat et al. 1999; Zanetta et al. 1999; Milingos et al. 2004). After the cyst is removed from the ovary, an endoscopic bag is then advanced through the umbilical 10–12 mm port, and the cyst is placed in the bag. If a 5 mm umbilical port was used for initial survey, this port can be exchanged for a 10–12 mm port. The bag is then advanced up to the umbilical incision, and the port is removed while advancing the edges of the bag through the skin incision. The bag is then opened and triangulated to facilitate removal of the cyst intact if small enough or with morcellation carefully avoiding any spillage out of the bag. Prior to removal, the cyst may need to be drained while

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in the bag. Once the specimen is small enough, the bag is removed with the specimen through the incision. Other options for removing the specimen include a minilaparotomy or colpotomy. If colpotomy is performed, antibiotics are recommended. If concern about the benign nature of the cyst exists, the cyst wall should be sent for frozen section at the time of removal. If malignancy is confirmed or suspected, then the procedure should be converted to a laparotomy for continued appropriate surgical management. After removal of the bag and specimen, the 10–12 mm laparoscopic port is replaced through the umbilical incision and the camera advanced through the port. The ovary is then carefully inspected for hemostasis. Bleeding from the bed of the cyst in the ovary may require measures to obtain hemostasis. Hemostasis in the bed of the ovary at the site of the cystectomy has traditionally been accomplished with bipolar cautery. This may also be performed with use of other laparoscopic power sources or application of a hemostatic agent. Recent evidence suggests that the application of hemostatic sealants such as FloSeal (Baxter International Inc., Deerfield, IL) or Surgicel fibrillar (Ethicon, Inc., Somerville, NJ) results in improved ovarian reserve after cystectomy compared to cautery (Song et al. 2014). The edges of the ovarian capsule do not need to be reapproximated as is traditionally done with an open ovarian cystectomy. Some surgeons prefer to utilize an adhesion barrier product on the ovary to minimize postoperative adhesion formation. The procedure is completed by irrigation of the pelvis, and a careful survey of the pelvis for hemostasis with the intraperitoneal pressure decreased to 5 mmHg. The port sites are then inspected for hemostasis. After all port sites are inspected for hemostasis, the C02 peritoneum is then allowed to escape through the umbilical port. Care is taken to ensure that as much gas is expressed as possible to minimize postoperative discomfort for the patient and to avoid the bowel being pushed into the incision sites as residual gas

753

escapes. The incisions are then closed with suture, Steri-Strips, or a skin adhesive. Fascial closure is recommended for ports 10 mm or greater in size prior to skin closure to prevent subsequent development of an incisional hernia (Tonouchi et al. 2004). Simple cysts in postmenopausal women can also be removed laparoscopically since the vast majority is benign. However, salpingo-oophorectomy is generally considered the procedure of choice.

Contraindications to Laparoscopic Ovarian Cystectomy Absolute contraindications to ovarian cystectomy continue to be controversial. The presence of a known malignancy has traditionally been considered an absolute contraindication. As expertise increases with laparoscopy, there is currently disagreement regarding this concept. The use of laparoscopy in the setting of surgical management of malignancy continues to develop and expand. Laparoscopic staging and management of ovarian cancer have been reported (Fauvet et al. 2005; Lecuru et al. 2006). However, there are reports in the literature that suggest that laparoscopy may increase the risk of port-site metastases and intraperitoneal spread of cancer cells (Morice et al. 2004; Nagersheth et al. 2004; Ramirez et al. 2004). Continued experience will further define the role of laparoscopy in the surgical management of ovarian malignancy. Relative contraindications have also changed over the past 30 years since laparoscopy has improved with advances in surgical technique and equipment. Previously, obese patients or patients with a history of multiple abdominal surgeries or bowel obstructions were considered not to be candidates for the laparoscopic approach. Open laparoscopy, left upper quadrant access, and the use of trocars with optical access capabilities are now widely accepted techniques for such patients.

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Oophorectomy Indications for oophorectomy as the preferred procedure are noted in the Table 2 below (Valea and Mann 2015). Oophorectomy and most commonly laparotomy are the procedures of choice rather than cystectomy in women with an ovarian mass that is suspicious for malignancy. Oophorectomy is the preferred management for any ovarian mass that requires surgical intervention in postmenopausal women regardless of the suspicion for malignancy. Laparoscopic oophorectomy is usually performed as a salpingo-oophorectomy. The infundibulopelvic ligament and the ureter are carefully identified. The ureter is easily identified through the peritoneum in most patients. If the ureter is difficult to identify, the peritoneum must be opened and dissection carried out retroperitoneally to facilitate location of the ureter. The procedure is then carried out with ligation of the infundibular pelvic ligament, the utero-ovarian ligaments, and the fallopian tube next to the cornua of the uterus. This can be performed with a variety of techniques including bipolar electrocautery, ultrasonic cutting and coagulation devices (e.g., Harmonic scalpel), bipolar vesselsealing devices (e.g., LigaSure, EnSeal, GyrusPK), loop technique, or stapling devices. The ovary and fallopian tube are then placed in an endobag and brought up to the umbilical portsite incision and removed in a similar technique to the cystectomy. Cyst fluid may be carefully aspirated from the cyst while enclosed in the bag Table 2 Summary of indications for oophorectomy Benign ovarian neoplasms not amenable to treatment with cystectomy, enucleation, partial oophorectomy Elective or risk-reducing salpingo-oophorectomy Adnexal torsion with necrosis Ovarian malignancy Tubo-ovarian abscess unresponsive to antibiotics Definitive treatment for endometriosis but must consider long term health risks Gastrointestinal or other metastatic cancers Male pseudohermaphrodites Valea and Mann (2015)

C. S. Reinsch

to facilitate removal through the port-site incision with care taken to avoid any spillage into the peritoneal cavity. If malignancy is suspected, morcellation of the ovary is not recommended to preserve optimal pathologic evaluation. If the ovary cannot be removed via the bag through the laparoscopic port, then a larger incision is required for safe removal.

Conclusion Laparoscopic ovarian cystectomy has now evolved to become the gold standard of surgical management of benign cystic ovarian masses in premenopausal women. The development of improved laparoscopic camera systems and instruments has enabled surgeons to evolve and continually improve their laparoscopic surgical techniques. In addition, the role of minimally invasive approaches continues to gain increased acceptance with gynecologic oncologists in the management of possible malignancies.

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Comerci JT Jr, Licciardi F, Bergh PA, Gregori C, Breen JL. Mature cystic teratoma: a clinicopathologic evaluation of 517 cases and review of the literature. Obstet Gynecol. 1994;84(1):22–8. Curtin J. Management of the adnexal mass. Gynecol Oncol. 1994;55:542. de la Cuesta RS, Goff B, Fuller AJ, Nikrui N, Eichhorn J, Rice L. Prognostic importance of intraoperative rupture of malignant ovarian epithelial neoplasms. Obstet Gynecol. 1994;84:1–7. Eltabbakh GH, Charboneau AM, Eltabbakh NG. Laparoscopic surgery for large benign ovarian cysts. Gynecol Oncol. 2008;108(1):72–6. Fanfani F, Fagotti A, Ercoli A, Bifulco G, Longo R, Mancuso S, et al. A prospective randomized study of laparoscopy and minilaparoctomy in the management of benign adnexal masses. Hum Reprod. 2004;19: 2367–71. Fauvet R, Boccara J, Dufournet C, Poncelet C, Darai E. Laparoscopic management of borderline ovarian tumors: results of a French multicenter study. Ann Oncol. 2005;16:403–10. Goldberg A. Benign lesions of the ovaries. 2015. Medscape, from https://emedicine.medscape.com/arti cle/265548-overview Grimes DA, Jones LB, Lopez LM, Schulz KF. Oral contraceptives for functional ovarian cysts. Cochrane Database Syst Rev. 2009;2:CD006134. Hamilton C. Cystic teratoma. Medscape. Retrieved 1 Aug 2016, 2015. Helm C. Ovarian cysts workup. 2015. Medscape, from https://emedicine.medscape.com/article/255865workup Hilger WS, Magrina JF, Magtibay PM. Laparoscopic management of the adnexal mass. Clin Obstet Gynecol. 2006;49(3):535–48. Hughesdon PE. The structure of endometrial cysts of the ovary. J Obstet Gynaecol Br Emp. 1957;64(4):481–7. Hurd WH, Bude RO, DeLancey JO, Gauvin JM, Aisen AM. Abdominal wall characterization with magnetic resonance imaging and computed tomography. The effect of obesity on the laparoscopic approach. J Reprod Med. 1991;36(7):473–6. Jacobs I, Bast RC Jr. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod. 1989;4(1): 1–12. Killackey M, Neuwirth R. Evaluation and management of the adnexal mass: a review of 540 cases. Obstet Gynecol. 1988;71:319. Kinkel K, Lu Y, Mehdizade A, Pelte M, Hricak H. Indeterminate ovarian mass at US: incremental value of second imaging test for characterization -meta-analysis and Bayesian analysis. Radiology. 2005;236(1):236–85. Lecuru F, Desfaux P, Camatte S, Bissery A. Impact of initial surgical access on stagina dnd survival of patients with stage 1 ovarian cancer. Int J Gynecol Cancer. 2006;16:87–94.

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756 gynecological malignancies. Int J Gynecol Cancer. 2004;14(6):1070–7. Song T, Lee S-H, Woo Y. Additional benefit of hemostatic sealant in preservation of ovarian reserve during laparoscopic ovarian cystectomy. Hum Reprod. 2014;29(8):1659–65. Tonouchi H, Ohmori Y, Kobayashi M, Kusunoki M. Trocar site hernia. Arch Surg. 2004;139(11):1248–56. Valea F, Mann W. Oophorectomy and ovarian cystectomy. 2015. Uptodate, from http://www.uptodate.com Valentin L, Ameye L, Jurkovic D, Metzger U, Lecuru F, Van Huffel S, Timmerman D. Which extrauterine pelvic masses are difficult to correctly classify as benign or malignant on the basis of ultrasound findings and is there a way of making a correct diagnosis? Ultrasound Obstet Gynecol. 2006;27(4):438–44. Vilos GA, Ternamian A, Dempster J, Laberge PY, O. The Society of and C. Gynaecologists of. Laparoscopic

C. S. Reinsch entry: a review of techniques, technologies, and complications. J Obstet Gynaecol Can. 2007;29(5):433–65. Whiteside JL, Keup HL. Laparoscopic management of the ovarian mass: a practical approach. Clin Obstet Gynecol. 2009;52(3):327–34. Yuen P, Yu K, Yip S, Lau W, Rogers M, Chang A. A randomized perspective study of laparoscopy and laparotomy in the management of benign ovarian masses. Am J Obstet Gynecol. 1997;177:109–14. Zanetta G, Lissonni A, Torri V, Valle C, Trio D, Rangoni G, Mangioni C. Management of ovarian cysts with aspiration in expectant management of simple ovarian cysts: a randomised study. BMJ. 1996;313:1110. Zanetta G, Ferrari L, Mignini-Renzini M, Vignali M, Fadini R. Laparoscopic excision of ovarian dermoid cysts with controlled intraoperative spillage. Safety and effectiveness. J Reprod Med. 1999;44(9):815–20.

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Brianne D. Romeroso and William H. Parker

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758 Indications for Myomectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758 Benefits of Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Patient Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Preoperative Evaluation and Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History and Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Managing Preoperative Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussing Morcellation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

760 760 760 761 762 762 763

Operative Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anesthesia and Patient Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laparoscopic Port Placement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Strategies to Decrease Intraoperative Blood Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine Incision and Leiomyoma Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Repair of Uterine Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morcellation of Leiomyomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

764 764 765 765 765 766 766 767 767

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767

B. D. Romeroso (*) Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA e-mail: [email protected] W. H. Parker Department of Obstetrics, Gynecology, and Reproductive Services, UC San Diego School of Medicine, La Jolla, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_82

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758

B. D. Romeroso and W. H. Parker Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 Improvement of Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 New Leiomyoma Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 Pregnancy After Myomectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 Interval to Conception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 Risk of Uterine Rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769

Abstract

Leiomyomas are common benign pelvic tumors that can cause abnormal uterine bleeding, bulk-related symptoms, and effects on fertility and pregnancy, although most women are asymptomatic. Myomectomy is a surgical treatment option for women who desire uterine preservation. A laparoscopic approach provides the benefits of minimally invasive surgery while achieving outcomes similar to those of abdominal myomectomy. Appropriate patient selection, thorough patient counseling, careful preoperative preparation, and proper surgical technique are paramount to the safety and success of this procedure. Keywords

Fertility preservation · Fibroid · Laparoscopy · Leiomyoma · Minimally invasive · Myoma · Myomectomy · Uterine preservation

Introduction Leiomyomas, also known as fibroids or myomas, are benign monoclonal smooth muscle tumors. They are the most common type of pelvic tumor in women with a reported incidence of 70–80% by the age of 50 years (Baird et al. 2003). Although many women are asymptomatic, leiomyomas can cause a variety of symptoms, resulting in significant morbidity and high economic burden. Accordingly, many treatment options, both medical and surgical, are available. Women who desire uterine preservation for fertility or other reasons often opt for

myomectomy. This procedure can be performed via laparotomy (i.e., abdominal myomectomy) or by use of minimally invasive techniques. Laparoscopic myomectomy is an effective treatment option for appropriately selected patients in whom leiomyoma characteristics preclude a hysteroscopic or vaginal approach.

Indications for Myomectomy The indications for myomectomy are not absolute as they are based on the effects of leiomyomas on the patient’s quality of life and daily activities, which can be subjective. Many women with leiomyomas are largely asymptomatic; it is difficult to justify any intervention, surgical or otherwise, in these patients. The principal symptoms associated with leiomyomas include abnormal uterine bleeding (with or without anemia), pelvic pressure and pain (caused by uterine bulk and, occasionally, leiomyoma degeneration), urinary and gastrointestinal symptoms (e.g., urinary frequency, incontinence, hydronephrosis, and/or constipation resulting from uterine mass effect on the urinary and gastrointestinal systems), and adverse effects on fertility and pregnancy. Of these indications, the effects of leiomyomas on fertility and pregnancy may be the most controversial. Indeed, there are no high-quality data that prove that leiomyomas decrease fertility or increase the risk of adverse obstetric outcomes. However, the data that are available do support this notion, particularly for submucous leiomyoma or intramural leiomyomas that impinge on the endometrium. Retrospective studies demonstrate that endometrial

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cavity-distorting leiomyomas (i.e., submucosal leiomyomas; FIGO types 0–2) are associated with decreased fertility outcomes (i.e., clinical pregnancy, implantation, and live birth rates) and that these outcomes are improved with myomectomy. Subserosal leiomyomas (FIGO types 5–7) do not affect fertility and therefore should not be removed solely for this indication. Intramural leiomyomas that do not distort the endometrial cavity (FIGO types 3 and 4) are also associated with decreased fertility, but myomectomy has not been shown to improve outcomes (Pritts et al. 2009). The mechanism by which non-cavitydistorting intramural leiomyomas affect fertility remains unclear but may be related to the influence of these leiomyomas on endometrial receptivity (Rackow and Taylor 2010). Available data also demonstrate that leiomyomas are associated with only slightly increased risks of adverse obstetric outcomes, including abnormal placentation (1.4% versus 0.5%), fetal malpresentation (5.3% versus 3.1%), preterm prelabor rupture of membranes (PPROM) (3.3% versus 2.4%), placental abruption (1.4% versus 0.7%), preterm delivery (15.1% versus 10.5% before 37 weeks, 3.9% versus 2.4% before 34 weeks), intrauterine fetal demise (1.6% versus 0.7%), and postpartum hemorrhage (8.3% versus 2.9%). Only the risk of cesarean delivery is consistently increased (33.1% versus 24.2%) across studies (Stout et al. 2010; Qidwai et al. 2006). Interestingly, leiomyomas have not been consistently associated with a significantly increased risk of fetal growth restriction (Klatsky et al. 2008). Ultimately, surgical intervention to improve fertility outcomes and decrease the risks of future adverse obstetric outcomes must be balanced with the risks of preconception myomectomy. These risks include not only pain, infection, bleeding possibly requiring blood transfusion, damage to surrounding structures, and risks of anesthesia, but also delay of pregnancy (either spontaneous

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or using assisted reproductive technology), postoperative adhesion formation that may affect fertility, and possible need for cesarean delivery in subsequent pregnancy.

Benefits of Laparoscopy The advantages of laparoscopy over laparotomy are well established and include decreased morbidity and shorter recovery. Studies show that, compared to abdominal myomectomy, laparoscopic myomectomy is associated with increased operative time but decreased intraoperative blood loss, smaller drop in hemoglobin, decreased postoperative pain, more patients fully recovered by postoperative day number 15, and fewer overall complications. Furthermore, the incidence of major complications (e.g., hemorrhage, visceral injury, thromboembolism), new leiomyoma formation, and pregnancy was not significantly different between laparoscopic and open approaches (Jin et al. 2009). Available data also demonstrate that laparoscopic myomectomy results in less adhesive disease, which may affect fertility and subsequent small bowel obstruction (Bulletti et al. 1996). Robotic-assisted laparoscopic myomectomy may offer some advantages over conventional laparoscopy, such as ergonomic improvement for the surgeon and facilitation of laparoscopic suturing. However, overall outcomes, including rate of operative complications, may not be significantly different, while operative time and cost are greater (Nezhat et al. 2009). Furthermore, there is no evidence to suggest that robotic-assisted laparoscopic suturing results in a more secure hysterotomy closure than does conventional laparoscopic suturing or a lower risk of uterine rupture in subsequent pregnancy (Pitter et al. 2013).

Patient Selection Myomectomy should be considered in any patient with symptomatic uterine leiomyomas who desire uterine preservation for the purposes of fertility or other personal reasons. Myomectomy should not be performed in women in whom uterine preservation

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is contraindicated (e.g., uterine or cervical malignancy) nor in women in whom laparoscopy is contraindicated (i.e., due to medical comorbidities). The wide application of laparoscopic myomectomy is limited by the characteristics of leiomyomas that can be feasibly removed by this approach and the availability of gynecologic surgeons with advanced laparoscopic skills (i.e., laparoscopic suturing). The location, size, and number of leiomyomas determine whether a patient is a candidate for laparoscopic myomectomy, although these parameters vary with surgical expertise. Subserosal leiomyomas (FIGO types 5–7), especially those that are pedunculated (FIGO type 7), are the easiest to remove laparoscopically. However, completely intramural leiomyomas (FIGO types 3 and 4) can also be excised with this approach. Some surgeons feel comfortable removing submucosal leiomyomas (FIGO types 0–2) as well, although these are more often removed with hysteroscopy, depending on their size. Indeed, if only relatively small submucosal leiomyomas are planned to be removed, then a hysteroscopic approach should be used. Anterior and fundal leiomyomas are often easier to remove laparoscopically than are posterior leiomyomas. Proximity to important structures such as the uterine cornua and the uterine vessels should also be considered. Performing a laparoscopic myomectomy on large and/or many leiomyomas may be time-consuming because morcellation is usually necessary. Removal of such leiomyomas may also result in increased intraoperative blood loss. The optimal criteria for laparoscopic myomectomy have not been established and depend on the experience and skill of the surgeon. The largest study to investigate this issue included 2050 laparoscopic myomectomies and concluded that the following leiomyoma characteristics were associated with a significant increase in major complications (e.g., hemorrhage,

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visceral injury, failure to complete the planned procedure): size greater than or equal to 5 cm (odds ratio 6.88), intraligamentous location (odds ratio 6.44), and total number removed more than three (odds ratio 1.31) (Sizzi et al. 2007).

Preoperative Evaluation and Preparation History and Physical Exam Preoperative evaluation should start with a detailed history of the patient’s leiomyomarelated symptoms, such as abnormal uterine bleeding or bulk symptoms. It is important to document how these symptoms affect her quality of life and daily activities. Questionnaires, such as the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire, can be helpful to assess symptom severity (Spies et al. 2002). If abnormal uterine bleeding is present, then the patient should also be asked about the presence of symptoms of anemia. The medical history should include questions regarding a personal or family history of bleeding or clotting disorders, as well as other medical comorbidities that may affect the patient’s ability to tolerate general anesthesia and laparoscopic surgery. A thorough pelvic examination should be performed. On bimanual examination, uterine size, contour, and mobility should be noted along with any other abnormal findings such as the presence of adnexal masses. A fibroid uterus is usually enlarged, irregularly contoured, and/or firm on examination. Examination findings help guide surgical planning and the need for further evaluation including imaging studies.

Laboratory Tests As significant blood loss can occur during myomectomy, a blood type and screen as well as a complete blood count should be performed,

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especially if a history of anemia is present or suspected. Further evaluation for bleeding disorders such as von Willebrand disease should be performed in the presence of other suggestive symptoms or signs, such as a history of heavy menstrual bleeding since menarche. Premenopausal women aged 45 years or older with abnormal uterine bleeding and postmenopausal women with any uterine bleeding should undergo endometrial sampling to rule out endometrial hyperplasia and malignancy. Endometrial sampling should also be performed in women younger than 45 years with a history of unopposed estrogen exposure (e.g., obesity, polycystic ovarian syndrome), failed medical management, and persistent abnormal uterine bleeding (American College of Obstetricians and Gynecologists 2012). Although the primary objective of endometrial sampling is to detect endometrial malignancy, there are data to suggest that endometrial sampling can also play a role in the preoperative detection of leiomyosarcoma, with one study demonstrating that leiomyosarcoma was identified in 35.5% of preoperative endometrial sampling specimens assessed (Hinchcliff et al. 2016). The presence of a uterine malignancy is a contraindication to myomectomy. Although there are no laboratory tests that definitively differentiate a leiomyoma from a leiomyosarcoma, measurement of serum lactate dehydrogenase (LDH) isoenzymes can be informative. Elevated total lactate dehydrogenase (LDH) and LDH isoenzyme-3 should raise concern for leiomyosarcoma, as should a Uterine mass Magna Graecia (U.M.G.) risk index, defined as LDH isoenzyme-3 plus the quotient of 24 divided by LDH isoenzyme-1 [U.M.G ¼ LDH3 þ (24/LDH1)], greater than 29 (Goto et al. 2002; Di Cello et al. 2019).

Imaging Studies Clinically significant subserosal and intramural fibroids can usually be palpated on bimanual examination. Imaging studies can be used to confirm the presence, number, location, and size of leiomyomas. They can also detect the presence of

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other lesions, such as adnexal masses, which may impact surgical planning. Typically, pelvic ultrasound using a combination of transabdominal and transvaginal approaches is the initial study performed as it is the most readily available and least costly imaging technique. Ultrasonography is reasonably reliable for the evaluation of smaller uteri with four or fewer leiomyomas. Saline infusion sonohysterography, during which sterile saline is instilled into the endometrial cavity to provide contrast, allows for better delineation of submucosal leiomyomas and their intracavitary involvement. However, ultrasound has significant operator-dependent variability, resulting in inconsistent accuracy and poor reproducibility. Furthermore, ultrasonography has a limited field of view and does not capture most anatomic landmarks, making it difficult to use its images to create a three-dimensional representation of the uterus and its adjacent anatomy (Falcone and Parker 2013). A preoperative hysterosalpingogram is an alternative for women seeking fertility. Pelvic magnetic resonance imaging (MRI) has been shown to have superior sensitivity and reproducibility in the detection of leiomyomas when compared to other imaging modalities, including ultrasonography, saline sonohysterography, and hysteroscopy (Dueholm et al. 2001). More accurate information regarding leiomyoma number, location, and size helps determine whether a laparoscopic approach is feasible for myomectomy. Furthermore, unlike during abdominal myomectomy in which even small leiomyomas can be palpated, tactile sensation is limited during laparoscopy; MRI may help a laparoscopic surgeon avoid missing any leiomyomas intraoperatively. MRI is considered the best imaging modality for the detection of adenomyosis, a condition characterized by the presence of endometrial glands and stroma within the myometrium (Champaneria et al. 2010). Adenomyosis can mimic leiomyomas in its clinical presentation as both can cause abnormal uterine bleeding, abdominal/pelvic pain, and uterine enlargement. MRI features consistent with

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adenomyosis include a thickening of the junctional zone (the interface between the endometrium and the myometrium) of at least 8–12 mm, a ratio of maximum junctional zone thickness to myometrial thickness of greater than 40%, and/or a difference between maximum and minimum junctional zone thicknesses of greater than 5 mm. Other suggestive MRI findings include a poorly defined junctional zone, the presence of linear striations radiating from the endometrium into the myometrium, and myometrial cysts (Chapron et al. 2020). Pelvic MRI is also indicated if uterine sarcoma is suspected. Due to their increased vascularity, leiomyosarcomas may demonstrate increased enhancement on gadolinium-enhanced timed MRI (Goto et al. 2002). Other MRI findings that may suggest leiomyosarcoma include irregular margins, hemorrhage, necrosis, and restriction on diffusion-weighted imaging (Tong et al. 2019; Santos and Cunha 2015). Although rapid growth of a uterine mass (i.e., increasing by 6 weeks’ gestational size within 1 year) being a sign of a potential uterine sarcoma is a commonly held belief, it has been shown that this is almost never true in premenopausal women (Parker et al. 1994). Ultimately, women in whom there exists a strong preoperative suspicion for uterine sarcoma or other uterine malignancy should not undergo laparoscopic myomectomy.

Managing Preoperative Anemia Anemia resulting from heavy menstrual bleeding is a common symptom of leiomyomas. Preoperative anemia increases the risks of blood transfusion and perioperative morbidity and mortality. Iron supplementation is often used to increase preoperative hemoglobin levels. Oral iron is the first-line therapy in nonurgent situations due to its ease of administration and cost-effectiveness. However, the response is relatively slow, requiring at least 1–2 weeks before any increase in hemoglobin occurs, and patients often report gastrointestinal side effects. Intravenous iron produces a more rapid rise in hemoglobin without gastrointestinal side effects but has the potential

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to cause allergic reactions, including anaphylaxis, although rare. Epoetin, a recombinant form of erythropoietin, a hormone that stimulates red blood cell production, can also produce more rapid correction of preoperative anemia but is more expensive than iron supplementation. Another approach toward the management of preoperative anemia is to treat the patient’s heavy menstrual bleeding while she is awaiting surgery, resulting in an increase in hemoglobin. Pharmacological agents that can decrease menstrual bleeding and/or induce amenorrhea include cyclic or continuous combined hormonal contraception, oral or parenteral progesterone, gonadotropinreleasing hormone (GnRH) agonists such as leuprolide, and GnRH antagonists such as elagolix (Lethaby et al. 2001; Schlaff et al. 2020). Although GnRH agonists can also decrease leiomyoma size, many surgeons report that, in patients with prior GnRH agonist use, leiomyoma enucleation is noticeably more difficult because the tissue plane between the leiomyoma and the myometrium becomes obscured; however, this belief has not been proven in any study.

Informed Consent Preoperative informed consent should include a discussion of alternatives to myomectomy, including expectant management, medical management, interventional radiology procedures such as uterine leiomyoma embolization and magnetic resonance-guided focused ultrasound (MRgFUS), and other surgical options. Hysterectomy can be discussed with women who are not interested in preserving fertility. Some studies have suggested that quality-of-life outcomes following hysterectomy may be better than those following myomectomy (Spies et al. 2010). However, it should be noted that, unlike myomectomy, hysterectomy has been associated with increased risk of future pelvic organ prolapse, both in multiparous and nulliparous women, and increased risk of

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future cardiovascular disease in women aged 50 years or younger, even in the setting of ovarian conservation (Husby et al. 2022; Ingelsson et al. 2011). Furthermore, multiple studies have demonstrated that perioperative morbidity is not significantly different between myomectomy and hysterectomy and may even be less with myomectomy with regard to risk of visceral injury and infection (Pundir et al. 2013; Sawin et al. 2000; Iverson et al. 1996). Possible complications of myomectomy should be discussed. Complications include excessive bleeding requiring blood transfusion or, in the rare situation that life-threatening bleeding occurs and is unable to be controlled with other measures, hysterectomy. Patients who plan to become pregnant should be counseled about the potential need for cesarean delivery and the risk of uterine rupture. New leiomyoma formation and recurrence or persistence of leiomyomaassociated symptoms should also be discussed. Conversion to laparotomy is a possibility with all laparoscopic procedures. The informed consent discussion should be documented in the medical record and on the surgical consent form. Leiomyoma morcellation, if planned, must be discussed in detail.

Discussing Morcellation Morcellation is a surgical technique used to reduce the size of leiomyomas, uteri, or other specimens by creating smaller pieces to allow the tissue to be removed through small incisions, such as those used in laparoscopy. The safety of power morcellation during laparoscopic myomectomy and hysterectomy has come into question by the United States Food and Drug Administration (FDA), prompted by a widely publicized case report in which uncontained power morcellation was used in the presence of an undiagnosed leiomyosarcoma. After performing a limited literature review that included nine studies (eight

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publications and one abstract) with 9160 women of whom only 5.5% were from prospective studies, the FDA concluded that 1 in 498 women undergoing myomectomy or hysterectomy for the treatment of presumed leiomyomas is found to have an unsuspected leiomyosarcoma (U.S. Food and Drug Administration 2014a, b). Only studies in which a leiomyosarcoma was identified were included; studies of women undergoing surgery for presumed leiomyomas in which no leiomyosarcoma was identified were excluded. Other, more thorough studies have demonstrated a much lower prevalence. In 2015, a meta-analysis of 133 studies, 64 of which were prospective, including 30,193 women determined that the prevalence of leiomyosarcoma in patients undergoing surgery for presumed leiomyomas is 1 in 1960, or 0.051% (Pritts et al. 2015). In 2017, a meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) that included 160 studies and 136,195 women determined that unexpected leiomyosarcoma is found in fewer than 1–13 of every 10,000 surgeries performed for presumed leiomyomas, or 0.01–0.1%. Also, 29% of these data came from prospective studies (Hartmann et al. 2017). Based on its likely inflated estimated prevalence of leiomyosarcoma, the FDA issued a Safety Communication in 2014 that discouraged the use of laparoscopic power morcellation during surgery for presumed leiomyomas, stating that the procedure can spread malignant cells within the abdomen and pelvis if an unexpected sarcoma is present (U.S. Food and Drug Administration 2014a, b). Since this Safety Communication, use of laparoscopic myomectomy and hysterectomy has decreased, and use of abdominal myomectomy and hysterectomy has increased (Harris et al. 2016; Stentz et al. 2017). Concurrently, rates of major surgical complications excluding blood transfusion, minor surgical complications, and hospital readmission within 30 days have significantly increased (Harris et al. 2016;

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Multinu et al. 2018). These data underscore the well-established advantages of laparoscopy over laparotomy with regard to procedure-related morbidity as well as the importance of being able to continue to offer women the option of minimally invasive gynecologic surgery. In 2020, the FDA updated its Safety Communication, recommending that morcellation be performed using a containment system specifically designed and marketed for the purpose of limiting tissue dissemination (United States Food and Drug Administration 2020). However, several studies have demonstrated that containment bags can perforate and leak and can result in increased operative time (Cohen et al. 2016; Vargas et al. 2015). These findings may be due to the cumbersome nature of these bags and impaired visualization of the specimen and of surrounding structures while using them. Furthermore, cellular spread has been shown to occur from the time of uterine incision during both abdominal and laparoscopic myomectomy, well before morcellation would occur during laparoscopic myomectomy (Sandberg et al. 2016; Toubia et al. 2016). Following morcellation, careful inspection of the peritoneal cavity for and removal of tissue fragments and copious irrigation and suctioning of fluid can remove residual tissue and cells without the use of containment bags (Yu et al. 2018). This technique can also help decrease the risk of disseminating benign disease suggested by some studies (Tulandi et al. 2016). Unfortunately, leiomyosarcoma is an aggressive malignancy with a poor prognosis, regardless of stage at presentation. Stage I disease, in which the cancer is confined to the uterus, is associated with a 55.4% 5-year survival rate (Seagle et al. 2017). Currently available evidence that morcellation of a leiomyosarcoma affects prognosis is limited. The 2017 AHRQ meta-analysis found no significant differences in 5-year survival rate among women with leiomyosarcoma who underwent power (electromechanical) morcellation, manual

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(scalpel) morcellation, and no morcellation (Hartmann et al. 2017). Regardless of whether morcellation is performed during myomectomy, if leiomyosarcoma is diagnosed, then minimal time to reoperation to perform total hysterectomy and achieve minimal residual disease is imperative. As leiomyosarcoma spreads rapidly through hematogenous and peritoneal routes, a delay in reoperation may increase the risk of disease progression and metastasis (Parker 2018). The American College of Obstetricians and Gynecologists (ACOG) recently published a Committee Opinion regarding morcellation for presumed leiomyomas in which it recommends a shared decision-making process between the patient and her healthcare provider. Careful preoperative evaluation must be performed, as well as a discussion of the benefits and risks of minimally invasive surgery versus open surgery, the risks of morcellation including possible disease dissemination and visceral injury, and the prevalence of leiomyosarcoma and its overall poor prognosis (American College of Obstetricians and Gynecologists 2021). As with any preoperative counseling, the discussion about morcellation should be documented in the medical record and on the surgical consent form.

Operative Technique Anesthesia and Patient Positioning As with most laparoscopic gynecologic procedures, the patient should be placed under general endotracheal anesthesia and in the supine or lithotomy position. Lithotomy is required if the surgeon chooses to place a uterine manipulator that can be used to improve intraoperative visualization. A uterine manipulator also allows for instillation of indigo carmine or methylene blue dye if chromopertubation is planned or to determine whether the endometrial cavity is entered during the procedure. The patient should also be placed in lithotomy if concomitant hysteroscopy is performed. Tucking of the bilateral upper extremities often provides surgeons with the best

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access to the operative field. Adequate intravenous access should be established by the anesthesiologist before the arms are padded and tucked. Both the abdomen and the vagina are surgically prepared. An indwelling catheter is inserted into the bladder to decrease the risk of intraoperative bladder injury and monitor urine output. The catheter can also be used to backfill the bladder should delineation of its borders become necessary.

Prophylaxis Virtually all laparoscopic myomectomies are at least 30 minutes in duration and are therefore considered major surgeries. As such, they pose at least low to moderate risk of venous thromboembolism. Therefore, prior to induction of anesthesia, each patient should receive venous thromboembolism prophylaxis, mechanical and/or pharmacological, tailored to her individual risk factors, or lack thereof (American College of Obstetricians and Gynecologists 2007). A benefit of laparoscopic surgery is that patients regain postoperative mobility more rapidly than after laparotomy, thereby decreasing the risk of postoperative venous thromboembolism. Antibiotic prophylaxis is not indicated for laparoscopic procedures. The risk of surgical-site infection is low in procedures during which the bowel or vagina is not entered (American College of Obstetricians and Gynecologists 2009).

Laparoscopic Port Placement Laparoscopic port placement is based on the location and size of the leiomyomas to be removed. The initial port is often placed at the umbilicus but may also be placed in the left upper quadrant (i.e., Palmer’s point) if the uterine fundus extends to or above the umbilicus or if significant umbilical adhesions are anticipated. Once the initial port is placed, the laparoscope is inserted into the peritoneal cavity and the abdomen and pelvis are examined. If there are findings that preclude safe completion of a laparoscopic myomectomy such

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as the presence of extensive adhesive disease, then the procedure can be converted to laparotomy. Typically, three additional laparoscopic ports are placed. To make laparoscopic suturing more ergonomic, two right-sided ports are placed if the surgeon is right-handed or two left-sided ports if the surgeon is left-handed. The first port is placed approximately 2 cm superior and medial to the anterior superior iliac spine. This port should be 12 mm in size to allow for the passage of curved needles for suturing and for the insertion of the morcellation device, if used. A second, 5 mm port is placed medial and slightly superior to the first port. Another 5 mm port is placed in the contralateral lower quadrant but may also be placed above the umbilicus if large fibroids are present.

Strategies to Decrease Intraoperative Blood Loss Intraoperative blood loss can be decreased with pharmacological and/or mechanical intervention. Perhaps the method most commonly used during laparoscopic myomectomy is the use of vasopressin, a pharmacological agent that causes vasoconstriction. Vasopressin is injected into the myometrium at the site of the planned uterine incision. Injection can be performed using a long needle inserted through a laparoscopic port or directly through the anterior abdominal wall. Care should be taken to avoid intravascular injection by withdrawing the plunger of the syringe to check for blood prior to injection. Even in the absence of intravascular injection, vasopressin can cause systemic hemodynamic changes and has been associated with rare cases of cardiovascular collapse and death (Falcone and Parker 2013). Clear communication should occur between the surgeon and the anesthesiologist; the surgeon should notify the anesthesiologist when vasopressin is being administered and, in turn, the anesthesiologist should notify the surgeon of any signs of hemodynamic instability in the patient. Furthermore, a maximum dose of vasopressin should be determined prior to surgery. Although the maximum safe dose of vasopressin

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has not been definitively established, a total dose of 4–6 units per procedure is widely used. Dilution of the vasopressin (e.g., 20 units of vasopressin in 100 ml of normal saline) helps limit the total dose (Frishman 2009). Prophylactic administration of tranexamic acid (TXA), a pharmacological agent that inhibits fibrinolysis, can also be used to decrease intraoperative blood loss. An intravenous dose of 10 mg/kg or 1 g is typically administered prior to incision. This strategy has been associated with reduced blood loss in both obstetric and gynecologic surgery, including myomectomy (Abdul et al. 2019; Caglar et al. 2008). Its effect may be even more pronounced in patients with multiple (i.e., three or more) leiomyomas (Shaaban et al. 2016). Although the use of tranexamic acid is generally avoided in patients with a history of thrombosis or thrombophilia, a recent large systematic review and meta-analysis found that intravenous TXA, regardless of dose, is not associated with an increased risk of thromboembolic events (Taeuber et al. 2021). Uterotonics have also been used to decrease intraoperative blood loss. Small studies have demonstrated that both vaginal dinoprostone and vaginal misoprostol significantly decrease blood loss during myomectomy; however, the latter has not been shown to decrease the risk of blood transfusion. There is no evidence that the use of oxytocin decreases intraoperative blood loss or the risk of blood transfusion (Kongnyuy and Wiysonge 2014). Mechanical interventions, such as the use of tourniquets or clamps, can be used to decrease intraoperative blood loss by occluding the uterine blood supply from the uterine and ovarian arteries. However, it is difficult to secure a tourniquet using laparoscopic instruments. Accordingly, they are not used as often during laparoscopic myomectomy as they are during abdominal myomectomy. Intraoperative blood salvage (e.g., Cell Saver) may be used in procedures in which significant blood loss is anticipated, thereby avoiding allogeneic blood transfusion and its associated complications. This technology involves suction of blood from the surgical field, separation and washing of the red blood cells, and eventual

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reinfusion into the patient. Intraoperative blood savage is less commonly used during laparoscopic myomectomy than during abdominal myomectomy, likely because significant blood loss is more often anticipated during the removal of larger and/or more numerous leiomyomas, characteristics that may necessitate an open approach.

Uterine Incision and Leiomyoma Removal A transverse incision is made on the uterus directly over the leiomyoma and extended deeply until the leiomyoma is clearly seen. A monopolar device such as the hook or an ultrasonic cutting and coagulating device such as the Harmonic Shears may be used. The transverse direction allows for more ergonomic suturing of the uterine defect when compared with a vertical incision. Care should be taken to avoid the uterine cornua, the ascending uterine artery and venous plexus lateral to the uterus, and the site where the uterine artery enters the uterus at the level of the internal cervical os. The leiomyoma is grasped with a tenaculum to provide traction. A combination of traction–countertraction, blunt and sharp dissection, and/or electrosurgery is used to dissect under the pseudocapsule and separate the plane between the leiomyoma and the surrounding myometrium, thereby enucleating the leiomyoma.

Repair of Uterine Defects As is performed during an abdominal myomectomy, all uterine incisions are closed in one or more layers, depending on the depth of the incision. Size 0 delayed absorbable monofilament suture such as poliglecaprone (Monocryl) or polydioxanone (PDS) is often used. Although a polyfilament suture such as polyglactin 910 (Vicryl) can also be used, its braided nature exhibits high tissue drag, traumatizing the tissue through which it passes, and can cause the suture to fray during extracorporeal knot-tying. Absorbable barbed suture may also be used to close the myometrium. This suture not only obviates the need for knot-

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tying but also maintains tension on the myometrium, thereby facilitating laparoscopic suturing. Indeed, expeditious closure of uterine defects significantly impacts intraoperative blood loss.

Morcellation of Leiomyomas For leiomyomas that are too large to be removed from the abdomen directly through one of the laparoscopic port sites, morcellation using an electromechanical device may be performed. To decrease the risk of visceral injury, the blade of the morcellation device should be under direct laparoscopic visualization at all times, including during its insertion and removal from the abdomen. Furthermore, the blade should be directed toward the anterior abdominal wall as much as possible. After all leiomyomas have been morcellated, the device should be removed from the abdomen and a thorough inspection of the peritoneal cavity for tissue fragments must be performed. Copious irrigation and suctioning should be used to remove blood and any residual tissue and cells.

Closure At the close of the procedure, hemostasis should be assured throughout the peritoneal cavity. Measures to prevent adhesion formation, such as placement of adhesion barrier products (e.g., Interceed, Seprafilm), may be taken if desired. The fascia of any laparoscopic port site that is 10 mm or larger should be closed to decrease the risk of incisional hernia development (Montz et al. 1994).

Complications Complications of laparoscopic myomectomy are like those of abdominal myomectomy, including blood loss, infection, and adhesion formation. Complications unique to a laparoscopic approach include conversion to laparotomy and those related to trocar insertion, such as trocar-related bowel or vascular injury.

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Postoperative Care Laparoscopic myomectomy is typically performed as an outpatient procedure. Overnight inpatient observation may also be considered. The patient may resume her routine activities including vaginal intercourse as soon as she feels comfortable. She may return to work once she has regained sufficient strength and mobility, usually within 2 weeks. A routine postoperative outpatient visit should occur within 2–6 weeks. During this visit, details of the surgery and pathology results are reviewed, the abdomen and incisions are examined, the uterus is evaluated for hematoma formation, and the patient is assessed for any potential complications.

Outcomes Improvement of Symptoms Data regarding the rate of symptom relief following laparoscopic myomectomy are limited. A prospective cohort study that included 28 patients undergoing laparoscopic myomectomy demonstrated significant improvements in symptom severity and quality of life, as measured by the UFS-QOL questionnaire, during the 27-month follow-up period. This study also included 52 patients undergoing abdominal myomectomy who experienced similar improvements (Rodriguez-Triana et al. 2021).

New Leiomyoma Formation The rate of new leiomyoma formation at 5 and 8 years after myomectomy has been reported to be 53% and 85%, respectively. However, rates of reoperation, arguably more significant for patients, were much lower at 7% and 16%, respectively. Risk factors for new leiomyoma formation include multiple leiomyomas present at the time of surgery, uterine size of 13 weeks or larger, and age younger than 36 years (Yoo et al. 2007). The rates of new leiomyoma formation are not significantly different between laparoscopic myomectomy and abdominal myomectomy (Jin et al. 2009).

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Pregnancy After Myomectomy Interval to Conception It is recommended that patients wait at least 3 months after myomectomy before attempting to conceive. A small prospective study used serial MRI to investigate the amount of time necessary for the uterine structure to reach a stable state following myomectomy. Uterine length and volume were stable 6 weeks after surgery, and the endometrium was stable 12 weeks after surgery. Furthermore, even gadolinium contrast was visualized at the hysterotomy site in all cases 12 weeks after surgery. Based on these findings, the authors concluded that the recovery process is complete at 12 weeks in the absence of hematoma or edema formation in the myometrium on MR images (Tsuji et al. 2006).

Risk of Uterine Rupture Although cases of uterine rupture during labor in patients with prior myomectomy, whether abdominal or laparoscopic, have been reported, the actual risk of rupture and the factors associated with an increased risk are unknown. Myomectomy in which the endometrial cavity is entered or the myometrium is otherwise significantly compromised is thought to incur risk similar to that of a prior classical cesarean delivery, the reported incidence of which ranges from 1% to 12%. Accordingly, it is recommended that women with prior myomectomy in which the myometrium may have been significantly compromised be delivered by cesarean at 36–38 weeks of gestation. Myomectomy in which only pedunculated leiomyomas (FIGO type 7) are removed is thought to incur significantly less risk of uterine rupture. Therefore, women with prior myomectomy requiring minimal or no myometrial dissection are given the option of a trial of labor (Spong et al. 2011). It remains controversial whether laparoscopic myomectomy results in as strong a hysterotomy

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closure as that following abdominal myomectomy. Proposed mechanisms by which myometrial wound healing may be compromised following laparoscopic myomectomy, resulting in increased risk of uterine rupture in subsequent pregnancy, include inadequate closure of myometrial defects due to the technical challenge of laparoscopic suturing, lack of hemostasis within myometrial defects with subsequent hematoma formation, and the excessive use of electrosurgery with subsequent devascularization of the myometrium. However, more recent studies have demonstrated that the incidence of uterine rupture following laparoscopic myomectomy is similar to that following abdominal myomectomy and may even be similar to that following a primary cesarean delivery (Flyckt and Falcone 2015; Claeys et al. 2014). Multiple-layer closure of uterine defects and prudent use of electrosurgery are recommended to limit this risk (Parker et al. 2010).

Conclusion Laparoscopic myomectomy is a safe, effective, and minimally invasive alternative to abdominal myomectomy for women with symptomatic uterine leiomyomas who desire uterine preservation. Thorough preoperative evaluation and preparation ensure that appropriate patients are selected for this surgery. Outcomes are like that of abdominal myomectomy while providing the benefits of decreased morbidity and quicker recovery that are afforded by laparoscopy. The wide application of laparoscopic myomectomy is limited by certain leiomyoma characteristics and the availability of gynecologic surgeons with advanced laparoscopic skills.

Cross-References ▶ Laparoscopic Hysterectomy ▶ Management of Fibroids

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B. D. Romeroso and W. H. Parker Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006;107(2 Pt 1):376–82. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–34. Rodriguez-Triana VM, Kwan L, Kelly M, Olson TH, Parker WH. Quality of life after laparoscopic and open abdominal myomectomy. J Minim Invasive Gynecol. 2021;28(4):817–23. Sandberg EM, van den Haak L, Bosse T, Jansen FW. Disseminated leiomyoma cells can be identified following conventional myomectomy. BJOG. 2016;123(13):2183–7. Santos P, Cunha TM. Uterine sarcomas: clinical presentation and MRI features. Diagn Interv Radiol. 2015;21(1):4–9. Sawin SW, Pilevsky ND, Berlin JA, Barnhart KT. Comparability of perioperative morbidity between abdominal myomectomy and hysterectomy for women with uterine leiomyomas. Am J Obstet Gynecol. 2000;183(6):1448–55. Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, Barnhart KT, Bradley LD, Carr BR, Feinberg EC, Hurtado SM, Kim J, Liu R, Mabey RG Jr, Owens CD, Poindexter A, Puscheck EE, Rodriguez-Ginorio H, Simon JA, Soliman AM, Stewart EA, Watts NB, Muneyyirci-Delale O. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328–40. Seagle BL, Sobecki-Rausch J, Strohl AE, Shilpi A, Grace A, Shahabi S. Prognosis and treatment of uterine leiomyosarcoma: a National Cancer Database study. Gynecol Oncol. 2017;145(1):61–70. Shaaban MM, Ahmed MR, Farhan RE, Dardeer HH. Efficacy of tranexamic acid on myomectomyassociated blood loss in patients with multiple myomas: a randomized controlled clinical trial. Reprod Sci. 2016;23(7):908–12. Sizzi O, Rossetti A, Malzoni M, Minelli L, La Grotta F, Soranna L, Panunzi S, Spagnolo R, Imperato F, Landi S, Fiaccamento A, Stola E. Italian multicenter study on complications of laparoscopic myomectomy. J Minim Invasive Gynecol. 2007;14(4):453–62. Spies JB, Coyne K, Guaou Guaou N, Boyle D, SkyrnarzMurphy K, Gonzalves SM. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol. 2002;99(2):290–300. Spies JB, Bradley LD, Guido R, Maxwell GL, Levine BA, Coyne K. Outcomes from leiomyoma therapies: comparison with normal controls. Obstet Gynecol. 2010;116(3):641–52. Spong CY, Mercer BM, D’Alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstet Gynecol. 2011;118(2 Pt 1):323–33.

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Stentz NC, Cooney LG, Sammel M, Shah DK. Changes in myomectomy practice after the U.S. Food and Drug Administration safety communication on power morcellation. Obstet Gynecol. 2017;129(6):1007–13. Stout MJ, Odibo AO, Graseck AS, Macones GA, Crane JP, Cahill AG. Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. Obstet Gynecol. 2010;116(5):1056–63. Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, Messroghli L, Zacharowski K, Choorapoikayil S, Meybohm P. Association of intravenous tranexamic acid with thromboembolic events and mortality: a systematic review, meta-analysis, and meta-regression. JAMA Surg. 2021;156(6):e210884. Tong A, Kang SK, Huang C, Huang K, Slevin A, Hindman N. MRI screening for uterine leiomyosarcoma. J Magn Reson Imaging. 2019;49(7):e282–94. Toubia T, Moulder JK, Schiff LD, Clarke-Pearson D, O’Connor SM, Siedhoff MT. Peritoneal washings after power morcellation in laparoscopic myomectomy: a pilot study. J Minim Invasive Gynecol. 2016;23(4): 578–81. Tsuji S, Takahashi K, Imaoka I, Sugimura K, Miyazaki K, Noda Y. MRI evaluation of the uterine structure after myomectomy. Gynecol Obstet Investig. 2006;61(2): 106–10. Tulandi T, Leung A, Jan N. Nonmalignant sequelae of unconfined morcellation at laparoscopic hysterectomy or myomectomy. J Minim Invasive Gynecol. 2016;23(3):331–7. U.S. Food and Drug Administration. Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication [Internet]. 2014a [cited 2022 Apr 13]. Available from: https://wayback.

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Robotic Surgery in Gynecology: Indications, Advantages, Avoiding Complications, Training, and Future Platforms–Update 2022

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774 Early Days . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774 Single Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777 Robotic Advantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780 Gynecology Adoption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782 Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782 Myomectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 Sacrocolpopexy and Pelvic Support Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 Endometriosis and Chronic Pelvic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 Reproductive Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785 Ovarian Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786 Direct and Indirect Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786 Preventing Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787 Credentialing and Privileging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787 Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789 Future Robotic Surgery Platforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791

J. P. Lenihan Jr. (*) Department of Obstetrics and Gynecology, University of Washington School of Medicine, Surgical Science North America, Seattle, WA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_55

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J. P. Lenihan Jr. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795

Abstract

Keywords

The use of computers to assist surgeons in the operating room has been an inevitable evolution in the modern practice of surgery. Robotic-assisted surgery has been evolving now for over two decades and has finally matured into a technology that has caused a monumental shift in the way gynecologic surgeries are performed. Prior to robotics, the only minimally invasive options for most GYN procedures, including hysterectomies, were either vaginal or laparoscopic approaches. However, even with over 100 years of vaginal surgery experience and more than 30 years of laparoscopic advancements, most gynecologic surgeries in the United States are still performed through an open incision. That changed in 2005 with the introduction of the DaVinci™ Surgical Robotic Platform. Over the last 16 years, the trend across the country has now dramatically shifted to less open and more minimally invasive procedures. Robotic-assisted procedures now include not only hysterectomy but also most of all the other commonly performed gynecologic procedures, including myomectomies, pelvic support procedures, and reproductive surgeries. This success, however, has not been without controversies, particularly around costs and complications. The evolution of computers to assist surgeons and make minimally invasive procedures more common is clearly a trend that is not going away. In fact, there are many new robotic surgical systems that are about to enter the market giving gynecologists more choices in how to utilize computer-assisted surgeries for their procedures. It is now incumbent on surgeons, hospitals, and medical societies to determine the most cost-efficient and productive use for this rapidly growing technology.

Robotic-assisted surgery · Hysterectomy · Myomectomy · Credentialing and privileging · Computer-assisted surgery · Robotic surgery training

Introduction Robotic surgery is surgery that is performed by a skilled surgeon with the assistance of a computer utilizing a remote telesurgery platform (Pugin et al. 2011). Remote surgery has been a dream for the last century. In the late 1980s, Defense Advanced Research Projects Agency (DARPA) funded a remote surgery program targeted for the battlefield. Researchers at Stanford University (Stanford Research Institute or SRI) developed early technologies around telepresence. Many civilian companies and labs also worked on robotics such as IBM, which developed remote center technology, MIT, which developed cable-driven technology for low friction manipulators, and Computer Motion, which developed the first surgical robot, ZEUS. In 1990, researchers at SRI formed a company that licensed these technologies and started the long process of turning a good idea into a product. They merged with their primary competitor at the time, Computer Motion, and formed Intuitive Surgical (Sunnyvale, CA), the developer of the da Vinci Robotic Surgery System™. This system was the only commercially available robot from the late 1990s until 2018. Today, other manufacturers are entering the marketplace with novel new robotic systems.

Early Days Initially, the surgical robot was designed for battlefield use with predominantly vascular capabilities. However, urologists soon found the robot

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was a great surgical approach to prostate cancer surgery, and the commercial version took off. Lonnie Smith, the first CEO of Intuitive Surgical, said that initially the company “aimed for the heart but hit the prostate instead.” In June 2005, the FDA approved the da Vinci Robot™ for use by gynecologists. Because hysterectomies are the second most common surgery performed in the United States, it did not take long for GYN procedures to become the highest volume robotic surgical procedures. The initial da Vinci Robot™, the “Standard” system (Fig. 1) evolved

Fig. 1 daVinci Standard Robot, 2005

Fig. 2 da Vinci S Robot, 2006

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after 5 years to an “S” model with improved high-definition 3-D vision and easier docking technology (Fig. 2). The next-generation “Si” model had a more flexible bedside cart (the actual robot) as well as improved technology that allowed the development and use of newer instruments such as vessel sealers, staplers, as well as new imaging modalities such as infrared and fluorescence (Fig. 3). It also was the platform for the first robotic single-site technology that allowed surgeons to perform single-incision surgery with the help of the computer to make it less

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challenging for surgeons who were used to operating in a 2-D laparoscopic world. (Fig. 4). The current robot model was introduced in 2014: the “Xi.” This robotic platform is designed for complex multiquadrant abdominal surgery such as

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cancer surgery. Intuitive Surgical subsequently introduced a “single port” robotic platform (SP) as well as a basic three-arm-only system that was less costly (SE) as part of the “fourth generation Xi family” (Fig. 5). More recently, Intuitive

Fig. 3 da Vinci Si Robot, 2009

Fig. 4 da Vinci Si Single Site Platform, 2015

Fig. 5 da Vinci Xi Fourth Generation Family of Robots, 2014–2018

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Fig. 6 The Asensus “Senhance™” Robotic-Laparoscopic System

Surgical, in a move to remain the leader in this evolving area, developed a comprehensive surgeon and hospital support network called the “Intuitive EcoSystem™,” which involves product support, training updates, and direct hospital robotics program support (. ref 2: https://www. intuitive.com). There are other robotic companies in addition to Intuitive Surgical that are currently approved for use both in the United States and overseas. Asensus (formerly Transenterix) has a laparoscopy-based robot called “Senhance™,” which was approved by the FDA for GYN use in 2018 (Fig. 6). In 2021, Memic, rebranded as Momentum Surgical in 2020, received FDA approval for the Hominis system, now renamed Anovo. (Fig. 10) This is a robotic-assisted surgical platform that is designed for transvaginal gynecologic procedures, including benign hysterectomy. The Merecompany, Korea, had their da Vinci-like robot platform ™called Revo™ approved in Korea in 2019. CMR (Cambridge Medical Robotics) had their versatile and novel “Versius™” robot approved in the United Kingdom in 2019, and is now being used in Australia, India and other EU and Asian countries. The Multiport “Hinotori™” robot manufactured

by Medicaroid, a subsidiary of Kawasaki, was approved in 2020 in Japan for urology, and is looking for a US launch for Gynecology in 2025. The German company Avatera Medical has developed the “Avaterra™” multi-arm robot that was approved in the EU in 2020 as well (Fig. 7). Distalmotion, a Swiss-based company, has launched a system called Dexter, which has received CE mark approval in Europe in 2020. (Fig. 8) This is designed as a hybrid system, part laparoscopic and part robotic, that allows for a swift transition from one modality to another. The first GYN case with Dexter™ was carried out in Lausanne, Switzerland in 2021.

Single Site Reduced port laparoscopic surgery has been the goal of most minimally invasive surgeons since the emergence of laparoscopy. The drawback of fewer ports is that the surgeon has a reduced ability to utilize instruments in a typical comfortable fashion in order to dissect tissue and particularly to sew. Laparoscopic single-site techniques such as single-incision laparoscopic surgery (SILS), laparoendoscopic single site (LESS), and

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Fig. 7 Avateramedical’s “Avetera™” Multi-arm open cockpit surgical robot

Fig. 8 The Distalmotion “Dexter™” Laparoscopy-Robot System

single-site surgery (SSS) have been reported since the 1990s, but these techniques have been slow to catch on with most gynecologic surgeons primarily due to the long learning curves and the requirement for exceptional innate ability to perform laparoscopy (Hart et al. 2010). In 2014, Intuitive Surgical released a modification of their Si robot that allowed surgery to be performed robotically through a single site. Their four-channel port

housed the camera, an accessory channel, and two non-wristed robotic instruments. The robotic microprocessors converted the surgeon’s hand control to operate the left arm instrument with the surgeon’s right hand, which was now on the patient’s right side, and vice versa. This allowed the surgery to proceed like normal robotic surgery and not require “cross-vision” as was typical of straight-stick single-site laparoscopy. In 2014,

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Intuitive received FDA approval for their new SP™ (single port) robot. This robot has a 2.5 cm port that allows a flexible camera and three wristed-elbowed instruments to operate through a single incision. It has been utilized now by almost every specialty but requires significant skill and training to become proficient on this platform (Fig. 9).

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Several other robotic surgery companies are in or moving into this market. As mentioned earlier, in 2021, Memic (Momentus) received FDA approval for the Hominis (Anovo) system (Fig. 10). This system allows the instrument to be inserted via the vaginal cul de sac and then operate back on itself with a view of the same as an abdominal laparoscopic approach. Titan

Fig. 9 The da Vinci SP robotic platform, 2018

Fig. 10 The Memic “Hominus™” (now Momentus Anovo™) vaginal insertion robot

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Fig. 11 Titan “Enos” Single Port Robotic System

Medical, a Canadian company, signed a licensing agreement with Medtronic in 2020 and has developed a wristed instrument, cost-effective system called Enos™ that allows most noncomplex GYN surgeries to be performed through a single abdominal incision (Seeliger et al. 2019) (Fig. 11). Like the other single-site platforms, it expects to compete on a value-based proposition with lower costs for the robot, robotic instruments, and service agreements. Titan will likely release its singleport robot in 2025.

Robotic Advantages The computer-assisted enhancement of robotics has many advantages over straight-stick laparoscopy. The most significant advantage acknowledged by most of all surgeons is the advantage to see the operative field in high-definition 3-D with a stable camera platform controlled by the surgeon. Additional advantages for most of all the current and evolving systems include wristed instruments with articulation that go beyond the normal ability to manipulate instruments, scaled motion to allow for more precise movements, and a significant ergonomic benefit of being able to sit comfortably in a console rather than standing upright at the bedside trying to watch a remote video monitor while moving rigid instruments into small spaces. Disadvantages of robotic

surgery pointed out by many include the loss of haptic feedback (touch), which many surgeons feel is integral to being a good surgeon. Another drawback is the limited ability to communicate with the OR team while the surgeon is taskfocused in the robotic console. Team training with “cockpit communication” techniques employed by the aviation industry helps to minimize this limitation (Rivers et al. 2003). Many newer robotic platforms have therefore gone to an “open” surgical cockpit to allow better communication and awareness of the operating room by the robotic surgeon. Surgeons who previously did not feel comfortable performing hysterectomies or other complex gynecologic procedures with traditional laparoscopy have now found the robot to be an enabling device, allowing them to convert most of their open procedures to minimally invasive operations (Papalekas and Fisher 2018). As robotic technology evolves, there are now enhancements to the robot that provide even more advantages to the surgeon. The Si and Xi robots have the capability of visualizing infrared light spectrum without additional equipment. This enables surgeons to see infrared ureteral catheters (Stryker Infra-Vision™), which may help identify ureters in the face of complex pathology and thereby prevent an inadvertent ureteral injury (Fig. 10). Fluorescent imaging utilizing dyes that fluoresce with laser stimulation such as

54

Robotic Surgery in Gynecology: Indications, Advantages, Avoiding Complications. . .

781

Fig. 12 Stryker Infrared Ureteral Catheters

Fig. 13 da Vinci Firefly Fluorescent Imaging using ICG Dye

indo-cyanine-green dye (ICG dye) has proven very useful in identifying sentinel lymph nodes, aberrant blood vessels, and even endometriosis implants, again enabling surgeons to see structures that might otherwise not be visible with the

naked eye (Daskalaki et al. 2015) (Fig. 13). Future developments being studied now include improved single-port capabilities, “GPS” guidance for surgeons using overlayed patient-specific imaging technology such as ultrasound and

782

MRI, and even remote co-surgery using Internetconnected consoles to allow expert surgeons in academic centers to operate with primary surgeons in their local facilities.

Gynecology Adoption Initially, the robot’s primary value was that it enabled surgeons to successfully perform complex minimally invasive procedures more easily than they could with laparoscopy. Laparoscopy is a minimally invasive technique that has been utilized by gynecologists since the mid-1970s. In the 1980s, surgeons started attempting more complex procedures requiring dissection and sewing; and in 1989, Dr. Harry Reich reported the first total laparoscopic hysterectomy (Reich 1989). In 2003, Dr. Arnold Advincula, a true pioneer in the development of robotic gynecologic surgery, reported an initial series of robotic myomectomies that at that time were typically accomplished by almost all gynecologists as an open procedure (Advincula et al. 2004a). Subsequently, after the da Vinci Robot™ was approved for gynecology surgeons, many reports were published evaluating it as a new tool compared with laparoscopy (Advincula and Song 2007). Learning curves were defined as being more extensive than was initially suspected and adoption hit some road bumps as complications were reported in national media, prompting the legal profession to become interested in robotic surgery and to subsequently start advertising for patients injured by the robot (Carreyrou 2010). It became clear that while robots were enabling, they were not a substitute for good surgical technique and judgment. Based on this, professional societies sought to provide guidance for the proper utilization of this expensive technology as well as recommendations for training and credentialing (ACOG Committee Opinion Summary 2020; AAGL Guidelines 2014). The rapid adoption of computer-assisted telesurgery by gynecologists had led to a dramatic change in the route of hysterectomy in the United States. Traditionally, the rates of abdominal hysterectomy surgery have been very

J. P. Lenihan Jr.

high, approaching 60–70% (CDC-MMWR 2002; Jacobsen et al. 2006). The minimally invasive approaches to hysterectomy seemed to be stuck at 25% for several decades for the vaginal approach and less than 15% for the laparoscopic approach. With the adoption of robotic hysterectomy in 2005, the rate of TAH has dropped across the country to 500 g. J Minim Invasive Gynecol. 2014;21(1):115–9. Clarke-Pearson DL, Geller EJ. Complications of hysterectomy. Obstet Gynecol. 2013;121(3):654–73.

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Sheth SS. Vaginal hysterectomy as a primary route for morbidly obese women. Acta Obstet Gynecol Scand. 2010;89(7):971–4. Silva-Filho AL, Rodrigues AM, de Castro V, Monteiro M, da Rosa DG, Pereira e Silva YM, Werneck RA, Bavoso N, Triginelli SA. Randomized study of bipolar vessel sealing system versus conventional suture ligature for vaginal hysterectomy. Eur J Obstet Gynecol Reprod Biol. 2009;146(2):200–3. Solomon ER, Muffly TM, Barber MD. Common postoperative pulmonary complications after hysterectomy for benign indications. Am J Obstet Gynecol. 2013;208(1):54.e1–5. Summitt RL Jr, Stovall TG, Lipscomb GH, Ling FW. Randomized comparison of laparoscopy-assisted vaginal hysterectomy with standard vaginal hysterectomy in an outpatient setting. Obstet Gynecol. 1992;80(6):895–901. Summitt RL Jr, Stovall TG, Bran DF. Prospective comparison of indwelling bladder catheter drainage versus no catheter after vaginal hysterectomy. Am J Obstet Gynecol. 1994;170(6):1815–8. discussion 1818–1821 Sutton C. Hysterectomy: a historical perspective. Baillieres Clin Obstet Gynaecol. 1997;11:1–22. Sutton C. Past, present and future of hysterectomy. J Minim Invasive Gynecol. 2010;17(4):421–35. Swenson CW, Berger MB, Kamdar NS, Campbell DA Jr, Morgan DM. Risk factors for venous thromboembolism after hysterectomy. Obstet Gynecol. 2015;125(5): 1139–44. Teeluckdharry B, Gilmore D, Flowerdew G. Urinary tract injury at benign gynecologic surgery and the role of cystoscopy: a systematic review and meta-analysis. Obstet Gynecol. 2015;126:1161. E pub ahead of print

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Christina E. Dancz, Amin Tavakoli, and Morgan Elizabeth Fullerton

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850 Anatomy/Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level 1: The Cardinal and Uterosacral Ligament Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level 2: The Endopelvic Fascia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level 3: The Perineal Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

851 851 852 852

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensory Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

852 852 853 853 853

Complications of Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854 Nonsurgical Management of Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855 Pessary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855 Pelvic Floor Muscle Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859 Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860 Anterior Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860 Anterior Colporrhaphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860 Vaginal Paravaginal Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862 Site-Specific Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863

C. E. Dancz (*) University of Southern California, Los Angeles, CA, USA e-mail: [email protected] A. Tavakoli · M. E. Fullerton Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_70

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C. E. Dancz et al. Graft and Mesh Augmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863 Types of Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863 Transvaginal Mesh for Anterior/Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864 Concomitant Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864 Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865 Vaginal Approach for Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866 Mayo/McCall Culdoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866 Uterosacral Ligament Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867 Outcomes and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867 Sacrospinous Ligament Fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868 Outcomes and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868 Alternative Vaginal Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869 Abdominal Approach to Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sacral Colpopexy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obliterative Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique/Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Total Colpectomy/Colpocleisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Partial/LeFort Colpocleisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

870 870 871 871 872 872

Posterior Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872 Outcomes and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878

Abstract

Pelvic organ prolapse (POP) is defined as the descent of any of the following: the anterior vaginal wall, the posterior vaginal wall, the uterus (cervix), or the apex of the vagina (vaginal vault or cuff scar after hysterectomy). POP is extremely common and is one of the leading reasons for surgery in the United States. The main symptom of prolapse is the sensation of bulge or pressure in the vagina. Severe prolapse may interfere with successful urination, defecation, or sexual function. Prolapse diagnosis is usually based on physical exam with several formal staging systems. Asymptomatic or minimally symptomatic prolapse may not require any intervention. Patients with significant bother may elect to use a device called a pessary to hold their prolapsed organs in place, or they may elect

for surgery. There are a variety of surgical procedures for prolapse, depending on the patient’s health, preferences, degree, and location of prolapse. Keywords

Pelvic organ · Prolapse · Pessary · Surgery

Introduction Pelvic organ prolapse (POP) is defined as the descent of any of the following: the anterior vaginal wall, posterior vaginal wall, uterus (cervix), or apex of the vagina (vaginal vault or cuff after hysterectomy) (Haylen et al. 2010). POP is estimated to affect 3.3 million women in the United States alone, and the number of women affected is projected to increase by nearly 50% by 2050

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 1 Pelvic organ prolapse. (Photograph courtesy of Dr. Begüm Özel)

(Wu et al. 2009). Prolapse is one of the most common reasons for surgery in the United States and is projected to increase from 166,000 surgeries annually in 2010 to 245,970 in 2050 (Wu et al. 2011). The most common symptom of prolapse is the sensation or discomfort of vaginal or uterine tissue prolapsing from the vagina and between the legs (Fig. 1). Severe prolapse may be associated with sexual complaints and urinary symptoms such as voiding difficulty, bladder outlet obstruction, and detrusor overactivity (Romanzi et al. 1999). It is rare that prolapse will cause significant morbidity or mortality, but it is commonly associated with sexual, urinary, and defecatory symptoms that may interfere with activities of daily living and affect quality of life. Some women may need to digitally reduce their prolapse, known as splinting, in order to urinate or defecate. In extreme cases, obstructed urination may result in obstructive uropathy causing hydronephrosis and even progressing to renal failure (Sudhakar et al. 2001). Many patients with prolapse will elect for conservative management or go without treatment altogether (Culligan 2012). Conservative management strategies include pelvic floor muscle

training and pessaries. A variety of surgical options are available depending on the type and degree of prolapse in addition to patient preference and comorbidities. The necessity of hysterectomy at the time of prolapse repair is controversial, as is the need for mesh or graft to augment native tissue repairs.

Anatomy/Pathophysiology Pelvic organ prolapse is the result of disruption of one or more of the supports that normally hold the pelvic organs in place. There are three primary supports of the uterus and upper vagina: (1) the cardinal/uterosacral ligament complex, (2) the lateral/paravaginal attachments of the endopelvic fascia, and (3) the perineal membrane (DeLancey 1992).

Level 1: The Cardinal and Uterosacral Ligament Complex A note on terminology: Although the cardinal and uterosacral ligaments are commonly described as ligaments, true ligaments attach bone to bone,

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while the cardinal and uterosacral “ligaments” are more of a condensation of fibrous tissue, collagen, muscle, and nerves. The cardinal ligament stretches between the base of the uterus and the lateral wall of the pelvis, thereby preventing inferior movement of the uterus. The uterosacral ligament connects the lateral edge of the uterus to the anterior surface of the sacrum, which prevents the uterus from being displaced inferiorly and anteriorly (Drake et al. 2008). These ligaments may be disrupted through surgical or obstetric trauma. However, it is more common that these ligaments are intact, but stretched out by consistent downward traction of the uterus and vagina. Collagen vascular disorders may also be associated with lengthening and stretching of these ligaments resulting in pelvic organ prolapse.

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confluence of connective tissue that provides additional support to the vulva and lower vagina. Disruption of this layer may occur during childbirth or from chronic traction of the uterus and vagina due to defects in the upper two levels of support.

Risk Factors

A note on terminology: The “endopelvic fascia” is not a true fascial layer. It is instead a condensation of areolar and connective tissue that is referred to as “fascia.” The endopelvic fascia is essentially the tendinous insertion of the levator ani complex attaching on the arch of the pelvis. This tendinous arch (arcus tendineus fascia pelvis) runs from the bottom of the pubic symphysis to the ischial spine on either side. Injury to this fascial layer or disruption of these lateral attachments is commonly seen after childbirth, even in the absence of a perineal laceration. This is thought to be one of the primary causative factors for pelvic organ prolapse.

The cause of prolapse can be multifactorial. Genetics may be a factor as a family history of prolapse is associated with increased risk as is being Caucasian or Hispanic when compared to Asian and African Americans. The most common risk factors include vaginal childbirth, increasing age, and increasing body mass index. Vaginal childbirth is strongly associated with anatomic disruption of the pelvic organ supports, and pregnancy is associated with laxity or stretching of the pelvic floor ligaments. Increasing age is thought to be associated with changes in the collagen composition of the ligamentous supports resulting in increased risk of prolapse. Body mass index is likely a risk factor for prolapse due to chronic increases in abdominal pressure and straining. In fact, other causes of chronic increase in abdominal pressure such as constipation or chronic coughing have also been associated with prolapse (Koelbl et al. 2013). Although there have not been any proven effective strategies to reduce risk, it is reasonable to think that weight loss, reduction of heavy lifting, treatment of constipation, modification of obstetric risk factors, and pelvic floor physical therapy may be effective in preventing the development or progression of pelvic organ prolapse.

Level 3: The Perineal Body

Diagnosis

The perineal body is the third and most distal level of support. This layer is made up of the superficial perineal muscles that form the anterior urogenital triangle (bulbocavernosus, ischiocavernosus, and transverse perineal). Within the triangle is a

Patient History

Level 2: The Endopelvic Fascia

Since pelvic organ prolapse is rarely associated with significant morbidity or mortality, the most important principle in prolapse evaluation is

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

assessing the effect POP has on a patient’s quality of life. The most effective strategy in managing POP is to allow the patient to express what aspect of the prolapse bothers her most. This allows the practitioner to tailor treatment plans to the patients’ needs and wishes, rather than focusing on the anatomic outcomes that may or may not change the patient’s quality of life. The most specific complaint of women with POP is the sensation of bulge or pressure in the vagina. This sensation may be difficult to distinguish from the sensation of pressure in the lower abdomen. Low abdominal pressure is often nonspecific and in the absence of vaginal pressure is unlikely to be due to prolapse. Urinary, defecatory, and sexual symptoms are also common and should be evaluated in women with suspected POP.

Physical Exam Pelvic organ prolapse can almost always be evaluated with physical exam alone as ancillary radiologic testing is rarely indicated. A comprehensive physical exam is indicated when considering any surgical intervention for pelvic organ prolapse. A complete evaluation should include basic sensory testing, visual inspection of the external genitalia and cervix, bimanual and rectovaginal examination, and visual assessment of prolapse with Valsalva. Additional testing for incontinence may be indicated in patients with urinary or fecal incontinence, and some advocate for occult incontinence testing in women with prolapse who are considering surgical intervention.

Sensory Exam Sensation to the vulva and perineum is primarily provided by the pudendal nerve, a branch of the S2–S4 nerve root. Intact sensation to the inner thigh and perineum to light touch and pinprick confirms function of the pudendal nerve to the cerebral cortex. The anal wink reflex or clitoral reflex requires an intact levator ani and pudendal nerves, as well as connection to the cerebral

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cortex. The anal wink may be checked by gently stroking perianally with the soft edge of a cotton swab; a positive test will result in contraction of the external anal sphincter. The clitoral reflex may be checked by gently squeezing the clitoris and looking for contraction of the pelvic floor. Both of these tests are specific but not sensitive, meaning that a positive test confirms intact nerves, but the absence of the reflex is not diagnostic of neurologic disruption.

Pelvic Exam A careful speculum, bimanual, and rectovaginal exam is important to look for other etiologies of bulge in the vagina and to screen for cervical, vaginal, and vulvar abnormalities including cancers. The presence of prolapse does not increase the risk for any type of cancer, but prolapse may exist concomitantly with other gynecologic conditions, and these need to be ruled out. Careful evaluation of the degree of prolapse must be documented for all patients complaining of prolapse. The maximum amount of prolapse that can be elicited should be documented. This usually requires the patient to perform Valsalva or cough and may require the patient to stand in order to demonstrate the maximum descent of her prolapse. Often, it is appropriate to separate a speculum and use the lower half to thoroughly evaluate both upper and lower compartments. The posterior wall may be reduced in order to completely see and evaluate the anterior wall, and vice versa. There are a variety of staging systems that have been proposed for prolapse. The most common are the Baden-Walker grading system and the Pelvic Organ Prolapse Quantification (POP-Q) staging system (Bump et al. 1996), which have been developed and endorsed by the International Continence Society and the International Urogynecological Association (Haylen et al. 2010). The Baden-Walker grading system divides the vagina into three compartments: anterior, apical, and posterior. The anterior compartment consists

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of the upper vagina between the cervix and urethra and generally corresponds to the area just under the bladder and urethra. The apical compartment is the upper vagina and cervix, while the posterior compartment is the pelvic floor between the cervix and perineal body. The maximum descent of each compartment is evaluated separately. Prolapse in the upper half of the vagina is considered grade 1, in the lower half of the vagina is grade 2, coming out halfway is grade 3, and completely everted is considered grade 4 (Table 1). Such a grading system is easy to understand and remember so it is often used by primary care physicians, gynecologists, and urologists to document the degree of prolapse (Baden and Walker 1992). To further quantify prolapse and to describe and compare treatment outcomes, the POP-Q examination was developed. This technique is more complicated to learn, but it is more quantitative and uses clear anatomic landmarks. It uses nine points, all of which are measured in centimeters and relative to the hymen. Inside of the body are negative values, and outside of the body are measured as positive values. GH, PB, and TVL are measured at rest (Table 2). The remainder of Table 1 Baden-Walker grading system for pelvic organ prolapse Grade of prolapse Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Extent of prolapse in relationship to the hymen Normal position for each respective site Descent halfway to the hymen Descent to the hymen Descent halfway past the hymen Maximum possible descent for each site

the points should be measured with the maximum prolapse elicited. Prolapse may be elicited with patient using the Valsalva maneuver, with standing, or both (Table 2).

Complications of Prolapse Significant complications from untreated pelvic organ prolapse are rare. The most common complications include vaginal abrasions, bleeding, and urinary retention. In rare cases, the prolapse may become so edematous that it is difficult or impossible to reduce leading to an incarcerated prolapse. Vaginal abrasions or ulcerations with bleeding may be avoided with reduction of prolapse, either surgically or with pessary (Fig. 2). Vaginal abrasions related to atrophy may be treated with topical estrogen cream. Occasionally, the vaginal epithelium is so dry and irritated that additional treatment with Vaseline or vitamin A and D ointment is necessary. Symptoms of urinary retention may be treated with reduction of prolapse. A recent study showed that in women with stage 3–4 prolapse, the prevalence of hydronephrosis was up to 55% (Dancz et al. 2015; Hui et al. 2011). Therefore, in women who decline intervention, it may be indicated to screen for retention with post-void residual, creatinine level, and renal ultrasound. Prolapse that is related to trauma, usually from a fall or other inadvertent harsh manipulation of the prolapse, may become edematous and irreducible. These usually can be reduced with adequate pain control and gentle, consistent pressure. The

Table 2 POP-Q staging system for pelvic organ prolapse Aa – anterior wall 3 cm proximal to the urethral meatus (range,
3 to +3) gh – genital hiatus Mid-urethral meatus to the posterior fourchette Ap – posterior wall 3 cm proximal to the hymenal remnant (range,
3 to +3)

Ba – anterior wall Most distal part of the anterior wall pb – perineal body Posterior fourchette to the mid-anus Bp – posterior wall Most distal part of the posterior wall

C – cervix or cuff Most distal descent of the cervix/vaginal cuff tvl – total vaginal length Greatest depth of the vagina when prolapse is reduced D – posterior fornix (omitted if there is no cervix)

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 2 Pelvic organ prolapse with ulcerations. (Photograph courtesy of Dr. Begüm Özel)

fundus must be gently aimed directly into the body to return the uterus to the pelvis.

Nonsurgical Management of Prolapse Pessary Pessaries are devices of various shapes and sizes that are placed in the vagina to reduce pelvic organ prolapse and restore normal anatomy. Pessary use can be temporary or long term. It often provides immediate relief from pelvic organ prolapse symptoms, but it does require some maintenance. Long-term pessary use may be an alternative to surgery in women with multiple comorbidities or in women who prefer to avoid surgical risks (Culligan 2012). Pessary use has been shown to be as effective as surgery in improving patients’ symptoms of prolapse including bowel complaints, bladder complaints, sexual function, and overall quality of life (Abdool et al. 2011).

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Pessary Fitting The success of a pessary relies heavily on proper fitting. Pessaries can be successfully fitted 60–90% of the time (Clemons et al. 2004; Lone et al. 2011). When a pessary is successful at the 4 week point, most women continue to use a pessary for 5 years (Lone et al. 2011). When choosing a pessary, the provider needs to consider the stage of pelvic organ prolapse, the size of vaginal vault, and the ability of the patient to manage their own pessary. The goal is to find the smallest pessary that effectively treats their prolapse symptoms. Initial fitting may require a trial of several different pessary types and/or sizes to adequately and comfortably reduce a patient’s prolapse (Culligan 2012). Ring with support pessaries (Fig. 3) is widely available and is the most used type of pessary (Cundiff et al. 2000). The initial choice of pessary size should be based on the examiner’s bimanual exam and appreciation of the width of the vaginal canal (Culligan 2012). Once the exam is performed, the provider should identify the appropriate size and shape for the pessary. The pessary should be placed by the provider and tested by the patient. Initial tests for correct sizing can be performed by having the patient cough or stand with the pessary in place. If it stays in place, then the patient should attempt a Valsalva maneuver while sitting. If the pessary continues to remain in place with these measures and is comfortable, it is likely the correct size. The patient should also be able to ambulate and urinate with the pessary in place. Well-fit pessaries should not be felt by the patient. Once a pessary is successfully fitted, the patient should return for close follow-up. Typically the patient is given a return appointment in 1–2 weeks to make sure the pessary continues to comfortably reduce the patient’s prolapse and allow for normal daily functions (Trowbridge and Fenner 2007). If the patient is uncomfortable or has lost the pessary with activity, the provider should change the pessary size or type accordingly. The follow-up visit also provides a good opportunity to educate a motivated patient on how to remove and clean her pessary so that she can manage her pessary at home. Once a patient is

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Fig. 3 Ring with support pessary

comfortable and has learned to manage her pessary, she can then be followed every 3–6 months. She should be instructed to remove and clean the pessary with soap and water approximately once a week. If the patient cannot change her own pessary, then she should be seen every 2–3 months for outpatient pessary maintenance by her provider (Culligan 2012; Trowbridge and Fenner 2007).

Types of Pessaries There are two general categories of pessaries – support and space filling. Support pessaries typically sit between the pubic symphysis and posterior fornix. They reduce prolapse by elevating the superior vagina and often have perforations that allow the escape of vaginal secretions. Examples of support pessaries are the ring, ring with support, Gehrung, and Hodge. Space-filling pessaries work by elevating the prolapse and maintaining the normal anatomic position by creating a barrier within the vagina that is larger than the genital hiatus. The cube pessary (Fig. 4) may be used for refractory cases, as it stays in place by creating suction to the vaginal walls. A commonly used option is the Gellhorn pessary (Fig. 5), which acts both as suction and barrier (Cundiff et al. 2000). A randomized crossover trial showed no difference in patient satisfaction or symptom relief from the ring versus Gellhorn pessary (Cundiff et al. 2007).

The ring with support pessary is relatively easy to place/remove and is well tolerated by patients (Cundiff et al. 2000). If the ring with support does not work, the next choice is typically the Gellhorn. If neither of these work, chances of successful prolapse management with pessary are unlikely (Culligan 2012). A variety of other pessaries may be used, each with slightly different features. Overall, these pessaries are typically more difficult for patients to manage (Culligan 2012; Trowbridge and Fenner 2007). The Inflatoball (Fig. 6) is an option for women with stage 3 or 4 pelvic organ prolapse who desire the ability to manage their pessary at home. The advantage of this pessary is that it is more easily placed and removed by the patient compared to a Gellhorn or donut pessary because it can be inflated after insertion and deflated prior to removal. The disadvantage is the stem protrudes from the vagina and may cause discomfort for the patient (Trowbridge and Fenner 2007). Pessaries are generally made of surgical-grade silicone; therefore, patients with latex allergies may use them without concern. Over time, the silicone may develop some discoloration. The structural integrity of the pessary is not affected, and discolored pessaries may be used indefinitely. The Inflatoball pessary (Fig. 6) is the only pessary that is made of rubber. The rubber material in the Inflatoball pessary may absorb a slight odor, and the rubber may dry out over time. Inflatoball

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Fig. 4 Cube pessary

Fig. 5 Gellhorn pessary

pessaries should be checked and replaced periodically.

Complications Reported complication rates from pessaries vary, but in a large study of over a 1000 women, 88.5% had no complications (Hanson et al. 2006). The

most reported complications are vaginal discharge, vaginal ulcerations, and abrasions. It is normal for women to have increased vaginal discharge with a pessary in place, but there is concern for infection if they report itching, foul odor, or burning sensation. With a pessary in place, the vaginal flora is altered and women are more

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Fig. 6 Inflatoball pessary

predisposed to bacterial vaginosis (Alnaif and Drutz 2000). A vaginal wet prep will distinguish between bacterial vaginosis and physiologic discharge and should be used prior to administration of antibiotics. If the patient is bothered by the physiologic vaginal discharge, it may be alleviated by more frequent removal and cleaning of the pessary. Vulvovaginal hygiene cleaning and drying techniques may also be beneficial. Vaginal ulcerations or abrasions due to local pressure effects are also common and typically occur if the pessary is left in place over time. Symptoms of vaginal ulcerations or abrasions include discharge, odor, and bleeding. To avoid complication patients can be instructed to remove the pessary for a few hours at a time or overnight if they are able to. In addition, a speculum exam should be performed to evaluate for the presence of any ulcerations or abrasions at each follow-up visit. The patient should also be instructed to make an appointment if she notices any vaginal bleeding. Vaginal abrasions and ulcerations may be treated with removal of the pessary for a few weeks in addition to vaginal estrogen cream on a daily basis for a short-term course (Clemons et al. 2004; Trowbridge and Fenner 2007). The patient should be followed regularly until the ulceration has resolved. Once the ulceration has resolved, the pessary may be replaced with continued use of vaginal estrogen cream two to three times per

week (Trowbridge and Fenner 2007). Vulvovaginal hygiene cleaning and drying techniques may also be beneficial. Another potential side effect of pessary is urinary incontinence. Typically, it is the reduction of prolapse and return of normal anatomic positioning of the urethra that may unmask occult incontinence or worsen existing incontinence. In cases with incontinence, a specific incontinence pessary (incontinence ring, incontinence dish, or incontinence dish with support) may be used. The incontinence pessaries have an additional knob to provide support at the urethrovesical junction (Trowbridge and Fenner 2007). Severe complications with pessary are rare. Pessary impaction can occur if a pessary is in place for a prolonged period without removal. There have been case reports of severe complications from pessaries, including impaction of or erosion into the urethra, rectum, or cervix (Figs. 7 and 8). Potential for compression of the urethra should be evaluated at pessary placement. Anyone who cannot urinate should have the pessary removed and replaced by a smaller one. Obstructed voiding may lead to urinary retention, infection, and urosepsis (Wheeler et al. 2004). Rectal compression can lead to obstructed defecation or bowel obstruction (Roberge et al. 2001). Some pessaries are designed with a central space, through which the cervix may prolapse and

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 7 Computed tomography (CT) of intravesical pessary demonstrating a Gellhorn pessary (a) located in the bladder (b). (Originally published in Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J 2012; 23: 1311–1313; with kind permission of © Springer Science+Business Media. All Rights Reserved)

Fig. 8 Intraoperative image of pessary (a) within the bladder (b). (Originally published in Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J 2012; 23: 1311–1313; with kind permission of © Springer Science+Business Media. All Rights Reserved)

become incarcerated (Thubert and Deffieux 2014). There are also case reports of pessaries left in situ for years that then erode into the bladder or rectum (Arias et al. 2008; Rogo-Gupta et al. 2012). These severe complications may be avoided with regular pessary removal and replacement. Patients can also be advised to inform a family member or close friend about their use of a pessary; this way in case of an accident or incapacitation, someone will be aware that they have a pessary that needs to be removed at least every 3 months.

Pelvic Floor Muscle Training Pelvic floor muscle training has been suggested as management for mild to moderate prolapse. It consists of sessions with a trained therapist to assess muscle strength and to learn exercises for muscle strengthening in addition to regimented exercise programs for patients to complete at home on their own. The goal of pelvic floor muscle training is to increase muscle volume and thereby diminish the size of the levator hiatus

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and provide improved structural support for the pelvic organs (Bø 2006). A prospective randomized trial demonstrated that with regimented pelvic floor muscle training over the course of 6 months, women with up to stage 3 pelvic organ prolapse were able to symptomatically and objectively improve their pelvic organ prolapse (Braekken et al. 2010). This study also demonstrated increased muscle thickness, elevated location of the bladder and rectum, and decreased hiatal size with the regimented exercises. Similar improvement in symptoms and reduction of prolapse have been reported in women with stage 2 prolapse training in as little as 14 weeks. Of note, the majority showed no change or reduction of stage 1 prolapse (Hagen et al. 2009; Stüpp et al. 2011). Limitations of this therapy include patient motivation and access to trained therapists.

Surgical Management A variety of surgical treatments are available for pelvic organ prolapse. The choice of surgery depends on many factors including compartment of prolapse, severity of prolapse, patient health and overall treatment goals, prior surgeries, and surgeon preference. Graft or mesh augmentation may be considered in select cases. The surgical techniques used for pelvic organ prolapse can broadly be categorized by compartment: anterior, apical, and posterior.

Anterior Prolapse The anterior compartment is the most common site of pelvic organ prolapse and the most difficult to repair. Anatomic and symptomatic outcomes after surgical repair are generally good, but when prolapse recurs, it is most commonly in the anterior compartment.

Anterior Colporrhaphy The mainstay of surgical management of anterior prolapse is the anterior colporrhaphy (Fig. 9). During this procedure, a transverse incision is

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made at the apex of the anterior vagina (if concurrent hysterectomy has been performed, then the anterior colpotomy site may be used). The anterior vagina is then put on traction using Allis clamps to essentially evert the anterior wall (or ceiling of the vagina). Using Metzenbaum scissors, the anterior vaginal epithelium is undermined to separate it from the underlying muscularis. This epithelium is then incised in a linear fashion from the apex of the vagina to approximately 3–4 cm below the urethral meatus. Allis clamps or Pratt-Smith clamps may be placed on the cut edge of the epithelium and the epithelium dissected off the underlying muscularis. This dissection is extended laterally to the pelvic sidewall. The underlying muscularis is then plicated with a series of U stitches of 0 polyglactin suture. These stitches should be placed along the junction of where the epithelium has been dissected off the muscularis, taking care that the tissue plicated is the muscularis and not the vaginal epithelium. While these sutures are tied down, the underlying prolapsed tissue is reduced. The result is a midline reduction of the anterior prolapse. The excess vaginal epithelium is then trimmed, and the epithelium is plicated in the midline using 2–0 polyglactin suture. Studies on the success of prolapse repair are difficult to compare, as different outcomes are often reported. Symptomatic success does not necessarily require anatomic success, and often both are reported as separate measures. In general, the reported success rates of anterior colporrhaphy range from 80% to 100% in retrospective series, though in prospective studies, the rates are much lower (30–55%) (Menefee et al. 2011; Nguyen and Burchette 2008; Weber et al. 2001). Multiple procedures have been developed to try to improve anatomic and symptomatic outcomes of anterior colporrhaphy. Variations on the anterior colporrhaphy include the paravaginal (or ultralateral) repair, site-specific repair, anterior colporrhaphy with mesh augmentation, and anterior colporrhaphy with graft augmentation. Several studies have compared reoperation rates, as well as anatomic and symptomatic outcomes between these procedures. In general, anatomic outcomes are slightly better using mesh or graft

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Fig. 9 Traditional anterior colporrhaphy. (a) Initial midline anterior vaginal wall incision. (b) Midline incision is extended. (c) Sharp dissection of the bladder off the vaginal wall. (d) The bladder has been mobilized off the vagina. (e) Initial plication layer is placed. (f) Second plication layer is placed. (g) Trimming of excess vaginal

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epithelium. (h) Closure of vaginal epithelium. (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

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augmentation, but the symptomatic outcomes and reoperation rates are the same between procedures (Maher et al. 2013).

Vaginal Paravaginal Repair Some surgeons advocate an ultralateral approach to anterior colporrhaphy, referred to as a vaginal paravaginal repair (Fig. 10). The paravaginal

Fig. 10 Vaginal paravaginal repair. (a) Numerous sutures are passed through the arcus tendineus fascia pelvis (white line). (b) Each suture is passed through the edge of the detached fascia. (c) Each suture is passed through the vaginal wall excluding the epithelium. (Reprinted from

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repair is based on the theory that prolapse may be caused by a detachment of the underlying muscularis from its lateral attachments to the arcus tendineus fascia pelvis (ATFP). This technique involves opening the anterior vaginal wall, similar to the dissection used in a traditional anterior colporrhaphy as described above. The vaginal epithelium is dissected off the underlying muscularis farther laterally than for a traditional anterior colporrhaphy, and the paravaginal space

Surgical Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

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is developed between the obturator internus muscle and the vaginal muscularis layer. This space is extended along the ischiopubic rami using palpation in order to identify the ischial spines and the ATFP. The ATFP runs between the pubic symphysis and the ischial spine on either side. The ATFP is palpated and then visualized using BreiskyNavratil retractors. Upon clear identification of the ATFP, three to six sutures of 0 polyglactin suture are placed through the ATFP. These sutures may be held if a concomitant anterior colporrhaphy or apical suspension is being performed. The sutures through the ATFP are then brought through the muscularis tissue close to the midline, so that the muscularis is brought up and laterally toward the ATFP. The stitch is then carried to the underside of the vaginal epithelium. This technique obliterates the paravaginal space and essentially brings the epithelium, the muscularis, and the ATFP into close approximation. The excess vaginal epithelium is trimmed, and the vaginal epithelium is reapproximated in the midline. This technique has a high success rate (67–100%), which is tempered by complications including bilateral ureteric obstruction, retropubic hematomas, abscesses, and transfusion (Maher et al. 2013). This procedure may be performed abdominally or laparoscopically, but requires a high degree of surgical skill, and efficacy data is limited.

Site-Specific Repair An additional variation of the anterior colporrhaphy is a site-specific repair. The concept behind this repair is that although some cases of anterior prolapse are due to complete separation of the muscularis from its lateral attachments, other cases of anterior prolapse are due to specific defects in the muscularis. When these defects are sought out and identified during anterior colporrhaphy, they should be repaired individually. A midline plication may be performed at the same time as a site-specific repair.

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Graft and Mesh Augmentation Due to the relatively high failure rates of prolapse repairs, there has been significant interest in augmenting repairs with synthetic or biologic materials. Although mesh and graft augmentation has been used with wide success in the hernia repair literature, vaginal augmentation has been more controversial. Generally, mesh or graft augmentation may be considered for patients who fail a native tissue repair. The technique for the placement of synthetic mesh or biologic graft is essentially the same. Several companies have developed prefabricated meshes to fit the various vaginal compartments. These mesh kits vary in size and shape of the mesh, as well as the introducer to fix the mesh to the vaginal tissues. Many of the kits use a trocar introducer to fix the apical portion of the mesh to the sacrospinous ligament, and the lateral or distal portion of the mesh may be sutured to the ATFP (as described above for a paravaginal repair) or may be trocar guided through the obturator space. When a kit is not used, the mesh or graft may be cut to fit the patient’s anterior vaginal wall. The vaginal wall is incised in the midline, taking care to dissect full thickness through the vaginal muscularis down to the bladder. This contrasts with the anterior colporrhaphy, where the vaginal epithelium is split from the underlying muscularis. After dissection of the epithelium and muscularis off the bladder, the graft/mesh is placed loosely under the tissue and sutured to the ATFP laterally. The overlying vagina is not trimmed and is then reapproximated in the midline.

Types of Grafts Biologic Grafts Biologic grafts may be used as an alternative to synthetic mesh grafts. Biologic graft options include:

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• Autograft – graft material is harvested from the patient herself. Generally it is taken from the rectus sheath or fascia lata. The use of autologous fascia has the advantage of lower risk of infection and host rejection. The size of the graft is generally 6–8 cm long and 4 cm wide. The harvest of an autologous fascial graft of this size may be associated with significant morbidity and is rarely used. It may be considered in patients with contraindications to mesh (Cormio et al. 2015). • Allograft – fascial material is harvested from donor or cadaveric tissue. Several small studies have demonstrated success rates ranging from 81% to 100%, with acceptable complication rates, though the only randomized controlled trial failed to show an improvement over traditional anterior colporrhaphy. Concerns regarding prior transmission and residual antigenicity resulting in host-graft reactions have limited the acceptance of allograft materials for prolapse repair. • Xenograft – Porcine dermis, porcine small intestine submucosa, bovine pericardium, or bovine dermis. Xenografts have been used in the anterior compartment with mixed results. One study retrospectively compared anterior colporrhaphy, porcine dermis, and polypropylene graft, with the porcine dermis significantly less effective than the other two treatments, with a 21% rate of vaginal extrusion of the porcine dermis. Other groups have found much better success rates, with graft extrusion rates of 1–17% (Maher et al. 2013). A Cochrane meta-analysis found that when graft was used to augment the anterior compartment, the objective failure rate was higher than when no graft was used (Maher et al. 2013). Overall, some advocate biologic grafts as an alternative to synthetic mesh, although no subjective benefit has been reported by patients, and the complication rates are similar to synthetic meshes. Biologic grafts should be considered in patients who refuse synthetic meshes or those with contraindications to synthetic mesh. Synthetic mesh is contraindicated in patients who have had a prior

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mesh complication and those who desire future fertility (as the synthetic meshes do not stretch). Biologic grafts may be preferred to synthetic meshes in patients with impaired wound healing such as those with prior pelvic irradiation. Both meshes and grafts should be used with caution in patients with chronic pelvic pain, endometriosis, painful bladder syndrome, vulvodynia, and other vulvar pain disorders.

Transvaginal Mesh for Anterior/Apical Prolapse Starting in 2004, a variety of prepackaged kits were introduced to augment prolapse repair in the vagina (Figs. 11 and 12). These kits use a variety of techniques to augment the anterior, apical, and posterior compartments. There is reasonable evidence to support that anatomic outcomes in the anterior and apical compartments are improved relative to native tissue repairs (Maher et al. 2013). However, there is no difference in patient subjective improvement, quality of life measures, or reoperation rates for prolapse. The improvement in anatomic outcomes comes at the cost of increased complications related to the mesh, with mesh erosion rates reported up to 25% (Maher et al. 2013). The consequences of mesh complications can be significant and often result in reoperation. These findings prompted the FDA to release an alert about transvaginal mesh placement in 2011. The alert essentially states that mesh may improve outcomes, but the complications in most cases outweigh the benefits. In 2016, transvaginal meshes were removed from the market, and there are currently no commercial mesh kits available for use. Self-styled mesh augmentation may be considered in select cases where other forms of prolapse repair have failed or are contraindicated.

Concomitant Hysterectomy The role of concomitant hysterectomy for anterior prolapse is controversial. The uterus, if

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 11 Mesh augmentation of anterior wall prolapse repair. (a) Anterior prolapse is visualized. (b) Midline plication is completed. (c–d) Self-styled mesh is sutured in place. (Reprinted from Surgical Management of Pelvic

Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

normal and not significantly prolapsed, may be left in situ during anterior colporrhaphy. However, anterior prolapse rarely occurs in isolation and is most often associated with apical (uterine) prolapse. Support of the apex is important to creating a durable and effective repair of the anterior wall (Hsu et al. 2008; Rooney et al. 2006). Many of the apical suspension techniques described below can be adapted to leave the uterus in situ. The decision to remove the uterus must be approached by the physician in consultation with the patient and take into account the

patient’s comorbidities, degree of prolapse, and preferences, as well as the surgeon’s experience with the surgical procedures.

Apical Prolapse Apical prolapse includes descent of the uterus and the vault after prior hysterectomy. Apical prolapse repairs generally have good results, and there are a variety of approaches to apical prolapse. Apical repairs can broadly be categorized into vaginal,

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Fig. 12 Transvaginal mesh kit for anterior/apical prolapse. The elevate incisionless mesh (American Medical Systems) is bilaterally anchored to the sacrospinous ligament and obturator internus muscle near the distal end of the arcus tendineus fascia pelvis. (Reprinted from Surgical

Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137 (Maher and Karram 2013); with kind permission from Elsevier)

abdominal, and obliterative approaches. Abdominal repairs may be performed via laparotomy, laparoscopy, or robotically.

examined for hemostasis. The vaginal cuff is transfixed to the cut edges of the uterosacral ligaments in order to suspend the cuff within the vagina. One to three sutures are placed through the uterosacral ligament as high as possible. Sequential bites are taken superficially across the peritoneum overlying the rectum until the opposite uterosacral ligament is sutured. When tied down, the uterosacral ligaments are plicated in the midline, and the posterior cul-de-sac is obliterated. Variations on this procedure are commonly performed, but outcome data is limited. The few retrospective studies available show success rates of up to 85%, with reoperation rates ranging from 0% to 14% (Barber and Maher 2013).

Vaginal Approach for Apical Prolapse Mayo/McCall Culdoplasty One of the most common procedures for apical suspension, the Mayo/McCall culdoplasty, is often performed at the time of vaginal hysterectomy for non-prolapse indications. There are a number of variations, but there are several key steps to the Mayo/McCall culdoplasty (Fig. 13). After removal of the uterus, the vaginal cuff is

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Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 13 Modified McCall culdoplasty. (a) The cul-de-sac is palpated and excessive peritoneum and posterior vaginal wall are noted. (b) A wedge of tissue (dotted line) is excised to decrease the caliber of the upper portion of the posterior vaginal wall. (c) External McCall stitches are placed in the traditional fashion. (d) Tying these sutures

Uterosacral Ligament Suspension Technique Much of the support of the uterus comes from the cardinal/uterosacral ligament complex (Level 1 support). Uterosacral ligament suspension uses the patient’s own ligaments to suspend the vaginal cuff above the level where the uterus has been amputated (Fig. 14). After the uterus is removed, the cuff is examined for hemostasis (if hysterectomy is not performed, the vaginal apex is grasped and incised). The ischial spines are identified and palpated intraperitoneally. The cut edge of the uterosacral ligament is grasped with Allis clamps on either side (at approximately 5:00 and 7:00 on the clockface). Traction allows for palpation of the uterosacral ligaments. Several sutures of permanent or delayed absorbable suture are placed through the uterosacral ligament at the level of the ischial spine. This procedure is repeated on the opposite side. The distal edge of the uterosacral ligaments is then plicated in the midline to obliterate the cul-de-sac. The highest delayed absorbable suture is placed full thickness through the posterior vaginal wall. If necessary, an anterior colporrhaphy may be performed. The vagina is trimmed and

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obliterates the cul-de-sac, supports the vaginal cuff, and increases posterior vaginal wall length. (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Karram MM, Ridgeway BM, Walters MD. Surgical treatment of vaginal apex prolapse, p360–382. (Karram et al. 2015); with kind permission from Elsevier)

closed with 0 or 2–0 absorbable suture. After closure of the vagina, the uterosacral sutures are tied down on either side with suspension of the vault. Abdominal and laparoscopic approaches to this procedure have also been described.

Outcomes and Complications Outcomes after uterosacral ligament suspension are generally good, with anatomic success ranging from 81% to 98%, and symptomatic improvement in 82–100% of patients (Margulies et al. 2010). In a recent large, prospective, randomized, controlled trial, the composite outcome of anatomic success and subjective success and lack of reoperation were reported to be 59.2% (Barber et al. 2014). The most commonly identified complication is ureteral injury or kinking, which should be looked for and identified intraoperatively. Ureteral kinking can be managed by removal of the offending suture and usually requires no further intervention. The incidence of ureteral injury or kinking ranges from 1% to 11% (Margulies et al. 2010) with most studies reporting a low incidence. However, intraoperative cystoscopy is highly recommended to ensure ureteral patency.

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Fig. 14 Uterosacral ligament suspension. The vaginal cuff is fixed to the cut uterosacral ligaments on either side at the level of the ischial spines. (Originally published in Cvach K, Dwyer P. Surgical management of pelvic organ prolapse: abdominal and vaginal approaches. World J Urol 2011;30(4): 471–7; with kind permission of Springer Science+Business Media. All Rights Reserved)

Sacrospinous Ligament Fixation Technique The sacrospinous ligaments extend from the ischial spines to the lower portion of the sacrum and coccyx and should be palpated prior to initiation of the procedure. The vagina is typically fixed unilaterally to the sacrospinous ligament, though bilateral fixations have been described. The posterior vaginal wall is incised in the midline and the vaginal epithelium dissected off the rectovaginal fascia. If an enterocele is encountered, it should be dissected off the posterior vaginal wall and closed with a high purse-string suture. The dissection of the epithelium off the rectovaginal fascia is extended laterally to identify the arcus tendineus fascia pelvis. The perirectal space is identified in this area by using blunt or sharp dissection and by mobilizing the rectum medially. The ischial spine is identified, and the sacrospinous ligament is palpated dorsal and medial to the ischial spine. Once the ligament is identified, a rectal exam should be performed to confirm that no inadvertent injury has occurred. A suture is then passed through the sacrospinous ligament. The position of the ligament makes this suture passage difficult, and a variety of instruments have been designed to facilitate passage of the suture through the sacrospinous

ligament. Commonly used techniques include the long-handled Deschamps ligature carrier, the Miya Hook, or proprietary instruments such as the Capio Suture device (Boston Scientific) (Figs. 15 and 16) or the Nichols-Veronikis ligature carrier (Cooper).

Outcomes and Complications Overall, outcomes for sacrospinous ligament fixation are similar to uterosacral ligament suspension. A large randomized trial compared the two and found no significant difference in composite outcome of 60.5% at 2 years (composite outcome combines: anatomic success and subjective success and no reoperation) (Barber et al. 2014). The most commonly reported complication of sacrospinous ligament fixation is buttock pain, which is seen in 12.4% of cases (Barber et al. 2014). Such pain is usually self-limiting and should resolve completely by 6 weeks postoperatively. Additional rare but serious intraoperative complications have been reported, including hemorrhage (0.2%) and rectal injury (0.4%) (Sze and Karram 1997). Hemorrhage may result from laceration of the inferior gluteal vessels, the hypogastric venous plexus, or the internal pudendal vessels. If a rectal injury occurs, it can usually be repaired transvaginally.

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Fig. 15 Suture device for sacrospinous ligament fixation. The sacrospinous ligament is palpated at the level of the ischial spine. The suture device is placed medial to the operator finger, and the suture is passed through the ligament. (Image reproduced with kind permission from Boston Scientific)

Fig. 16 Sacrospinous ligament fixation. The apex of the vagina is fixed unilaterally to the sacrospinous ligament. (Image reproduced with kind permission from Boston Scientific)

Alternative Vaginal Approaches Several procedures have been described for the suspension of the vaginal vault, with or without hysterectomy. The most notable of which are the

levator myorrhaphy and the iliococcygeus fascial suspension. The technique for the levator myorrhaphy involves a wide plication of the levator muscles and fixation of the vaginal cuff to the plicated

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muscles (Francis and Jeffcoate 1961). Packing is placed in the rectum to avoid narrowing of the rectum. Comparative studies to uterosacral ligament suspension have shown no difference in anatomic success or subjective outcomes; however, the total vaginal length was shorter after levator myorrhaphy (7.9 vs. 8.9 cm, p ¼ 0.04) (Natale et al. 2010). Iliococcygeus fascial suspension is also known as the Inmon technique (Inmon 1963). It is used to suspend the vaginal apex to the iliococcygeus fascia just below the ischial spine. The initial studies describing the procedure reported a case series of 152 patients. In that initial series, four intraoperative complications occurred (one rectal and one bladder laceration and two cases of hemorrhage requiring transfusion) (Shull et al. 1993; Meeks et al. 1994). Retrospective reviews have shown that iliococcygeus fascial suspension is similar in outcomes to abdominal procedures and sacrospinous ligament fixation (Barber and Maher 2013). However, there are no randomized trials that evaluate this technique.

Fig. 17 Abdominal sacral colpopexy. The vaginal cuff is fixed to the anterior longitudinal ligament over the sacral promontory, using a piece of mesh or graft. (Originally published in Cvach K, Dwyer P. Surgical management of

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Abdominal Approach to Apical Prolapse Sacral Colpopexy Sacral colpopexy has been shown to be effective and durable for the correction of apical prolapse. Traditionally, sacral colpopexy is performed via laparotomy; however, laparoscopic and robotic approaches are also commonly used. Regardless of approach, the basic steps of the procedure stay the same (Fig. 17). The peritoneal cavity is entered, and if indicated, hysterectomy is performed and the cuff is closed. The vagina is elevated using a sponge stick, probe, or end-toend anastomosis sizer. The bladder is dissected off of the anterior vagina. Attention is then turned to the posterior vagina, and the peritoneum over the posterior wall is incised and dissected off of the vaginal tissue for several centimeters on either side. The mesh is trimmed to fit the anterior and posterior vaginal walls and transfixed using three to six stitches of nonabsorbable suture. Sutures are placed full thickness through the fibromuscular

pelvic organ prolapse: abdominal and vaginal approaches. World J Urol 2011;30(4):471–7; with kind permission of Springer Science+Business Media. All Rights Reserved)

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layer of the vagina, but not through the vaginal epithelium. The mesh is placed such that it reaches approximately two-thirds of the way down the anterior vagina, and a separate piece is placed at least halfway down the posterior vaginal wall. The two meshes are then sutured together above the cuff. The cul-de-sac is then obliterated using a Halban or Moschcowitz procedure. Attention is then turned to the sacral promontory. The sigmoid colon, right ureter, aortic bifurcation, and common iliac vessels should be identified. The peritoneum over the sacral promontory is incised longitudinally and the underlying fatty tissue dissected off of the promontory. The middle sacral artery and vein should be identified at this step. The mesh is then transfixed to the anterior longitudinal ligament using two to three stitches of nonabsorbable suture. The mesh should be tensioned to avoid undue traction on the vagina. The peritoneum is then closed over the mesh. Additional procedures at the time of sacral colpopexy may be indicated. A large randomized controlled trial showed that the addition of Burch urethropexy at the time of open sacral colpopexy reduced the rate of postoperative stress incontinence at 2 years from 57% to 37% in women who did not have stress incontinence preoperatively (Brubaker et al. 2008). As apical prolapse rarely occurs in isolation, repair of posterior prolapse may also be indicated at the time of colpopexy.

Outcomes and Complications The success rate of abdominal sacral colpopexy for apical suspension ranges from 78% to 100% (Barber and Maher 2013). Over time, anatomic and subjective success rates tend to decrease, as prolapse tends to recur between 2 and 7 years (Nygaard et al. 2013). Severe intraoperative complications specific to colpopexy are rare and include hemorrhage from the sacral vascular plexus; complications from laparotomy may include enterotomy, ureteral damage, cystotomy, and wound infections. The most common long-term complications after sacral colpopexy include recurrent prolapse, de novo stress incontinence, and mesh exposure.

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The median reoperation rates are 4.4% for recurrent prolapse, 4.9% for postoperative stress incontinence, and 3.4–5.1% for mesh exposure (Nygaard et al. 2004, 2013).

Abdominal Uterosacral Ligament Suspension The abdominal approach to the uterosacral ligament suspension involves the same principles as the vaginal approach as described previously. The remnants of the uterosacral ligament are identified and tagged at the level of the ischial spines. The ureters are identified, and the uterosacral ligaments are fixed to the vaginal cuff using permanent or delayed absorbable sutures.

Obliterative Procedures All the above procedures focus on reconstructing the vagina. An alternative approach is to obliterate the vagina. This approach may be considered in women who are no longer sexually active and do not have plans to have vaginal intercourse in the future. Obliterative procedures may be performed for post-hysterectomy vault prolapse or for uterovaginal prolapse (colpectomy/colpocleisis). The uterus may be left in situ (LeFort colpocleisis) or removed. Even with removal of the uterus, these procedures offer a relatively quick operative time, low risk of morbidity, and high rate of success.

Technique/Considerations As these procedures are generally performed on older women with multiple comorbidities, the focus of the preoperative evaluation should be on optimization of their functional status and control of their comorbidities. These patients should be carefully counseled on the procedure and the permanent loss of access to the vagina for sexual function. When the uterus is to be left in situ, these patients should be carefully screened for risk factors for endometrial and cervical pathology. They should be screened for postmenopausal vaginal

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bleeding and consider a pelvic ultrasound to evaluate the endometrium. Cervical cytologic screening should be up to date and negative.

Total Colpectomy/Colpocleisis Total colpocleisis refers to the removal of the vaginal epithelium (Fig. 18) within the hymenal ring posteriorly to within 0.5–2 cm of the external urethral meatus anteriorly (FitzGerald et al. 2006). Generally, the vaginal tissue is grasped and everted. The vaginal epithelium is excised in strips from the underlying vaginal muscularis. The muscularis is then inverted using a series of purse-string stitches. Once the prolapse is reduced, an aggressive perineorrhaphy and/or levator plication is performed. The anterior and posterior epithelia are sutured together with closure of the vagina.

Partial/LeFort Colpocleisis A partial colpocleisis refers to when portions of the vaginal epithelium are left in place (Fig. 19). The LeFort modification is when the uterus is left in situ, and the epithelium is reconstructed in a manner to leave channels, through which vaginal discharge or blood can escape. The procedure is started by grasping the cervix and applying gentle traction. Rectangle sections are marked on the anterior and posterior vaginal walls; these are the areas to be denuded. The uterus is then reduced, and the cut edges of the remaining epithelium above and below the cervix are sewn together using interrupted sutures, such that the epithelium is inverted and it creates a tunnel in front of the cervix. A urinary catheter may be placed in this tunnel to ensure it is adequate and patent. The plication sutures are then continued laterally on either side to create lateral channels. As these sutures are placed, the prolapse is gradually reduced until it is entirely within the body. The final sutures may be placed at the level of the hymenal ring. The anterior and posterior epithelia are then reapproximated, using care to leave the

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lateral channels open. As above, an aggressive perineorrhaphy and levator plication are often performed to augment this repair (Evans et al. 2015). Multiple studies have shown low rates of prolapse recurrence, high rates of patient satisfaction, and low rates of regret in appropriately counseled patients. Major complications of these procedures tend to be related to the performance of procedures on the elderly (cardiac, pulmonary, and cerebrovascular complications) and occur at a rate of approximately 2% (FitzGerald et al. 2006). Specific complications of the procedure include hemorrhage and pyelonephritis and appear at a rate of about 4%.

Posterior Prolapse Women with symptomatic pelvic organ prolapse often have defects of the posterior vaginal wall. One study found that in women undergoing surgery for prolapse, 40% had posterior vaginal wall defects (Olsen et al. 1997). The posterior vaginal wall must usually be addressed separately from an anterior or apical suspension.

Technique The traditional repair for posterior vaginal wall defects is the posterior colporrhaphy (Fig. 20). Two Allis clamps are placed on the perineum, which is then incised in a transverse fashion. If a perineorrhaphy is to be included, an inverted triangle of the skin is removed from the perineal body. The posterior vaginal wall is placed on gentle tension, and the vaginal epithelium is undermined using the Metzenbaum scissors up to the apex of the rectocele. The edges of the incision are grasped, and the epithelium is dissected off the underlying rectovaginal fascia bilaterally to expose the lateral attachments to the levator ani muscles. At this point, a traditional midline plication or a site-specific repair may be performed.

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Fig. 18 Total colpectomy/colpocleisis. (a, b) The vagina is circumscribed and marked into quadrants. Each quadrant is removed by sharp dissection. (c) Purse-string sutures are placed; the leading edge is inverted by the tip of the forceps. Purse-string sutures are tied 1 before 2 and 2 before 3, with progressive inversion of the tissue. (d) The final

relationship is shown in cross section. (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse, p400–410 (2015); with kind permission from Elsevier)

Midline Plication The rectovaginal fascia is plicated in the midline with interrupted sutures, starting proximally and

progressing toward the hymenal ring. Placement of these sutures should incorporate good purchase of the fibromuscularis and should be placed close

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Fig. 19 LeFort colpocleisis. (a) A rectangular piece of the vagina has been removed. (b) A similar rectangular piece of the posterior vagina has been removed. (c) The cut edge of the interior incision is sewn to the distal cut edge of the posterior incision. Once the cervix is inverted, the sutures are continued up the lateral edges of the incisions on either side. (d) The entire vagina is inverted and the proximal

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incisions are sewn together horizontally. Note: draining channels are left in the lateral portions of the vagina to allow drainage of cervical discharge or uterine bleeding. (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse, p400–410 (2015); with kind permission from Elsevier)

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Fig. 20 Traditional posterior colporrhaphy. (a) The perineal skin is incised in the midline. (b) The posterior vaginal epithelium is mobilized off the rectum. (c, d) The enterocele sac is mobilized and entered. (e) The enterocele sac is excised or reduced, and the fibromuscular layer of the vagina is plicated in the

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midline. (f) A second layer may be plicated across the midline. (g) Perineorrhaphy is performed. (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Karram M. Surgical Correction of posterior pelvic floor defects, p139–164; with kind permission from Elsevier)

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Fig. 20 (continued)

to the junction with the epithelium to avoid injury to the rectum. The redundant vaginal epithelium is trimmed and the incision closed in a running, locked fashion. The caliber of the vagina at the end of the procedure should allow three fingerbreadths to fit comfortably.

Site-Specific Repair The operator finger is placed in the rectum, and specific, palpable, or visual defects are repaired using interrupted, delayed, absorbable sutures (Fig. 21). If diffuse attenuation of the fascia is identified, a site-specific repair may not be technically

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Fig. 21 Site-specific posterior defect repair. With finger in the rectum, discrete defects in the fibromuscular layer are identified. These defects are subsequently repaired using interrupted sutures. (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Karram M. Surgical Correction of posterior pelvic floor defects, p139–164; with kind permission from Elsevier)

feasible, and a midline plication is preferred. The redundant vaginal epithelium is trimmed and the incision closed in a running, locked fashion.

Graft or Mesh Augmentation A posterior colporrhaphy may be augmented using graft or mesh. The material is cut to fit the space and sewn with permanent suture to the rectovaginal fascia at the level of the attachment to the levator ani muscles on either side. If the patient is undergoing a concomitant apical suspension, the graft may be fixed to the apical support sutures. The distal end is sutured to the perineum using absorbable sutures. The epithelium is then closed over the graft or mesh.

in 11–27% after traditional posterior colporrhaphy, with de novo dyspareunia reported in 4–16% (Arnold et al. 1990; Lopez et al. 2001; Mellgren et al. 1995; Maher 2004). A three-way randomized controlled trial comparing traditional colporrhaphy to site-specific repair to porcine-derived graft showed that traditional colporrhaphy and sitespecific repair had similar anatomic and functional outcomes. Porcine-derived graft augmentation resulted in improvement in symptoms similar to the other methods, but graft augmentation had significantly greater anatomic failures than the other two techniques (Paraiso et al. 2006). Graft augmentation may be considered in selected patients who have failed primary native tissue repair, with adequate preoperative counseling.

Outcomes and Complications

Conclusion Traditional midline plication has success rates ranging from 76% to 97%. The most common complication of posterior colporrhaphy is dyspareunia. Postoperative dyspareunia is found

Pelvic organ prolapse is a common problem that affects the daily activities of millions of women. The sensation of bulge in the vagina can be easily

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assessed and characterized by pelvic examination. Many patients may elect for expectant management or conservative management with a pessary. Radiologic testing is rarely indicated. Ancillary urodynamic testing may be indicated if the patient desires surgical intervention. Surgical treatment of prolapse is highly varied and depends greatly on the location of the prolapse, the degree of prolapse, and the patients’ comorbidities and preferences. Surgical procedures are generally safe and well tolerated. Procedural success rates are hard to interpret, as success is generally considered anatomic success, symptomatic success, and absence of reoperation.

Cross-References ▶ Anatomy of the Female Genital System ▶ Impact of Obesity on Gynecological Diseases ▶ Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

References Abdool Z, Thakar A, Sultan AH, Oliver RS. Prospective evaluation of outcome of vaginal pessaries versus surgery in women with symptomatic pelvic organ prolapse. Int Urogynecol J. 2011;22(3):273–8. Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary users. Int Urogynecol J. 2000;11(4):219–23. Arias BE, Ridgeway B, Barber MD. Complications of neglected vaginal pessaries: case presentation and literature review. Int Urogynecol J. 2008;19(8):1173–8. Arnold MW, Stewart WR, Aguilar PS. Rectocele repair. Four years’ experience. Dis Colon Rectum. 1990;33(8):684–7. Baden WF, Walker T. Fundamentals, symptoms and classification. In: Baden WF, Walker T, editors. Surgical repair of vaginal defects. Philadelphia: J.B. Lippincott; 1992. p. 14. Barber MD, Maher C. Apical prolapse. Int Urogynecol J. 2013;24:1815–33. Barber MD, Brubaker L, Burgio KL, Richter HE, Nygaard I, Weidner AC, Menefee SA, Lukacz ES, Norton P, Schaffer J, Nguyen JN, Borello-France D, Goode PS, Jakus-Waldman S, Spino C, Warren LK, Gantz MG, Meikle SF. Comparison of 2 transvaginal surgical approaches and perioperative behavioral therapy for apical vaginal prolapse: the OPTIMAL randomized trial. JAMA. 2014;311(10):1023–34.

C. E. Dancz et al. Bø K. Can pelvic floor muscle training prevent and treat pelvic organ prolapse? Acta Obstet Gynecol Scand. 2006;85(3):263–8. Braekken IH, Majida M, Engh ME, Bø K. Can pelvic floor muscle training reverse pelvic organ prolapse and reduce prolapse symptoms? An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol. 2010;203(2):170e1–7. Brubaker L, Nygaard I, Richter HE, Visco A, Weber AM, Cundiff GW, Fine P, Chetti C, Brown MB. Two-year outcomes after sacrocolpopexy with and without Burch to prevent stress urinary incontinence. Obstet Gynecol. 2008;112(1):49–55. Bump RC, Mattiasson A, Bø K, Brubaker LP, DeLancey JOL, Klarskov P, Shull BL, Smith ARB. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol. 1996;175:10–7. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL. Patient satisfaction and changes in prolapse and urinary symptoms in women who were fitted successfully with a pessary for pelvic organ prolapse. Am J Obstet Gynecol. 2004;190(4):1025–9. Cormio L, Mancini V, Liuzzi G, Lucarelli G, Carrieri G. Cystocele repair by autologous rectus fascia graft: the pubovaginal cystocele sling. J Urol. 2015;194(3): 721–7. Culligan PJ. Nonsurgical management of pelvic organ prolapse. Obstet Gynecol. 2012;119(4):852–60. Cundiff GW, Weidner AC, Visco AG, Bump RC, Addison WA. A survey of pessary use by members of the American Urogynecologic Society. Obstet Gynecol. 2000;95(6):931–5. Cundiff GW, Amundsent CL, Bent AE, Coates KW, Schaffer JI, Strohbehn K, et al. The PESSRI study: symptom relief outcomes of a randomized crossover trial of the ring and Gellhorn pessaries. Am J Obstet Gynecol. 2007;196(4):405–8. Dancz C, Walker D, Thomas D, Özel B. Prevalence of hydronephrosis in women with advanced pelvic organ prolapse. Urology. 2015;86(2):250–4. DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol. 1992;166(6 Pt 1):1717–24; discussion 1724–28. Drake R, Vogl AW, Mitchell AWM, Ribbits R, Richardson P. Gray’s atlas of anatomy. Philadelphia: Elsevier Health Sciences; 2008. p. 229. Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive pelvic surgery. 4th ed. Philadelphia: Saunders; 2015. FitzGerald MP, Richter HE, Siddique S, Thompson P, Zyczynski H. Colpocleisis: a review. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(3):261–71. Francis W, Jeffcoate T. Dyspareunia following vaginal operations. J Obstet Gynaecol Br Commonw. 1961;68:1–10. Hagen S, Stark D, Glazener C, Sinclair L, Ramsay I. A randomized controlled trial of pelvic floor muscle

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training for stages I and II pelvic organ prolapse. Int Urogynecol J. 2009;20(1):45–51. Hanson LA, Schulz JA, Flood CG, Cooley B, Tam F. Vaginal pessaries in managing women with pelvic organ prolapse. Obstet Gynecol. 2006;108(1):93–9. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4–20. Hsu Y, Chen L, Summers A, Ashton-Miller JA, DeLancey JO. Anterior vaginal wall length and degree of anterior compartment prolapse seen on dynamic MRI. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(1): 137–42. Hui SY, Chan SC, Lam SY, Lau TK, Chung KH. A prospective study on the prevalence of hydronephrosis in women with pelvic organ prolapse and their outcomes after treatment. Int Urogynecol J. 2011;22(12): 1529–34. Inmon WB. Pelvic relaxation and repair including prolapse of vagina following hysterectomy. South Med J. 1963;56:577–82. Karram MM, Ridgeway BM, Walters MD. Surgical treatment of vaginal apex prolapse. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive pelvic surgery. 4th ed. Philadelphia: Elsevier; 2015. Koelbl H, Igawa T, Salvatore S, Laterza RM, Lowry A, Sievert KD, Sultan A. Pathophysiology of urinary incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 5th ed. Paris: European Association of Urology; 2013. Lone F, Thakar R, Sultan AH, Karamalis G. A 5 year prospective study of vaginal pessary use for pelvic organ prolapse. Int J Gynecol Obstet. 2011;114(1): 56–9. Lopez A, Anzen B, Bremmer S, Mellgren A, Nilsson BY, Zetterstrom J, et al. Durability of success after rectocele repair. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12:97–103. Maher C. Midline rectovaginal fascial plication for repair of rectocele and obstructed defecation. Obstet Gynecol. 2004;104(4):685–9. Maher C, Karram M. Surgical management of anterior vaginal wall prolapse. In: Maher C, Karram M, editors. Surgical management of pelvic organ prolapse. 1st ed. Philadelphia: Saunders, an imprint of Elsevier; 2013. Maher C, Feiner B, Baessler K, Schmid C. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev. 2013;30(4):CD004014. Margulies RU, Rogers MA, Morgan DM. Outcomes of transvaginal uterosacral ligament suspension: systematic review and meta-analysis. Am J Obstet Gynecol. 2010;202(2):124–34.

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Meeks GR, Washburne JF, McGehee RP, Wiser WL. Repair of vaginal vault prolapse by suspension of the vagina to iliococcygeus (prespinous) fascia. Am J Obstet Gynecol. 1994;171(6):1444–52; discussion 52–4. Mellgren A, Anzen B, Nilsson BY, Johansson D, Dolk A, Gillgren P, et al. Results of rectocele repair. A prospective study. Dis Colon Rectum. 1995;38(1):7–13. Menefee A, Dyer Y, Lukacz S, Simsiman J, Luber M, Nguyen N. Colporrhaphy compared with mesh or graft-reinforced vaginal paravaginal repair for anterior vaginal wall prolapse: a randomized controlled trial. Obstet Gynecol. 2011;118(6):1337–44. Natale F, La Penna C, Padoa A, Agostini M, Panei M, Cervigni M. High levator myorrhaphy versus uterosacral ligament suspension for vaginal vault fixation: a prospective, randomized study. Int Urogynecol J Pelvic Floor Dysfunct. 2010;21(5):515–22. Nguyen N, Burchette J. Outcome after anterior vaginal prolapse repair: a randomized controlled trial. Obstet Gynecol. 2008;111(4):891–8. Nygaard IE, McCreery R, Brubaker L, Connolly A, Cundiff G, Weber A, Zycynski H. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol. 2004;104(4):805–23. Nygaard I, Brubaker L, Zyczynski H, Cundiff G, Richter H, Gantz M, Fine P, Menefee S, Ridgeway B, Visco A, Warren LK, Zhang M, Meikle S. Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. JAMA. 2013;309(19):2016–24. Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol. 1997;89(4):501–6. Paraiso MFR, Barber MD, Muir TW, Walters MD. Rectocele repair: a randomized trial of three techniques including graft augmentation. Am J Obstet Gynecol. 2006;195:1762–71. Roberge RJ, Keller C, Garfinkel M. Vaginal pessaryinduced mechanical bowel obstruction. J Emerg Med. 2001;20(4):367–70. Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J. 2012;23:1311–3. Romanzi L, Chaikin D, Blaivas J. The effect of genital prolapse on voiding. J Urol. 1999;161(2):581–6. Rooney K, Kenton K, Mueller ER, FitzGerald MP, Brubaker L. Advanced anterior vaginal wall prolapse is highly correlated with apical prolapse. Am J Obstet Gynecol. 2006;195(6):1837–40. Shull BL, Capen CV, Riggs MW, Kuehl TJ. Bilateral attachment of the vaginal cuff to iliococcygeus fascia: an effective method of cuff suspension. Am J Obstet Gynecol. 1993;168(6 Pt 1):1669–74. Stüpp L, Resende APM, Oliveira E, Castro RA, Girão MJBC, Sartori MGF. Pelvic floor muscle training for treatment of pelvic organ prolapse: an assessor-blinded randomized controlled trial. Int Urogynecol J. 2011;22(10):1233–9.

880 Sudhakar A, Reddi V, Schein M, Gerst P. Bilateral hydroureter and hydronephrosis causing renal failure due to a procidentia uteri: a case report. Int Surg. 2001;86:173–5. Sze EH, Karram MM. Transvaginal repair of vault prolapse: a review. Obstet Gynecol. 1997;89(3):466–75. Thubert T, Deffieux X. Inside out: on rare occasions, ring pessaries can cause genital incarceration. Am J Obstet Gynecol. 2014;210(3):278.e1. Trowbridge ER, Fenner DE. Practicalities and pitfalls of pessaries in older women. Clin Obstet Gynecol. 2007;50(3):709–19.

C. E. Dancz et al. Weber A, Walters M, Piedmonte M, Ballard L. Anterior colporrhaphy: a randomized trial of three surgical techniques. Am J Obstet Gynecol. 2001;185:1299–306. Wheeler LD, Lazarus R, Torkington J, O’Mahony MS, Woodhouse KW. Lesson of the week: perils of pessaries. Age Ageing. 2004;33(5):510–1. Wu JM, Hundley AF, Fulton RG, Myers ER. Forecasting the prevalence of pelvic floor disorders in U.S. Women: 2010 to 2050. Obstet Gynecol. 2009;114(6):1278–83. Wu JM, Kawasaki A, Hundley AF, Dieter AA, Myers ER, Sung VW. Predicting the number of women who will undergo incontinence and prolapse surgery, 2010 to 2050. Am J Obstet Gynecol. 2011;205(3):230.e1–5.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882 Diagnosis and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additional Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

882 882 883 883 883

Stress Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology/Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Floor Muscle Training (PFMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incontinence Pessary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urethral Inserts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mid-urethral Sling (MUS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transobturator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pubovaginal (Autologous Sling) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Retropubic Urethropexy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urethral Bulking Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

884 884 885 885 885 885 886 886 886 887 887 888

Urgency Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conservative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Percutaneous Tibial Nerve Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intradetrusor Onabotulinum Toxin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sacral Neuromodulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Urinary Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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R. Rolston (*) · B. Özel Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_71

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891

Abstract

Urinary incontinence is defined as the complaint of involuntary leakage of urine. Urinary incontinence impacts physical, psychological, and social well-being. In order to achieve an accurate diagnosis, a detailed history and physical exam are important. An initial evaluation should include a detailed history, urinalysis, cough stress test, evaluation of post-void residual, focused neurologic assessment, and examination for urethral hypermobility and pelvic organ prolapse. Urodynamic testing and cystoscopy may be indicated in some patients. Treatment varies based on the type of urinary incontinence and symptom severity. First-line therapy should always consist of less invasive and more conservative treatment options as they have been shown to be highly effective with minimal risk. These therapies include pelvic floor exercises, biofeedback, bladder training, weight loss, modification in fluid and caffeine intake, urethral inserts, and incontinence pessaries. Depending on the type of incontinence characterized, more invasive treatment options can be implemented if no improvement with conservative management. Typically, women with stress incontinence who have failed conservative therapies are offered surgical intervention, whereas women with urgency incontinence may be treated with pharmacologic management, intradetrusor onabotulinum toxin A, or neuromodulation. Most incontinence can be made better with available therapies. Keywords

Stress urinary incontinence · Urgency urinary incontinence · Mixed urinary incontinence · Sling

Introduction Urinary incontinence is defined as the complaint of involuntary leakage of urine (Haylen et al. 2010). The prevalence of urinary incontinence is estimated to range from 12% to 55% depending on the population studied (Castro et al. 2015). Urinary incontinence has been reported to affect up to 75% of older women (ACOG 2015). Urinary incontinence is associated with both depression and anxiety in women who are affected (Felde et al. 2016) and can lead to decrease in quality of life and negative impact on sexual function (Lim et al. 2016).

Diagnosis and Evaluation History History is a key part of the evaluation of urinary incontinence, and careful attention should be made to understanding the patient’s complaints (Komesu et al. 2016). History should include duration of incontinence, precipitating events, severity, frequency of occurrence, the presence or absence of nocturia, daytime urinary frequency, hesitancy or dysuria, fluid intake, daily pad use, and interference with activities of daily living (Haylen et al. 2010). The history obtained can be used to characterize and classify the type of incontinence or to identify underlying conditions that may cause incontinence. Tools that can be utilized to aide in obtaining a detailed history include a bladder diary and validated questionnaires such as the urogenital distress inventory, incontinence impact questionnaire, questionnaire for urinary incontinence diagnosis, incontinence quality for life questionnaire, and incontinence severity index (Staskin et al. 2005). When completing a

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bladder diary, patients are asked to record the timing and amount of fluid intake, voids and voided volumes, leakage episodes, and activity during leakage for 24–72-h period. As part of the history, medications should be reviewed to determine whether any of them might be contributing to urinary symptoms, such as diuretics, caffeine, alcohol, narcotic analgesics, anticholinergic drugs, antihistamines, psychotropic drugs, alphaadrenergic blockers, alpha-adrenergic agonists, and calcium channel blockers (ACOG 2015).

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evaluation for sacral reflexes. A detailed neurologic examination is not necessary unless there is presence of sudden onset incontinence or new onset of neurologic symptoms. A simple test for the sacral reflexes is the anal wink in which the skin near the anus is stroked lightly with a soft cotton-tipped swab. A reflex contraction of the anus should be seen. However, the reflex can be absent in some neurologically intact women.

Additional Testing Physical Physical exam should include a pelvic exam, including evaluating for prolapse and an assessment of urethral mobility. When performing the pelvic exam, it is important to evaluate for pelvic organ prolapse and to exclude the presence of a urethral and/or pelvic mass. A urethral mass such as a diverticulum or pelvic masses such as fibroids may cause symptoms of urinary incontinence. As part of the pelvic exam, a speculum exam should be performed to evaluate for extraurethral urinary leakage which can occur if a fistula is present. A cough stress test during the pelvic exam, when positive, may confirm stress incontinence. The Q-tip or cotton-tipped swab test is a simple test to evaluate urethral hypermobility. Urethral hypermobility does not have an official definition from the International Continence Society/International Urogynecologic Association, but it can be defined as a resting angle or displacement angle of the urethra–bladder neck with maximum Valsalva of at least 30 degrees from the horizontal (Zyczynski et al. 2007). In the absence of prior anti-incontinence surgery, when point Aa is
1 or greater on the Pelvic Organ Prolapse Quantification Scale, nearly all patients demonstrate urethral hypermobility, and a Q-tip test may be deferred in these patients (Cogan et al. 2002). During the initial evaluation of all women with incontinence, a focused neurologic examination is indicated, including assessment of gait, sensation over the perineum and perianal skin, and

Before initiating further therapy, it is recommended to check a urinalysis to evaluate for urinary tract infection and hematuria; a urine culture may be performed if indicated. It may be necessary to check a post-void residual (PVR) via straight catheterization or bladder ultrasound to rule out retention and overflow incontinence in women with symptoms of incomplete bladder emptying or difficulty voiding, or in women with risk factors such as neurologic disease or diabetes mellitus. A PVR volume less than 50 mL is considered indicative of adequate bladder emptying (Haylen et al. 2010), and a PVR volume greater than 200 mL is considered indicative of inadequate emptying (Gehrich et al. 2007). An isolated finding of a raised PVR requires confirmation before being considered significant.

Urodynamics Cystometry is a graphic depiction of bladder and abdominal pressure relative to fluid volume during filling, storage, and voiding. The information obtained during cystometry can be used to assess bladder sensation, capacity, and compliance and to determine the presence and magnitude of voluntary and involuntary detrusor contractions. Uroflowmetry and pressure-flow studies measure the rate of urine flow and the mechanism of bladder emptying (Walters and Karram 2015). Urethral pressure profiles and Valsalva leak point pressures can also be measured to make the

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diagnosis of urodynamic intrinsic sphincter deficiency. Studies have suggested that low urethral pressure measurements may be associated with poorer continence outcomes; a reliable cutoff measure to accurately predict surgical failure has not been found (Lim et al. 2016). Although Valsalva leak point pressures have been found to be weakly associated with subjective measures of incontinence severity, they have not been able to reliably predict surgical outcomes. Neuromuscular activity of the pelvic muscles and urethral sphincter during voiding can also be assessed during cystometry by using electromyography. The main role of electromyography is detecting coordination between detrusor muscle contraction and simultaneous urethral sphincter relaxation (Haylen et al. 2010). Urodynamic testing should be used to evaluate patients with complicated urinary symptoms and inability to elicit evidence of stress urinary incontinence of cough stress test or to evaluate for occult stress incontinence in patients with pelvic organ prolapse. A multicenter randomized controlled study has demonstrated that for women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year; uncomplicated stress incontinence was defined as women with predominantly stress incontinence symptoms, negative urinalysis, PVR 64 oz. of fluid/day. Another behavioral modification is the management of constipation; constipation can exacerbate urinary incontinence and increase risk of urinary retention. Obesity is a known risk factor for urinary incontinence, and weight loss in obese women has been shown to reduce urinary incontinence in multiple welldesigned studies (Vissers et al. 2014; Wing et al. 2010).

Pelvic Floor Muscle Training (PFMT) In addition to behavioral and lifestyle modifications, pelvic floor muscle training is also grouped with conservative first-line treatment for SUI and has been shown to be very effective in treating stress incontinence. The Cochrane Review found that in 18 studies, there was high-quality evidence that PFMT is associated with cure of stress incontinence (RR, 8.38; 95% CI, 3.68–19.07) and moderate-quality evidence of cure or improvement of stress incontinence (RR, 17.33; 95% CI, 4.31–69.64) (Dumoulin et al. 2015). Pelvic muscle exercises, also called Kegel exercises, aim to strengthen the pelvic floor musculature to provide a backboard for the urethra and reflexively inhibit detrusor contractions. When performing pelvic muscle exercises, different regimens have been prescribed. One simple instruction is to tell the patient to contract her

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pelvic floor using the same muscles they would use to stop urine flow or gas. The basic regimen consists of three sets of 8–12 contractions sustained for 8–10 s each, performed three times a day.

Incontinence Pessary Incontinence pessary restores continence by stabilizing the proximal urethra and urethrovesical junction. Incontinence pessaries are thought to improve urinary incontinence in some women by increasing urethral functional length, urethral closure pressures, and cough profiles (McIntosh et al. 2015). The knob of the incontinence pessary should be placed at or below the bladder neck in order to stabilize the posterior urethra (McIntosh et al. 2015). A randomized controlled trial comparing the use of behavioral therapy alone (including pelvic floor muscle training), pessary alone, and combined behavioral therapy and pessary found that at 3 months pessaries were not as effective as behavioral therapy based in patient satisfaction. Therefore, although incontinence pessaries are a treatment option, they are not first line given the effectiveness of pelvic muscle exercise (Richter et al. 2010).

Urethral Inserts A urethral insert is an occlusive device that acts as a mechanical barrier to prevent urinary leakage by sealing the urethral lumen (Sirls et al. 2002). They are self-inserted and designed for single use. The only urethral insert currently available for use is the FemSoft (Rochester Medical, Stewartville, MN). The most common side effects are urethral discomfort, hematuria, urinary tract infections, and bladder irritation. Contraindications for the use of urethral inserts include pregnancy, significant urge incontinence and unstable bladder contractions, neuropathic bladder, a history of recurrent bladder infections, the use of anticoagulants, and inflammatory or malignant lesions of the lower urinary tract.

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Surgery Stress urinary incontinence should be demonstrated objectively before any surgery is performed. This can be done with a cough stress test or with simple or multichannel urodynamic testing. A positive cough stress test is the visualization of fluid loss from the urethra simultaneously with a cough. This test should be performed with a full bladder in the supine and/or standing position. If the cough stress test is negative and patient reports symptoms of SUI, it is appropriate to perform urodynamic testing as next step. Once stress incontinence is objectively identified, surgical options include mid-urethral sling, pubovaginal sling, and Burch colposuspension. The most common surgical intervention for SUI is the mid-urethral sling procedure (Lim and Swyer 2009).

pregnancy, active oral anticoagulation, and the presence of important structures in the path of the trocars or sling, which may include a pelvic kidney, vascular graft, and low ventral hernias. A retrospective study comparing retropubic MUS, transobturator tape (TOT), and pubovaginal sling in women with ISD showed that retropubic MUS and pubovaginal slings had similar cure rates – retropubic MUS (86.9%) versus pubovaginal sling (87.3%) (Jeon et al. 2008). Potential complications of retropubic slings include bladder perforation, pelvic visceral injuries, vascular injuries and hemorrhage, mesh exposure, de novo development of urgency and urge incontinence, bladder outlet obstruction, pelvic pain, and urinary tract infection.

Transobturator Mid-urethral Sling (MUS) The first commercially available mid-urethral sling (MUS) was the tension-free vaginal tape (TVT) (Gynecare, Ethicon Women’s Health and Urology, Somerville, New Jersey, USA), first described by Ulmsten in 1996 (Ulmsten et al. 1996) and introduced into the US market in 1998. According to the American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU), the polypropylene mesh is considered the standard of care in the surgical treatment of SUI. There are two types of mid-urethral slings the retropubic sling and the transobturator (TOT) sling. Mid-urethral slings function by providing a backboard for the urethra, facilitating compression of the mid-urethra when intra-abdominal pressure increases. When performing a retropubic MUS, a segment of synthetic material is inserted via the vagina and passed on each side of the urethra through the retropubic space through two exit incisions on the anterior abdominal wall. Once the sling is placed, position is assessed and confirmed to be tension-free. Absolute contraindications to the retropubic MUS include

In 2001, Delorme described the transobturator technique for mid-urethral sling placement which avoided going in the retropubic space and is associated with less bladder perforation and visceral and vascular injury (Delorme 2001). The TOT can be performed via inside out or outside in technique in which the entry/exit point is the medial border of the obturator foramen at the level of the clitoris. The needle passage avoids any significant passage through the space of Retzius and nearly eliminates the possibility of intraperitoneal passage. As a result, the risk of bladder injury is lower after the TOT compared to the retropubic sling (0.6 vs. 4.5%; RR 0.13, 95% CI 0.08–0.20). Major vascular or visceral injury and operative blood loss is also lower with the TOT sling (Ford et al. 2015). Another important complication is voiding dysfunction, which is less common after the TOT sling compared to the retropubic sling (RR 0.53, 95% CI 0.43–0.65) (Ford 2015). Groin pain appears more frequently after the TOT sling (6.4 vs. 1.3%; RR 4.12, 95% CI 2.71–6.27), whereas suprapubic pain is less common after the TOT (0.8 vs. 2.9%; RR 0.29, 95% CI 0.11–0.78). There is no difference in rates of mesh exposure or extrusion (Ford et al. 2015).

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One important study that compared the TOT sling with the retropubic sling was the trial of mid-urethral slings (TOMUS); this was a multicenter, randomized equivalence trial comparing outcomes with retropubic and TOT mid-urethral slings in women with stress incontinence (Richter et al. 2010). Objective and subjective outcomes at 12 months were similar between the two approaches, with objective outcome of about 80% for both groups. Clinically important complications included voiding dysfunction requiring surgery, the use of catheter, or both, which was seen in 2.7% in women who had the retropubic sling versus none of the women who had a TOT sling ( p ¼ 0.004) and neurologic symptoms, seen in 9.4% of women in the TOT sling versus 4% in the retropubic sling ( p ¼ 0.01). Overall, the lower risk of most complications seen with the TOT sling makes it an excellent option in appropriately selected patients; however, there is a higher rate groin pain and neurologic complications, which must be considered. Indications for TOT sling placement are the same as for retropubic MUS with the exception of intrinsic sphincter deficiency. In women with either a maximum urethral closure pressure of 20 cm H2O or less or a pressure rise from baseline required to cause incontinence (Δ Valsalva or cough leak point pressure) of 60 cm H2O or less, the retropubic sling appears to be more effective. Of the 138 women randomized in one study, objective failure as defined as urodynamic stress incontinence at 6 months follow-up, 45% of women who had the TOT sling and 21% of women who had the retropubic sling had USI, and 13% of women in the TOT sling group went on to have another anti-incontinence procedure (Schierlitz et al. 2008).

Autologous slings are placed at the bladder neck and are mainly reserved for women with severe stress urinary incontinence (SUI) and a nonmobile, fixed urethra, declining to have synthetic mesh implanted, recurrent SUI after a synthetic sling or history of a complication after a synthetic sling such as vaginal exposure or extrusion (Blaivas et al. 2013). It is also preferred to use an autologous sling in patients who have been irradiated, have had urethral injuries, and those who are undergoing either simultaneous or prior urethrovaginal fistula or diverticulum repair (Swierzewski and McGuire 1993). Compared to the mid-urethral sling, the pubovaginal sling is more invasive because it requires an abdominal incision to harvest fascia for the sling. Complications of the pubovaginal sling include injury to the bladder and urethra, pelvic visceral injury, voiding dysfunction, superficial wound infection, seromas, and fascial hernias (Walters and Karram 2015). In a meta-analysis, when compared to mid-urethral slings, the autologous sling is equally efficacious (RR 0.97 for incontinence at 12 months; 95% CI 0.78–1.20) but had longer operating time (mean difference 60 min; 5% CI 57–63 min), greater perioperative complications (RR, 1.59; 95% CI, 1.03–2.44), and greater de novo detrusor overactivity (RR, 3.21; 95% CI, 1.29–8.03) (Rehman et al. 2011). When compared to the Burch urethropexy, in a well-designed multicenter randomized trial, at 24 months of followup, success rates were found to be higher for women who had an autologous sling compared to the Burch urethropexy, but there were more urinary tract infections, difficulty voiding, and postoperative urgency incontinence after the autologous sling (Albo et al. 2007).

Pubovaginal (Autologous Sling)

Retropubic Urethropexy

Autologous slings work by supporting the proximal urethra and bladder neck achieving continence by providing a direct compressive force on the urethra/bladder outlet. Long-term success is based on the healing and fibrosis of the sling which passes through the endopelvic fascia.

Retropubic procedures include the Burch colposuspension and the Marshall-MarchettiKrantz (MMK) procedure. The MMK procedure is generally no longer performed but involved in the use of permanent suture to secure the paravaginal tissue to periosteum of pubic symphysis; a

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known complication is osteitis pubis, a painful, noninfectious inflammation of the pubic symphysis. The Burch colposuspension involves the use of suture to secure paravaginal tissue to Cooper’s ligament. The Burch colposuspension requires a low transverse incision to assess the space of Retzius. Two delayed absorbable or nonabsorbable sutures are placed through the pubocervical fascia; one is placed 2 cm lateral to the mid-urethra, and the other is 2 cm lateral to bladder wall at the level of the urethrovesical junction bilaterally. The suture is then passed through Cooper’s ligament. With a hand in the vagina to elevate the pubocervical fascia, the sutures are tied down; a suture bridge is created. Healing occurs by fibrosis in the space of Retzius, and support for the urethra is created. The Burch colposuspension can be utilized in patients with SUI undergoing a concomitant abdominal procedure or in women who decline the use of mesh. Studies comparing the Burch colposuspension to slings (both mid-urethral and autologous) show similar effectiveness at 12 months (RR, 1.24; 95% CI, 0.93–1.67) (Lapitan and Cody 2016). There is a lower risk of voiding dysfunction with the Burch colposuspension compared to slings (RR, 0.41; 95% CI, 0.26–0.67). There is no difference in overall risk of perioperative complications between the Burch urethropexy and the mid-urethral slings (RR, 1.11; 95% CI, 0.66–1.87). However, women undergoing open retropubic colposuspension were nearly twice at risk of developing new or recurrent prolapse compared to those undergoing sling procedures (33.9 vs. 20.1%; RR, 1.85; 95% CI, 1.25–2.75) (Lapitan and Cody 2016).

Urethral Bulking Agents Urethral bulking agents consist of nonbiodegradable and nonimmunologic material which is injected transurethral or periurethral into the periurethral tissue around the bladder neck and proximal urethra to increase urethral resistance. Durasphere EXP (Carbon Medical Technologies, St. Paul, Minnesota, USA),

Coaptite (Boston Scientific, Franksville, Wisconsin, USA), and Macroplastique (Cogentix Medical, Minnetonka, Minnesota, USA) are the bulking agents that are currently available. The most common indications for urethral bulking agents include intrinsic sphincter deficiency with or without urethral hypermobility, persistent SUI after sling or urethropexy, and in women who cannot tolerate the risk of general anesthesia; other indications include women who cannot discontinue anticoagulation, are young and desire future fertility, and have SUI and poor bladder emptying (Cespedes and Serkin 2009). Urethral bulking agents have been shown to be less effective than surgery and usually require the need for repeat injections. Metaanalysis for the efficacy of Macroplastique found improvement rate of 75% (95% CI 69–81%) and cure/dry rates of 43% (95% CI 33–54%) at shortterm follow-up (Ghoniem and Miller 2013). This is similar to success rates with other products (Reynolds and Dmochowski 2012). Managing patient expectations of outcome is important. Relative contraindications to the use of urethral bulking injections include active urinary tract infection, high post-void residual urine (>100 mL), urinary stricture/obstruction, severe detrusor overactivity, and fragile urethral mucosa. If no relief after two or three injections, further injections should not be attempted (Walters and Karram 2015).

Urgency Incontinence Urgency urinary incontinence (UUI) is the complaint of involuntary urine leakage associated with urgency defined as the complaint of sudden compelling desire to pass urine that is difficult to defer, and overactive bladder (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection (UTI) or other obvious pathologies (Haylen et al. 2010). UUI is more common in older women and may be associated with comorbid conditions that occur with age. It is believed to result from detrusor overactivity, leading to involuntary detrusor muscle contractions during bladder filling (Lukacz 2016).

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The American Urological Association has identified behavioral therapy as the first-line treatment option and pharmacologic treatment as the second-line treatment option for nonneurogenic OAB in adults.

In patients with UUI refractory to behavioral and pharmacologic management, sacral nerve stimulation and intradetrusor injection of onabotulinum toxin A may be recommended (Singh et al. 2015).

Conservative Pelvic floor exercises have been demonstrated to be effective in the treatment of UUI. They are more effective when combined with biofeedback or verbal feedback. Weight loss with diet and exercise, caffeine reduction, and 25–50% reduction in fluid intake gave all been demonstrated to be efficacious and should comprise the initial management (Olivera et al. 2016). Bladder training has been shown to be effective for women with urgency incontinence. Bladder training starts with timed voiding. Patients should keep a voiding diary to identify their shortest voiding interval. Patients are instructed to void by the clock at regular intervals based on the shortest time interval identified between voids in voiding diary. Urgency between voiding is controlled with either distraction or relaxation techniques. When the patient can go 2 days without leakage, the time between scheduled voids is increased. The intervals are gradually increased until the patient is voiding every 3–4 h without urinary incontinence or frequent urgency. Successful bladder training can take up to 6 weeks (Lukacz 2016).

decreased urgency (Lukacz 2016). The currently available antimuscarinic drugs for the treatment of UUI and OAB are listed in Table 1. Treatment should be started at the lowest dose and titrated up if there is insufficient response in treatment and minimal side effects. Improvement in symptoms may take up to 4 weeks. A systematic review, including 23 studies, concluded that improvement with anticholinergics, either alone or combined with bladder training, is significantly greater than improvement with bladder training alone (Castro et al. 2015). Despite the effectiveness of antimuscarinics therapy, it has a low adherence rate secondary to their side effect profile including dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, and decreased cognitive function. Antimuscarinics are contraindicated in patients with gastric retention and untreated angle-closure glaucoma. In patients that have contraindications to antimuscarinic or cannot tolerate antimuscarinics, β3adrenergic agonist may be an option. The current β3 agonist on the market is mirabegron, and it has been shown to be effective in the management urgency. Mirabegron acts by promoting relaxation of the detrusor muscle and increasing the bladder capacity without increasing the residual volume (Castro et al. 2015). Patients with severe or uncontrolled hypertension should not be prescribed mirabegron. Vaginal estrogen therapy is another medication used for treatment of either stress or urgency incontinence. Vaginal atrophy can lead to Table 1 Antimuscarinic medications for treatment of women with urgency urinary incontinence or overactive bladder Medication Darifenacin Fesoterodine Oxybutynin

Pharmacologic Management If behavioral treatments fail, the next step is a trial of antimuscarinics. Antimuscarinics block the basal release of acetylcholine during bladder filling resulting in increasing bladder capacity and

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Solifenacin Tolterodine Trospium

Available formulations Extended release Extended release Immediate release Extended release Transdermal patch Transdermal gel Extended release Immediate release Extended release Immediate release Extended release

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symptoms of urinary frequency and dysuria and can contribute to incontinence, and correction of vaginal atrophy with topical estrogen may improve urinary symptoms. Vaginal estrogen therapy can be in the form of a cream, ring, or tablet (Cody et al. 2012). Evidence suggests that vaginal estrogen therapy may improve continence (RR, 0.74; 95% CI, 0.64–0.86). There are 1–2 fewer voids in 24 h among women treated with vaginal estrogen, and there is less urgency and frequency (Cody et al. 2012).

Percutaneous Tibial Nerve Stimulation Percutaneous tibial nerve stimulation (PTNS) delivers neuromodulation to the pelvic floor through the S2–4 junction of the sacral nerve plexus via the posterior tibial nerve. A 34-gauge needle electrode is inserted above the ankle, and the tibial nerve is accessed. This area has projections to the sacral nerve plexus, creating a feedback loop that modulates bladder innervation. Initial therapy consists of 12-weekly 30-min treatments (Gaziev et al. 2013). In a randomized trial of 220 adults, the 13-week subject global response assessment for overall bladder symptoms demonstrated statistically significant improvement in bladder symptoms from baseline with PTNS over sham therapy; 54.5% reported being moderately or markedly improved with PTNS compared to 20.9% of participants who received the sham therapy ( p < 0.001) (Peters et al. 2010).

Intradetrusor Onabotulinum Toxin A Onabotulinum toxin A blocks neuromuscular transmission by binding to receptor sites on nerve terminals and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings (Balchandra and Rogerso 2014). The most commonly recommended dose for nonneurogenic UUI/DO is BoNT-A 100 units. It is administered under

cystoscopic visualization by evenly distributed intradetrusor injections across 20 sites approximately 1 cm apart, sparing the trigone of the bladder (Liao and Kuo 2015). Onabotulinum toxin A is indicated in urgency refractory to medical treatment. Contraindications include active infection, acute urinary retention, unwillingness or inability to self-catheterize, and known hypersensitivity to the toxin (Liao and Kuo 2015). In a large, randomized controlled trial of onabotulinum toxin A compared to placebo, at 12 weeks, onabotulinum toxin A significantly decreased urinary incontinence episodes per day(
2.95 vs.
1.03, p < 0.001), and reduction in all OAB symptoms as assessed by validated quality of life questionnaires was significantly greater with onabotulinum toxin A compared to placebo (Chapple et al. 2013). The need to self-catheterize occurred in 6.9% of participants, and urinary tract infections were seen in 20.4%, which was the most common complication seen (Chapple et al. 2013).

Sacral Neuromodulation Sacral neuromodulation consists of the surgical implantation of electrodes in the S3 sacral nerve root and of an electric impulse generator, which is implanted in the subcutaneous tissue. It is reserved for severe cases of urgency refractory to conventional treatments. The mechanism of action is not fully understood, but electrical impulses are believed to act in both afferent and efferent fibers. The electrode implantation is performed in two stages in order to reduce complications and falsenegative rates (Balchandra and Rogerso 2014). The first stage is the testing phase in which the electrode is implanted and positioned using radioscopy. The definitive implant is offered to patients who exhibit a positive response at least a 50% symptom improvement in the first stage after 1–4 weeks. Cure and improvement rates are 30–50% and 60–90%, respectively (Castro et al. 2015; Yamanishi et al. 2015). Complication rates are low and include adverse change in bowel habits, electrically induced discomfort, pain at the implantable pulse generator site, and infection (Olivera et al. 2016).

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Mixed Urinary Incontinence Mixed urinary incontinence is defined as the complaint of involuntary loss of urine associated with urgency and also with effort or physical exertion or on sneezing or coughing. The pathophysiology is poorly understood. Initial treatment is conservative and should aim at treating both the SUI and UUI components. Subsequent therapy needs to be individualized to the patient’s primary complaint and degree of bother from the SUI and UUI. Typically, outcomes with anti-incontinence surgery for women with MUI are poorer than women with SUI alone. Persistent DO after antiincontinence surgeries is seen in up to 74% of women, typically leading to lower satisfaction with outcome of surgery (Bandukwala and Gousse 2015). Preoperative counseling on persistent UUI and DO after surgery is important when offering these women surgical treatment (Komesu et al. 2016).

Conclusion Urinary incontinence is a treatable medical condition that significantly affects quality of life. A variety of conservative, pharmacologic, and interventional therapies exist to treat this condition.

Cross-References ▶ Minimally Invasive Procedures for Incontinence and Lower Urinary Tract Disorders: Indications and Avoiding Complications ▶ Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Christina E. Dancz, Amin Tavakoli, and Anastasiya Shabalova

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894 Delayed Complications Presenting in the Immediate Postoperative Period (Within 2 Weeks) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurologic Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Femoral Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lateral Femoral Cutaneous Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ilioinguinal and Iliohypogastric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genitofemoral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Peroneal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sciatic Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obturator Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

894 894 895 895 896 896 896 896 897

Wound Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897 Cuff Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899 Cuff Evisceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900 Delayed Complications Presenting in the Early Postoperative Period (Within 3 Months) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901 Urinary Tract Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901 Rectovaginal and Enterovaginal Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903 Thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904

C. E. Dancz (*) · A. Shabalova University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] A. Tavakoli Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_73

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C. E. Dancz et al. Delayed Complications Presenting in the Late Postoperative Period (Months to Years) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906 Pelvic Organ Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909

Abstract

Surgical complications are an inevitable occurrence for any surgeon. Such complications may be a source of significant morbidity and even mortality. Delayed surgical complications typically present after the patient is discharged from the hospital. This chapter describes the presentation, evaluation, and management of the most common delayed postoperative complications. Delayed complications may be broadly categorized into those found in the early postoperative period and those in the later postoperative period. The first 2 weeks after surgery is a key time to evaluate and diagnose nerve injuries and wound complications, including infectious complications. Genital tract fistulae and thromboembolism may also present in this time period, but are also commonly seen in the first 3 months after surgery. Pelvic organ prolapse and cuff complications may present months to years after surgical intervention. The surgeon must be vigilant in the postoperative period for any sign of a delayed surgical complication, as prompt diagnosis and management is critical to minimize the effect upon the patient. Keywords

Coagulation · Cuff complications · Fistula · Nerve injury · Postoperative · Prolapse · Thromboembolism · Wound

Introduction Some of the most common surgical procedures are performed by obstetrician/gynecologists. Cesarean section and hysterectomies are among the most commonly performed major surgeries in

the United States, accounting for 1.8 million procedures in 2010 alone (National Center for Health Statistics (NCHS) 2010). These procedures are generally safe; however, occasionally complications may occur. Surgical complications range in both severity and acuity. When injuries occur during surgery, they may be immediately repaired, often with minimal impact on the patient. Intraoperative injuries that are not recognized until the postoperative period generally have worse outcomes than those repaired at the time of surgery. In order to minimize the impact on patients, it is critical for any surgeon to promptly identify and appropriately manage any complications of these common surgical procedures.

Delayed Complications Presenting in the Immediate Postoperative Period (Within 2 Weeks) Neurologic Injury Neurologic injury complicates approximately 1–2% of gynecologic surgery. Many injuries are due to improper positioning or self-retaining retractors; however, direct surgical trauma, suture entrapment, or hematoma formation can also be involved (Bohrer et al. 2009; Warner et al. 2000). Symptoms almost always present soon after surgery, and although most resolve completely with appropriate treatment, some patients continue to have long-term neurologic consequences. Therefore, prevention, early recognition, and treatment initiation are paramount. Nerves that may be injured after pelvic surgery include femoral, lateral femoral cutaneous, ilioinguinal, iliohypogastric, genitofemoral, common perineal, sciatic, and obturator.

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Femoral Nerve The femoral nerve (L2–L4) is the largest branch of the lumbar plexus; it courses between the psoas and the iliacus muscles in the abdomen, then passes under the inguinal ligament, and enters the thigh. Gynecologic surgeries, particularly abdominal hysterectomies, are the most frequent causes of iatrogenic injury to the femoral nerve (Moore and Stringer 2011). Injury to the femoral nerve can occur throughout its course due to variable mechanisms. The most frequent cause is related to the use of selfretaining retractors. Retractor blades placed on the psoas muscle cause injury by compressing the nerve, particularly with the use of longer retractor blades. The retractor can also compress the nerve where it traverses the abdominal wall by lateral displacement of the psoas muscle. Patients with diabetes, gout, uremia, alcoholism, and malnutrition are all at higher risk of nerve injury due to nerve devascularization and lesser ability of the nerve to withstand insult. To avoid such injury, the shortest retractor blades should be used, particularly in thin patients – as risk of injury is increased with a thin body habitus. Folded laparotomy sponges or towels can be placed between the retractor and the abdominal wall to elevate the retractor blades off the psoas muscle. Bladeless disposable retractors distribute pressure more evenly can be used. Any techniques to reduce operative time can reduce the risk of injury, as nerve injury risk is directly related to length of surgery. Another mechanism of injury of the femoral nerve is patient positioning. In dorsal lithotomy position, excessive hip flexion, external rotation, or abduction can compress the nerve against the inguinal ligament. Close attention to proper positioning is imperative to decrease the risk of compression injury. Thighs should not be excessively abducted or externally rotated, and hip flexion should not exceed 80–90
. Although less common, injury can also occur due to direct transection, incorporation into a suture, or a hematoma causing nerve compression.

895

The classic presentation of postoperative femoral nerve injury is a patient who cannot climb stairs or falls when trying to get out of bed. The motor deficits include inability to flex the hip or extend the knee as well as an absent patellar reflex. Sensory deficits usually involve paresthesia over the anterior-medial thigh and leg. If a neurologic injury is suspected after surgery, a thorough neurological examination may provide the diagnosis. Electromyography and nerve conduction studies may narrow down the location of injury. Imaging studies such as MRI, CT scan, or ultrasound can be used to detect formation of a hematoma or other fluid collections causing nerve compression. After diagnosis, treatment should be initiated immediately. In cases of suspected transection or suturing, surgical re-exploration and repair may be needed. Nerve compression from a hematoma can be relieved with drainage. Physical therapy should be initiated as soon as possible to prevent muscle atrophy. Knee stabilizers may be used to counteract thigh muscle weakness during standing. Most patients will achieve full recovery, although time till recovery varies and may take up to several months (Bradshaw and Advincula 2010; Chan and Manetta 2002; Clarke-Pearson et al. 2013; Craig 2013; Irvin et al. 2004).

Lateral Femoral Cutaneous Nerve The lateral femoral cutaneous nerve (L2–L3) courses over the iliacus muscle and passes under the inguinal ligament near the anterior superior iliac spine. Similar to the femoral nerve, it is at risk of compression from excessive hip flexion in dorsal lithotomy position as well as from inappropriate placement of lateral retractor blades. Neurologic deficits associated with this nerve are loss of sensation, paresthesia, and pain over the anterior lateral thigh from the inguinal ligament to the knee, a condition sometimes referred to as meralgia paresthetica (Bradshaw and Advincula 2010; Craig 2013; Irvin et al. 2004).

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Ilioinguinal and Iliohypogastric

Genitofemoral

The ilioinguinal (T12–L1) and iliohypogastric (T12–L1) nerves are frequently grouped together due to difficulty in distinguishing individual effects. These nerves run laterally through the head of the psoas muscle, pass diagonally along the anterior surface of the quadratus lumborum, penetrate the transversus abdominis, and enter the anterior abdominal wall. The nerves are susceptible to injury if a transverse abdominal incision is extended laterally, particularly beyond the edge of the rectus muscle at which point the edge of the fascia is close to the nerve branches. Injury from trocar placement in laparoscopic surgery has also been reported. The nerve damage typically occurs from direct surgical injury or nerve incorporation during fascial closure as well as scar formation after surgery. To decrease the risk of injury, the width of a transverse incision should be kept within the width of the rectus muscle, and laparoscopic trocars should be placed at least two fingerbreadths medial to the anterior superior iliac spines. Neuropathy typically manifests with burning or pain at the incision site that radiates to the groin as well as paresthesia over mons pubis, labia, and inner thigh. The symptoms typically improve after infiltration with local anesthetic. Treatment typically includes pharmacologic agents such as tricyclic antidepressants or gabapentin; however, nerve blocks, trigger point injection, or surgical nerve resection may also be necessary. Resecting the nerve requires extending the prior transverse incision to the anterior superior iliac spine and exposing the interface between the external oblique and the internal oblique muscle. The two nerves course between these two muscles and can be identified and sectioned close to the lateral sidewall. Complete relief of pain can occur after nerve resection in more than 70% of patients. Ilioinguinal and iliohypogastric nerve entrapment is typically underrecognized and should be considered in cases of chronic pelvic pain associated with history of abdominal surgery (Bradshaw and Advincula 2010; Clarke-Pearson et al. 2013; Irvin et al. 2004).

The genitofemoral nerve (L1–L2) runs along the ventral surface of the psoas muscle, lies lateral to the external iliac artery, and branches near the inguinal ligament. Similar to the femoral nerve, it is at risk of compression during laparotomy with the use of self-retaining retractors. In addition, it can be directly damaged during retroperitoneal dissection, during removal of pelvic masses adherent to the sidewall, or with removal of external iliac lymph nodes. During such dissections, the nerve should be isolated and preserved if possible. Neural deficits include groin pain and paresthesia over the ipsilateral mons, labia, and anterior thigh below the inguinal ligament (Bradshaw and Advincula 2010; Irvin et al. 2004).

Common Peroneal The common peroneal nerve (L4–S2) courses laterally across the knee in close proximity to the bone with little superficial protection. It can be injured due to poor positioning of the knee and lower leg by pressing against the hard surface of stirrups. The nerve may be pressed against the fibular head; therefore, careful positioning, avoiding pressure on the lateral knee, and use of padding may decrease the chance of injury. Neurologic deficits include paresthesia over the lateral lower leg and dorsum of the foot, weakness of ankle extension, or foot dorsiflexion. The patients typically present with foot drop (Bradshaw and Advincula 2010; Craig 2013; Irvin et al. 2004).

Sciatic Nerve The sciatic nerve (L4–S3) courses beneath the piriformis muscle and through the greater sciatic foramen as it exits the pelvis to travel down the posterior thigh to the popliteal fossa. Injury during open surgery is rare but may result in an event of a sudden hemorrhage requiring placement of sutures deep within lateral pelvis to control bleeding. The injury has also been reported with

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pelvic exenteration surgery. Symptoms of injury typically involve pain as well as weakness affecting most of the lower leg musculature and hamstrings while sparing hip flexion, extension, abduction, adduction, and knee extension. Sensory loss involves the lower leg. The ankle reflex is absent, while the knee reflex is normal (Craig 2013; Irvin et al. 2004).

Obturator Nerve The obturator nerve (L2–L4) courses through the psoas muscle, passes behind the common iliac arteries and laterally to the internal iliac artery and ureter, then runs along the lateral wall of the pelvis anterior to the obturator vessels to the obturator foramen, and enters the thigh through the obturator canal. In gynecologic surgery, it is most frequently injured during retroperitoneal dissection for malignancies or endometriosis resection (Cardosi et al. 2002). The nerve can be exposed with gentle medial or lateral traction on the external iliac artery and vein. If perioperative injury is diagnosed, the damage should be immediately repaired with microsurgical technique. Nerve injury can also occur during mid-urethral sling operations, particularly the transobturator tape (TOT) procedure (Aydogmus et al. 2014). Nerve injury presents postoperatively with loss of sensation over the inner thighs and motor loss in the hip adductors. Postoperative physical therapy should be initiated promptly including neuromuscular electrical stimulation, electromyographic biofeedback, exercise, and home-treatment regimen. Complete motor recovery is common after physiotherapy (Craig 2013; Irvin et al. 2004).

Wound Complications Wound complications are one of the most common causes of postoperative morbidity. Gynecologic procedures particularly pose a challenge since potential pathogenic organisms from the vagina or endocervix can migrate to operative sites and cause infection (Lachiewicz et al. 2015). Wound

897

complications (separation, hematoma, seroma, and infection) are estimated to affect 2–5% of abdominal incisions (Sherertz et al. 1992). Poor wound healing or collections of fluid/blood under the skin may cause the incision to separate and predispose the wound to infection. Wound complications usually present as swelling, pain, and/or drainage of fluid from the incision, most often within 3–10 days after surgery. When infected, the wound is often erythematous, indurated, and tender. Wound infections may be accompanied by fever and/or leukocytosis. Patients presenting in the postoperative period with any of these symptoms should be carefully evaluated with a thorough history and physical exam. Most of these complications may be managed without imaging or surgical intervention. Wound Separation Wound separation is defined as separation of the superficial layers of the wound (subcutaneous fat and skin). The underlying fascia is intact. Wound separation in the absence of a fluid collection or infection is uncommon, and if identified within 7–10 days of the initial surgery, delayed surgical re-approximation of the wound may be considered. Seroma and Hematoma A seroma is a collection of serum under the skin, while a hematoma is a similar collection of blood. A seroma or hematoma separates the superficial layers under the skin and prevents adequate wound healing. These wound complications are commonly related to obesity, immunocompromise, and inadequate hemostasis. The fluid collects under the skin and gradually leaks out from the incision line. Small hematomas and seromas ( ¼ 3 is high. In patients with a low pretest probability based on clinical criteria, a high-sensitivity D-dimer assay may be used to rule out DVT. If the D-dimer assay is positive, or if the patient is older/has significant comorbidities, then further testing is indicated. Doppler ultrasound testing of the venous system is recommended for anyone with intermediate or high scoring of clinical criteria. Doppler ultrasound of the calf may be negative; therefore, if suspicious of DVT confined to the calf, repeat ultrasound testing or contrast venography may be indicated. If suspicious for pulmonary embolism, pretest assessment of clinical factors should similarly be performed. Wells criteria to predict PE include six different clinical factors, and similar to the Wells score for DVT, the Wells score for PE is scored as low, intermediate, or high probability; a score of 0–1 is low risk, 2–6 is intermediate risk, and > ¼ 7 is high risk. Clinical parameter to predict PE (van Belle et al. 2006) Previous PE or DVT Heart rate > 100 beats per minute Recent surgery or immobilization Clinical signs of deep venous thrombosis Alternative diagnosis less likely than pulmonary embolism Hemoptysis Cancer

Score +1.5 +1.5 +1.5 +3 +3 +1 +1

If the clinical suspicion for DVT or PE is high, it is reasonable to begin treatment while the workup confirms the diagnosis. The risks of

906

untreated DVT or PE are high and may outweigh the risks of a brief treatment of anticoagulation, even if such treatment is ultimately unnecessary. Once diagnosed, the mainstay of treatment for DVT or PE is anticoagulation. Low-molecularweight heparin (LMWH) should be used for initial inpatient treatment of DVT. LMWH is superior to unfractionated heparin for the treatment of DVT for ease of dosing and maintenance, as well as an overall reduction in mortality and major bleeding. Treatment is generally administered for 3–6 months for DVT due to provoked VTE from transient risk factors such as surgery. Outpatient treatment is reasonable and may consist of daily injections with LMWH or transition to an oral treatment, such as a vitamin K antagonist. Compression stockings should be used to prevent postthrombotic syndrome, a chronic syndrome of leg pain, swelling, and ulceration that occurs in up to half of patients with DVT. The stockings should be worn starting within 1 month of DVT diagnosis and continued for at least a year (Vazquez and Kahn 2010).

Delayed Complications Presenting in the Late Postoperative Period (Months to Years) Pelvic Organ Prolapse Pelvic organ prolapse is the descent of any of the pelvic organs. Hysterectomy is a known risk factor for the development of pelvic organ prolapse. A large study of community-dwelling women found that women with prolapse were 1.68 more likely to have undergone a prior hysterectomy (Lawrence et al. 2008). The incidence of prolapse after hysterectomy is higher for women who had a hysterectomy for prolapse (1.6–11.6%) compared to women who had a hysterectomy for other indications (0.3–1.8%) (Mant et al. 1997; Marchionni et al. 1999). Route of hysterectomy does not appear to be a factor in development of prolapse (Gabriel et al. 2021). The main symptom of pelvic organ prolapse is the sensation of pressure or bulge in the vagina

C. E. Dancz et al.

(Fig. 6). Severe complications of prolapse are rare. A diagnosis of prolapse is usually based on physical exam, though several formal staging systems exist. Asymptomatic or minimally symptomatic prolapse may not require any intervention. Patients with significant discomfort may elect to use a plastic device (pessary) to hold their prolapsed organs in place, or they may elect for surgery. There are a variety of surgical procedures for prolapse, depending on the patient’s health, preferences, degree, and location of prolapse.

Cuff Complications Granulation Tissue The most common abnormal postoperative finding at the vaginal cuff is granulation tissue. Granulation tissue is an over-proliferation of healing tissue that may be found on any wound. Granulation tissue is usually described as beefy red and friable (see Fig. 7). Most cases of vaginal granulation tissue are asymptomatic, but may also cause vaginal bleeding, particularly after intercourse. Granulation tissue at the cuff is benign and may be treated with topical cautery using silver nitrate sticks or may be excised (Saropola and Ingsirorat 1998). Excision may be preferred when the tissue is large and symptomatic or if the diagnosis is in question. Other conditions may occasionally be mistaken for granulation tissue, including malignancy or fallopian tube prolapse (Song et al. 2005). Fallopian Tube Prolapse Fallopian tube prolapse is a rare complication of hysterectomy, whereby the fallopian tube either is incorporated into the vaginal cuff or prolapses through an open cuff. This complication usually presents with severe lower abdominal pain or a pulling sensation and tenderness to palpation of the cuff. The tube may be visible at the apex of the vagina, and biopsy or excisional biopsy can confirm the diagnosis (Fig. 8). If the diagnosis is confirmed, revision of the cuff is usually necessary to relieve symptoms.

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907

Fig. 6 Pelvic organ prolapse after hysterectomy

This revision may be performed vaginally; the cuff is opened up, the damaged tube is often excised, and the remaining cuff is closed. Laparoscopic/open approach may also allow confirmation of diagnosis and evaluation for additional etiologies of the pain.

Conclusion All surgical procedures carry risk of postoperative complications. These complications may be immediate or delayed. Delayed postoperative complications can have serious effects for patients, and prompt diagnosis and management is critical. This chapter discusses a variety of complications that can be managed clinically or operatively. A thorough understanding of the mechanism of neurologic injury allows for insight into prevention and recognition, which can reduce

the effect on the patient. Wound complications can generally be managed conservatively, and only the most severe infections or fascial dehiscence need surgical management. Fistulae are among the most dreaded complications by surgeons, as they typically represent unrecognized surgical injury; however, with prompt recognition and surgical treatment, most fistulae can be completely cured. Thromboembolism is the most dangerous of the postoperative complications, though studies have shown improvement of morbidity and mortality with aggressive prevention and early diagnosis. Finally, pelvic organ prolapse and cuff complications are varied and require clinical insight into diagnosis and management. There is no such thing as a surgeon without complications, but with enough understanding, preparation, and care, a surgeon can minimize their complications and mitigate the impact upon their patients.

908 Fig. 7 Granulation tissue at cuff. (Originally published in: Stember et al. 2003; with kind permission of Springer Science + Business Media. All rights reserved)

Fig. 8 Fallopian tube prolapse. (Originally published in: Bower et al. 1940; with kind permission of Elsevier. All rights reserved)

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910 editors. Te Linde’s operative gynecology. 10th ed. Philadelphia: J.B. Lippincott; 2011. p. 973–93. Moore AE, Stringer MD. Iatrogenic femoral nerve injury: a systematic review. Surg Radiol Anat. 2011;33:649–58. https://doi.org/10.1007/s00276-011-0791-0. National Center for Health Statistics. National Hospital Discharge Survey, 2010. [Internet] Number of all-listed procedures for discharges for short-stay hospitals, by procedure category and age: United States, 2010. [Cited 2016 Mar 15]. Available from: http:// www.cdc.gov/nchs.data/ndsp/4procedures/2010pro4_ numberprocedureage.pdf Nick AM, Lange J, Frumovitz M, Soliman PT, Schmeler KM, Schlumbrecht MP, dos Reis R, Ramirez PT. Rate of vaginal cuff separation following laparoscopic or robotic hysterectomy. Gynecol Oncol. 2011;120:47–51. Partsinevelos GA, Rodolakis A, Athanasiou S, Antsaklis A. Vaginal evisceration after hysterectomy: a rare condition a gynecologist should be familiar with. Arch Gynecol Obstet. 2008;279(2):267. Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, Bass EB, Weiss KB, Green L, Owens DK. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57–62. Saropola N, Ingsirorat C. Conservative treatment of vaginal vault granulation tissue following total abdominal hysterectomy. Int J Gynecol Obstet. 1998;62:55–8. Sherertz RJ, Garibaldi RA, Marosok RD, Mayhall CG, Scheckler WE, Berg R, Gaynes RP, Jarvis WR, Martone WJ, Lee JT. Consensus paper on the surveillance of surgical wound infections. Infect Control Hosp Epidemiol. 1992;13(10):599. Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal J, Bass E, Weiss KB, Green L, Owens DK. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American

C. E. Dancz et al. Academy of Family Physicians. Ann Intern Med. 2007;146(3):204–10. Song YS, Kang JS, Park MH. Fallopian tube prolapse misdiagnosed as vault granulation tissue: a report of three cases. Pathol Res Pract. 2005;201(12):819–22. Stember DS, Scarpero HM, Nitti VW. Vaginal granulation tissue secondary to bone anchors: experience in two patients. J Urol. 2003;169(6):2300–1. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358(10):1037–52. Teeluckdharry B, Gilmour D, Flowerdew G. Urinary tract injury at benign gynecologic surgery and the role of cystoscopy: a systematic review and meta-analysis. Obstet Gynecol. 2015;126(6):1161. van Belle A, Buller HR, Huisman MV, Huisman P, Kaasjager K, Kamphuisen PW, Kramer MHH, Kruip MJHA, Kwakkel-vanErp JM, Leebeek FWG, Nijkeuter M, Prins MH, Sohn M, Tick LW. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, d-dimer testing and computed tomography. JAMA. 2006;295:172. van Ramshorst GH, Nieuwenhuizen J, Hob WCJ, Arends P, Boom J, Jeekel J, Lange JF. Abdominal wound dehiscence in adults: development and validation of a risk model. World J Surg. 2010;34(1):20–7. Vazquez SR, Kahn SR. Postthrombotic syndrome. Circulation. 2010;121:e217–9. Warner MA, Warner DO, Harper CM, Schroeder DR, Maxson PM. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology. 2000;93: 938–42. Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350:1795–8. Wild TT, Bradley CS, Erickson BA. Successful conservative management of a large iatrogenic vesicovaginal fistula after loop electrosurgical excision procedure. Am J Obstet Gynecol. 2012;207(3):e4–6.

Part IX Management of Gynecologic Neoplasms and Cancers

Diagnosis and Management of Gestational Trophoblastic Disease

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Jocelyn Garcia-Sayre, Antonio V. Castaneda, Lynda D. Roman, and Koji Matsuo

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

914 914 915 915

Management of Primary GTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Low-Risk GTN: Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Low-Risk GTN: Adjuvant Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High-Risk GTN: Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of PSTT/ETT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

917 917 919 920 921

Management of Refractory/Persistent Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Low-Risk Refractory GTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High-Risk Refractory/Recurrent GTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-gestational Trophoblastic Tumors (Non-GTT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental Therapies for Chemoresistant GTN: Immunotherapy, High-Dose Chemotherapy, and Molecularly Targeted Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

922 922 922 923 923

Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924 Vaginal Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924 Brain Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925

J. Garcia-Sayre · L. D. Roman · K. Matsuo (*) Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected]; [email protected] A. V. Castaneda Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] © This is a U.S. Government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_11

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J. Garcia-Sayre et al. Reproductive Outcomes After Treatment for GTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-molar Prophylactic Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phantom Beta-hCG, Quiescent GTD, and Physiologic Beta-hCG . . . . . . . . . . . . . . . . . . . . . Surveillance/Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927

Abstract

Gestational trophoblastic disease (GTD) refers to all tumors that arise from the maternal placenta. Gestational trophoblastic neoplasm (GTN) is a subset of GTD and refers to choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Persistent GTD may develop after treatment of a molar pregnancy and is also referred to as GTN. The treatment of GTN is stratified based on whether the patient is low risk or high risk as determined by the World Health Organization (WHO) score and International Federation of Gynecology and Obstetrics (FIGO) staging system. Low-risk GTN is treated with singleagent chemotherapy, whereas high-risk GTN should be treated with combination regimens. GTN that does not respond to first-line treatment is said to be resistant or refractory. Resistance to a particular chemotherapeutic regimen is evidenced by a plateau or rise in beta-hCG levels. The overall prognosis for GTN is excellent, even in the setting of refractory disease. GTN affects women of reproductive age, and comprehensive counseling must be performed prior to initiation of gonadotoxic treatment. This chapter also discusses the management of GTN with special considerations such as brain and vaginal metastasis, role of secondary curettage, and post-molar prophylactic chemotherapy. Keywords

Gestational trophoblastic neoplasm · Persistent gestational trophoblastic disease · Invasive mole · Choriocarcinoma · Placental site trophoblastic tumor · Epithelioid trophoblastic tumor · High-risk gestational trophoblastic

neoplasm · Low-risk gestational trophoblastic neoplasm

Introduction Gestational trophoblastic disease (GTD) is the general term used to describe growth disturbances of the placental trophoblast. GTD encompasses the complete mole, partial mole, placental site nodules, atypical placental site nodules, invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Gestational trophoblastic neoplasia (GTN) is a subset of GTD and refers to the latter four. The term persistent GTD is often used interchangeably with GTN when referring to the diagnosis of posthydatidiform mole trophoblastic neoplasia. Typically, GTN will arise after a molar pregnancy but can occur in the setting of a normal pregnancy and in rare cases may not be associated with pregnancy. With the advent of various chemotherapeutic regimens, the prognosis for GTN is excellent.

Epidemiology The overall incidence of GTD and GTN is low within the general population. The incidence varies widely based on geographical location and race. Southeast Asia and Japan have the highest incidence of GTD. It is unknown at this time why various ethnicities have a higher incidence of GTD and GTN. Currently, the incidence of GTD is documented at 1–3 per 1000 pregnancies (Froeling and Seckl 2014). Given that GTN typically arises from GTD, the incidence of GTN is much lower. In North America, the incidence is quoted to be 1 in 40,000 and at 9 per 40,000 in Southeast Asia and Japan (Lurain 2010).

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Presentation The presentation of GTN is diverse and dependent on the type of neoplasm. Benign moles such as the complete hydatidiform mole present most often with vaginal bleeding and significantly elevated beta-hCG. The elevation in beta-hCG often correlates to the burden of trophoblastic disease (Froeling and Seckl 2014). A single elevated beta-hCG should not be used to make the diagnosis of GTD or GTN. When an ultrasound is performed, hydropic villi are observed, and this is often referred to as a snowstorm appearance (Froeling and Seckl 2014). Following evacuation of GTD, beta-hCG levels should steadily decline. The majority of patients will have normal beta-hCG levels around 12–14 weeks after evacuation. A plateauing or increase of the beta-hCG is concerning for the development of GTN or persistent GTD. Regression curves have been developed to help identify patients at risk (Schlaerth et al. 1981). Persistent GTD develops when molar tissue invades into the myometrium. Typically, this is seen with the invasive mole but can also be seen in choriocarcinoma, PSTT, and ETT. Table 1 describes the criteria for the diagnosis of post-hydatidiform mole trophoblastic neoplasia or GTN (Committee 2002). GTN can be diagnosed if any one of the criteria is established. Histologically, the invasive mole appears as excessive growth of the trophoblastic tissue which invades into the myometrium of the uterus. Invasive moles often have local invasion and are less often associated with metastasis. Choriocarcinoma is a highly malignant tumor associated with hemorrhage, widespread metastasis, and sheets of anaplastic cytotrophoblasts and syncytiotrophoblasts. Choriocarcinomas are typically

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very chemosensitive. Placental site trophoblastic tumor is a rare form of GTN that arises after a term pregnancy and histologically consists of intermediate trophoblasts. PSTT has slow growth within the uterus and only metastasizes late in its course. Patients with PSTT usually present with low levels of beta-hCG and irregular vaginal bleeding. Surgery of the primary tumor and multi-agent chemotherapy are the mainstays of treatment for PSTT (Lurain 1990; Abrão et al. 2008; Papadopoulos et al. 2002). Epithelioid trophoblastic tumor is an extremely rare type of GTN with little documentation in the literature. ETT can arise from either a previously gestation or without a previously documented gestation. ETT is chemoresistant; therefore, surgery is the mainstay of treatment when confined to the uterus. Histologically, ETT develops from the chorionic-type intermediate trophoblast (Allison et al. 2006; Lurain 1990) (Table 2).

Treatment Overview The treatment for GTN is determined by whether the patient is found to be low risk or high risk. There are two classification systems for GTN: International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO). The FIGO staging criteria defines stage based on extent of disease (Table 3). The World Health Organization (WHO) proposed a classification system that divides patients into low-risk and high-risk categories with the purpose of defining the best course of treatment (Table 4). It uses independent prognostic factors to risk stratify patients based on the likelihood of being successfully treated with single-agent versus multi-agent chemotherapy. Low-risk patients are

Table 1 Criteria for the diagnosis of post-hydatidiform mole trophoblastic neoplasia GTN may be diagnosed when the plateau of beta-hCG lasts for four measurements over a period of 3 weeks or longer, that is, days 1, 7, 14, and 21a GTN may be diagnosed when there is a rise of beta-hCG of three weekly consecutive measurements or longer, over at least a period of 2 weeks or more, days 1, 7, and 14a GTN is diagnosed when the beta-hCG level remains elevated for 6 months or more Adopted and modified from FIGO committee report on FIGO staging for gestational trophoblastic neoplasia 2000 (Committee 2002) a A difference of 10% or less between measurements is considered stable and should not be interpreted as a change

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Table 2 Summary of clinical presentation and histopathologic findings GTN type Invasive mole

Choriocarcinoma

Placental site trophoblastic tumor (PSTT)

Epithelioid trophoblastic tumor (ETT)

Presentation/behavior Presents with irregular bleeding after dilation and curettage Associated with localized invasion; however, 15% metastasize to the lung or vagina High levels of beta-hCG Associated with irregular bleeding after dilation and curettage 50% arise from hydatidiform moles Increased risk of hemorrhage and vaginal bleeding Highly malignant tumor with propensity for widespread metastasis via vascular channels – spreading to the lung, liver, and brain High levels of beta-hCG Rare Presents with nonspecific vaginal bleeding Chemoresistant, persistent low levels of beta-hCG Presence of human placental lactogen (hPL) Metastasizes via lymphatics Can be associated with placental site nodules Rare Majority occur after term pregnancy Presents with nonspecific vaginal bleeding Chemoresistant Elevated beta-hCG but usually less than 2500 Can be associated with placental site nodules

Histopathology Molar tissue which invades the myometrium

Management Chemotherapy

Growth of trophoblastic tissue with the presence of chorionic villi invading myometrium Sheets of anaplastic cytotrophoblasts and syncytiotrophoblasts with absence of chorionic villi

Chemotherapy

Intermediate trophoblastic tissue without chorionic villi seen invading into the myometrium

Hysterectomy
Chemotherapy

Mononucleate trophoblastic cells arranged in cords associated with eosinophilic, fibrillary, and necrotic debris

Hysterectomy
Chemotherapy

Adopted and modified from Lurain (2010)

likely to achieve 90% response to single-agent chemotherapy, whereas high-risk patient will need multi-agent chemotherapy (Lurain et al. 1991). Of note, the WHO classification system does not apply to PSTT and ETT as their clinical characteristics are quite different and they are less chemosensitive prompting alternative management which is reviewed separately.

After successful treatment for GTD, it is imperative to follow the patient with serial beta-hCG levels weekly until undetectable levels are noted for 3 weeks. Monthly beta-hCG measurements should then be drawn for 6–12 months. Six-month follow-up may be sufficient if the decline in beta-hCG follows the normal regression curve as detailed by Morrow et al. (1977).

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However, 12-month follow-up is recommended if regression is irregular. During the monitoring for declining serial beta-hCG, it is necessary for the patient to be on effective contraception. A concomitant pregnancy at the time of beta-hCG evaluation will lead to an inability to monitor for disease recurrence. The intrauterine device, however, is not recommended as birth control for patients with GTD given the risk for uterine perforation. Oral contraceptive pills and implantable devices are both safe for use (Berkowitz and Goldstein 2009).

Management of Primary GTN Primary GTN is highly curable with chemotherapy. Primary treatment is dictated by the WHO and FIGO score as above. A WHO score of 6 or Table 3 FIGO staging system Stage I II

Extent of disease Limited to the uterus Extension beyond uterus to adnexa, broad ligament, or the vagina Extension to the lungs with or without extension to genital tract Other metastatic sites

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less with FIGO stages I–III is considered to be low-risk disease and can be treated with a single chemotherapeutic agent. A score of 7 or greater with FIGO stages I–III or FIGO stage IV is considered to be high-risk disease and calls for treatment with a combination of agents.

Low-Risk GTN: Chemotherapy As mentioned above, low-risk GTN is usually treated with single-agent chemotherapy. Two agents are typically used for treatment of low-risk disease, methotrexate and actinomycin D, with cure rates of approximately 100%. Etoposide was historically used for low-risk disease, but this has fallen out of favor due to the slightly increased risk of secondary malignant tumors, especially leukemia (Rustin et al. 1996). Several different dosing regimens have been studied for methotrexate and actinomycin D; these are discussed below. Table 5 summarizes the regimens and includes their primary remission rates.

(a) Methotrexate 0.4 mg/kg intramuscularly (IM) for 5 days, repeated every 2 weeks. The primary failure rate is approximately 11% for IV nonmetastatic disease (Lurain and Elfstrand Adopted and modified from FIGO Committee on Gynecologic Oncology (2009) 1995). The response rate in women with III

Table 4 WHO prognostic scoring system Score assigned Age at diagnosis Prior pregnancy Interval between index pregnancy (months) Pretreatment beta-hCG Tumor size (cm), including uterine mass size Metastatic location Number of metastases Failed chemotherapy

0 Less than 40 Mole Less than 4

1 40 or greater

2 –

4 –

Abortion 4–6

Term 7–12

– More than 1 year

Less than 1000 Less than 3

1000–10,000

10,000–100,000

Greater than 3 but less than 5 Kidney/spleen 1–4 –

5 or greater

Greater than 100,000 –

GI 5–8 Single agent

Brain or liver 9 or more Multi-agent

Lunga 0 –

Adopted and modified from FIGO Committee on Gynecologic Oncology (Abrão et al. 2008; FIGO Committee on Gynecologic Oncology 2009) a Lung metastases should only be included in the WHO score if seen on chest X-ray (CXR). Lung CT scan may be used but should not influence the score because of the likely presence of lung micrometastases. If counted, they would increase the score without adding any clinical benefit. While a lung metastasis receives a score of 0, it may be included when counting the total number of metastatic lesions if visualized on CXR

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Table 5 Response rate for chemotherapy regimens for low-risk GTN Regimen (a) MTX 0.4 mg/kg IM for 5 days, repeated q2 weeks (b) MTX 50 mg IM or 1 mg/kg QOD for four doses with leucovorin 15 mg or 0.1 mg/kg administered 24–30 h after each MTX dose (c) MTX 30 mg/m2 or 50 mg/m2 IM given weekly (d) Act-D 1.25 mg/m2 IV q2 weeks (pulse regimen) (e) Act-D 12 μg/kg for 5 days, repeated q2 weeks (f) (i) MTX 20 mg IM on D1–D5 with 500 μg Act-D IV on D1–D5 q2 weeks (ii) Act-D 0.6 mg/m2 on D1 and D2 with MTX 100 mg/m2 IV push and then infusion of 300 mg/m2 on D1–D2 followed by leucovorin for 2 weeks

Primary remission rate (%) 87–93 74–90 49–74 69–90 77–94 100

Adopted and modified from Lurain (2011) MTX methotrexate, Act-D actinomycin D, QOD every other day, q2 week every 2 weeks

metastatic disease has been quoted to be 60% (e) Actinomycin D 12 μg/kg for 5 days. This is an (Soper et al. 1994). alternative to the 5-day methotrexate regimen. (b) Methotrexate with folinic acid (leucovorin) This regimen has shown to be effective in rescue: Methotrexate 50 mg IM or 1 mg/kg patients who failed to respond to the every other day for four doses with leucovorin 1.25 mg/m2 pulse actinomycin D regimen 15 mg or 0.1 mg/kg administered 24–30 h with an 80% response rate (Kohorn 2002). after each methotrexate dose. In patients with (f) Combined methotrexate and actinomycin D: nonmetastatic disease, only 7.7% of those The following dosing regimens have been treated with methotrexate alone developed used for this combination regimen: resistant disease requiring a change in chemo(i) Methotrexate 20 mg IM on D1–D5 with therapy for induction of remission, while 500 μg actinomycin D IV on D1–D5 27.5% of patients initially treated with the every 14 days (Abrão et al. 2008). leucovorin rescue required a change in regi(ii) Actinomycin D 0.6 mg/m2 on D1 and D2 men to achieve remission. Thus, the frequency with methotrexate 100 mg/m2 IV push of drug resistance is significantly higher in and then infusion of 300 mg/m2 on those treated with the leucovorin rescue D1–D2 followed by leucovorin for (Matsui et al. 2005). However, the use of 14 days (Eiriksson et al. 2012). Higher methotrexate alone has been shown to be remission rates have been reported when more toxic than the methotrexate-folinic acid the combination is used as compared to combination. each drug alone. It is has also proven to (c) Methotrexate 30 mg/m2 or 50 mg/m2 IM lead to a cure faster, requiring a fewer number of cycles (Eiriksson et al. 2012). given weekly. This regimen was used in The combination regimens ultimately GOG-174 to compare response rates to those 2 yielded a greater number of grades 3 and of actinomycin D 1.25 mg/m IV every 4 toxicities as defined by the Common 2 weeks (Osborne et al. 2011). Actinomycin Terminology Criteria of Adverse Events D was found to be more effective with a (CTCAE). Therefore, taking into considresponse rate of 70% compared to 53% for eration the frequency of toxic effects and weekly methotrexate. a modest increase in remission rate, a (d) Actinomycin D 1.25 mg/m2 IV every 2 weeks combined regimen may be better suited (pulsed regimen). Actinomycin D is associfor second-line therapy (Abrão et al. ated with alopecia and is therefore less favored 2008). by patients.

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Most recently, GOG-275, a multicenter phase III randomized control trial comparing the use of multiday methotrexate versus pulse actinomycin D in treating patients with low-risk GTN, attempted to answer the question of which regimen should be used as first-line treatment for GTN (Alazzam et al. 2012a). While GOG-174 initially attempted to answer this question, it used the weekly methotrexate regimen which has been shown to be inferior to the multiday regimen. A Cochrane review meta-analysis concluded that actinomycin D is much more likely to achieve a primary cure when compared to methotrexate (82% in the actinomycin D group compared to 53% in the methotrexate group); however, the review included data from different dosing regimens making it difficult to draw a clear conclusion. Unfortunately, GOG-275 closed prematurely due to slow accrual, enrolling a total of 57 patients of the planned 384. The complete response rate for multiday methotrexate was 88% and the complete response rate for pulse actinomycin D was 79%; however, the difference was not statistically significant. In terms of toxicity and patient-reported outcomes, the methotrexate regimens were significantly more likely to cause mucositis and eye disorders and were significantly less convenient than the pulse actinomycin D regimen. Interestingly, alopecia which is cited as a common concern with actinomycin D was not identified as an issue in either the toxicity measurement or the quality of life evaluation. Given that there was no significant difference in complete response rates, the convenience of administration, and favorable toxicity profile with pulse actinomycin D, one might conclude that the pulse actinomycin D regimen be favored over the multiday methotrexate regimen. In general, treatment should be continued beyond the first negative beta-hCG titer; this is known as consolidation therapy (Lybol et al. 2012). Usually, two to three cycles of chemotherapy are recommended, especially if the decrease in beta-hCG is slow or if there is extensive disease.

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Low-Risk GTN: Adjuvant Surgery Second Curettage Attempts have been made to curtail chemotherapy in the setting of low-risk GTN. The theory behind a second curettage is that debulking the tumor will lead to a decreased need for chemotherapy. Single institution retrospective studies have reported varying outcomes. The Dutch published a retrospective cohort study evaluating the effect of a second curettage on low-risk GTN (van Trommel et al. 2005). Their primary outcome measures were the need for chemotherapy and the number of chemotherapy courses required. Unfortunately, only 9.4% of patients were cured after curettage and required no further chemotherapy. However, those patients who received a second curettage required a fewer number of chemotherapy cycles, and the authors concluded that the second curettage offers a “debulking” effect. A second curettage is not without complications; 4.8% of patients in this study had a major complication such as uterine perforation and hemorrhage. Another retrospective study from the United Kingdom concluded that 60% of their patients did not require chemotherapy after a second evacuation (Pezeshki et al. 2004). Until recently, there was only one published prospective study from Iran evaluating the clinical response to a second curettage, with a small sample size of 12 (Yarandi et al. 2014): 83% of patients did not require chemotherapy and were cured by a second curettage. Eight percent of patients experienced a complication such as uterine perforation. A second curettage has not been considered standard practice. Most practitioners believe that a second curettage should be reserved for patients who experience significant vaginal bleeding and anemia after the first curettage. The GOG recently published a multicenter prospective phase II study evaluating the efficacy and safety of a second curettage in lieu of chemotherapy for patients with low-risk GTN (persistent GTD). The study population included women with nonmetastatic low-risk GTN. Patients whose first curettage

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revealed choriocarcinoma, PSTT, or ETT were excluded. Patients with previously treated low-risk GTN were excluded. The method of evacuation was not specified by the study but could include intraoperative ultrasound localization of the residual trophoblast or directed hysteroscopic resection. Forty percent of the patients were cured after the second curettage with only 10% of patients experiencing a complication. 1.6% of patients experienced uterine perforation that was managed by observation, 6.7% grade 1, and 1.6% grade 3 incidents of uterine hemorrhage as defined by the CTCAE 3.0. They concluded that a second curettage as initial treatment for low-risk GTN cures 40% of patients without significant morbidity (Osborne et al. 2016). Table 6 provides a summary of the abovereferenced studies evaluating the use of second curettage in the setting of low-risk GTN. Generally, the decision for second curettage should not be taken lightly, and patients must be counseled regarding the risks including hysterectomy if profuse bleeding and/or uterine perforation is encountered. Whether or not to perform a second curettage should be determined on a case-by-case basis given that methotrexate and actinomycin D are generally well tolerated and have excellent response rates.

disease (Suzuka et al. 2001). They treated 115 women with single-agent chemotherapy (the majority treated with etoposide) and then performed interval hysterectomy. Adjuvant hysterectomy decreased the total dose of etoposide given to achieve primary remission in women with nonmetastatic disease. There was no difference in the number of chemotherapy cycles required for remission in patients with metastatic disease. Thus, the authors concluded that adjuvant hysterectomy is a viable option for women who have completed childbearing and whose disease is confined to the uterus. Another study also concluded that adjuvant hysterectomy significantly reduced the amount of chemotherapy used to achieve remission (Hammond et al. 1980).

High-Risk GTN: Chemotherapy Unlike treatment of low-risk GTN, high-risk GTN should be treated with combination regimens, as opposed to single-agent therapy. High-risk GTN patients are at risk of developing drug resistance to methotrexate when it is used as a single agent. Below are the most widely studied combination regimens and associated toxicities:

(a) Cyclophosphamide, hydroxyurea, Adjuvant Hysterectomy actinomycin D, methotrexate, doxorubicin, Historically, the accepted indications for hystermelphalan, and vincristine (CHAMOMA). In ectomy in women with GTN were removal of 1981 the GOG instituted a prospective ranchemoresistant disease and to control hemorrhage domized protocol comparing CHAMOMA or infection in emergency cases. However, a hysand methotrexate, actinomycin D, and terectomy can be employed to help decrease the chlorambucil (MAC) (Curry et al. 1989). At amount of chemotherapy required for treatment of that time, MAC was the standard of care for low-risk GTN. The Japanese published a prospecpatients with high-risk disease, and their goal tive trial evaluating the efficacy of adjuvant hyswas to find a less toxic and more effective terectomy in women with and without metastatic Table 6 Efficacy of second curettage for persistent GTD/low-risk GTN Author van Trommel et al. (2005) Pezeshki et al. (2004) Yarandi et al. (2014) Osborne et al. (2016) a

Year 2005 2004 2014 2016

Study type Retrospective, multicenter Retrospective, multicenter Prospective, single institution Prospective, multicenter

Patients who underwent second curettage for persistent GTD

No.a 85 282 12 60

Response rate (%) 9.4 60 83 40

Complication rate 4.8% n.a. 8% 10%

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(b)

(c)

(d)

(e)

Diagnosis and Management of Gestational Trophoblastic Disease

regimen. The study, however, concluded the opposite; the CHAMOMA regimen was more toxic and possibly less effective. It closed prematurely because of a 30% death rate in the CHAMOMA arm, compared to a 4% death rate in the MAC arm. MAC: This regimen has a response rate of approximately 77% and was routinely used up until the 1990s when the combination regimen of EMA-CO was found to be well tolerated and has a response rate of approximately 83% (Curry et al. 1989; Bower et al. 1997). EMA-CO has now become the preferred first-line combination regimen in the United States and Europe. MEA: This regimen, like EMA-CO, uses etoposide, methotrexate, and actinomycin D but omits the use of etoposide and Oncovin (vincristine); it has a 74.4% response rate (Matsui et al. 2000). It has been favored by some European centers because of its tolerability. 5-Flurouracil, methotrexate, etoposide (5-FUME): This regimen is mostly used in China and has an 80.8% remission rate in high-risk patients, which appears to be comparable to the published results seen with EMA-CO. It also appears that the toxicity profile of this regimen may be slightly better than that of EMA-CO. However, this regimen is far less studied, and further investigation is warranted (Wang et al. 2006). EMA-CO: In the late 1970s, it was discovered that etoposide was a very effective chemotherapeutic agent for GTD. EMA-CO was subsequently formulated by Newlands et al. (1986).

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Table 7 outlines the treatment regimen. As mentioned above, complete response rates and long-term survival rates of well over 80% have been reported with this regimen (Newlands et al. 1991). The toxicities of this regimen are manageable with the most common being anemia and neutropenia which may require a treatment delay of about a week (Schink et al. 1992; Escobar et al. 2003). Colony-stimulating factors (G-CSF 300 μg subcutaneous) can be administered on days 9–14 of the cycle if any neutropeniarelated treatment delays are experienced. Treatment delays should be minimized as resistance can develop if interruption is experienced. This regimen is now the preferred first-line regimen for high-risk GTN.

Management of PSTT/ETT Table 2 reviews the clinical presentation and histopathologic findings of PSTT/ETT. They are slower growing, more chemoresistant, metastasize later, and more frequently involve the lymph nodes compared to other forms of GTN. As such, the treatment approach is different and their management is not dictated by the WHO classification system given that the use of single-agent chemotherapy is not appropriate. Treatment is determined by a stage-adapted model using two independent poor prognostic factors: (1) an interval of 48 months from the causative pregnancy and (2) stage IV disease. An interval of 48 months since causative pregnancy is a significant independent predictor of survival

Table 7 EMA-CO regimen Day 1

2

8

Agents Etoposide Actinomycin D Methotrexate Etoposide Actinomycin D Folinic acid Cyclophosphamide Vincristine

Dosing 100 mg/m2 IV over 30 min 0.5 mg IV push 100 mg/m2 IV and 200 mg/m2 IV in 1000 mL of D5W over 12 h 100 mg/m2 IV over 30 min 0.5 mg IV bolus 15 mg IM or PO every 12 h for four doses starting 24 h after initiation of methotrexate 600 mg/m2 IV 1.0 mg/m2 IV push

Adopted and modified from Escobar et al. (2003) Repeat cycle on days 15, 16, and 22 (every 2 weeks)

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and helps to identify patients who would benefit from high-risk platinum-containing or investigational regimens. This applies to both PSTT and ETT. Specimens must be sent for genetic analysis to determine the causative pregnancy. Patients presenting less than 48 months from causative pregnancy have a 10-year overall survival of 95%, as opposed to a 10-year overall survival of 20 % for those presenting greater than or equal to 48 months from causative pregnancy. In general, stage I tumors are offered surgery including total hysterectomy and removal of suspicious/enlarged retroperitoneal lymph nodes. They do not benefit from adjuvant chemotherapy if the index pregnancy was less than 48 months from presentation as the 10-year survival is 100%. If the patient has stage I disease and the causative pregnancy was 48 months from presentation, then both surgery and systemic therapy are indicated. This also stands for patients with stages II–III disease. Patients with stage IV disease should be offered aggressive systemic therapy, irrespective of time frame from index pregnancy, as their 10-year overall survival is 40% (Table 3).

Management of Refractory/Persistent Disease GTN that does not respond to first-line treatment is said to be resistant or refractory. Resistance to a particular chemotherapeutic regimen is evidenced by a plateau or rise in beta-hCG levels. Approximately 5% of low-risk patients and 25% of highrisk patients will have an incomplete response or

experience a recurrence following the first-line therapy (Lurain and Nejad 2005). In this setting, salvage chemotherapy and surgical resection, when appropriate, are employed. A new WHO score must be assigned, and treatment is once again determined based on low- versus high-risk WHO score.

Low-Risk Refractory GTN In treating low-risk GTN, if resistance to methotrexate is noted, it is common practice to use the sequential 5-day actinomycin D, followed by MAC or EMA-CO if further salvage treatment is required (Alazzam et al. 2012b).

High-Risk Refractory/Recurrent GTN Patients with persistent or recurrent high-risk GTN who develop resistance to methotrexatecontaining regimens should be treated with platinum-containing combination regimens. EMA-EP substitutes etoposide and cisplatin for cyclophosphamide and Oncovin in the EMA-CO protocol and is commonly the initial approach employed for patients who responded to EMA-CO and have plateauing beta-hCG levels or experience a recurrence (Table 8) (Lurain and Nejad 2005). Response rates can be as high as 75% in patients who previously failed EMA-CO. This regimen is moderately toxic; in particular, it can be nephrotoxic and myelosuppressive; thus, renal function must be closely monitored (Newlands et al. 2000).

Table 8 EMA-EP schedule Day EP 1 EMA 1

2

Agents

Dosing

Etoposide Cisplatin

150 mg/m2 IV in 250 mL NS over 30 min 25 mg/m2 IV in 1 L NS þ 20 mmol KCL 4 h

Etoposide Methotrexate Actinomycin D Folinic acid

100 mg/m2 IV in 250 mL NS over 30 min 300 mg/m2 IV in 1 L NS over 12 h 0.5 mg IV bolus 15 mg PO or IMa BID for four doses 24 h after start of methotrexate

Adopted and modified from Newlands et al. (2000) EP and EMA are alternated at weekly intervals a The decision as to route of administration depends on development of nausea and ability to tolerate oral intake

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Other regimens have also been described for use in this setting: BEP (bleomycin, etoposide, and cisplatin), VIP (vinblastine, ifosfamide, and cisplatin), ICE (ifosfamide, cisplatin, and etoposide), and TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide) (Lurain and Nejad 2005; Wang et al. 2008). At the Brewer Trophoblastic Disease Center, BEP is the first choice for treating highrisk patients who are resistant to EMA-CO/EMAEP (Lurain and Nejad 2005). Charing Cross Hospital in London has presented TP/TE as an effective, relatively well-tolerated salvage regimen for patients with heavily pretreated high-risk GTN (Wang et al. 2008). Figure 1 provides a proposed chemotherapy treatment algorithm for both low-risk/high-risk GTN and refractory disease as described above. It is important to note that refractory cases should be referred to a trophoblastic disease center for consultation.

Non-gestational Trophoblastic Tumors (Non-GTT) In the setting of high-risk refractory GTN, one must also think of and evaluate for non-gestational trophoblastic tumors (Alifrangis Fig. 1 Proposed chemotherapy treatment algorithm. (Abbreviations: WHO World Health Organization, EMA-CO etoposide, methotrexate, actinomycin D, cyclophosphamide, and Oncovin, EMA-EP etoposide, methotrexate, actinomycin D, etoposide, and cisplatin, BEP bleomycin, etoposide, and cisplatin, ICE ifosfamide, cisplatin, and etoposide, TP/TE paclitaxel, cisplatin/ paclitaxel, and etoposide)

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et al. 2013). These are choriocarcinomas that are not associated with pregnancy. Oftentimes, the distinction can be made on histopathology by finding the absence of syncytiotrophoblasts. However, some non-GTTs can exhibit trophoblastic differentiation making the distinction difficult. Genetic testing of the tumor with microsatellite genotyping can be employed to examine the genetic origin of these tumors (Fisher et al. 2007). Non-GTTs do not respond to chemotherapy and have a very poor prognosis; being able to distinguish between GTT and non-GTT helps optimize patient care.

Experimental Therapies for Chemoresistant GTN: Immunotherapy, High-Dose Chemotherapy, and Molecularly Targeted Agents Recently, immunotherapy has been found useful in the setting of chemoresistant GTN as invasive moles, and choriocarcinomas strongly express programmed death ligand 1 (PDL1). Several case reports have described promising results. In one series, pembrolizumab, an anti-PD1 checkpoint inhibitor, was administered to four patients

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with chemoresistant GTN. Three of the four patients had complete and durable responses. All the patient’s tumors had >90% PDL1 expression on immunohistochemistry. In addition, the three patients who responded to pembrolizumab were noted to have tumor-infiltrating lymphocytes (TILs) which were not present in the patient who did not respond. This may indicate that TILs are involved in response to anti-PD1 therapy. Two of the four patients in this series had PSTT/ETT. Both of these patients were responders. PSTTs and ETTs express PD-L1 to a lesser degree than invasive moles and choriocarcinomas; nevertheless, anti-PD1 treatment has been found promising in these histologic types as well. It has proven difficult to pursue prospective clinical trials due to the rarity of this tumor, particularly in the setting of chemoresistant disease. Thus far, there has been one reported phase II clinical trial evaluating immunotherapy in GTN. Avelumab, an anti-PDL1 agent, was administered to 15 patients with low-risk GTN who progressed after first-line chemotherapy with methotrexate and folinic acid; the primary endpoint was rate of hCG normalization. Eight patients (53%) had hCG normalization after a median of nine cycles and none had a subsequent relapse. This can be considered rather low when compared to the approximate 75% complete remission rate for second-line actinomycin D chemotherapy, which is the standard regimen given to similar patients. Avelumab had a favorable toxicity profile but not much different when compared to actinomycin D. One must also consider the potential longlasting effects of immunotherapy in patients with low-risk GTN, especially related to fertility, though one patient treated with avelumab was reported to have a successful pregnancy. At present, until further studies are performed, immunotherapy may best be employed in the treatment of high-risk refractory/recurrent disease. The avelumab TROPHIMMUN trial will go on to investigate the efficacy of avelumab in patients with resistance to combination chemotherapy in cohort B. There is also a planned phase II trial investigating the use of pembrolizumab for chemoresistant GTN on patients who have failed

J. Garcia-Sayre et al.

multi-agent chemotherapy. These trials will help define the role of immunotherapy in this difficultto-treat patient population. Another potential therapy for this challenging patient population is high-dose chemotherapy with peripheral blood stem cell support which has been used in the setting of refractory choriocarcinomas and poor-prognosis PSTT/ETT. It appears to be active in this patient population with reported 41% remission rates, but it is not without significant toxicity, reporting three treatment-induced deaths. Antiangiogenic and molecularly targeted agents may also have a potential role in chemoresistant disease. One case report describes the use of bevacizumab in combination with an anti-endoglin monoclonal antibody in a patient who failed multiple lines of combination chemotherapy including high-dose chemotherapy with stem cell support who achieved a durable complete remission.

Special Considerations Vaginal Metastases The incidence of vaginal metastasis in choriocarcinoma is 8.6% (Yingna et al. 2002). The vagina is the second most common metastatic site in GTN, with the lung being the most common. These patients present with friable, vascular lesions located in the anterior wall of the lower vagina. Though performing a biopsy for diagnostic conformation may be tempting, it puts the patient at great risk for hemorrhage and is therefore discouraged when metastatic GTN is suspected. If patients present with spontaneous hemorrhage, vaginal packing with the use of hemostatic agents should be employed. Selective angiographic embolization by interventional radiology is another viable option in the setting of acute hemorrhage. Treatment for vaginal metastasis includes systemic treatment with chemotherapy as well as local injection with 5-FU (Yingna et al. 2002).

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Brain Metastases Metastases to the brain and central nervous system (CNS) are observed in up to 10–15% of patients with GTN. CNS involvement is frequent enough that it is one of the criteria used to assign patients to the high-risk category. Treatment of CNS metastasis has evolved to include whole brain radiation (WBRT). It has shown to have significant therapeutic benefit in the treatment of GTN with improved overall survival. The survival of patients with metastatic GTN to the brain is excellent if extracranial disease is controlled (Schechter et al. 1998). It is recommended that WBRT be initiated simultaneously with the start of multi-agent systemic chemotherapy (Yordan et al. 1987). Should chemotherapy be initiated before WBXRT, there is increased risk of intracranial hemorrhage. Treatment initiation with WBRT can reduce the incidence of hemorrhage and resultant sequela in the first 2 weeks of chemotherapy administration (Schechter et al. 1998). When treating patients with brain metastases, the systemic dose of methotrexate administered IV must be increased because the concentrations of methotrexate in the cerebrospinal fluid have been found to be less than 5% of plasma concentrations. The use of high-dose methotrexate regimens without concomitant WBRT has achieved remission rates as high as 69%; the addition of WBRT can increase remission rates to 78% (Schechter et al. 1998). Intrathecal chemotherapy in conjunction with systemic chemotherapy has also been evaluated in the setting of CNS metastasis and has yielded excellent survival rates (Small et al. 1996). A direct comparison between intrathecal chemo administration and WBRT has yet to be made. However, it appears that treatment with WBRT is more commonly employed. WBRT is not without toxicity. It can lead to long-term sequelae including impaired cognitive function, dementia, behavioral changes, and ataxia. For this reason, in the setting of a solitary brain lesion, craniotomy with surgical resection should be employed in efforts to avoid WBRT. More recently, the use of stereotactic radiosurgery

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has been employed and reported by Charing Cross to treat multiple brain metastases or solitary lesions in locations that are inaccessible with surgery (Soper et al. 2007). If a CNS recurrence is suspected during surveillance and no lesion is noted on imaging, a plasma to spinal fluid ratio can be obtained. In the absence of brain metastases, the spinal fluid beta-hCG level is proportional to that of plasma. A plasma to spinal fluid ratio less than 60 is confirmatory of CNS recurrence (Bagshawe and Harland 1976). Overall patients with brain metastases have a good prognosis; however, those who develop brain metastases during treatment with systemic therapy or recur to brain after WBRT have the poorest prognosis (Evans et al. 1995).

Reproductive Outcomes After Treatment for GTN GTN affects women of reproductive age; thus, fertility and reproductive outcomes following treatment are of utmost importance. Studies evaluating the reproductive outcome of patients treated for both low- and high-risk GTN have concluded that reproductive outcomes do not differ from the general population. In addition, the chemotherapy regimen does not affect reproductive performance when comparing single-agent methotrexate to multi-agent therapy (Woolas et al. 1998). However, data regarding the risk of congenital malformation appears to be conflicting; while some studies conclude that the risk is similar to that of the general population in both frequency and type for both single- and multi-agent therapy, another concluded that the risk of congenital heart abnormalities (particularly ventricular septal defects) is higher in the group receiving multi-agent treatment (Goto et al. 2004). The overall risk of congenital anomalies is relatively low but should be discussed with patients receiving multi-agent therapy for GTN. The American Society of Clinical Oncology stresses the importance of discussing the potential for infertility with all patients undergoing treatment for cancer. While treatment for GTN appears to

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have minimal effect on reproductive outcomes, the possibility of infertility should be addressed and documented.

Post-molar Prophylactic Chemotherapy To date, the use of chemotherapy for primary prevention of post-molar GTN remains controversial as there is conflicting data regarding efficacy (Ayhan et al. 1990). Patients with high-risk hydatidiform moles, as defined in Table 9, have up to a 50% chance of developing post-molar GTN (Uberti et al. 2009). It has been argued that chemotherapy administered at the time of uterine evacuation in this patient population can prevent the development of GTN; however, studies have shown that prophylactic chemotherapy is not without risk. Those who receive chemoprophylaxis are known to have prolonged hospital stays and chemotherapy-related toxicities and require more courses of chemotherapy to cure subsequent GTN, all of which may seem too risky for a disease with an excellent cure rate. Nevertheless, it does not affect reproductive outcomes and has also been shown to reduce psychological angst, medical visits, and operational costs associated with management of post-molar GTN/persistent GTD (Uberti et al. 2009). Though the use of

chemoprophylaxis is not widely accepted, most agree that its use is most appropriate for patients with high-risk moles in settings where serial betahCG levels cannot be followed and in those with poor compliance, such as in the adolescent population (Uberti et al. 2006). Table 9 offers a scoring system for the prediction of developing GTN in women with a molar pregnancy. Women with a score of greater than or equal to 4 are deemed to be high-risk of developing GTN and may benefit from post-molar prophylactic chemotherapy. Table 10 provides a summary of the published studies evaluating the efficacy of post-molar chemoprophylaxis. Methotrexate administered at 0.4 mg/kg IM for 5 days did not prove effective for post-molar prophylaxis. However, actinomycin D at 1.25 mg/m2 IV X 1 dose has shown to reduce the rate of post-molar GTN in high-risk molar pregnancies.

Phantom Beta-hCG, Quiescent GTD, and Physiologic Beta-hCG After treatment for GTN is complete, it is recommended that quantitative serum beta-hCG levels be followed monthly for 6–12 months after normalization as the risk of relapse is about 3% during the first year and significantly decreases thereafter (Lurain 2011). Women with persistent

Table 9 Risk scoring system for the prediction of developing GTN in women with a molar pregnancy Score Ultrasound diagnosis of HM in current pregnancy Uterine size for gestational age at diagnosis of molar pregnancy Beta-hCG levels (mU/mL) Diameter of theca lutein cyst (cm)} Patient’s age (years) Associated medical complicationsa

0 Partial

1 Complete

2 Recurrent

3 –

Size ¼ or < dates

Size 4 weeks greater than corresponding gestational age

Size 8 weeks greater than corresponding gestational age

Size 12 weeks greater than corresponding gestational age

˂50,000

50,000–100,000

100,000–1,000,000

>1,000,000

–

10

– –

–

Adopted and modified from Uberti et al. (2006) Final score of 1 mm Stage II Tumor of any size with extension To lower one third of the urethra, Lower one third of the vagina, Lower one third of the anus with negative nodes Stage III Tumor of any size with extension to upper part of adjacent perineal structures, or with any number of nonfixed, nonulcerated lymph node IIIA Tumor of any size with disease extension to upper two thirds of the urethra, Upper two thirds of the vagina, bladder mucosa, rectal mucosa, Or regional lymph node metastases 5 mm IIIB Regional lymph node metastases >5 mm IIIC Regional lymph node metastases with extracapsular spread Stage IV Tumor of any size fixed to bone, or fixed, Ulcerated lymph node metastases, or distant metastases IVA Disease fixed to pelvic bone, or fixed or Ulcerated regional lymph node metastases IVB Distant metastases Depth of invasion is measured from the basement membrane of the deepest, adjacent, dysplastic Tumor-free rete ridge (or nearest dysplastic rete peg) to the deepest point of invasion Regional refers to inguinal and femoral lymph nodes

The point of changes is that FIGO staging of vulvar cancer has been based mainly on clinical and pathological examinations, but this concept has been revised in the 2021 version of staging, and staging can now be determined by diagnostic imaging if diagnostic imaging (r) is available. Stage IIIA includes extension into the upper two thirds of the urethra, vagina, bladder, and rectal mucosa – they were all stage IVA in 2009 staging. There is no longer a limit to the number of metastases in the lymph nodes in stage IIIA and IIIB. It is expected that these changes will make

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the staging more reflective of the prognosis (Fig. 2).

Tumor Imaging There is currently only limited data available on the efficacy of various imaging modalities for the diagnosis and treatment of primary vulvar cancer, although imaging techniques, such as MRI, CT, and PET/CT, currently play important roles in the diagnosis of local, regional, and distal metastasis for treatment planning. This is especially true in advanced vulvar carcinoma, since these patients need more individualized treatment planning, including surgery and chemo-radiation, to minimize morbidity. Kim et al. reported that imaging with MRI was the most accurate modality for evaluation of the primary lesions. To detect lymph nodal metastasis, combined ultrasound imaging and ultrasoundguided aspiration biopsy was found to be the most reliable method, with its high specificity (82–100%) and sensitivity (80–93%). The sensitivity of MRI for detecting nodal metastasis was moderate (50–89%), but the specificity was high (89–100%). CT may be an important staging tool for nodal and distant metastasis and for surveillance monitoring after treatment, although CT is less sensitive for detecting a nodal metastasis with size 85% of them occurring in less developed countries (Bray et al. 2018).

The Role of Human Papillomavirus and Vaccines Against It Virtually all cases of cervical cancer are caused by specific types of human papillomavirus (HPV). There are more than 100 types of HPV, of which more than 40 can be sexually transmitted. Among these, at least 13 are considered to be high-risk cancer-causing types (Bouvard et al. 2009). Two of these high-risk types, HPV-16 and HPV-18, cause about 70% of cervical cancers worldwide (Wheeler et al. 2009). HPV is mainly transmitted through sexual contact, and most people are infected with HPV shortly after their first sexual encounter. Despite the high prevalence of HPV, the majority of HPV infections clear up, and only a minority persist and progress to cervical intraepithelial neoplasia (CIN) or invasive cancer. The 2 year clearance rate of HPV infections is as high as 90% (Ho et al. 1998). As our understanding of the role played by HPV infections in cervical cancer has improved, vaccines against HPV have emerged as an important cancer prevention tool. Initially, two first-generation vaccines, the bivalent vaccine Cervarix (GSK, Belgium) and the quadrivalent vaccine Gardasil (Merck, USA), can protect against HPV-16/18 and HPV-16/18/6/11, respectively. Such vaccines were found to be highly effective at preventing CIN, adenocarcinoma in situ, and invasive cervical cancers due to HPV-16 and HPV-18 as well as the anogenital warts associated with HPV types 6 and 11 in previously unexposed women (Ault and Group FIS 2007).

Epidemiology Prevalence Worldwide, cervical cancer is the fourth most common form of cancer affecting women, with approximately 570,000 new cases arising in 2018 and accounts for 6.6% of all female cancer. It is estimated that cervical cancer causes 311,000

Risk Factors The risk factors for cervical cancer are mostly associated with an increased risk of acquiring an HPV infection. They include first having sexual intercourse at a young age, having multiple sexual partners, delivering your first child at a young age, experiencing an increased number of full-term

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pregnancies (Berrington de González et al. 2007; Muñoz et al. 2002), and having a history of sexually transmitted infections (Anttila et al. 2001). Oral contraceptive use appears to be associated with an increased risk of cervical cancer, especially adenocarcinoma (Appleby et al. 2007), and cigarette smoking seems to be associated with an increased risk of squamous cell carcinoma but not adenocarcinoma (Berrington de González et al. 2007). As people living with HIV/AIDS are susceptible to infection by oncogenic viruses including HPV, cervical cancer is considered to be an AIDS-defining cancer together with Kaposi’s sarcoma and some types of lymphoma (Rubinstein et al. 2014).

Diagnosis

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tumor of the endocervix, or an ulcerative tumor. Tumors that arise in the endocervical canal can result in an enlarged, indurated cervix with a smooth surface (referred to as a “barrel-shaped cervix”). Tumor size and parametrial involvement are best assessed using a rectovaginal examination. Palpation of the liver, supraclavicular lymph nodes, and groin should be used to diagnose distant metastasis. In women with visible lesions, a suspected diagnosis of cancer must be confirmed by a biopsy of the lesion. Symptomatic women without visible lesions and those who only present with abnormal cervical cytological findings should undergo a colposcopy-directed biopsy (followed by endocervical curettage) and, if necessary, diagnostic conization. Conization can also be used to determine whether conservative or radical surgery is required in cases of microinvasive cancer.

Clinical Manifestations Early cervical cancer patients are frequently asymptomatic; therefore, cancer screening is important for identifying such patients. The first symptom of early cervical cancer is usually a watery or mucinous vaginal discharge, but this often goes unnoticed by the patient. The most common presenting symptom is irregular, intermenstrual, or abnormal vaginal bleeding after sexual intercourse (vaginal bleeding, after sexual intercourse). As the cervical tumor enlarges, the bleeding episodes become heavier and more frequent. Indicators of more advanced disease include pain that seems to arise from the flank or leg (such pain is usually a secondary symptom of pelvic wall or sciatic nerve involvement); dysuria, hematuria, or rectal bleeding resulting from bladder or rectal invasion; fatigue; weight loss; loss of appetite; or a single swollen leg caused by lymphatic or venous blockade.

Taging Clinical Staging The International Federation of Gynaecology and Obstetrics (FIGO) cancer committee revised the staging system in 2018 (Bhatla et al. 2019). Although the FIGO classification of cervical cancer has originally been based on the results of clinical examinations, in the new staging system, imaging is formally incorporated as a source of staging information and as a supplement to clinical examination (i.e., examinations performed under anesthesia, cystoscopy, sigmoidoscopy, intravenous pyelography, or colposcopy) to obtain an accurate description of tumor spread (Table 1).

Diagnostic Studies Diagnosis During physical examinations, the cervix and entire vagina should be inspected and palpated to identify overt tumors or subepithelial vaginal extension. The lesion can manifest as an exophytic tumor in the exocervix, an infiltrating

Tumor Size and Local Spread It remains unclear whether imaging studies can assess tumor size and local spread more accurately than clinical examinations in cervical cancer patients. However, a prospective multiinstitutional study involving 208 women with early-stage cervical cancer showed that magnetic

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Table 1 2018 FIGO staging system for carcinoma of the cervix uteria, b Stage Stage I IA IA1 IA2 IB IB1 IB2 IB3 Stage II IIA IIA1 IIA2 IIB Stage III IIIA IIIB IIIC IIIC1 IIIC2 Stage IV IVA IVB

Descriptions Carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded) Invasive carcinoma that can be diagnosed only with microscopy, with maximum depth of invasion, 5 mmc Stromal invasion 2 cm and  4 cm in greatest dimension Tumor measures >4 cm in greatest dimension Carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall Limited to the upper two-thirds of the vagina without parametrial involvement Lesion 4.0 cm in greatest dimension Lesion >4 cm in greatest dimension With parametrial involvement but not up to the pelvic wall The tumor involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes Involves the lower third of the vagina, with no extension to the pelvic wall Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney from tumor Involvement of pelvic and/or para-aortic lymph nodes, irrespective of tumor size and extentd Pelvic lymph node metastasis only Para-aortic lymph node metastasis The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV Spread of the growth to adjacent organs Spread to distant organs

a

Adopted and modified from the original source Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathologic findings supersede imaging and clinical findings c The involvement of vascular/lymphatic spaces should not change the stage allotment d Stage IIIC should be annotated with r (radiology) or p (pathologic analysis) to indicate the method used to allocate this stage. Imaging modality or pathologic technique should also be documented. When in doubt, the lower staging should be assigned b

resonance imaging (MRI) is superior to computed tomography (CT) and clinical examinations for evaluating tumor size (Mitchell et al. 2006). Moreover, in a meta-analysis of 57 studies, it was suggested that MRI is superior to CT for evaluating parametrial involvement (Bipat et al. 2003).

Lymph Node and Distant Metastases The information regarding the lymphatic spread of cervical cancer is important in determining its prognosis and the most appropriate treatment. Currently, the options for evaluating for lymph node metastasis include lymph node dissection,

imaging studies, or both. The initial evaluation of the lymph nodes is usually performed with CT to minimize costs, but positron emission tomography (PET) and PET/CT can evaluate patients’ lymph node status more accurately. According to a meta-analysis of 72 studies involving 5042 women (Selman et al. 2008), the sensitivity and specificity of the abovementioned imaging modalities for detecting lymph node metastases are as follows: PET, 75% and 98%, respectively; MRI, 56% and 93%, respectively; and CT, 58% and 92%, respectively. PET/CT can also be useful in detecting distant metastasis. According to a previous report, the

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sensitivity, specificity, positive predictive, and negative predictive values for detecting distant metastasis were 54.8%, 97.7%, 79.3%, and 93.1%, respectively. Considering the high diagnostic performance, PET/CT should be included in the staging evaluation of patients with cervical cancer.

Histology Squamous cell carcinoma is the most common histological subtype, accounting for 60–70% of invasive carcinomas. Adenocarcinoma and adenosquamous carcinoma comprise 20–25% of all cases, and the other types account for 10–15% of cases. However, the proportion of cervical adenocarcinoma has recently been increasing (Smith et al. 2000).

Spread and Metastasis Direct Invasion Cervical cancer principally spreads via direct local invasion of the adjacent tissues and lymphatic system and, less commonly, through blood vessels. Initially, the malignant cells penetrate the basement membrane, and then progressively infiltrate into the underlying stroma. Cervical tumors grow laterally into the paracervical and parametrial areas and can also invade the uterine cavity and vagina, before progressing into the urinary bladder and rectum.

Lymphatic Spread The lymphatic spread of cervical cancer occurs relatively early, and the risk of lymph node metastasis increases with the depth of invasion. The former FIGO staging systems did not take lymph node involvement into account, but the reported incidence of lymph node metastasis in each stage of cervical cancer was as follows: stage IA1, 0–0.8%; stage IA2, 0–7.4%; stage IB,

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11.7–23.2%; stage IIA, 10.0–26.8%; and stage IIB, 35.2–48.6% (Buckley et al. 1996; Cosin et al. 1998; Creasman et al. 1998; Elliott et al. 2000; Hirai et al. 2003; Kasamatsu et al. 2002; Lee et al. 1989, 2006; Östör and Rome 1994; Poynor et al. 2006; van Meurs et al. 2009). Moreover, according to a recent study involving 62,212 women identified from the National Cancer Database from 2004 to 2015, the incidence of lymph node metastasis according to the 2018 FIGO staging for cervical cancer is 1.6% for stage IA1, 5.5% for stage IA2, 9.3% for stage IB1, 19.5% for stage IB2, 29.0% for stage IB3, 17.5% for stage IIA1, 30.9% for stage IIA2, 31.1% for stage IIIA, 34.6% for stage IIIB, 41.7% for stage IVA, and 73.5% for stage IVB (Wright et al. 2019). The lymphatic spread of cervical cancer usually occurs in an orderly fashion from the pelvic lymph nodes, most commonly the obturator or external iliac lymph nodes, to the common iliac lymph nodes, and then the para-aortic lymph nodes (PALN). However, cervical cancer can directly metastasize to the PALN, although this is very rare. According to a retrospective study involving 61 patients with invasive cervical cancer who displayed solitary positive lymph nodes after radical hysterectomy (RH) plus systematic lymphadenectomy, metastasis to each nodal site occurred at the following frequencies: external iliac lymph nodes, 43%; obturator lymph nodes, 26%; parametrial lymph nodes, 21%; common iliac lymph nodes, 7%; presacral lymph nodes, 1%; and PALN, 1% (Bader et al. 2007). Ovarian involvement due to direct invasion is rare. Instead, it usually occurs via lymphatic spread. In a previous study of patients with stage IB cervical cancer, the Gynecologic Oncology Group reported that ovarian involvement was detected in 4 of 770 patients (0.5%) with squamous cell carcinoma and 2 of 121 patients (1.7%) with adenocarcinoma (Sutton et al. 1992). Moreover, a more recent retrospective study conducted in Japan has suggested that the incidence of ovarian metastasis was 0.7% (27 of 3710) in patients with squamous cell carcinoma and 2.2% in patients with adenocarcinoma or adenosquamous carcinoma (42 of 1915) (Matsuo et al. 2018).

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Hematogenous Metastasis Hematogenous metastasis can also occur in cervical cancer patients. The most common sites of hematogenous spread are the lungs, liver, and bone.

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PET/CT over the surgical staging of the PALN, in terms of the complications rate and survival, are currently being evaluated in a well-designed randomized trial (PALDISC trial) (Tax et al. 2018).

Treatment Surgical Staging of the PALN PALN metastases are seen in 9–24% of stage II cases, 12–38% of stage III cases, and 13–50% of stage IVA cases (Heller et al. 1990; Michel et al. 1998). However, even when PET is employed, false-negative results in the PALN have been recorded in 12–22% of patients (Gouy et al. 2012). Failure to detect metastases to the PALN can lead to suboptimal treatment and lower survival. Pretreatment surgical staging might be beneficial as it allows adequate histological evaluations of the retrieved PALN and can lead to treatment modification in certain cases. In addition, debulking enlarged positive lymph nodes during surgical staging might be of therapeutic benefit. However, pretreatment surgical staging is associated with an increased postoperative morbidity rate and treatment delays. According to a previous report, the mean complication rate of surgical PALN staging procedures is 9% (range: 4–24%) (Fine et al. 1995; Hughes et al. 1980). Retrospective studies have suggested that a retroperitoneal approach, laparoscopic surgery, and robotic surgery are all associated with lower rates of postoperative complications compared with an intraperitoneal approach (Smits et al. 2014). Recently, the results from a randomized study evaluating the survival benefit of pretreatment surgical staging, including removal of bulky lymph nodes, in patients with locally advanced cervical cancer have been reported. In this study, the disease-free survival of surgical staging group was slightly superior to that of clinical staging group, but the difference was not statistically significant (Marnitz et al. 2020). Currently, the comparative advantages of

The treatment of invasive cervical cancer involves the management of both the primary lesion and any metastatic disease. For early-stage cervical cancer, both surgery and radiotherapy can be used to treat the primary lesion. In contrast, radiotherapy is the only curative treatment for advanced disease. The choice of treatment should be based on the extent of the cervical cancer, the patient’s age and general health, and the complications of the patient. The advantages of a primary surgical approach are as follows: First, it facilitates accurate tumor staging. Second, it allows ovarian function to be preserved in premenopausal patients. Third, it makes it possible to remove bulky lymph nodes that cannot be cured with external beam radiotherapy. The main advantage of radiotherapy is that it is applicable to almost all patients, whereas radical surgery cannot be used to treat patients with medically inoperable disease.

Surgical Treatment Classification of Radical Hysterectomy The first case series in which RH was used to treat cervical cancer was reported by Ernst Wertheim in 1912 and was followed by a study by Okabayashi (1921; Werheim 1912). Today, RH is commonly categorized according to the amount of the parametrium that is resected. In 1974, Piver et al. published a classification of RH (Piver et al. 1974) (Table 2). This classification is still widely used, although a newer classification has been proposed to overcome the ambiguities of the original one (Querleu and Morrow 2008) (Table 3).

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Table 2 Classification of radical hysterectomy according to Piver, Rutledge, and Smitha Class Description Class I: Extrafascial hysterectomy Deflection and retraction of the ureters without dissection of the ureteral bed Uterine artery is laterouterine sectioned and ligated Uterosacral ligament and cardinal ligament are not removed No vaginal portion is excised Class II: Modified radical hysterectomy (Wertheim) Ureters are freed from the paracervical position but are not resected from the pubovesical ligament Uterine arteries are ligated just medial to the ureter Uterosacral ligaments are resected midway between the uterus and their sacral attachments Medial half of the cardinal ligaments are removed Upper one-third of the vagina is removed Elective pelvic lymphadenectomy Class III: Classical radical hysterectomy (Meigs’) Complete dissection of the ureter from the pubovesical ligament to entry into the bladder except for a small lateral part of the pubovesical ligament Uterine vessels are ligated at the origin of the internal iliac artery Uterosacral ligaments are resected at their sacral attachments Cardinal ligaments resected as close to the pelvic wall Upper half of the vagina is removed Routine pelvic lymphadenectomy Class IV: More radical than class III in three aspects (i) Complete dissection of the ureter from the pubovesical ligament (ii) The superior vesicle artery is sacrificed (iii) Upper three-fourths of the vagina is removed Class V: More radical than class IV Involved portions of the distal ureter or bladder are excised a

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Morbidities Associated with Radical Surgery for Cervical Cancer RH is associated with various postoperative morbidities, including bladder dysfunction, sexual dysfunction, and colorectal motility disorders. Accidental damage to the pelvic autonomic nerves during surgery is considered to be a major cause of such morbidities. According to previous studies, bladder dysfunction including incomplete bladder emptying and a need to strain to micturate occur in 16–40% of patients (Bergmark et al. 2006; Kenter et al. 1989), 9–18% of patients suffer constipation (Bergmark et al. 2006; Sood et al. 2002), fecal or flatal incontinence is seen in 33% of patients (Kenter et al. 1989), fistulas develop in 1–6.7% of patients (Kenter et al. 1989; Lee et al. 1989), lymphedema

occurs in 3–19% of patients (Bergmark et al. 2006; Pieterse et al. 2006), and 19–36% of patients experience sexual dysfunction (Bergmark et al. 2006; Pieterse et al. 2006).

Nerve-Sparing Radical Hysterectomy In an effort to reduce the postoperative morbidity rate, nerve-sparing RH (NSRH), which protects the pelvic nerves that can be damaged during RH, was developed by Japanese gynecologists, and the procedure has been improved over the last 20 years (Fujii et al. 2007). A recent meta-analysis suggested that although NSRH exhibited a significantly longer operating time than RH, NSRH results in greater postoperative recovery of pelvic organ function and a lower postoperative morbidity rate than RH (Long et al. 2014).

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Table 3 Classification of radical hysterectomy according to Querleu and Morrowa Class Description Type A: minimum resection of paracervix (extrafascial hysterectomy) The position of the ureters is determined by palpation or direct vision without freeing the ureters from the ureteral bed The paracervix is transected medial to the ureter, but lateral to the cervix The uterosacral and vesicouterine ligaments are not transected at a distance from the uterus Vaginal resection is generally at a minimum, routinely less than 10 mm, without removal of the vaginal part of the paracervix (paracolpos) Type B: transection of paracervix at the ureter (modified or proximal radical hysterectomy) B1: Without removal of lateral paracervical lymph nodes B2: With removal of lateral paracervical nodes The ureter is unroofed and rolled laterally, permitting transection of the paracervix at the level of the ureteral tunnel The caudal (posterior, deep) neural component of the paracervix caudal to the deep uterine vein is not resected At least 10 mm of the vagina from the cervix or tumor is resected Type C: Transection of paracervix at junction with internal iliac vascular system (classical radical hysterectomy) C1: With nerve preservation C2: Without preservation of autonomic nerves Transection of the uterosacral ligament at the rectum and vesicouterine ligament at the bladder The ureter is mobilized completely The length of the vaginal cuff is adjusted to the vaginal extent of the tumor Type D: Laterally extended resections D1: Resection of the entire paracervix at the pelvic sidewall, along with the hypogastric and obturator vessels, exposing the roots of the sciatic nerve D2: Resection of the entire paracervix, along with the hypogastric vessels and adjacent fascial or muscular structures. This resection corresponds to the LEER (laterally extended endopelvic resection) procedure D1 Resection of the entire paracervix at the pelvic sidewall along with the hypogastric vessels, exposing the roots of the sciatic nerve The resection of the inferior gluteal, internal pudendal, and obturator vessels that arise from the internal iliac system D2 D1 plus resection of the entire paracervix with the hypogastric vessels and adjacent fascial or muscular structures a

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Radiotherapy Radiotherapy is an extremely useful treatment for cervical cancer because the uterine cervix is able to tolerate high-radiation doses. Radiotherapy can be used to treat all stages of cervical cancer; however, as the volume of the primary cervical lesion increases, the likelihood of sterilizing it with radiation decreases. Thus, for patients with bulky tumors or locally advanced disease, the risk of locoregional recurrence remains significant, leading to poor survival. Pelvic external beam radiotherapy involving a dose of 50 Gy combined with brachytherapy concurrently with weekly cisplatin is the gold standard treatment for cervical cancer. During such treatment, initial external beam radiotherapy

involving the delivery of 40–45 Gy to the whole pelvis is often necessary to induce tumor shrinkage and facilitate the intracavitary installation of the radiation source. Extended-field radiation therapy is indicated for cervical cancer patients with para-aortic lymph node metastasis. In cases involving gross disease in the parametrial or pelvic lymph nodes, an external beam boost to 60–65 Gy can be administered.

Prognosis The survival outcomes of cervical cancer patients were examined according to the 2018 FIGO staging for cervical cancer in a study of 62,212 women identified from the National Cancer Database

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Table 4 Prognosis of cervical cancer according to 2018 FIGO stagea Overall survival (%) at 5 years IA1 IA2 IB1 IB2 IB3 IIA1 IIA2 IIIA IIIB IIIC1 IIIC2 IVA IVB a

95.8 95.0 91.6 83.3 76.1 70.3 65.3 40.7 41.4 60.8 37.5 24.0 14.7

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from 2004 to 2015, and the results are shown in Table 4 (Wright et al. 2019).

Conclusion Cervical cancer remains a significant health problem for women worldwide. However, the introduction of widespread screening and/or HPV vaccines would significantly reduce its impact. Moreover, the use of multidisciplinary approaches to the treatment of cervical cancer has led to marked improvements in patient outcomes.

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Fertility-Sparing Treatment for Early-Stage Cervical Cancer

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Seiji Mabuchi, Hiromasa Kuroda, K. Kozasa, and Tadashi Kimura

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 Candidate Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 Conization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982 Radical Tracherectomy Plus Pelvic Lymphadenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oncological Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

983 983 983 984 984

Surgical Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984 Adjuvant Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 Neoadjuvant Chemotherapy Followed by Radical Trachelectomy for Tumors 2–4 Cm in Diameter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 Hysterectomy in the Post-Childbearing Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 Reproductive Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fertility Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obstetric Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cesarean Section for Women Who Undergo Radical Trachelectomy . . . . . . . . . . . . . . . . . .

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Oocyte Cryopreservation for Women with Advanced Disease . . . . . . . . . . . . . . . . . . . . . 986

S. Mabuchi (*) Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan e-mail: [email protected] H. Kuroda · K. Kozasa · T. Kimura Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan e-mail: [email protected] © Springer Nature Switzerland AG 2023 D. Shoupe (ed.), Handbook of Gynecology, https://doi.org/10.1007/978-3-031-14881-1_6

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S. Mabuchi et al. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986

Abstract

Fertility preservation is of paramount importance for young women that are diagnosed with early-stage cervical cancer. Women with stage IA1 disease can be treated with conization. Radical trachelectomy has been developed as a surgical method for preserving reproductive function, and the radical trachelectomy procedure has evolved significantly over the last 30 years. The candidates for radical trachelectomy include women of reproductive age with early-stage disease (stage IA2 or IB1) who do not possess any risk factors for recurrence (i.e., a lesion size of >2 cm, lymph node metastasis, or unfavorable histology). Lymphovascular space invasion within the tumor is a risk factor for lymph node recurrence, but is not a contraindication for fertilitysparing surgery in cases in which it is the only risk factor present. Recently, neoadjuvant chemotherapy followed by fertility-preserving surgery has been proposed as an option for patients with larger lesions. Pregnancy after radical trachelectomy is associated with an increased risk of obstetric complications, including preterm delivery, infection, and preterm premature rupture of membranes. However, there are no effective interventions for preventing these complications. Keywords

Cervical cancer · Fertility-preserving surgery · Trachelectomy

Introduction In the United States, 46% of uterine cervical cancers are diagnosed in women below the age of 44 (National Cancer Institute: Browse the SEER Cancer Statistics Review (CSR) 1975–2010).

Thus, information regarding fertility-sparing options is an important part of pretreatment counseling, especially for women of childbearing age that are diagnosed at an early stage. The fertility-sparing options for such patients include conization and radical trachelectomy. Observational studies have suggested that these procedures result in good oncological and obstetric outcomes in carefully selected patients with early-stage cervical cancer.

Candidate Selection Conization Conization Alone Stage IA1 disease without LVSI can be a candidate for conization. A cohort study of stage IA1 squamous cell carcinoma of the uterine cervix that analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database showed that there was no difference between the 5-year survival rates of patients that were treated with conization and those that underwent hysterectomy (98% vs. 99%) (Wright et al. 2010). Thus, stage IA1 patients without lymphovascular space involvement (LVSI) are indicated for conization alone. In cases in which the margins of the excised cone are positive, repeated conization or simple trachelectomy is recommended. Clinicians have to recognize that the risk of preterm delivery is increased after conization if the depth of the excised cone is >10 mm (Kyrgiou et al. 2006). Conization Plus Pelvic Lymphadenectomy As a previous report has shown that 8.2% of stage IA1 patients with LVSI have lymph node metastasis, compared with 0.8% of those without LVSI (Mota 2003). Thus, pelvic lymphadenectomy

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should be included in the fertility-sparing surgical options for stage IA1 patients with LVSI or greater diseases. Although trachelectomy (either simple or radical) plus pelvic lymphadenectomy may be a safer approach for stage IA1 disease when LVSI is present, for women with stage IA1 disease and LVSI, conization plus pelvic lymphadenectomy might also be a useful treatment option (Maneo et al. 2011).

into the endocervical canal, and the length of the canal. According to a previous report, MRI has a high specificity of 98% and positive predictive value of 95% for predicting the distance between the tumor and the internal os of less than or equal to 5 mm (Bhosale et al. 2016).

Neoadjuvant Chemotherapy Before Conization Plus Pelvic Lymphadenectomy Recently, a prospective trial CONTESSA/NEOCON-F aiming to evaluate feasibility and the oncologic outcomes of downstaging tumors >2 cm with neoadjuvant chemotherapy with three cycles of platinum/paclitaxel in women with stage IB2 (2–4 cm) cervical tumors has been initiated (Plante et al. 2019).

Surgical Outcomes

Radical Tracherectomy Plus Pelvic Lymphadenectomy The criteria for radical trachelectomy vary slightly among institutions but remain essentially unchanged from the original set proposed by Roy et al. in 1998 (Table 1) (Roy and Plante 1998). Magnetic resonance imaging (MRI) plays a vital role in the pre-operative assessment of potential candidates for radical trachelectomy as it allows determination of tumor size, extension Table 1 Criteria of radical trachelectomy 1. A strong desire for fertility 2. Histologically proven invasive cervical cancer 3. Squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, without high-risk histology (e.g., neuroendocrine carcinoma) 4. Stage IA1 with lymphovascular space invasion, stage IA2, or stage IB1 5. Tumor size
2 cm 6. Upper endocervical involvement is not present (tumor within 1 cm of the isthmus on MRI is not a candidate) 7. No evidence of lymph node metastasis and distant metastasis

Outcomes

Approximately 10% of planned radical trachelectomy procedures have to be abandoned because of the presence of lymph node metastasis on frozen sections or positive endocervical margins (Plante et al. 2004; Smith et al. 2020).

Surgical Complications Intraoperative Complications The intraoperative complications rate of vaginal radical tracherectomy (VRT) seems to be higher than that of abdominal radical tracherectomy (ART) (5.6% vs. 0.7%) (Pareja et al. 2013; Plante et al. 2011). The most common intraoperative complication of VRT is urinary tract damage. However, in comparisons of laparoscopic-assisted VRT versus laparoscopic-assisted vaginal radical hysterectomy (Marchiole et al. 2007) or ART versus ARH (Cao et al. 2013), all the procedures exhibited similar perioperative complication rates, indicating that radical trachelectomy can be performed safely in carefully selected cases of early-stage cervical cancer. Postoperative Complications The immediate postoperative complications associated with radical trachelectomy include bladder dysfunction, lymphedema, and lymphocele, which are comparable to the complications associated with RH (Pareja et al. 2013). In addition, the specific long-term postoperative complications associated with radical trachelectomy include cervical stenosis, dyspareunia, dysmenorrhea, prolonged amenorrhea, and chronic discharge. Similar rates of these complications are seen after VRT and ART (Beiner and Covens

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2007; Cao et al. 2013; Pareja et al. 2013). The incidence of cervical stenosis is 10–15% of patients. However, the use of anti-stenosis tools may result in reduced incidence. In a review of 1547 patients undergoing radical trachelectomy, the incidence of cervical stenosis in patients with or without anti-stenosis tools was 4.6% or 12.7%, respectively (Li et al. 2015).

Oncological Outcomes A previous study suggested that the oncological outcomes of patients who undergo ART or VRT are similar to those of patients treated with ARH. According to a recent review, these procedures result in recurrence and death rates of approximately 3–5% and 1–2%, respectively (Smith et al. 2020). The site of recurrence is predominantly in the parametrium or pelvis (Beiner and Covens 2007).

Prognostic Factors The risk factors for recurrence have been intensively investigated, and tumors that measure >2 cm in diameter are consistently associated with an increased risk of recurrence. In addition, some studies have suggested that the presence of LVSI (Marchiole et al. 2007; Mathevet et al. 2003; Plante et al. 2011) and deep stromal invasion (DSI) of >10 mm (Diaz et al. 2008) are risk factors for recurrence; however, others have found that they are not associated with a higher risk of recurrence (Hertel et al. 2006; Plante et al. 2011). Although the prognostic significance of LVSI and DSI needs to be investigated further in larger studies, they are not considered to be contraindications for radical trachelectomy, when LVSI or DSI is the only risk factor present.

Surgical Procedures Radical trachelectomy can be performed either through a vaginal, abdominal, extraperitoneal, or minimally invasive (laparoscopic or robotic) approaches.

S. Mabuchi et al.

The first successful trachelectomy procedure was performed via a vaginal approach by Dargent et al. in 1986, and the oncological and reproductive outcomes of patients who underwent VRT were presented at the Society of Gynecologic Oncologists meeting in 1994 (Ribeiro Cubal et al. 2012). A laparoscopic pelvic lymph node evaluation should be performed prior to VRT to rule out lymph node metastasis. The abdominal approach was first reported by Smith et al. in 1997 (Ribeiro Cubal et al. 2012). The main advantages of ART are its greater radicality and feasibility compared with VRT. The extraperitoneal approach, that can remove cervix, parametrial tissue, and pelvic lymph nodes without entering the abdominal cavity, was introduced by Mabuchi et al. in 2016 (Mabuchi et al. 2017). Radical trachelectomy can also be performed via either a laparoscopic (Marchiole et al. 2007) or robotic approach (Persson et al. 2008). A previous retrospective study involving a relatively small number of patients suggested that these approaches are feasible, less invasive, and similarly effective, i.e., achieve comparable oncological outcomes, to conventional vaginal or abdominal approaches (Marchiole et al. 2007). Basically, the procedure for radical trachelectomy begins with the creation of paravesical and pararectal spaces and the dissection of the caudal bladder. Then, after the vesicouterine ligaments and cardinal ligaments have been divided, the cervix is removed. Finally, the uterine corpus and vaginal stump are reconstructed. It remains unclear whether uterine artery preservation should be the norm when performing radical trachelectomy. The endocervical margin of the specimen needs to be evaluated after the cervix has been removed to ensure that no residual disease remains. It is well known that the outcomes of post-conization pregnancies are influenced by the depth and size of the excised cervical tissue specimen (Kyrgiou et al. 2006), which also holds true for post-radical trachelectomy pregnancies. As a shorter cervix can provide an easy route for

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ascending infections, which increase the risk of premature delivery, most clinicians aim to preserve at least 5 mm–1 cm of the endocervix during both procedures. There is no clear consensus regarding whether cervicoisthmic cerclage should be performed during radical trachelectomy or only after a patient has become pregnant. When performed, the knot of the cerclage is tied posteriorly to avoid a theoretical risk of erosion into the bladder.

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Hysterectomy in the Post-Childbearing Period So far, there is no evidence that hysterectomy has beneficial effects in patients that do not want any more children.

Reproductive Issues Fertility Issues

Adjuvant Treatments The recommendations for post-trachelectomy adjuvant therapy are based on the presence/absence of pathological risk factors, such as nodal metastasis, parametrial involvement, LVSI, or DSI. Clinicians have to recognize that adjuvant radiotherapy affects patients’ fertility (Beiner and Covens 2007; Hertel et al. 2006; Marchiole et al. 2007). Chemotherapy is an alternative adjuvant therapy. However, the clinical efficacy of adjuvant chemotherapy remains unclear.

Neoadjuvant Chemotherapy Followed by Radical Trachelectomy for Tumors 2–4 Cm in Diameter Neoadjuvant chemotherapy (NACT) is the only way to reduce the size of cervical tumors, which might allow some patients with bulky tumors to undergo radical trachelectomy. Previous retrospective studies have suggested that NACT followed by radical trachelectomy is feasible and effective (Plante 2015). A recent review of 18 articles including 249 patients with cervical tumors of 2–4 cm suggested that the recurrence and death rates were 6.1% and 1.8%, respectively (Gwacham et al. 2021). To draw a definitive conclusion regarding the oncologic safety of NACT followed by radical tracherectomy in this patient population, the results from an ongoing international phase II clinical trial are anticipated (NCT04016389).

There is no clear consensus about the optimal interval between radical trachelectomy and attempts to get pregnant. However, as the tissue healing process can last at least 3 months, most authors suggest that patients should wait for 6–12 months before attempting to get pregnant. Fertility might be impaired after radical trachelectomy because of anatomical and physiological changes, such as adhesion, cervical stenosis, and a loss of cervical function. A recent review of 47 articles including 2,566 women treated with radical tracherectomy showed that pregnancy rates were 37.8% for those who underwent vaginal, 10.4% for abdominal, and 9.2% for laparoscopic radical trachelectomy (Smith et al. 2020). The reasons for the worse fertility outcomes of the ART or laparoscopic group remain to be elucidated; however, the increased peritoneal damages caused by abdominal or laparoscopic approaches and resulting periadnexal adhesions can be a possible explanation for this.

Obstetric Outcomes Clinicians should inform patients who undergo radical trachelectomy that post-radical trachelectomy pregnancies are associated with an increased risk of obstetric complications. The rate of first trimester miscarriage in women who had been treated with radical tracherectomy is comparable to the healthy population, but second trimester deliveries are more common (10% versus 3%). Preterm delivery

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(