Progestogens in Obstetrics and Gynecology [2 ed.] 9783030525088, 3030525082

574 177 6MB

English Pages [237] Year 2020

Report DMCA / Copyright

DOWNLOAD FILE

Polecaj historie

Progestogens in Obstetrics and Gynecology [2 ed.]
 9783030525088, 3030525082

Table of contents :
Foreword
Preface to the Second Edition
Contents
Chapter 1: Physiology of Progesterone
1 Introduction
2 The Mechanisms of the Cellular Action of Progesterone
2.1 Genomic Actions of Progesterone and the Cytosolic Progesterone Receptor
2.2 The Role of Co-Regulators in Progesterone Signaling
2.3 Non-genomic Actions of Progesterone
3 The Physiologic Effects of Progesterone
3.1 The Effect of Progesterone on the Immune System
3.2 The Role of Progesterone in Non-pregnant Women
3.2.1 Progesterone and the Menstrual Cycle
3.2.2 Progesterone and the Myometrium in the Non-pregnant Uterus
3.2.3 The Effect of Progesterone on the Uterine Cervix during the Menstrual Cycle
3.3 Progesterone and Pregnancy
3.3.1 The Role of Progesterone in the Maintenance of Normal Pregnancy and Parturition
3.3.2 The Nuclear Progesterone Receptor in the Myometrium during Pregnancy and Parturition
3.3.3 The Membrane Progesterone Receptor during Pregnancy and Parturition
3.3.4 Progesterone Oxytocin Responsiveness and Ca2+ Fluxes
3.3.5 The Interplay Between NFκB and Progesterone in Pregnancy Maintenance and in the Onset of Labor
3.3.6 Changes in Myometrial Progesterone Co-Regulators during Pregnancy
3.3.7 Progesterone Receptor in Fetal Membranes, Decidua, Placenta
3.3.8 The Effect of Progesterone on the Cervix During Pregnancy
3.3.8.1 Collagen Remodeling
3.3.8.2 Changes in Glycosaminoglycans
3.3.8.3 Suppression of Metalloproteinases
3.3.8.4 Modulation of the Inflammatory Response in the Uterine Cervix
4 Conclusions
References
Chapter 2: Pharmacology of Progestogens
1 Introduction
2 Classification of Progestogens
3 Pharmacokinetics and Pharmacology of Progestogens
4 Thrombotic Risk of Progestogens
5 Conclusions
References
Chapter 3: Progestogens in Infertility Practice
1 Introduction
2 Role of Progesterone in Endometrial Ripening
3 Role of Progesterone in Implantation
3.1 Cytokines Acting in Implantation
3.2 Action of Progesterone on Cytokines
4 Luteal Phase Insufficiency
4.1 Formation of the Corpus Luteum (CL)
4.2 Evaluation of the Luteal Phase
4.3 Luteal Insufficiency in Stimulated Cycles
4.3.1 Non ART Cycles
4.3.2 ART Cycles
5 Types of Hormone Supplementation in Infertility
5.1 Human Chorionic Gonadotropin (hCG)
5.2 Micronized Progesterone
5.3 Intramuscular Progesterone
5.4 Estradiol Plus Progesterone
5.5 Progesterone with Gonadotrophin-Releasing Hormone
5.6 Synthetic Progestogens
6 Conclusions
References
Chapter 4: Progestogens in Threatened Miscarriage
1 Introduction
2 Natural History
3 Diagnosis of Luteal Deficiency
3.1 Progesterone Levels
3.2 Other Markers of Luteal Phase Insufficiency
3.3 Cause of Luteal Phase Insufficiency
4 Confounding Factors
5 Effect of Progestogen Supplementation
6 Subgroups of Threatened Miscarriage
6.1 Subchorionic Hematoma
6.2 Threatened Miscarriage After Recurrent Miscarriage
7 Safety and Side Effects
8 Conclusions
References
Chapter 5: Progestogens and Recurrent Miscarriage
1 Introduction
2 The Role of Progesterone
2.1 Potential Mechanisms of Action of Progestogens in Preventing RM
2.1.1 Disturbed Metabolism of Cholesterol and Progesterone in Recurrent Miscarriages
2.2 Effects of Progesterone on the Uterus and the Endometrial Environment
2.2.1 Endometrial Development and Luteal Phase Deficiency
2.2.2 Induction of Uterine Quiescence
2.3 Immunological Role of Progestogens
2.3.1 Involvement of Progesterone in Maternal Cytokine Production
2.3.2 Involvement of Progesterone in Maternal Natural Killer (NK) Cells
2.3.3 Involvement of Progesterone in Anti-trophoblast Antibodies
3 The Evidence for Progesterone Use in Recurrent Miscarriage
4 Safety of Progestogens for Prevention of Recurrent Miscarriage
4.1 Safety of the Mother
4.2 Safety of the Fetus
5 Future Research
6 Conclusions
References
Chapter 6: Progestogens in Preterm Labour Prevention: An Update
1 Introduction
2 Role of Progesterone in Obstetrics
3 Routes of Administration: Key Differences
3.1 Oral Administration
3.2 Intramuscular Administration
3.3 Vaginal Administration
3.4 Rectal Administration
4 Progesterone and PTB: “Which, When and How”
5 Progesterone and Twin-Pregnancy
6 Progesterone as a Tocolytic Agent and/or for Maintenance Therapy?
7 Future Strategies on PTB Prevention
8 Conclusions
References
Chapter 7: Abnormal Uterine Bleeding
1 Introduction
2 Physiology of Menstruation
2.1 Pathophysiology of Anovulatory Bleeding
3 Diagnosis of AUB
3.1 Imaging
3.1.1 Ultrasound
3.1.2 Hydrosonography
3.1.3 Magnetic Resonance Imaging (MRI)
3.1.4 Hysteroscopy
4 Biopsy
5 Bleeding Dyscrasias
6 Principles of Treatment
6.1 Acute Uterine Bleeding
6.1.1 High Dose Intravenous Estrogen
6.1.2 Hemodynamically Stable Patients
6.2 Abnormal Uterine Bleeding in Adolescents
6.3 Perimenopausal Bleeding
6.4 Chronic Abnormal Bleeding
7 LNG-IUS
8 Endometrial Hyperplasia
9 Other Forms of Treatment
9.1 Receptor Modulators
9.2 NSAIDS
9.3 Antifibrinolytic Drugs
References
Chapter 8: Progestogens in Contraception
1 Development and Classification of Protestogens in Contraception
1.1 The Time of Introduction into the Market
1.2 Classification According to Molecular Structure
1.2.1 Derivatives of Testosterone
1.2.2 Derivatives of Progesterone
1.2.3 Derivatives of Spironolactone
1.3 Classificiation According to Interaction with Steroid Receptors
2 Progestogens in Combined Hormonal Contraceptives
2.1 Health Risks of Combined Hormonal Contraceptives in Relation to the Different Progestogens
3 Progestogen Only Contraception
3.1 Common Features of Progestogen Only Contraception
3.1.1 General Principle of Action
3.1.2 Very Low or Absence of Cardiovascular Risks [26, 27]
3.1.3 Contraindications for Progesterone Only Contraception
3.1.4 Side Effects
3.1.5 Additional Benefits and Therapeutic Indications
3.1.6 High Efficacy in Typical Use
3.2 Oral Preparations [28]
3.2.1 Health Risks
3.2.1.1 Bone Health
3.2.2 Side Effects
3.2.3 Special Benefits
3.2.4 Contraindications
3.3 Progestogen Implants [30, 31]
3.3.1 The Etonogestrel Releasing Hormonal Implant Implanon®
3.3.1.1 Efficacy
3.3.1.2 Health Risks
3.3.1.3 Side Effects
3.3.1.4 Additional Benefits
3.3.1.5 Contraindications
3.4 Injections (Intramuscular and Subcutaneous) [32]
3.4.1 Efficacy
3.4.2 Health Risks
3.4.3 Side Effects
3.4.4 Benefits
3.4.5 Contraindications
3.5 Levonorgestrel Containing Intrauterine Systems [34]
3.5.1 Efficacy
3.5.2 Health Risks
3.5.3 Side Effects
3.5.4 Additional Benefits
3.5.5 Contraindications
References
Chapter 9: Progestogens and Endometriosis
1 Introduction
2 Mechanisms of Progesterone Resistance in Endometriosis
2.1 Environmental Toxicants in Progesterone Resistance
2.2 Retinoid Resistance
3 Inflammatory Reaction Around Endometriotic Deposits
3.1 Effect of Sex Hormones on Inflammatory Reaction
4 Genetic Basis of Endometriosis
4.1 Epigenomics and Epigenetics
5 Evasion of Immune Clearance
6 Comorbity of Endometriosis
7 Progesterone Actions in the Female Brain
8 Progestogens as Treatment
8.1 Mode of Action
8.2 Different Progestogens
8.2.1 Dydrogesterone
8.2.2 Dienogest
8.2.3 Medroxy Progesterone Acetate (MPA)
8.2.4 Cyproterone Acetate
8.2.5 Levonorgestrel Intrauterine System (LNG-IUS)
8.2.6 Norethindrone Acetate (NETA)
8.2.7 Effect of Progestogens on Endometriosis Related Infertility
8.3 Oral Contraceptive Pill (OCP)
8.4 Anti-Progestogens (Gestrinone)
8.5 Choice of Treatment
9 Other Modes of Treatment
9.1 AKR1C3
10 Conclusions
References
Chapter 10: Progestogens and Breast Cancer
1 Introduction
2 Progesterone Receptors
3 Breast Cancer -the Progesterone Effect
4 Local Production and Action of Progestogens
5 Progesterone and Migration of Breast Cancer Cells
6 Protease Activated Receptors and Progesterone
7 RANK/RANKL and Progesterone
8 Progesterone and E-Cadherin
9 Bazedoxifene
10 Conclusion
References
Chapter 11: Progestogens in Endometrial Cancer
1 Introduction
2 Progesterone for Fertility Preservation
2.1 Are There Any Risks?
2.2 Workup Prior to Treatment
2.2.1 Tissue Biopsy
2.2.2 Imaging
2.2.3 Additional Invasive Procedures
2.2.4 Genetic Counseling
2.3 Prognostic Factors
2.4 Types of Progesterone
2.5 Outcome
2.5.1 Repeat Treatment for Recurrence After Complete Response?
2.5.2 Outcome for Progestin Releasing Intrauterine Devices
2.5.3 Combined Progestins Treatment and Hysteroscopy
2.6 Follow Up
3 Progesterone in Advanced Endometrial Cancer
4 Novel Approaches
4.1 Fourth-Generation Progestins
4.2 Progesterone Receptor Expression and Reversal of Progesterone Resistance
5 Conclusions
References
Chapter 12: Progestogens and the Menopause
1 Introduction
2 Progestogens and Osteoporosis
3 Progesterone, Hot Flushes and Night Sweats
4 Progesterone and Venous Thromboembolism
5 Progesterone and the Brain
5.1 Progesterone in Alzheimer’s Disease
5.2 Traumatic Brain Injury (TBI)
6 Cardiovascular
7 Conclusions
References
Chapter 13: Progestogens and Autoimmunity
1 Sexual Dimorphism in Autoimmunity
2 The Mechanism Mediating the Immunomodulatory Effects of Progestogens
2.1 Progestogen Signaling
2.2 Innate and Adaptive Immunity
2.2.1 The Innate Immune System
2.2.2 The Adaptive Immune System
3 Progestogens Effect on Specific Autoimmune Diseases
3.1 Rh Rheumatoid Arthritis (RA)
3.2 Multiple Sclerosis (MS)
3.3 Systemic Lupus Erythematous (SLE)
3.4 Autoimmune Thyroid Disease (AITD)
4 Immunomodulation and Prevention of Preterm Birth
5 Progestogen Hypersensitivity
References
Chapter 14: Progestogens in Non Gynecological Indications
1 Introduction
2 Progesterone in Evolution
3 Progesterone in Males
3.1 Progesterone Receptors
3.2 Effects of Progesterone in the Male
3.3 Progesterone and Prostate Cancer
3.3.1 Anti-Androgenic Effect
3.3.2 Anti-Gonadotrophic Effect
3.3.3 Cytotoxic Effect
4 Progesterone, the Neurotrophic Hormone
4.1 Multiple Sclerosis (MS)
4.2 Brain Trauma and Stroke
4.3 Peripheral Neuropathy
4.4 Epilepsy
4.5 Parkinson’s Disease
4.6 Progesterone and Spinal Cord from Neurodegeneration.
4.7 Progesterone in ADD, and ADHD
4.8 Anxiety
5 Other Therapeutic Effects of Progesterone
5.1 Progesterone and Statin Use
5.2 Asthma
5.3 Arthritis
5.4 Carpal Tunnel Syndrome
6 Conclusions
References

Citation preview

Howard J.A. Carp  Editor

Progestogens in Obstetrics and Gynecology Second Edition

Progestogens in Obstetrics and Gynecology

Howard J. A. Carp Editor

Progestogens in Obstetrics and Gynecology Second Edition

Editor Howard J. A. Carp Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Ramat Gan, Israel Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel

ISBN 978-3-030-52507-1    ISBN 978-3-030-52508-8 (eBook) https://doi.org/10.1007/978-3-030-52508-8 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved 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

Foreword

In 1930, WM Allen and GW Corner used the name progestin (later renamed progesterone in 1935) to describe a hormone which was responsible for implantation, end embryo survival. They could not have imagined the profound relevance of the hormone and implications for the development of a class of drugs, which are in widespread use and affect our daily lives. For many years, progesterone was thought of as a hormone only affecting pregnancy, and the wider implications of triggering the progesterone receptor were relatively ignored. In the 1960s, the contraceptive pill became available and caused a revolution in the way that women could plan their pregnancies. Progestogens were introduced to modulate the estrogen used to inhibit ovulation in the contraceptive pill. Since then a whole host of synthetic drugs known as progestogens have come into clinical use. The main use of progestogens is in pregnancy. Progestogens are used in luteal support, to prevent miscarriage, and to prevent preterm labor. Progestogens are used outside of pregnancy, for abnormal uterine bleeding, cycle control, hormone replacement therapy, and even in the prevention and treatment of endometrial cancer. Today, we know that progesterone is found in nonmammalian vertebrates. Progesterone had a physiological role as an anti-inflammatory agent and neurosteroid long before mammalian pregnancy had evolved. Therefore, it is hardly surprising that progestogens are being used as possible anti-inflammatory agents in endometriosis, and even in male in traumatic brain injury, and in multiple sclerosis. Just as the early investigators in the 1930s could not realize the implications of their discovery, it is difficult to prophesy the future. A new field of development is receptor modulators. Mifepristone is a progesterone receptor modulator. It was introduced as an abortifacient. However, today new uses are being developed for receptor modulators. Experimental work with uterine fibroids may entirely change the management of fibroids and affect the whole approach to surgery for gynecological conditions. This book brings together all the aspects of progestogens in gynecological (and non-gynecological) practice. There are chapters governing basic scientific topics such as physiology and pharmacology. The major applications of progestogen v

vi

Foreword

t­herapy in luteal support, miscarriage, preterm labor, contraception, abnormal uterine bleeding, etc. have been described in depth. However, in clinical practice, there are always controversies, leaving the clinician puzzled as to how to help the patient. The different progestogens with their overlapping effects on estrogen, androgen, glucocorticoid, and mineralocorticoid receptors are described in order to allow the clinician to make the most appropriate choice of progestogen. It is hoped that this book will be read by gynecologists, endocrinologists, general practitioners, and associated disciplines, who wish to keep up to date and gain a comprehensive view of developments. Gynecology and Obstetrics  Andrea R. Genazzani University of Pisa, Pisa, Italy International Society of Gynecological Endocrinology (ISGE) European Society of Gynecology (ESG) International Academy of Human Reproduction (IAHR)

Preface to the Second Edition

Since the first edition of this book, much new knowledge has accumulated regarding the progestogens. In the field of infertility, the Lotus trials have added new opportunities for supporting the luteal phase. Similarly, in miscarriage, new research has clarified the role of progestogens, but alas, has brought up as many questions and controversies as have been clarified. Hence, Chaps. 4 and 5 have been updated considerably to show the current trends and new controversies. Chapter 14 on “Progestogens in Non-gynecological Indications” was a novel concept in the first edition. The subject has been broadened. Today progestogens are used in a wide variety of neurological conditions, which has necessitated rewriting the entire chapter. In addition, the use of progestogens has become modified in both endometrial and breast tumors requiring updates of these two important subjects. With all the changes mentioned above, progestogens are still probably the most widely used class of drugs in medical practice. Millions of women use progestogens in the contraceptive pill daily for many years. Progestogens are widely used to protect the endometrium in postmenopausal replacement therapy, cycle regulation, abnormal uterine bleeding, and endometriosis. However, the clinician is often in a quandary, as to which progestogen is most appropriate in any clinical situation. The vii

viii

Preface to the Second Edition

actions of progestogens overlap with other steroids. Progestogens have estrogenic or antiestrogenic actions, androgenic or antiandrogenic actions, and glucocorticoid or mineralocorticoid actions. Each may have advantages or disadvantages depending on the clinical situation. Additionally, much evidence has accumulated regarding the pro-thrombotic effects of certain progestogens. Hence, definite choices are necessary for prescribing endocrine contraception, where thrombosis may be a risk in healthy women. Progestogens also have other side effects including stimulatory effects on the breast, possibly predisposing to breast carcinoma, breakthrough bleeding, acne mood changes, loss of libido, and dryness of the vagina. All of the above actions of progestogens have been incorporated into this book, which discusses the actions and uses of progestogens in depth. The book is planned for general gynecologists and specialists working in the field. Each contributing author is an authority on a specific area of progestogen use. I would like to thank each author for the time and effort taken in preparing the manuscript to make the publication of this second edition possible. Tel Aviv, Israel  Howard J. A. Carp

Contents

  1 Physiology of Progesterone���������������������������������������������������������������������    1 Edi Vaisbuch, Offer Erez, and Roberto Romero   2 Pharmacology of Progestogens ��������������������������������������������������������������   31 Adolf E. Schindler   3 Progestogens in Infertility Practice��������������������������������������������������������   39 Ameet S. Patki and Mrinmayi Dharmadhikari   4 Progestogens in Threatened Miscarriage����������������������������������������������   55 Howard J. A. Carp   5 Progestogens and Recurrent Miscarriage����������������������������������������������   69 Narmada Katakam and Luciano G. Nardo   6 Progestogens in Preterm Labour Prevention: An Update��������������������   83 Di Renzo Gian Carlo, Tosto Valentina, Neykova Konstantsa, and Giardina Irene   7 Abnormal Uterine Bleeding��������������������������������������������������������������������   97 Eran Zilberberg and Howard J. A. Carp   8 Progestogens in Contraception ��������������������������������������������������������������  117 Johannes Bitzer   9 Progestogens and Endometriosis������������������������������������������������������������  137 Matityahu Zolti and Howard J. A. Carp 10 Progestogens and Breast Cancer������������������������������������������������������������  157 Eitan Pe’er 11 Progestogens in Endometrial Cancer����������������������������������������������������  169 Oded Raban and Walter Gotlieb 12 Progestogens and the Menopause����������������������������������������������������������  193 Eitan Pe’er ix

x

Contents

13 Progestogens and Autoimmunity������������������������������������������������������������  203 Abraham Tsur, Grant C. Hughes, and Yehuda Shoenfeld 14 Progestogens in Non Gynecological Indications������������������������������������  213 Howard J. A. Carp, Matityahu Zolti, and Christa Nadjafi-Triebsch

Chapter 1

Physiology of Progesterone Edi Vaisbuch, Offer Erez, and Roberto Romero

1  Introduction The corpus luteum was first discovered in 1672 by Reinier de Graaf and named in 1689 by Marcelo Malpighi. Malpighi proposed that the corpus luteum produces the ovarian follicles and that the yellow substance, like egg yolk, serves to nourish the ovum. In 1903, Fraenkel demonstrated that excission of the corpora lutea of rabbits, before implantation, prevented implantation. Moreover, lutectomy in early pregnancy (