Advanced Practice in Endocrinology Nursing [1st ed.] 978-3-319-99815-2, 978-3-319-99817-6

Table of contents :
Front Matter ....Pages i-xxxiii
Front Matter ....Pages 1-1
The Importance of Auxology for Growth Assessment (Terri H. Lipman, Megan K. Lessig)....Pages 3-11
Short Stature, Growth Hormone Deficiency, and Primary IGF-1 Deficiency (Bin Moore, Amanda Whitehead, Kate Davies)....Pages 13-37
Disorders of Sex Development (DSD) (Kate Davies)....Pages 39-61
Puberty: Normal, Delayed, and Precocious (Eileen Pyra, Wendy Schwarz)....Pages 63-84
Treatment Issues in the Care of Pediatric Patients with Endocrine Conditions (Peggy Kalancha, Nicole Kirouac, Eileen Pyra)....Pages 85-100
Transition from Paediatric to Adult Services (Susie Aldiss)....Pages 101-117
Front Matter ....Pages 119-119
Genetics and Family History (Kelly Mullholand Behm)....Pages 121-161
Congenital Hyperinsulinism (CHI) (Claire Gilbert, Kate Morgan, Louise Doodson, Khalid Hussain)....Pages 163-177
Genetic Syndromes Presenting in Childhood Affecting Hypothalamic Function (Kathryn Clark)....Pages 179-194
Genetic Syndromes Presenting in Childhood Affecting Gonadotropin Function (Sharron Close, Ana Claudia Latronico, Marina Cunha-Silva)....Pages 195-206
McCune–Albright Syndrome (Beth Brillante, Lori Guthrie)....Pages 207-228
Front Matter ....Pages 229-229
Anatomy and Physiology of the Hypothalamic-Piuitary Axis (Kathryn Evans Kreider)....Pages 231-243
Metabolic Effects of Hypothalamic Dysfunction (Cecilia Follin)....Pages 245-254
Sella and Suprasellar Brain Tumours and Infiltrarive Disorders Affecting the HPA-Axis (Christine Yedinak)....Pages 255-275
Dynamic Investigations and Diagnostic Testing (Christine Yedinak, Kate Davies)....Pages 277-303
Diagnostic Imaging (Christine Yedinak)....Pages 305-319
Non-functioning Pituitary Adenomas (Judith P. van Eck, Sebastian J. C. M. M. Neggers)....Pages 321-334
Thyroid Stimulating Hormone Secreting Adenoma (TSHoma) (Christine Yedinak)....Pages 335-342
Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia (Christine Yedinak)....Pages 343-363
Growth Hormone Producing Adenomas: Acromegaly (Karen J. P. Liebert, Daphne T. Adelman, Elisabeth Rutten, Christine Yedinak)....Pages 365-394
ACTH Producing Adenomas: Cushing’s Disease (Raven McGlotten)....Pages 395-414
Pituitary Surgery (Jürgen Honegger)....Pages 415-432
Pituitary Surgery: Nursing Implications (Sarah Benzo, Christina Hayes)....Pages 433-446
Radiotherapy (Ahmed Al Sajwani, Mark Sherlock)....Pages 447-468
Hypopituitarism and Growth Hormone Deficiency in Adults (Sofia Llahana, Anne Marland, Mila Pantovic, Vera Popovic)....Pages 469-494
Front Matter ....Pages 495-495
Thyroid Anatomy and Physiology (Chloe Broughton, Bushra Ahmad)....Pages 497-503
Thyroid Investigations (Victoria J. Stokes, Rabia Arfan, Theingi Aung, Violet Fazal-Sanderson)....Pages 505-518
Hyperthyroidism in Adults (Violet Fazal-Sanderson, Niki Karavitaki, Radu Mihai)....Pages 519-555
Thyroid Cancer (Ingrid Haupt-Schott, Geraldine Hamilton, Petros Perros)....Pages 557-579
Diagnosis and Management of Hypothyroidism in Adults (Raluca-Alexandra Trifanescu, Catalina Poiana)....Pages 581-592
Thyroid Eye Disease (Rebecca Ford, Violet Fazal-Sanderson)....Pages 593-608
Disorders of the Thyroid in Childhood and Adolescence (Suma Uday, Christine Davies, Helena Gleeson)....Pages 609-628
Thyroid Disease in Pre- and Post-Pregnancy (Dev A. Kevat, Lucy Mackillop)....Pages 629-641
Front Matter ....Pages 643-643
Anatomy and Physiology of the Adrenal Gland (Phillip Yeoh)....Pages 645-655
Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults (Alessandro Prete, Chona Feliciano, Irene Mitchelhill, Wiebke Arlt)....Pages 657-678
Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas, and Adrenocortical Cancer (Andrew P. Demidowich, Miriam Asia, Jérôme Bertherat)....Pages 679-704
Diagnosis and Management of Adrenal Insufficiency in Children and Adults (Sofia Llahana, Irene Mitchelhill, Phillip Yeoh, Marcus Quinkler)....Pages 705-736
Front Matter ....Pages 737-737
Anatomy and Physiology of the Female Reproductive System (Artemis Vogazianou)....Pages 739-752
Assessment and Management of Women with Polycystic Ovary Syndrome (PCOS) (Rhonda Garad, Soulmaz Shorakae, Helena Teede)....Pages 753-769
Diagnosis and Management of Turner Syndrome in Children and Adults (Helen E. Turner, Irena R. Hozjan)....Pages 771-801
Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy (Gerard S. Conway)....Pages 803-815
The Endocrine System and Pregnancy (Margaret Eckert-Norton, Saundra Hendricks)....Pages 817-835
Front Matter ....Pages 837-837
Anatomy and Physiology of the Hypothalamic-Pituitary-Gonadal (HPG) Axis (Andrew A. Dwyer, Richard Quinton)....Pages 839-852
Classification of Hypothalamic-Pituitary-Gonadal (HPG) Axis Endocrine Disorders (Andrew A. Dwyer, Richard Quinton)....Pages 853-870
Evaluation of Endocrine Disorders of the Hypothalamic-Pituitary-Gonadal (HPG) Axis (Andrew A. Dwyer, Frances J. Hayes)....Pages 871-883
Testosterone Therapy in Adult Men with Hypogonadism (Sofia Llahana)....Pages 885-902
Spermatogenesis and Assisted Fertility Treatment (Andrew A. Dwyer, Elizabeth Williamson, Margaret G. Au, Channa Jayasena)....Pages 903-923
Diagnosis and Management of Erectile Dysfunction in Men (Fiona Holden, Clare Akers, Sofia Llahana)....Pages 925-941
Genetic Counselling and Psychosexual Considerations in Male Health and Reproduction (Margaret G. Au, Sue Jackson)....Pages 943-954
Front Matter ....Pages 955-955
Hyperparathyroidism and Hypoparathyroidism (Amy Mundy, Rachel Crowley)....Pages 957-974
Calcium Disorders (Arthur D. Conigrave, Marsha M. van Oostwaard)....Pages 975-987
Congenital and Acquired Bone Disorders in Children and Adults (Kirtan Ganda, Klaus Sommer, Anne L. Ersig)....Pages 989-1003
Osteoporosis (Sherwin Criseno)....Pages 1005-1035
Vitamin D Deficiency and Treatment in Children and Adults (Yuk Fun Chan, Kerry-Lee Milner, Chris White, Pauline Musson)....Pages 1037-1062
Front Matter ....Pages 1063-1063
Dietary and Behavioural Interventions in the Management of Obesity (Clare Grace, Adrian Brown)....Pages 1065-1083
Assessment of the Patient with Obesity and Bariatric Surgical Interventions (Saira Hameed, Harvinder Chahal)....Pages 1085-1099
Lipid Disorders and Familial Hypercholesterolaemia (Alison Pottle)....Pages 1101-1120
Front Matter ....Pages 1121-1121
Transition of Childhood Cancer Survivors (Tanya L. Urquhart-Kelly, Jerry K. Wales)....Pages 1123-1132
Endocrinopathy After Childhood Cancer Treatment (Cecilia Follin)....Pages 1133-1147
Neurocognitive Dysfunction and Psychosocial Issues (Katharina Roser, Gisela Michel, Katrin Scheinemann)....Pages 1149-1160
Front Matter ....Pages 1161-1161
Management of Hyponatraemia in Adults and Children (Phillip Yeoh, Anne Marland)....Pages 1163-1181
Prevention and Management of Adrenal Crisis in Children and Adults (Sofia Llahana, Kathrin Zopf, Irene Mitchelhill, Ashley Grossman)....Pages 1183-1205
Thyroid Emergency: Thyroid Storm and Myxoedema Coma (Paul V. Carroll)....Pages 1207-1215
Diagnosis and Management of Pituitary Apoplexy in Adult Patients (Stephanie E. Baldeweg)....Pages 1217-1225
Front Matter ....Pages 1227-1227
Neuroendocrine Tumours (Mike Tadman, Philippa Davies, Tara Whyand, Lee Martin)....Pages 1229-1257
Multiple Endocrine Neoplasia (Mike Tadman, Lee Martin)....Pages 1259-1278
Front Matter ....Pages 1279-1279
Conceptualization, Definition, and Competencies of Advanced Practice Nursing with a Focus on Endocrinology (Sofia Llahana, Andrew A. Dwyer, Christine Yedinak)....Pages 1281-1302
Role Development and Performance Facilitators in Advanced Practice Nursing (Sofia Llahana)....Pages 1303-1319
Research and Evidence-Based Practice: The Nurse’s Role (Lesley Baillie, Debbie Carrick-Sen, Anne Marland, Margaret F. Keil)....Pages 1321-1337

Citation preview

Under the auspices of the European Society of Endocrinology

Advanced Practice in Endocrinology Nursing Sofia Llahana Cecilia Follin Christine Yedinak Ashley Grossman Editors With Paediatric Editors Kate Davies and Margaret F. Keil

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Advanced Practice in Endocrinology Nursing

Sofia Llahana  ·  Cecilia Follin Christine Yedinak · Ashley Grossman Editors

Advanced Practice in Endocrinology Nursing With Paediatric Editors Kate Davies and Margaret F. Keil

Editors Sofia Llahana School of Health Sciences, City University of London London UK

Cecilia Follin Department of Oncology Skåne University Hospital Lund Sweden

Christine Yedinak Northwest Pituitary Center Oregon Health and Sciences University Portland, OR USA

Ashley Grossman Churchill Hospital University of Oxford Oxford UK

ISBN 978-3-319-99815-2    ISBN 978-3-319-99817-6 (eBook) https://doi.org/10.1007/978-3-319-99817-6 Library of Congress Control Number: 2018968596 © Springer Nature Switzerland AG 2019 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, express 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

Sofia Llahana Dedicated to my daughter Elise-Katerina, my husband Richard, and my parents and role models Eirini and Vasilis Cecilia Follin Dedicated to Anders, Jesper and Alexander Christine Yedinak Dedicated to my husband and cheerleader Marty Ashley Grossman Dedicated to my daughters: Emily, Sophie, Annabel, Camilla, Cordelia, and Elizabeth

Foreword

Endocrinology nursing is a fast-developing specialty with nurses performing advanced roles and expanding their practice to cover key roles in the future multidisciplinary centres of excellence like the PTCOE (Pituitary Tumor Centers of Excellence). This book has the merit of providing a comprehensive guide for nurses practising in all areas of endocrinology including bone metabolic diseases, obesity, and lipid disorders. Particularly interesting and modern are the chapters devoted to endocrine emergencies and endocrine abnormalities consequent to cancer treatment. Moreover, the book is suitable for nurses serving in both paediatric and adult endocrine units and at any level of expertise. The book has been written by an international team of eminent nurses, physicians, surgeons, psychologists, and other healthcare professionals, which makes this book a valuable resource not only for nurses but also for other members of any multidisciplinary team. Patient advocacy groups have also contributed to most chapters with case studies and examples of collaborative working with healthcare professionals to improve patient care. This is the first book ever published specifically for nurses working in endocrinology, but it is also an excellent resource for nurses working in other specialties such as internal medicine, gynaecology, urology, and rheumatology due to the wide range of topics covered in the book from fertility to osteoporosis and erectile dysfunction. Specialty trainees, general practitioners, students, psychologists, and expert patients wanting in-depth information will also find this book a useful resource. The editors have led the way in advancing nursing practice, and this book is a reflection of their dedication to developing a solid doctrinal body for the discipline of endocrine nursing worldwide. Andrea Giustina Milan, Italy

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Preface

We are extremely pleased and proud that our ambitious idea to write the first ever published book for endocrine nurses has finally come to fruition. We wanted this to be a useful resource for endocrine nurses across the globe working at different settings and levels of practice, from novice to expert and from bedside nursing to advanced practice nursing running independent nurse-led services. We recognised that this would be a challenging project to undertake, especially as the endocrinology nursing role varies significantly from country to country. We were, however, overwhelmed by the interest we received from colleagues who wanted to contribute to this book, echoing the great need for such a resource and especially from physicians and other healthcare professionals who recognise the endocrine nurse as a vital member of the multidisciplinary team. The European Society of Endocrinology (ESE) formed our initial working hub and supported this textbook from its inception. We created a strong collaborative European and international network; 118 eminent authors from 15 countries contributed to this book. Most of our authors are nurses, but physicians, surgeons, psychologists, dieticians and geneticists have also contributed, emphasising the multidisciplinary focus of this book. Built on the growing body of knowledge, expertise and the expanding nature of advanced practice in endocrinology nursing, this book provides a comprehensive resource to support nurses to develop their competence at different levels of their career. The authors in each chapter have done a tremendous job presenting a comprehensive review of anatomy, pathophysiology, diagnosis and treatment of different endocrine conditions supported by the latest evidence and clinical guidelines. Patient stories, case studies and good clinical practice examples are included to illustrate the impact of endocrine conditions on patients and their families, to stimulate the readers’ critical thinking and reflection and to make information in this book applicable to their clinical practice. Many patient advocacy groups have contributed with case studies and educational resources, supporting the emphasis this book places on user involvement and shared decision-making in patient care. Comprising of 13 parts and a total of 69 chapters, this book is a comprehensive resource for paediatric and adult nurses working in endocrinology but should also be useful for specialty trainees, general practitioners, students and expert patients. It also covers endocrine-related topics within other specialties such as fertility, osteoporosis, oncology, urology, gynaecology, obesity and metabolic disorders. Each part covers conditions within a specific ix

Preface

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endocrine gland (pituitary, adrenal, thyroid, parathyroid and bone disorders and male and female reproduction) and other relevant endocrine conditions such as late effects of cancer treatment, neuroendocrine tumours, endocrine emergencies, obesity and metabolic disorders. There are two paediatric-specific parts (11 chapters); paediatric aspects have also been incorporated in many other chapters, where relevant. The final part focuses on advanced practice nursing (APN) presenting an overview of role development, definition and components of APN, including research, with many useful resources to support career progression within endocrinology nursing. The work by our part editors has been vital as they invited authors and coordinated and edited the chapters in each part; we could not have completed this book without their amazing contribution. We hope and trust this book will assist and advise all our colleagues to ensure the best possible patient care. London, UK Lund, Sweden Portland, OR, USA Oxford, UK

Sofia Llahana Cecilia Follin Christine Yedinak Ashley Grossman

Acknowledgements

This book is a testament of a successful global collaboration of healthcare professionals, learned societies and patient advocacy groups, and it would not have been possible without the great effort that everyone put into this project. We express our deep gratitude to our 118 authors who contributed to this book; this was an international multidisciplinary collaboration of nurses, physicians, surgeons, psychologists, geneticists, dieticians and nurse academics from 15 different countries. This book covers adult and paediatric topics; we are indebted to Kate Davies (UK) and Margaret Keil (USA) for editing the paediatric parts and for inviting and supporting authors who contributed with paediatric aspects to many other chapters where relevant in the book. Our gratitude also goes to our part editors who invited contributing authors and edited the chapters in each part: Judith van Eck (the Netherlands), Violet Fazal-Sanderson (UK), Gerard Conway (UK), Andrew Dwyer (Switzerland/USA), Ann Robinson (Australia), Philip Yeoh (UK), Anne Marland (UK) and Michael Tadman (UK). Their names are listed in the respective textbook parts. The textbook was initiated and developed under the auspices of the European Society of Endocrinology (ESE) and has its full endorsement. We are very grateful to Professor AJ van der Lely, ESE President (2015–2019); Helen Gregson, ESE Chief Executive Officer; Professor Jérôme Bertherat, Chair of ESE Clinical Committee; members of the ESE Executive Committee; and, in particular, Professor Andrea Giustina, incoming ESE President (2019), who has supported this textbook since its inception in 2015. Special thanks go to Professor Philippe Bouchard, past President of the ESE, and Professors Pia Burman and Richard Ross, past members of the ESE Executive Committee. Their support was instrumental in developing and establishing the ESE Nurses Committee, through which we met and worked together on this book and on other European and international projects.

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Acknowledgements

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We are also grateful to the following Nursing Organisations for their support and for approving this textbook as a valuable resource for endocrine nurses: • The Federation of International Nurses in Endocrinology (FINE) • The Endocrine Nurses Society (ENS)—USA • The Endocrine Nurses’ Society of Australia (ENSA)—Australasia • The Pediatric Endocrinology Nursing Society (PENS)—USA, Canada Representatives from many Patient Advocacy Groups across the globe contributed with case studies and educational resources; we are very grateful and have acknowledged their input in each respective chapter. We would also like to express our gratitude to patients and their families who shared their stories to help our readers understand the impact of endocrine conditions. We all learn so much from our patients and are grateful for the opportunity to be a part of their lives and to support them throughout different stages of living with their condition. Very special thanks go to Nathalie L’Horset-Poulain, our Senior Publishing Editor, for her amazing guidance throughout this project. We have been very privileged to work with Nathalie and would not have been able to complete this book without her outstanding support. Special thanks also go to MarieElia Come-Garry (Associate Editor), Sushil Kumar Sharma (Project Coordinator), Vishal Anand (Project Manager) and all the other members of the Springer Nature Team for their support. Finally, we would like to express our sincere gratitude to our families, but also the families of all of our authors, for their patience and support during the past 3 years. We sacrificed many weekends and evenings to produce this book and would not have been able to complete it without their unlimited and unconditional support and encouragement. Sofia Llahana Cecilia Follin Christine Yedinak Ashley Grossman

Contents

Part I Growth and Development Kate Davies and Margaret F. Keil 1 The Importance of Auxology for Growth Assessment����������������    3 Terri H. Lipman and Megan K. Lessig 2 Short Stature, Growth Hormone Deficiency, and Primary IGF-1 Deficiency�����������������������������������������������������   13 Bin Moore, Amanda Whitehead, and Kate Davies 3 Disorders of Sex Development (DSD)������������������������������������������   39 Kate Davies 4 Puberty: Normal, Delayed, and Precocious��������������������������������   63 Eileen Pyra and Wendy Schwarz 5 Treatment Issues in the Care of Pediatric Patients with Endocrine Conditions�����������������������������������������������������������   85 Peggy Kalancha, Nicole Kirouac, and Eileen Pyra 6 Transition from Paediatric to Adult Services������������������������������  101 Susie Aldiss Part II Endocrine Disorders and Genetics in Childhood Kate Davies and Margaret F. Keil 7 Genetics and Family History��������������������������������������������������������  121 Kelly Mullholand Behm 8 Congenital Hyperinsulinism (CHI)����������������������������������������������  163 Claire Gilbert, Kate Morgan, Louise Doodson, and Khalid Hussain 9 Genetic Syndromes Presenting in Childhood Affecting Hypothalamic Function ����������������������������������������������������������������  179 Kathryn Clark 10 Genetic Syndromes Presenting in Childhood Affecting Gonadotropin Function ����������������������������������������������������������������  195 Sharron Close, Ana Claudia Latronico, and Marina Cunha-Silva xiii

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11 McCune–Albright Syndrome��������������������������������������������������������  207 Beth Brillante and Lori Guthrie Part III Hypothalamus and Pituitary Christine Yedinak and Judith P. van Eck 12 Anatomy and Physiology of the Hypothalamic-Piuitary Axis��������������������������������������������������������������������������������������������������  231 Kathryn Evans Kreider 13 Metabolic Effects of Hypothalamic Dysfunction������������������������  245 Cecilia Follin 14 Sella and Suprasellar Brain Tumours and Infiltrarive Disorders Affecting the HPA-Axis����������������������������  255 Christine Yedinak 15 Dynamic Investigations and Diagnostic Testing��������������������������  277 Christine Yedinak and Kate Davies 16 Diagnostic Imaging������������������������������������������������������������������������  305 Christine Yedinak 17 Non-functioning Pituitary Adenomas������������������������������������������  321 Judith P. van Eck and Sebastian J. C. M. M. Neggers 18 Thyroid Stimulating Hormone Secreting Adenoma (TSHoma)����������������������������������������������������������������������������������������  335 Christine Yedinak 19 Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia����������������������������������������������������������������  343 Christine Yedinak 20 Growth Hormone Producing Adenomas: Acromegaly��������������  365 Karen J. P. Liebert, Daphne T. Adelman, Elisabeth Rutten, and Christine Yedinak 21 ACTH Producing Adenomas: Cushing’s Disease������������������������  395 Raven McGlotten 22 Pituitary Surgery ��������������������������������������������������������������������������  415 Jürgen Honegger 23 Pituitary Surgery: Nursing Implications ������������������������������������  433 Sarah Benzo and Christina Hayes 24 Radiotherapy����������������������������������������������������������������������������������  447 Ahmed Al Sajwani and Mark Sherlock 25 Hypopituitarism and Growth Hormone Deficiency in Adults������������������������������������������������������������������������������������������  469 Sofia Llahana, Anne Marland, Mila Pantovic, and Vera Popovic

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Part IV The Thyroid Gland Violet Fazal-Sanderson 26 Thyroid Anatomy and Physiology������������������������������������������������  497 Chloe Broughton and Bushra Ahmad 27 Thyroid Investigations ������������������������������������������������������������������  505 Victoria J. Stokes, Rabia Arfan, Theingi Aung, and Violet Fazal-Sanderson 28 Hyperthyroidism in Adults������������������������������������������������������������  519 Violet Fazal-Sanderson, Niki Karavitaki, and Radu Mihai 29 Thyroid Cancer������������������������������������������������������������������������������  557 Ingrid Haupt-Schott, Geraldine Hamilton, and Petros Perros 30 Diagnosis and Management of Hypothyroidism in Adults��������  581 Raluca-Alexandra Trifanescu and Catalina Poiana 31 Thyroid Eye Disease����������������������������������������������������������������������  593 Rebecca Ford and Violet Fazal-Sanderson 32 Disorders of the Thyroid in Childhood and Adolescence ����������������������������������������������������������������������������  609 Suma Uday, Christine Davies, and Helena Gleeson 33 Thyroid Disease in Pre- and Post-Pregnancy������������������������������  629 Dev A. Kevat and Lucy Mackillop Part V The Adrenal Gland Sofia Llahana 34 Anatomy and Physiology of the Adrenal Gland��������������������������  645 Phillip Yeoh 35 Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults��������������������������������������������  657 Alessandro Prete, Chona Feliciano, Irene Mitchelhill, and Wiebke Arlt 36 Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas, and Adrenocortical Cancer ��������������������������������������������������������������������������������������������  679 Andrew P. Demidowich, Miriam Asia, and Jérôme Bertherat 37 Diagnosis and Management of Adrenal Insufficiency in Children and Adults������������������������������������������������������������������  705 Sofia Llahana, Irene Mitchelhill, Phillip Yeoh, and Marcus Quinkler

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Part VI Female Endocrinology and Reproduction Sofia Llahana and Gerard S. Conway 38 Anatomy and Physiology of the Female Reproductive System������  739 Artemis Vogazianou 39 Assessment and Management of Women with Polycystic Ovary Syndrome (PCOS)��������������������������������������������������������������  753 Rhonda Garad, Soulmaz Shorakae, and Helena Teede 40 Diagnosis and Management of Turner Syndrome in Children and Adults������������������������������������������������������������������  771 Helen E. Turner and Irena R. Hozjan 41 Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy ������������������������������������������  803 Gerard S. Conway 42 The Endocrine System and Pregnancy����������������������������������������  817 Margaret Eckert-Norton and Saundra Hendricks Part VII Male Endocrinology and Reproduction Andrew A. Dwyer and Sofia Llahana 43 Anatomy and Physiology of the Hypothalamic-Pituitary-­Gonadal (HPG) Axis����������������������������  839 Andrew A. Dwyer and Richard Quinton 44 Classification of Hypothalamic-­Pituitary-­Gonadal (HPG) Axis Endocrine Disorders ������������������������������������������������  853 Andrew A. Dwyer and Richard Quinton 45 Evaluation of Endocrine Disorders of the Hypothalamic-Pituitary-Gonadal (HPG) Axis����������������������������  871 Andrew A. Dwyer and Frances J. Hayes 46 Testosterone Therapy in Adult Men with Hypogonadism��������������������������������������������������������������������������������  885 Sofia Llahana 47 Spermatogenesis and Assisted Fertility Treatment ��������������������  903 Andrew A. Dwyer, Elizabeth Williamson, Margaret G. Au, and Channa Jayasena 48 Diagnosis and Management of Erectile Dysfunction in Men ��������������������������������������������������������������������������������������������  925 Fiona Holden, Clare Akers, and Sofia Llahana 49 Genetic Counselling and Psychosexual Considerations in Male Health and Reproduction������������������������������������������������  943 Margaret G. Au and Sue Jackson

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Part VIII Parathyroid, Calcium and Bone Disorders Ann Robinson and Cecilia Follin 50 Hyperparathyroidism and Hypoparathyroidism������������������������  957 Amy Mundy and Rachel Crowley 51 Calcium Disorders ������������������������������������������������������������������������  975 Arthur D. Conigrave and Marsha M. van Oostwaard 52 Congenital and Acquired Bone Disorders in Children and Adults ��������������������������������������������������������������������������������������  989 Kirtan Ganda, Klaus Sommer, and Anne L. Ersig 53 Osteoporosis������������������������������������������������������������������������������������ 1005 Sherwin Criseno 54 Vitamin D Deficiency and Treatment in Children and Adults ����� 1037 Yuk Fun Chan, Kerry-Lee Milner, Chris White, and Pauline Musson Part IX Obesity and Disorders of Lipid Metabolism Cecilia Follin 55 Dietary and Behavioural Interventions in the Management of Obesity���������������������������������������������������������������� 1065 Clare Grace and Adrian Brown 56 Assessment of the Patient with Obesity and Bariatric Surgical Interventions�������������������������������������������������������������������� 1085 Saira Hameed and Harvinder Chahal 57 Lipid Disorders and Familial Hypercholesterolaemia���������������� 1101 Alison Pottle Part X Late Effects of Cancer Treatment in Relation to Endocrinology Cecilia Follin 58 Transition of Childhood Cancer Survivors��������������������������������� 1123 Tanya L. Urquhart-Kelly and Jerry K. Wales 59 Endocrinopathy After Childhood Cancer Treatment���������������� 1133 Cecilia Follin 60 Neurocognitive Dysfunction and Psychosocial Issues���������������� 1149 Katharina Roser, Gisela Michel, and Katrin Scheinemann Part XI Endocrine Emergencies Philip Yeoh and Anne Marland 61 Management of Hyponatraemia in Adults and Children���������� 1163 Phillip Yeoh and Anne Marland

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62 Prevention and Management of Adrenal Crisis in Children and Adults �������������������������������������������������������������������������������������� 1183 Sofia Llahana, Kathrin Zopf, Irene Mitchelhill, and Ashley Grossman 63 Thyroid Emergency: Thyroid Storm and Myxoedema Coma�������� 1207 Paul V. Carroll 64 Diagnosis and Management of Pituitary Apoplexy in Adult Patients���������������������������������������������������������������������������� 1217 Stephanie E. Baldeweg Part XII Neuroendocrine Tumours and Multiple Endocrine Neoplasia Mike Tadman 65 Neuroendocrine Tumours�������������������������������������������������������������� 1229 Mike Tadman, Philippa Davies, Tara Whyand, and Lee Martin 66 Multiple Endocrine Neoplasia������������������������������������������������������ 1259 Mike Tadman and Lee Martin Part XIII Advanced Practice Nursing in Endocrinology Sofia Llahana 67 Conceptualization, Definition, and Competencies of Advanced Practice Nursing with a Focus on Endocrinology�������������������������������������������������������������������������������� 1281 Sofia Llahana, Andrew A. Dwyer, and Christine Yedinak 68 Role Development and Performance Facilitators in Advanced Practice Nursing������������������������������������������������������ 1303 Sofia Llahana 69 Research and Evidence-Based Practice: The Nurse’s Role�������� 1321 Lesley Baillie, Debbie Carrick-Sen, Anne Marland, and Margaret F. Keil

Contents

About the Editors

Sofia  Llahana, DNSc, MSc, BSc(Hons), RN, INP  is a Senior Lecturer, Education and Research, and Programme Director for Advanced Clinical Practice at City, University of London. Dr Llahana was the first consultant nurse in endocrinology in the United Kingdom and worked at University College Hospital in London where she continues to maintain an honorary position. Her clinical and research interest is in ­pituitary and adrenal ­conditions, reproductive endocrinology, men’s health, self-management, adherence to medication and behavioural medicine. Her current research portfolio includes ongoing and new investigator-led and collaborative national and European studies in adrenal insufficiency, testosterone replacement therapy, male reproduction, growth hormone deficiency, and type 2 diabetes. Dr Llahana is the Chair of the Nurses Committee and a member of the Executive Committee of the European Society of Endocrinology (ESE), a board member of the Federation of International Nurses in Endocrinology (FINE), and the only nurse member in the Scientific Committee for the International Congress in Men’s Health. She also holds affiliations with several learned societies and patient advocacy groups in endocrinology. Cecilia Follin  graduated as a registered nurse from the Institution of Healthcare Science at the Medical Faculty of Lund University in Sweden. Dr Follin has over 15 years of experience from the field of endocrinology. She holds particular interests in late complications after childhood cancer and pituitary and hypothalamic disorders. Cecilia is initiator and chair of the Nordic Network of Endocrine Nurses. In 2010, Dr. Follin was awarded with a PhD degree in endocrinology. The thesis was titled “Late complications of childhood acute lymphoblastic leukemia (ALL), with special reference to hormone secretion, xix

About the Editors

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cardiovascular risk and bone health.” In 2010–2012, Cecilia had a postdoc position at the Institution of Clinical Sciences, and currently she has a position as researcher and senior teacher at Lund University. Dr. Follin has published numerous papers. Christine  Yedinak, DNP, FNP-BC, MN, Grad DipEd, RN  is a doctor of nursing practice and a board-certified family nurse practitioner. She is an assistant professor at the Northwest Pituitary Center, Oregon Health & Sciences University, Portland, Oregon, USA.  Dr. Yedinak completed her undergraduate training in Australia and received her postgraduate diploma in tertiary education at the University of Southern Queensland, Toowoomba. She completed her postgraduate and doctoral studies at Oregon Health & Sciences University, Portland, Oregon. Her ongoing research focus is on quality of life and clinical outcomes for patients with pituitary diseases. Dr. Yedinak is president of the Endocrine Nurses Association (USA) and a board member of the European Society of Endocrinology Nurses’ Group. She is co-founder and president of the Federation of International Nurses in Endocrinology (FINE). Ashley  Grossman, BA, BSc, MD, FRCP, FMedSci  initially graduated with a BA in psychology and social anthropology from the University of London, then entered University College Hospital Medical School in London, and received the University Gold Medal in 1975. He also obtained a BSc in ­ neuroscience. Professor Grossman joined the Department of Endocrinology at St. Bartholomew’s Hospital where he spent most of his career, eventually as professor of neuroendocrinology, but then moved to become professor of endocrinology at the University of Oxford in the Oxford Centre for Diabetes, Endocrinology and Metabolism. Most recently, he has moved to the Royal Free London where he has specialized in neuroendocrine tumors. In 1999, he was appointed a fellow of the Academy of Medical Sciences, and in 2011, he was made a fellow of Green Templeton College at the University of Oxford. Professor Grossman has published more than 900 research

About the Editors

xxi

papers and reviews. He has a major interest in tumors of the hypothalamo-pituitary axis, especially Cushing’s disease, but his clinical concern and research have expanded increasingly to include broad areas of endocrine oncology, most especially neuroendocrine tumors of all types, including pheochromocytomas, paragangliomas, adrenocortical cancer, medullary thyroid cancer, and hereditary endocrine tumor syndromes. He is past president of the European Neuroendocrine Association (ENEA), past chairman of the UKI Neuroendocrine Tumour Society (UKINETS), and past president of the Society of Endocrinology and the Pituitary Society. He was previously editor of the journal, Clinical Endocrinology; is on the editorial board of the major textbook, Endocrinology, by De Groot and Jameson; is vice chairman of the major online textbook, Endotext.org; and serves on the editorial boards of many journals.

About the Part Editors Kate  Davies, RN(Child) BSc(Hons) MSc PGDip  has over 25 years of experience as a children’s nurse, with over 18 years in pediatric endocrinology. She has subspecialized in growth and puberty, Cushing’s syndrome, multiple endocrine neoplasia in children, neuroendocrine late effects of childhood brain tumors, adrenal disorders, and disorders of sex development. She is currently a senior lecturer in children’s nursing and course director of the PGDip/ MSc Children’s Advanced Nurse Practitioner program at London South Bank University, UK. She has been chair of the Royal College of Nursing Paediatric Endocrine Special Interest Group (2002–2008), a member of the UK Society of Endocrinology Nurse Committee (2012–2017), and is currently secretary of the European Society of Paediatric Endocrine Nurses Group. She was awarded the BSPED Ipsen Paediatric Endocrine Nurse Award in 2014. Kate is a fellow of the Higher Education Academy, a NMCregistered nurse teacher, and a children’s advanced nurse practitioner.

About the Editors

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Margaret F. Keil, PhD, CRNP  is a board-certified pediatric nurse practitioner with 30+ years of experience in pediatric nursing caring for children with chronic medical conditions in a variety of clinical settings. Dr. Keil received her PhD in nursing from the Uniformed Services University of the Health Sciences and is a graduate of the University of Colorado and Georgetown University. Dr. Keil is a clinical researcher at the National Institutes of Health; her research focuses on biobehavioral outcomes of early life adversity and quality of life and other outcomes associated with chronic endocrine disorders in children. Dr. Keil has authored or co-authored numerous articles published in peer-reviewed journals on pediatric endocrine disorders, including Cushing syndrome, quality of life outcomes, congenital adrenal hyperplasia, obesity, and pituitary tumors. She holds leadership positions in the Pediatric Endocrinology Nurses Society and the Cushing Support and Research Foundation and is a member of the European Society of Endocrinology and the Federation of International Nurses in Endocrinology. Judith  P.  van Eck  is one of the first advanced practice nurses specialized in endocrinology in the Netherlands. Her career in nursing started in 2004 when she received her bachelor degree in nursing science. Afterward, she worked from 2004 to 2008 as a registered nurse on the clinical department of internal medicine at the Erasmus Medical Center in Rotterdam, the Netherlands. From 2008 to 2010, she followed the Master in Advanced Nursing Practice at Rotterdam University of Applied Sciences. From 2010 until 2018, she worked as a nurse practitioner for the Pituitary Center at the Erasmus Medical Center in Rotterdam, the Netherlands. She was also running a nurse-led clinic for patients with radiation induced hypopituitarism. Currently, she works as a nurse practitioner at the department of Pediatric Endocrinology at Erasmus MC- Children’s Hospital in Rotterdam, The Netherlands. She also runs a nurse-led clinic for patients with radiation induced hypopituitarism. She has been a member of the ESE nurses working group from 2013 to 2017, and currently, she is a member of the Dutch Endocrine Nurses Group.

About the Editors

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Violet  Fazal-Sanderson’s, RGN, BSc(Hons), MSc, IP  nursing career took off in Oxford where she worked for several years as a staff nurse in the intensive care unit at the Oxford University Hospitals NHS Foundation Trust. She graduated with a BSc (hons) in critical care nursing at Oxford Brookes University. From 2000 to 2016, she worked in the endocrine investigations unit as an advanced nurse practitioner at the Oxford Centre for Diabetes, Endocrinology and Metabolism. She developed an interest in acromegaly and thyroid nurse-led clinics and involved herself in 40 research projects from which emerged several published abstracts and 2 nurse awards. In 2017, she gained an MSc in endocrinology and now works as a senior endocrine clinical specialist nurse at the Royal Berkshire Hospital NHS Foundation Trust, Reading, and continues to work in endocrinology and thyroid virtual nurse-led clinics. Violet is a member of the British Society for Endocrinology Nurse Committee and the UK TEDct. Gerard S. Conway  is a consultant endocrinologist at University College London Hospitals and professor of clinical medicine in the Institute for Women’s Heath, University College London. His clinical practice covers general endocrinology including pituitary, adrenal, thyroid, and reproductive endocrinology. His clinical research interests are in the field of reproductive endocrinology particularly polycystic ovary syndrome, ovarian and testicular function, disorders of sexual development, and Turner syndrome. This research has formed the basis of over 160 academic publications. Professor Conway qualified from the Royal London Hospital in 1981 and trained in diabetes, endocrinology, and general medicine in several centers in Central London. He has been professor of clinical medicine in the Institute for Women’s Health UCL since 2012. With a major interest in teaching, Professor Conway lectures in reproductive endocrinology, for the Society for Endocrinology, the Royal College of Obstetricians and Gynaecologists, and internationally with the endocrine societies in the USA, Sri Lanka, India, New Zealand, Australia, Japan, and throughout Europe.

About the Editors

xxiv

Andrew  A.  Dwyer, PhD, FNP-BC, FNAP  is a board-certified family nurse practitioner with 18+ years of experience in reproductive endocrinology and translational research at the Massachusetts General Hospital (MGH) in Boston (USA) and the University Hospital of Lausanne (CHUV) in Switzerland. Professor Dwyer specializes in genetic disorders of growth/puberty and has helped develop and test structured transitional programs for young adults with chronic endocrine conditions. He presents internationally and has authored/ co-authored more than 50 articles on these topics. He holds leadership positions in several organizations including the European Society of Endocrinology, Pediatric Endocrine Nursing Society, European Society of Paediatric Endocrine Nursing, International Society of Nurses in Genetics, and Global Genomic Nursing Alliance. In 2018, Professor Dwyer was inducted into the National Academies of Practice (nursing) as a distinguished fellow. Ann Robinson  is an endorsed nurse practitioner (NP) with experience in both public and private sectors. With a background in diabetes and endocrine nursing, her main area of clinical work is now bone health and fracture prevention in highrisk populations. In addition, Ann sits on the governing board of the SOS Fracture Alliance and is past president of the Endocrine Nurses Society of Australasia. Ann works at Gold Coast Health as a nurse practitioner collaborating between hospital and community services to improve osteoporosis awareness and reduce the burden of osteoporotic fractures. She collaborates with the orthopedic teams and has an interest in when to commence treatment, for how long, and when, if ever to stop treatment.

About the Editors

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Phillip Yeoh, RN, BSc, MSc, PhD(c)  completed registered nurse training in London, BSc from the University of Manchester, and MSc from Brunel University. Philip is currently doing a PhD in Nursing at King’s College in London. He is consultant nurse in endocrinology and manager for Endocrine and Diabetes Department within the London Clinic, providing inpatient and outpatient care. His interests in endocrinology focus on adrenal diseases, pituitary conditions, Cushing’s disease, acromegaly, neuroendocrine conditions, parathyroid diseases, thyroid cancers, Conn’s syndrome, endocrine malignancy such as adrenocortical carcinoma, endocrine testing, endocrine nurse clinical roles, and endocrine nurse educations. He is co-author of Competency Framework for Adult Endocrine Nursing (Society for Endocrinology) editions I and II. Currently, he is involved in various research projects looking at dynamic function tests and endocrine nurse role in continuous subcutaneous hydrocortisone infusion pump for patients with adrenal insufficiency. He is coordinator for Federation of International Nurses in Endocrinology. He was a nurse committee member for European Society of Endocrinology and Society for Endocrinology. He is also a trustee for Addison’s Disease Self-Help Group UK. Anne Marland, RGN, INP, BSc, MSc, PhD(c)  is advanced nurse practitioner in adult endocrinology and independent nurse prescriber (INP) at the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) in the UK. Anne worked in the Neuroscience Department in Oxford, and in 1998, she took on a senior research nurse role in OCDEM and, following this, advanced nurse practitioner. Anne has a keen interest in the clinical area of “late effects in endocrinology” and is currently studying for a PhD in this area. She is the patient and public involvement representative for the NIHR

About the Editors

xxvi

for endocrinology and rare disease in the UK. Anne has a keen interest in education and regularly lectures worldwide. She chairs the working party which developed the Society for Endocrinology MSc in Adult Endocrine Nursing in collaboration with Oxford Brookes University in the UK. Anne is the current chair for the British Society for Endocrinology Nurse Committee and member of the Public Engagement Committee. Mike  Tadman  is a cancer nurse specialist with over 20 years of experience both in practice and education, mainly within Oxford, but has also practiced in Edinburgh and briefly in Melbourne. He set up the Neuroendocrine Tumours Specialist Nursing Service at the Oxford University Hospitals NHS Foundation Trust in 2013. He is an active member of UKINETs and ENETs and has presented regularly at national and international conferences on NETs. He has completed a survey of how centers commence and he has recently published research into the use of somatostatin analogue test dosing and urine 5HIAA testing. He is author of the OUP Cancer Nursing Handbook, having just completed editing its 2nd edition.

Contributors

Daphne T. Adelman  Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Bushra Ahmad  Bristol Royal Infirmary, University of Bristol, Bristol, UK Clare Akers  Urology Department, Westmorland Street Hospital, University College London Hospitals NHS Foundation Trust, London, UK Ahmed  Al Sajwani Department of Endocrinology, Tallaght Hospital, Dublin and Trinity College, Dublin, Ireland Susie Aldiss  Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK Wiebke Arlt  Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Miriam  Asia Department of Endocrinology, Birmingham University Hospital, Birmingham, UK Margaret  G.  Au  Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA Theingi  Aung Centre for Diabetes and Endocrinology, Royal Berkshire Hospital NHS Foundation Trust, Reading, UK Lesley  Baillie  School of Health, Wellbeing and Social Care Nursing, The Open University, Milton Keynes, UK Stephanie  E.  Baldeweg Department of Diabetes and Endocrinology, University College London Hospitals, London, UK Kelly Mullholand Behm  Orlando, FL, USA Sarah Benzo  Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Jérôme Bertherat  Service d’Endocrinologie, Hôpital Cochin, Paris, France Beth Brillante  National Institutes of Health, National Institute of Dental and Craniofacial Research, Craniofacial and Skeletal Diseases Branch, SCSU, Bethesda, MD, USA

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Chloe Broughton  North Bristol NHS Trust, Bristol, UK Adrian Brown  Imperial College London, London, UK Debbie  Carrick-Sen School of Nursing, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Paul V. Carroll  Department of Endocrinology, Guy’s & St. Thomas’ NHS Foundation Trust, DEDC 3rd Floor Lambeth Wing, St. Thomas’ Hospital, London, UK Harvinder Chahal  Imperial Weight Centre, St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK Yuk  Fun  Chan  Department of Endocrinology and Metabolism, Prince of Wales Hospital, Randwick, NSW, Australia Kathryn Clark  University of Michigan Hospital, Ann Arbor, MI, USA Sharron  Close Emory School of Medicine, Emory University School of Nursing, The eXtraordinarY Clinic at Emory, Atlanta, GA, USA Arthur  D.  Conigrave Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia Gerard  S.  Conway Institute for Women’s Health, University College London, London, UK Sherwin Criseno  University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Rachel Crowley  St. Vincent’s University Hospital and University, College Dublin, Dublin, Ireland Marina  Cunha-Silva Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, São Paulo, Brazil Christine  Davies Children’s Hospital for Wales, Cardiff and Vale UHB University Hospital of Wales (UHW), Cardiff, UK Kate  Davies Department of Advanced and Integrated Practice, London South Bank University, London, UK Philippa  Davies NET Unit, Royal Free London NHS Foundation Trust, London, UK Andrew P. Demidowich  National Institutes of Health, Bethesda, MDUSA Louise  Doodson Great Ormond Street Hospital for Children NHS Trust, London, UK Andrew A. Dwyer  William F. Connell School of Nursing, Boston College, Chesnut Hill, MA, USA Margaret Eckert-Norton  SUNY Downstate, Brooklyn, NY, USA

Contributors

Contributors

xxix

Anne  L.  Ersig UW-Madison School of Nursing, UW Health American Family Children’s Hospital, Madison, WI, USA Violet  Fazal-Sanderson Centre for Diabetes and Endocrinology, Royal Berkshire Hospital NHS Foundation Trust, Reading, UK Chona  Feliciano Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Cecilia  Follin Department of Endocrinology, Skane University Hospital, Lund, Sweden Rebecca Ford  Bristol Eye Hospital, University Hospitals Bristol NHS Trust, Bristol, UK Kirtan Ganda  Concord Hospital, Sydney, NSW, Australia Rhonda  Garad  Monash Centre for Health Research and Implementation (MCHRI), Monash University, Clayton, VIC, Australia Claire  Gilbert Great Ormond Street Hospital for Children NHS Trust, London, UK Helena  Gleeson Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Clare Grace  Relish Nutrition Consultancy, North Yorkshire, UK Ashley Grossmann  Royal Free Hospital, London, UK Green Templeton College, University of Oxford, Oxford, UK Barts and the London School of Medicine, London, UK Lori Guthrie  National Institutes of Health, National Institute of Dental and Craniofacial Research, Craniofacial and Skeletal Diseases Branch, SCSU, Bethesda, MD, USA Saira  Hameed Imperial Weight Centre, St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK Geraldine Hamilton  Macmillan Support Line, Macmillan Cancer Support, Glasgow, UK Ingrid Haupt-Schott  Velindre NHS Trust, Velindre Cancer Centre, Cardiff, UK Christina  Hayes Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Frances  J.  Hayes  Endocrine Division, Harvard Massachusetts General Hospital, Boston, MA, USA

Medical

School,

Saundra  Hendricks Department of Medicine, Center of Bioenergetics, Houston Methodist Hospital, Houston, TX, USA Fiona  Holden  Urology Department, Westmorland Street Hospital, University College London Hospitals NHS Foundation Trust, London, UK

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Jürgen  Honegger  Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany Irena  R.  Hozjan Endocrine Program, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada Khalid  Hussain Great Ormond Street Hospital for Children NHS Trust, London, UK Sue  Jackson  Psychology Department, University of the West of England, Bristol, UK Channa  Jayasena Reproductive Endocrinology and Andrology, Imperial College and Hammersmith Hospital, London, UK Peggy  Kalancha  Clinical Resource, Pediatric Endocrine and Gynecology Clinics, Alberta Children’s Hospital, Calgary, AB, Canada Niki Karavitaki  Institute of Metabolism and Systems Research, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK Margaret F. Keil  Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA Dev  A.  Kevat Monash Health and Western Health, Melbourne, VIC, Australia Nicole Kirouac  St. Amant Inc., Winnipeg, MB, Canada Kathryn  Evans  Kreider Duke University School of Nursing and Duke University Medical Center, Durham, NC, USA Ana  Claudia  Latronico Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil, São Paulo, Brazil Megan  K.  Lessig Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Karen J. P. Liebert  Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA Terri  H.  Lipman Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Sofia  Llahana School of Health Sciences, City, University of London, London, UK Lucy Mackillop  Nuffield Department of Women’s and Reproductive Health, University of Oxford, Level 6, Women’s Centre, John Radcliffe Hospital, Oxford, UK Anne Marland  Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Contributors

Contributors

xxxi

Lee Martin  Barts Health NHS Trust, The Royal London Hospital, London, UK Raven McGlotten  National Institutes of Health, Bethesda, MD, USA Gisela Michel  Department of Health Sciences and Health Policy, University of Lucerne, Luzern, Switzerland Radu  Mihai  Department of Endocrine Surgery, Churchill Cancer Centre, Oxford University Hospitals Foundation Trust, Oxford, UK Kerry-Lee  Milner  Department of Endocrinology and Metabolism, Prince of Wales Hospital, Randwick, NSW, Australia Irene Mitchelhil  Department of Endocrinology, Sydney Children’s Hospital (SCHN), Randwick, NSW, Australia Bin Moore  The Children’s Hospital, Westmead, NSW, Australia Kate  Morgan Great Ormond Street Hospital for Children NHS Trust, London, UK Amy Mundy  McGuire Veterans Medical Center, Richmond, VA, USA Pauline Musson  Southampton Children’s Hospital, Southampton, UK Sebastian  J.C.M.M.  Neggers  Department of Medicine, Section Endocrinology, Erasmus Medical Centre, Rotterdam, The Netherlands Milla  Pantovic  Department of Neuroendocrinology, Endocrinology, Clinical Center Serbia, Belgrade, Serbia

Clinic

for

Petro  Perros  Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK Catalina Poiana  Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Vera Popovic  Department of Neuroendocrinology, Clinic for Endocrinology, Clinical Center Serbia, Belgrade, Serbia Alison  Pottle Royal Brompton and Harefield NHS Foundation Trust, London, UK Alessandro  Prete Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Eileen  Pyra Alberta Children’s Hospital, Endocrine Clinic, Calgary, AB, Canada Marcus  Quinkler Department of Medicine for Endocrinology, Diabetes and Nutrition Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany Richard  Quinton  Newcastle-upon-Tyne Hospitals Foundation NHS Trust (Royal Victoria Infirmary), Newcastle-upon-Tyne, UK

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Rabia  Arfan Centre for Diabetes and Endocrinology, Royal Berkshire Hospital NHS Foundation Trust, Reading, UK Ann Robinson Gold Coast University Hospital, Parkwood, Queensland, Australia Katharina  Roser Department of Health Sciences and Health Policy, University of Lucerne, Luzern, Switzerland Elisabeth Rutten  Department of Endocrinology, Ghent University Hospital, Ghent, Belgium Katrin  Scheinemann Division of Hematology/Oncology, University Children’s Hospital Basel (UKBB), Basel, Switzerland Wendy  Schwarz Alberta Children’s Hospital, Endocrine Clinic, Calgary, AB, Canada Mark  Sherlock Department of Endocrinology, Tallaght Hospital, Dublin and Trinity College, Dublin, Ireland Soulmaz Shorakae  Monash Centre for Health Research and Implementation (MCHRI), Monash University, Clayton, VIC, Australia Klaus Sommer  Concord Hospital, Sydney, NSW, Australia Victoria  J.  Stokes Endocrinology and Metabolism, Oxford Radcliffe Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK Mike Tadman  Oxford University Hospitals NHS Foundation Trust, Oxford, UK Helena  Teede Monash Centre for Health Research and Implementation (MCHRI), Monash University, Clayton, VIC, Australia Raluca-Alexandra  Trifanescu Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Helen  E.  Turner The Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK Suma  Uday University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK Tanya L. Urquhart  Sheffield Hallam University, Sheffield, UK Judith  P.  van Eck Department of Medicine, Section Endocrinology, Erasmus Medical Centre, Rotterdam, The Netherlands Marsha  M.  van Oostwaard Department of Internal Medicine and Endocrinology, Veldhoven, The Netherlands Artemis Vogazianou  Department of Diabetes and Endocrinology, University College Hospital, London, UK Jerry K. Wales  Lady Cilento Children’s Hospital, Brisbane, QLD, Australia

Contributors

Contributors

xxxiii

Chris  White Department of Endocrinology and Metabolism, Prince of Wales Hospital, Randwick, NSW, Australia Amanda Whitehead  Leeds Children’s Hospital, Leeds General Infirmary, Leeds, UK Tara  Whyand NET Unit, Royal Free London NHS Foundation Trust, London, UK Elizabeth  Williamson Reproductive Medicine Unit, University College London Hospitals, London, UK Christine Yedinak  Northwest Pituitary Center, Oregon Health and Sciences University, Portland, OR, USA Phillip  Yeoh Department of Diabetes and Endocrinology, The London Clinic, London, UK Kathrin  Zopf Department of Medicine for Endocrinology, Diabetes and Nutrition Medicine, Charité Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany

Part I Growth and Development Kate Davies and Margaret F. Keil

1

The Importance of Auxology for Growth Assessment Terri H. Lipman and Megan K. Lessig

Contents 1.1

Importance of Growth Monitoring

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1.2

Stages of Growth and Growth Rates by Age

 4

1.3 M  easurements Used in Evaluation of Growth 1.3.1  Growth Parameters 1.4

Growth Charts

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1.5 T  ools for Adult Height Prediction 1.5.1  Bone Age X-Ray 1.5.2  Midparental Height 1.6

Conclusions

Auxology is the basis of a proper growth evaluation. It is through the history, physical exam, and auxology that we are able to properly assess a child’s growth. Auxology enables us to establish a child’s growth patterns and

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References

Abstract

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determine if growth is indeed normal. An accurate and reliable measurement, along with appropriate and accurate charting, is critical for a proper growth evaluation. Keywords

Auxology · Growth chart · Measurement T. H. Lipman (*) University of Pennsylvania School of Nursing, Philadelphia, PA, USA Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA e-mail: [email protected] M. K. Lessig Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA e-mail: [email protected]

Abbreviations BMI Body mass index CDC Center for Disease Control cm Centimeter in Inch kg Kilogram lb Pound

© Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_1

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T. H. Lipman and M. K. Lessig

4

LGA Large for gestational age m Meter MPH Midparental height MUC Mid upper arm circumference NHANES National Health and Nutrition Survey oz Ounce SD Standard deviation SGA Small for gestational age WHO World Health Organization Key Terms • Auxology: Science of human growth and development. • Accuracy: A measure of how close the measurement is to the actual measurement. • Diurnal variation: Normal fluctuations that occur over the course of a day. • Frankfort plane: Eye ear plane which is a standard horizontal cephalometric reference. • LGA (large for gestational age): Refers to infants who have birthweights greater than the 90th percentile for babies of the same gestational age. • Measurement error: Difference between a measured quantity (e.g., height) and its true value (e.g., actual height). • Reliability: This is the quality of the measurement. It predicts how likely a repeat measurement will be the same when repeated. Expressed in a percentage. • SGA (small for gestational age): Refers to infants who have birth weights below the 10th percentile for babies of the same gestational age.

Key Points

• Learners will be able to properly identify and obtain proper measurements for a growth evaluation. • Learners will be able to accurately interpret meaning of these measurements though proper charting.

1.1

Importance of Growth Monitoring

Linear growth is the single most important indication of the health of a child (Tanner 1986). Since healthy infants and children have predictable patterns of linear growth (length/height), normal growth is used as a standard for assessing child health and well-being. Children with growth pattern deviations (e.g., unexplained short or tall stature, growth failure, unexpected growth acceleration) should be evaluated to differentiate between normal growth variants and pathologic conditions. Growth is such a sensitive indicator of health that abnormal growth may be the earliest sign of pathology (Craig et al. 2011; Haymond et al. 2013). Pathological growth may result from nutritional disease, a genetic disorder, an endocrine cause, psychosocial problems, intrauterine growth retardation, or systemic disease and/or disease progression or exacerbation. (Haymond et al. 2013; Rogol and Hayden 2014; Richmond and Rogol 2014).

1.2

Stages of Growth and Growth Rates by Age

From infancy through adolescence, both cell number and cell size increase and body composition changes significantly in terms of absolute and relative changes in the amount of lipid, protein, water, and minerals (Beker 2006). Growth during childhood is tightly regulated and depends on the proper functioning of multiple systems including maternal nutrition and uterine size; genetic growth potential inherited from parents; and nutrition. Growth also is affected by the interaction of multiple hormones, including growth hormone (GH), thyroid hormone, insulin, and sex hormones, all of which effect growth at different points in development. Child growth generally is divided into six periods: (1) conception to birth, (2) infancy (birth to 1 year of age), (3) toddlerhood (1–3 years of age), (4) early childhood (3–6 years), (5) school-­ age (6–12  years), and (6) adolescence (12– 18 years) (Weintraub 2011).

1  The Importance of Auxology for Growth Assessment

1.3

Measurements Used in Evaluation of Growth

1.3.1 Growth Parameters 1.3.1.1 Length or Height Accurate measurement of linear growth is paramount when evaluating pediatric growth. (Foote et al. 2015) A multicenter study in eight cities in the United States demonstrated that only 30% of children in primary care practices were measured accurately (Lipman et al. 2004). To ensure accuracy, children younger than 24  months must be measured supine and have growth plotted on a length growth chart. When incorrectly obtaining a standing height on a child who is younger than 24  months, the measurement must be plotted on length growth chart—as the height growth chart begins at age 2. A supine measurement is greater than a standing measurement—particularly in children under two who stand with a marked lordosis. Therefore, a child who is measured standing before age 2, and plotted on a length chart, will appear to have linear deceleration which may result in an inappropriate referral for a growth evaluation. Children 24 months and younger should be measured, on a firm platform with a yardstick attached, a fixed head plate, and a moveable footplate (e.g., recumbent measuring board) (Rosenfeld and Arnold 1993; Wales et al. 2003) (Fig. 1.1). Due to slight changes in a child’s posture with each

Fig. 1.1 Measurement of infant length

5

measurement it is recommended that three consecutive linear measurements be obtained on each child. All children must be measured in centimeters rounded to the closest millimeter. The average of the three measurements is considered to be closer to the true height of the child (Voss and Bailey 1994; Foote et al. 2009). All children older than age 3 should be measured standing. Patients that are between 24 and 36  months can be measured either standing or supine. However, it is important that these children are then plotted on the correct growth chart. When obtaining height, children should be measured while standing against a wall mounted device (e.g., stadiometer) with a fixed right angle at the head (Foote et al. 2009). The child’s head, shoulders, buttocks, and heels should be against the wall and feet should be forward facing and together. Gentle traction should be placed under the child’s jaw to accurately position the head forward and the head plate should touch the child’s scalp, potentially causing hair accessories to be removed or hair styling to be flattened (Foote et al. 2009) (Fig. 1.2). All measurements should be obtained by personnel who have proper and regular training (Foote et al. 2009). Ideally, serial measurements should be taken at the same time of day due to diurnal variation. Studies have shown that there is minimal height loss that can range from 0.47 to 2.8  cm when children are measured in the afternoon versus the morning (Foote et al. 2009).

T. H. Lipman and M. K. Lessig

6 Fig. 1.2 Correct technique for measuring linear height. Reprinted with permission of Nichole Jonas, Graphic Designer. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD USA

Frankfort Plane

Calibrate the stadiometer Remove: shoes, hairpieces, heavy clothing Stand properly: similar to person in picture Head-Shoulders-Hips-Heels Measure-Reposition-Remeasure

1.3.1.2 Calibration of Measuring Devices Instruments must be calibrated at least monthly. Calibration should be more frequent if variance is noted or if recommended by the manufacturer (Voss 2000). A rod of known and fixed height/ length can be used to check the calibration of instruments (Foote et al. 2009). 1.3.1.3 Segment Measurements If full body recumbent length is measured in a child with spasticity, contractures, and/or other musculoskeletal abnormalities, measure the side of the body that is unaffected or less affected and

that can be extended the fullest. Record the side measured and the presence of spasticity, joint contractures, and/or other musculoskeletal issues. Alternative measurements, such as arm span, crown-rump length, sitting height, knee height, and other segmental lengths, may be taken to assess growth (Foote et al. 2009).

1.3.1.4 Arm Span Arm span, after 10  years of age, approximates height in normally proportioned children. It is obtained when it is not possible to obtain a standing height or when a child appears disproportionate. Arm span is the physical measurement of the

1  The Importance of Auxology for Growth Assessment

length from one end of an individual’s arms (measured at the fingertips) to the other when raised parallel to the ground at shoulder height at a 90° angle. The patient should be placed with the back to the wall and feet together. The measurer should stretch a measuring tape from the tip of the middle finger on one hand to the tip of the middle finger on the other hand. Measurements of arm span should be obtained in centimeters and rounded to the closest millimeter.

1.3.1.5 Sitting Height Sitting height should be measured by bringing the fixed right angle of a measuring device to the most superior midline of the head while the child is sitting in an erect position on a flat surface. Arching of the back should be avoided by applying upward pressure to the mastoid processes while the child breathes deeply and holds breath during the measurement (Fredriks et al. 2005). 1.3.1.6 Head Circumference Head circumference should be measured in all children under the age of 36 months and plotted on a head circumference growth chart to evaluate head growth over time. Two measurers are needed to obtain this measurement and it should be obtained with a tape measure that does not stretch. The tape is positioned across two land marks—the supraorbital ridge and the occiput. Measurements of head circumference should be obtained in centimeters and rounded to the closest millimeter. These measurements are so important in the early months of life, as these measurements are a reflection of intracranial volume and brain growth (Hall et  al. 1989). Identification of abnormal growth patterns can lead to early diagnosis of treatable conditions, such as hydrocephalous (Nellhaus 1968). 1.3.1.7 Weight Younger infants should be weighed nude or in a clean diaper on a calibrated beam or electronic scale. Weigh older infants in a clean, disposable diaper. Position the infant in the center of the scale tray. It is preferable to have two people when weighing an infant. One measurer weighs the infant and protects the child from falling and

7

reads the weight as it is obtained. The other measurer notes the measurement in the infant’s chart. Weigh the infant to the nearest 0.01  kilogram (kg) or 1/2 ounce (oz). A child older than 36 months who can stand without assistance should be weighed using a calibrated beam balance or electronic scale wearing only lightweight clothes or a gown. It is important to stand on the center of the platform of the scale. Children should be weighed to the closed 0.01 kg or ½ oz (Tanski et al. 2007).

1.3.1.8 BMI The body mass index (BMI) is utilized to quantify the amount of tissue mass in an individual and then categorize that person as underweight, normal weight, overweight, or obese. BMI is used to determine childhood overweight and obesity. Overweight is defined as a BMI at or above the 85th percentile and below the 95th percentile for children and teens of the same age and sex. BMI can be calculated using the following formulas:

(

English : Weight ( pound ( lb ) .) /

)

éë height inch ( in ) ´ height ( in ) ùû ´ 703 Metric : Weight ( kg ) /

éë height meter ( m ) ´ height ( m ) ùû

BMI is then plotted on growth chart for age and sex to determine BMI percentile (Tanski et al. 2007).

1.3.1.9 Waist Circumference Waist circumference is a useful measurement when evaluating a child for obesity or overnutrition. The measurement is obtained by measuring a child between the lower ribs and the ischial ridge at the level of the umbilicus at the end of a normal expiration (Tanski et al. 2007). Skinfold measurements, described in more detail below, can also be used when evaluating a child for weight concerns, as these measurements allow the practitioner to better estimate fat distribution. These measurements become more valuable clinically when used serially to establish a potential improvement from a clinical intervention. To obtain a waist cir-

T. H. Lipman and M. K. Lessig

8

cumference, have the child hold his gown above the waist, cross his arms, and then place hands on opposite shoulders, as if he is giving himself a hug. Next, mark the measurement site. To do this, the measurer should stand on the right side of the child, palpate the hip area to locate the right ilium of the pelvis, and with a cosmetic pencil draw a horizontal line just above the uppermost lateral border of the right ilium. It is important that the measurer ensures that this line crosses the midaxillary line, which is the line that extends from the armpit to the down the side of the torso. To obtain the actual measurement, the measurer should extend the measuring tape around the waist. The measuring tape should be positioned in horizontal plane at the same level as the measurement mark and the zero end of the tape should be positioned below the part of the tape containing the measurement value. The measurement tape should fit snug but should not compress the skin. The measurement should be measured to the nearest 0.1 cm at the end of a normal expiration. The National Health and Nutrition Survey (NHANES) and the Center for Disease Control (CDC) provide a table of ranges of waist circumferences based on age, race, and weight. This enables us to better interpret and use the data (https://www.cdc.gov/nchs/ data/series/sr_11/sr11_252.pdf).

1.3.1.10 Skinfolds Skinfold thickness is another measurement that can be used in conjunction with the waist circumference when evaluating an overweight child. Although four sites can be used, including the triceps, subscapular, biceps and suprailiac, the current National Health and Nutrition Examination Survey (NHANES) anthropology protocol recommends the triceps and subscapular skinfold measurements for patients 2 months of age and older (CDC 2007). In order to accurately obtain this measurement, a skinfold caliper must be used. THE NHANES recommends the Holtain skinfold caliper. Regardless of site, the skinfold measured must contain a double thickness of skin and underlying adipose tissue. To obtain the triceps skinfold, use the thumb and index finger to grasp a fold of skin and subcutaneous tissue at the midpoint of the dorsum of the upper arm. The

tips of the caliper jaws are then placed over the complete skinfold. Release the caliper handle to apply full tension while continuing to hold the skinfold in place so the measurement will register accurately. This should be held for approximately 3  seconds before the measurement is read and recorded. For the subscapular skinfold, the measurement is taken at the inferior angle of the right scapula while arms are in the relaxed position. It is important to not hold the caliper more than 3  seconds or repeat the measurement too frequently at the same spot, as the tissue can be compressed, and ultimately the measurement is falsely low (Hall et al. 1989). Just as in waist circumference, there are charts for normative values for skinfolds (CDC 2007, 2012). https://www.cdc.gov/nchs/data/series/sr_11/ sr11_252.pdf

1.3.1.11 M  id Upper Arm Circumference A mid upper arm circumference (MUAC) is a measurement that can be utilized when evaluating a child that is undernourished. This measurement is obtained using a flexible nonstretch tape measure. The tape measure is placed mid-way between the elbow and shoulder. The World Health Organization provides standards for arm circumference (http://www.who.int/childgrowth/ standards/ac_for_age/en/).

1.4

Growth Charts

To assess if a child’s growth pattern is normal, it is crucial that the length or height is plotted on a growth chart with established standards, plotted correctly, and plotted on the correct growth chart. To plot an infant or child, the correct growth chart needs to be identified (i.e., length chart for  20). An appropriate cortisol peak of 621  nmol/l (>500) was obtained. Bone age was delayed, being 3.5 years at a chronological age of 4.5 years. A diagnosis of isolated GH deficiency was declared and treatment with GH commenced at a dose of 4.5–6  mg/m2/week. This dose was reviewed 6 monthly (as per Australian guidelines) and adjusted according to increasing body surface area (BSA). Long-term progress has shown that no other pituitary deficiencies have evolved. At age 12.9 years, he had 4 ml testes and by 14.1  years has 8  ml testes, PH3, G3, and will continue on GH therapy until he reaches a bone age of 15.5  years or his growth has slowed down to be 2 SDS below the mean over 1 year or more than 1.5 SDS over a 2-year period. All of these variations should be evaluated when assessing a child’s growth pattern (Growth Hormone Research Society 2000; Cook et al. 2009).

2.5

Investigations and Diagnosis

Baseline investigations will help determine the likelihood of GHD which can effectively be excluded in children with a normal bone age and height velocity.

2  Short Stature, Growth Hormone Deficiency, and Primary IGF-1 Deficiency

Baseline investigations should include (Cook et al. 2009): • A full blood count • Blood chemistry, including thyroid stimulating hormone and free thyroxine level • Coeliac screen and IgA (Immunoglobulin A) levels • 25-OH Vitamin D level • Karyotype in all girls and boys with dysmorphism • IGF-1 More detailed laboratory evaluation for causes of growth failure may be carried out by a specialist once the initial evaluation is complete. IGF binding protein, hormones to evaluate puberty including luteinising hormone, follicle stimulating hormone, oestradiol, testosterone, and prolactin levels if concerned about pubertal delay should all be measured. Molecular testing or comparative genomic microarray for various genetic conditions may be considered. GH stimulation testing should be considered if the clinical criteria is insufficient to make the diagnosis of GHD (Chesover and Dattani 2016). Those with a known pituitary abnormality or deficiency of at least one other pituitary hormone, and with obvious growth failure, may not need testing. If there is enough information to determine the cause of growth failure, provocative testing for GHD may not be required (Grimberg et al. 2016). The most common test to assess GHD is a dynamic GH stimulation test (See Chap. 15). As GH is produced in a pulsatile fashion, it is able to be stimulated to assess pituitary function. A variety of tests are available using pharmacological stimuli and two stimuli are best used to capture the peak levels of GH produced. Provocative agents such as insulin, glucagon, arginine, and clonidine can all be used to assess GH levels. Various cut-off levels have been used, but GHD is generally defined as a value of 10  years and boys >11 years) is often done after priming with sex steroids for a few days prior to testing. This is

23

done to lessen the chance of a false diagnosis, but there is still some discussion as to whether this is necessary and so is not mandatory (Chesover and Dattani 2016; Rosenbloom 2011). Testing should be in a recognised testing facility by trained nurses due to the risk of hypoglycaemia associated with many of the stimulation tests. Finally, an MRI of the brain/pituitary gland will establish if there are any midline defects, structural abnormalities, or evidence of a tumour or cystic mass.

2.6

Treatment

Children with GHD are unlikely to reach their adult potential without treatment. Recombinant human growth hormone is the only treatment that can improve final height but can only influence the active growth phase whilst the bone epiphyses remain open. In many countries, GH treatment is commonly approved for those not only with GHD but other conditions of short stature as well, such as: • • • • •

TS—Turner syndrome SGA—Small for gestational age PWS—Prader-Willi syndrome CRI—Chronic renal insufficiency SHOX—Short stature homeobox-containing gene deficiency disorder • AGHD—Adult growth hormone deficiency • ISS—Idiopathic short stature (Raine et  al. 2011) More recently, GH has become available in some countries for use in adults with established GHD. Treatment involves daily subcutaneous injections of recombinant human growth hormone (rhGH), also known as somatropin. Prior to 1985 hGH (human growth hormone) was only used in those with severe GHD, but was withdrawn when concerns regarding its association with Creutzfeldt-Jakob disease (CJD) arose (Buchanan et al. 1991; Boyd et al. 2010). Treatment today uses a variety of recombinant human growth hormone products. Some products are a liquid formulation, whilst others require

24

powder and diluent to be mixed to maintain product stability. Doses are based on either patient’s weight or body surface area depending on which country they reside in, and the clinical indication they are being prescribed for. There are a number of different devices designed for giving injections, with some that can actually hide the needle tip, but as the needles used are small, they are in most cases well tolerated. Each company has a device designed specifically for their product, so they are not interchangeable. Subcutaneous injections are given daily usually in the evening prior to bed as GH is released in pulses during the night (See Fig. 2.1) and at a similar time each day where possible. Arms, legs, abdomen, and buttocks are used as injection sites, and the 4–6  mm needles used can usually be accommodated in most of these spots. Current practice is to use each area for approximately one week, rotating on a regular cycle. Families, parents, and older children are instructed on injection technique at the time GH injections are commenced, but regular review of technique should be encouraged to uncover any problems parents may be having that may impact on compliance. Adolescents giving their own injections should always be supervised by a parent. Assessment of the families understanding of why the treatment is being given should be part of the ongoing review at appointments. It is sometimes worthwhile reminding families that if injections are regularly missed the benefits of treatment may be compromised. Side effects with rhGH are uncommon but should be clearly explained at the time of commencement of injections. Usually, rhGH is safe and well tolerated (Quigley et  al. 2005; Quigley et  al. 2017; Carel et  al. 2012). Minor adverse effects such as bruising at injection sites usually diminish once treatment is established and parents become more confident at injecting their child. Occasionally, in the early stages of treatment some children may retain excess fluid and salt,

B. Moore et al.

causing headaches with some blurring of vision (benign intracranial hypertension). It is not commonly seen and usually disappears when the GH is ceased for a few days, and reintroduced at a lower dose, gradually increasing over time. If it does occur, referral to an ophthalmologist should be made for ongoing assessment in the first few months of treatment. Slipped capital femoral epiphysis (SCFE) has also been reported to be slightly more common in children receiving GH treatment (Rappaport and Fife 1985). This may cause pain in the hip and knee joints and appears to mostly occur in those with other risk factors such as obesity, trauma, other endocrine conditions, or those who have had previous radiation therapy, or very rapid growth. Scoliosis has also been observed in some children treated (Clayton and Cowell 2000), but is more the result of an increase in height velocity unmasking the tendency to a curved spine, than the GH itself. Depending on family history, there may be an increased risk of developing type 2 diabetes mellitus, but as the doses of GH prescribed are mostly physiological the risk is relatively low. Markedly elevated IGF-1 concentrations have been associated with colon, breast, and prostatic cancer: However, there is no evidence to suggest an increased risk of malignancies using the current dosage recommendations for rhGH. In general, GH should not be given with an active malignant condition. The absence of tumour growth or recurrence should be documented for 12  months before commencing treatment. The long-term safety of GH treatment is, however, uncertain. The most common questions asked by patients and parents alike when starting treatment is, how much will I grow, and how long will I need to take GH for? Rapid short-term growth is usually followed by normalisation of long-term growth. Treatment should be continued until final height or epiphyseal closure is achieved (Clayton

2  Short Stature, Growth Hormone Deficiency, and Primary IGF-1 Deficiency

et al. 2005). For girls this is when the bone age is around 13.5 years and for boys around 15.5 years. A good predictor of response to treatment is the height gain attained in the first year of treatment. Other factors that can impact on the response to treatment include age and height at the start of treatment, duration of treatment, and, in patients with isolated GHD, the pre-pubertal growth available when receiving treatment. Long-term monitoring of treatment is essential and should include:

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2.6.1 Compliance and Growth Hormone Device Choice

Growth hormone treatment involves a daily injection. For some families, the thought of injecting their child on a daily basis is confronting, and the emotional factors and anxiety around administration can overwhelm them (or their child). There are a number of devices for giving GH available but nearly all require a needle to be inserted into the subcutaneous fat. Many devices can hide the site of the actual needle if required, • Regular measurements, plotted on an age- and and for most children the procedure becomes sex-appropriate growth chart. easier over time. In some countries, allowing families some choice in the decision-making On average, puberty contributes 20–25 cm of around which device to use, compliance can be height in females and 25–30  cm in males, and shown to be improved. Compliance often waivthis is dependent on adequate GH and insulin-­ ers especially in the adolescent years, as growth like growth factor 1 (IGF-1) concentrations. is slow, an immediate response cannot be seen, and the idea of having to remember to give an • Frequency of monitoring patients with an injection each night does not always sit easily in acquired cause of GHD (e.g. tumours, radia- an adolescents life! Feedback regarding the tion) will depend on the individual condition. devices assists in compliance as the family or • All patients on GH should continue receiving young person feels they have contributed to their treatment until final height or epiphyseal clo- treatment in some way. This along with ongoing sure is achieved. positive support from nursing staff assists in • Prior to transition to an adult endocrinologist, improving the patient experience (Gau and reassessment of IGF-1 levels and possibly of Takasawa 2017). GH levels should be undertaken. • If after ceasing treatment the IGF-1 level remains in the normal range, GH stimulation 2.7 Nursing Considerations testing should be undertaken to establish if the young persons’ GH levels have normalised or When evaluating a child with short stature, it is remain low. important to think about the following quesThis will assist in determining whether after completion of growth and puberty patients with idiopathic isolated GHD are at risk of ongoing GHD and will ascertain the need for adult GH replacement (See Chap. 6). In many patients (25–75%), when testing is repeated, the GH response is in the normal range (Cook et al. 2009). The reason for this reversal of GHD is unclear. Pituitary hormone deficiencies can evolve with time, so regular monitoring, both clinically and with regular biochemical investigations, is recommended.

tions. Although the causes and clinical presentation of short stature vary by age group, the same questions are relevant for children of any age: –– –– –– ––

How short is the child? Is the child’s height velocity (HV) impaired? Are they in keeping with their family pattern? What is the child’s likely adult height?

By using these questions as a baseline for assessment, the health care professional can

26

determine if there is a growth problem and evaluate how concerned are they about their height. When assessing a child’s growth, there are four main aims: –– To determine if the growth pattern is normal or as expected for the child’s family background. –– To attempt to predict future growth and final adult height. –– To determine if there are any modifiable medical or other issues that will improve growth. –– To consider if there are any specific treatments that are possible and appropriate to improve growth. The most important assessment of growth is reliable, reproducible, and regular measurements, done at 3–6 monthly intervals, and plotted on an appropriate growth chart. Children under the age of 2 years should have their length measured, and between the ages of 2–3  years all children should be assessed in a lying and standing position, as this is the age that they are usually least cooperative. This will provide the most accurate assessment, as long as that the same piece of equipment is used, it is calibrated regularly, the same the observer takes the measurement, and the growth is plotted on the same growth percentile chart, and once plotted the growth velocity can be calculated. Growth velocity is one of the most useful parameters when assessing growth as it determines the change in height over time. It should be calculated over at least a 6-month period as any less can lead to inaccuracy or misleading results. It is calculated as the difference in height on two different occasions annualised over 1 year and is age and pubertal status dependent. Height that plots along a given percentile on the growth chart reflects normal growth velocity. Crossing percentiles or a decreasing velocity reflects poor growth velocity. Plotting the growth is helpful in establishing if a child is just short (compared to his peers) but growing at a consistent rate, or if are they growing at a slower rate than their peers over time.

B. Moore et al.

Any child with a growth velocity under the third centile at any time should have further evaluation no matter where they sit on the growth chart. One of the most important things to remember however is that all children should be treated according to their AGE and NOT their SIZE. It is very common when assessing a child who may look younger and be much smaller than their peers, to speak down to them, or treat them ­inappropriately for their age, and there is nothing worse for a child. Often on further questioning, or once a relationship begins to develop, you may be able to determine if they are being bullied at school or in the playground, and if this is of concern to them. The issues that children with endocrine conditions may encounter, particularly if they do not fit into the social and emotional norms of their peers, can add to the distress of “being different” and isolate them even further. Children who are shorter than most of their peers may find themselves being excluded from sporting teams or even just play dates as younger children. Some may find that they don’t have the energy to keep up with their friends particularly if they are severely growth hormone deficient, making interaction even more difficult. Online or cyber bullying and social media has created a whole new set of issues for those with body image and self-esteem concerns (Cohen and Dwyer 2018). A full social history should always be undertaken in all patients, particularly those who present with poor weight gain and failure to thrive. If growth hormone production is being assessed using a stimulation test, it is important that both the family and the child have an understanding of what the testing involves and what to expect both during and after the evaluation. Information sheets regarding the tests should be provided (see Appendix), and the opportunity to ask questions prior to testing, must be considered. The goal of growth hormone (GH) treatment should be to restore hormone levels as close to healthy levels as possible and allow the child to reach their target adult height potential. During the initial assessment and monitoring phase, it is important to establish a good relationship with the child and family. This allows time

2  Short Stature, Growth Hormone Deficiency, and Primary IGF-1 Deficiency

for consideration of the likelihood of managing daily GH injections when started on treatment, ongoing compliance with treatment, and also gives the opportunity to evaluate if height is of concern to them as an individual, or if it is more of a parental concern. Results of any tests done should be clearly explained in language that the family will ­understand to ensure they have a good comprehension of why GH is required. Once treatment is approved, the family and child should be educated in the day-to-day management of injections, the storage of medication and general information about expectations of treatment, and the importance of compliance.

2.7.1 Emotional and Social Elements It is important to provide emotional support for the child with GH deficiency and to emphasise the child’s many good and valuable characteristics, so that the child’s stature does not limit his opportunities. Society (unfortunately) still places an emphasis on height, and children who are short for their age can initially have problems because friends and teachers treat them as though they are younger rather than just smaller. Parental expectations are often decreased as they feel their child is unable to do the same tasks as other children their age, and in turn children may then not act their age because it is not expected of them. Schools are sometimes unaware of the problems that children who are very small for their age have to deal with such as practical difficulties of being unable to reach a peg or desk or sit on the toilet. Teasing and/or being called names such as “shorty” or “shrimp” or being carried around the playground because they are “cute and doll like” is not helpful in allowing the child to develop to their full potential. Sometimes a frank and open discussion with teachers and classmates may help alleviate some of the problems. Positive role modelling by parents is essential and as with all parenting issues, there must be consistency. Parents must agree on a unified approach to handling any problems. Discussing and role playing

27

hypothetical situations and encouraging practice of these role plays can help children anticipate situations that may develop. Comments when out shopping or on the sporting field cannot be monitored, but the child can work to control their responses. A “toolkit” of responses is one of the best support mechanisms that can be given to parents and children, and the nurse can suggest that families work with their child to practise responses. The best responses are ones that are polite yet assertive, never rude, easy to remember (even in situations of high anxiety), and comfortable for a child to use. Work with the child and family to come up with a short list of responses that he or she can use in social situations when comments are made about stature. When commencing GH treatment, it is important that the child and family have realistic expectations. It is important to emphasise that growth takes time and that they are not going to grow overnight. Ongoing reassurance may be needed when the child is not growing as expected. Once there has been an initial response to treatment the possible benefit may include a general increased self-esteem and overall happiness that is gained with the increase in height.

2.8

 rimary IGF-1 Deficiency/ P Growth Hormone Insensitivity Syndrome

Growth hormone insensitivity syndrome (GHIS) is a rare condition (3 years 6 cm per year) Advanced (at least 1 year) Elevated (widely range) Prepubertal range Suppressed or blunted

203

weight was 24.3  kg. Penile length was 10.3  cm, testicular size was 2.0  ×  1.0  cm2 at right and 2.0  ×  1.0  cm2 at left, and pubic hair was Tanner stage 4. Bone age (BA) was advanced, 6.0 years. His basal testosterone levels ranged from 1.5 to 40  nmol/L (prepubertal range: 10% of patients with a macroadenoma prior to age 30 and in 20% of children with macroadenomas (Vasilev et  al. 2012).

17.3.2 Multiple Endocrine Neoplasia Type 1 Syndrome (MEN-1) MEN-1 is a rare hereditary cancer syndrome characterized by the occurrence of endocrine and non-endocrine tumours. The three main components of MEN-1 are primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours and pituitary adenomas (Chandrasekharappa et  al. 1997). MEN-1 pituitary disease is dominated by prolactinomas, but systematic screening of MEN-1 patients shows a large number of non-­ symptomatic small non-functioning pituitary adenomas (De Laat et al. 2015). The diagnosis of MEN-1 is established in one of these scenarios: a patient with 2 or more MEN-1-associated tumours; a patient with one MEN-1-associated tumour and a first-degree relative with MEN-1; a mutant gene carrier, that is, an individual with a MEN1 mutation but no clinical, biochemical or structural evidence of MEN-1 (Thakker et  al. 2012). Genetic counselling and testing is recommended for family members diagnosed with MEN-1.

17.4 Clinical Manifestations of Non-­functioning Pituitary Adenomas Non-functioning pituitary adenomas account for 25–30% of all pituitary adenomas (Alexander et  al. 1990). Non-functioning pituitary adenomas (NFPAs) produce small ­ ­quantities of hormones (e.g. gonadotrophins

17  Non-functioning Pituitary Adenomas

(LH, FSH), TSH or fragments of hormones (e.g. alpha subunits). The production of small quantities of these hormones does not lead to classic clinical syndromes like acromegaly and Cushing’s disease (see Chaps. 8 and 9). Also, alpha subunits are not biologically active when beta-subunits are not produced (Edmonds et  al. 1975). These adenomas are therefore considered as ‘non-functioning’. Individuals harbouring a NFPA usually present with one or a combination of symptoms secondary to mass effect on surrounding tissues and include: visual field defects, double vision, loss of visual acuity, headache and hypopituitarism (Ferrante et  al. 2006; Greenman and Stern 2015). Visual field deficits are caused by suprasellar extension of the adenoma leading displacement of the optic pathways (Fig. 17.1). It results often in a unique bitemporal hemianopsia which is typical for large pituitary adenomas, or other visual field defects (Lee et al. 2015). Bitemporal hemianopsia is a visual field deficit in which all the vision in the peripheral temporal fields of both eyes is lost,

Left optic nerve

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leaving only the nasal or central visual fields to be perceived (Lee et al. 2015). Incomplete bitemporal visual field defects are much more common than true hemianopsia (Lee et  al. 2015). The visual acuity may also be decreased (Ogra et al. 2014). 40–70% of the patients with NFPA present with visual field defects (Ferrante et al. 2006; Lee et  al. 2015; Ogra et  al. 2014). When bitemporal hemianopsia and/or decreased visual acuity has/ have been demonstrated, there is a need for neurosurgical intervention in order to restore visual functions. When compression of the optic chiasm is left untreated complete blindness can ensue (Müslüman et al. 2011). Headache is a common presenting symptom and occurs in approximately 40–60% of patients harbouring a non-functioning pituitary adenoma (Ferrante et  al. 2006; Ebersold et  al. 1986; Comtois et al. 1991). The aetiology is not very clear, but studies have demonstrated an association between the presence of headache and tumour size, optic chiasm compression, sellar destruction and cavernous sinus invasion (Gondim et al. 2009; Cottier et al. 2000). Also,

Right optic nerve

Left optic tract Right optic tract Pituitary adenoma

Left visual cortex

Right visual cortex

Fig. 17.1  Compression of the optic chiasm by the pituitary adenoma leading to bitemporal hemianopsia

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a family history for headaches is a risk factor for patients harbouring a pituitary adenoma (Yu et  al. 2017). There are studies that show that neurosurgical resection of the pituitary adenoma may relieve the patients of some chronic headaches (Ebersold et al. 1986; Comtois et al. 1991; Wolf et  al. 2016). Another recent study demonstrated no significant improvement in headaches after pituitary surgery (Siegel et  al. 2017). For this reason headache alone may not be a valid indication for transsphenoidal ­pituitary surgery. Hypopituitarism. Hypopituitarism is the lack of production of one or more anterior pituitary hormones. It may result in growth hormone deficiency, hypogonadotropic hypogonadism, secondary hypothyroidism and secondary adrenal insufficiency. Hypopituitarism occurs in variable degrees and when assessed, found in the majority of patients with non-functional pituitary adenomas (Ferrante et al. 2006; Jaffe 2006; Nomikos et al. 2004). Hypopituitarism is caused by the mass effect of the pituitary adenoma on normal pituitary tissue or as a result of compression of the hypophyseal portal circulation by the tumour mass. Recovery from hypopituitarism after decompression surgery has been described (Berg et al. 2010; Fatemi et al. 2008; Jayasena et al. 2009; Yedinak et al. 2015), but is unlikely if hypothalamic or pituitary tissue has been destroyed (e.g. by radiation therapy, haemorrhage or surgery) (Vance 1994). Pituitary apoplexy is a rare endocrine emergency caused by an acute bleeding in a pituitary macroadenoma, resulting in a rapid increase in tumour size, that may lead to acute severe headache, visual field deficits, loss of vision and hypopituitarism (Rolih and Ober 1993; Brougham et al. 1950). Diagnosis is confirmed by Magnetic Resonance Imaging (MRI) and visual field examination. MRI is the radiologic investigation of choice and much more sensitive than a CT scan (Rajasekaran et al. 2011). Emergency pituitary surgery is indicated in case of severe visual field deficits, loss of visual acuity or severe headaches. Stress dose glucocorticoid replacement may be lifesaving in apoplexy.

J. P. van Eck and S. J. C. M. M. Neggers

17.5 Micro- Versus Macroadenomas Pituitary adenomas are being classified by size, confirmed by radiology assessment. Microadenomas have a tumour size smaller than 10 mm on radiology imaging. Tumours that exceed the size of 10  mm are classified as macroadenomas. In macroadenomas, the sella turcica is enlarged. Macroadenomas are often symptomatic due to the mass effect of the tumour. Microadenomas are located within the normal borders of the sella turcica. Symptomatology in non-functional microadenomas is often absent, due to normal secretion patterns of ­pituitary hormones and the fact that microadenomas also rarely give compression to surrounding structures. Small intrasellar non-functioning pituitary lesions occur in 10–20% of the population or more in some reports. They may require monitoring for growth but if non-functioning are not usually of clinical importance (Agustsson et  al. 2015). They may need to be further evaluated in the presence of symptoms of hypopituitarism.

17.5.1 Pituitary Incidentalomas Pituitary incidentalomas are lesions that are detected on examination of a patient for other reasons. Patients are most often asymptomatic with respect to the tumour. Incidentalomas may be found during imaging procedures for symptoms such as headaches, after head trauma or symptoms involving the neck or central nerve system (Paschou et  al. 2016). Pituitary incidentalomas can be microadenomas or macroadenomas. They can be functional and non-functional. When a pituitary incidentaloma is detected on imaging, hypopituitarism and hypersecretion need to be excluded (Molitch and Russell 1990). Non-functioning macro-incidentalomas should either be surgically removed or, if completely asymptomatic, followed closely with repeat scans (Molitch and Russell 1990). Recommendations vary regarding the interval of scanning. The interval decision is often based on symptoms, tumour

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growth, proximity to the optic chiasm and can be recommended from every 6  months up to every 5 years.

17.6.2 Hormonal Assessment

In patients harbouring non-functioning pituitary adenomas, biochemical hormonal assessment is essential in diagnosing and treatment of hypopitu17.6 Assessment and Therapeutic itarism. Hypopituitarism in patients with p­ ituitary Options adenomas is caused by interruption of the hypothalamic-pituitary-portal circulation by the 17.6.1 Radiology Assessment tumour mass or by a direct destruction of hormone-­producing tissue of the anterior p­ ituitary. 17.6.1.1 Magnetic Resonance Both contribute to possible necrosis of normal Imaging (MRI) pituitary gland which results in irreversible hypoAn MRI scan is considered the imaging modality pituitarism and possibly panhypopituitarism (loss of choice for the diagnosis of pituitary disorders of all anterior pituitary functions) (Arafah 1986). because of its multiplanar capability and its good In cases with pituitary insufficiency, defisoft tissue contrast (Ezzat et al. 2004). The use of ciency of the target organ hormones is found, MRI has preferred over the use of CT because without the expected compensatory rise in MRI allows better recognition of normal struc- ­pituitary hormone levels. Therefore, measuring tures and has a higher resolution in defining pituitary hormones alone is of limited or no value tumours. Imaging of the pituitary has been per- in diagnosing hypopituitarism. formed in coronal and sagittal planes at 1.5–2 mm In addition to measuring pituitary hormones, interval. Using this procedure, microadenomas of blood levels of target gland hormones are mea3–5  mm can be detected. Gadolinium is a non-­ sured by immunoassays under standardized ciriodinated and most often the contrast agent of cumstances or conditions in order to interpret the choice during this procedure and gives the oppor- results correctly (Table 17.1). tunity to detect the smallest pituitary lesions disThe anterior part of the pituitary produces tinguishing between pituitary tissue and the stimulating hormones for the production of pituitary lesion (Gao et al. 2001). It also clarifies the position of the adenoma in relation to sur- 1. The adrenal hormone cortisol rounding structures, e.g. the optic chiasm, and The hypothalamus-pituitary-adrenal axis arteria carotis interna (the internal carotid arter(HPA) has a diurnal day rhythm. The adrenal ies). It is important to note that patients with high hormone cortisol reaches a peak level between creatinine or renal disease are not candidates for 8.00 and 9.00 A.M. To evaluate the HPA-axis gadolinium contrast. Patients should be screened integrity morning cortisol is measured closely for metal implants or occupational risk of (Fig. 17.2). Further dynamic testing may also retained metal fragments and may need x-rays be needed (See Chap. 5). prior to MR scanning.

17.6.1.2 Computed Tomography (CT) In known pituitary lesions, computed tomography is used to evaluate bone changes of the sella and calcifications in suspected craniopharyngiomas. CT is a second choice procedure for imaging pituitary lesions in patients when there is a contra-indication for MRI because of metal items in situ, e.g. a pacemaker or arterial/ peripheral stents and claustrophobia (Pressman 2017).

Table 17.1  Anterior pituitary functions and end-organ hormones Pituitary hormone Thyroid Stimulating Hormone—TSH Adreno corticotroph releasing hormone—ACTH Gonadotrophic hormones: LH/FSH Growth hormone—GH Prolactin

Pituitary end organ and hormones Thyroid—FT4 Adrenals—cortisol Ovaries—estrogens (F)/ testis—testosterone (M) Liver—IGF-1

J. P. van Eck and S. J. C. M. M. Neggers

328 24.0

20.0 Acrophase: 0832 h (0759 h – 0905 h)

Cortisol (mcg/dL)

16.0

12.0

8.0

Nadir: 0018 h (2339 h – 0058 h)

4.0 MESOR: 5.2 mcg/dl (4.7 – 5.7) 22 23 24

1

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17 18 19 20 21

Clock time

Fig. 17.2  Circadian rhythm of cortisol. Adapted from: Debono, M., et al. (2009). ‘Modified-release hydrocortisone to provide circadian cortisol profiles’. The Journal of Clinical Endocrinology & Metabolism 94(5): 1548–1554 8 

TESTOSTERONE (ng/ml)

Fig. 17.3 Circadian rhythm of testosterone in men. Adapted from: Bremner, W. J., et al. (1983). ‘Loss of circadian rhythmicity in blood testosterone levels with ageing in normal men’. The Journal of Clinical Endocrinology & Metabolism 56(6): 1278–1281

 

7

 



 



YOUNG MEN

 



6

5 OLD MEN 4

0800

1200

2. Thyroid hormone To evaluate the hypothalamus-pituitary-­thyroid axis, FT4 is measured. TSH levels in pituitary patients are normal to low-normal and with pituitary damage and surgery TSH is no longer a reliable contribution in the evaluation of the hypothalamus-pituitary-thyroid axis.

1600

2000 2400 CLOCK TIME (HOURS)

0400

0800

3. Gonadal hormone Gonadal hormones are stimulated by LH and FSH and produced in the ovaria and testes (Fig.  17.3). LH, FSH and testosterone are measured in men. Testosterone reaches a peak level between 08:00 and 10:00 A.M. and therefore it is best measured in the morning.

17  Non-functioning Pituitary Adenomas

In women, LH, FSH and oestradiol are measured for evaluation of the hypothalamus-­ pituitary-­gonadal axis and results are time of the menstrual cycle and menopausal status dependent. 4. Growth hormone (GH) To evaluate the hypothalamus-pituitary-­growth hormone axis, insulin-like growth factor-­ 1 (IGF-1) is measured. It is produced by the liver after stimulation from growth h­ ormone produced in the pituitary. Growth hormone is secreted in a pulsatile fashion by the anterior pituitary and therefore a random sample is of little value in the evaluation of growth hormone deficiency or excess. The GH axis function requires further evaluation by dynamic tests (See Chap. 5). 5 . Prolactin Prolactin is inhibited by the production of dopamine in the hypothalamus, but can be slightly elevated in patients with a large non-­ functioning pituitary adenoma due compression of the pituitary stalk that can disrupt the dopamine inhibition of prolactin production in the anterior pituitary (Chahal and Schlechte 2008). For more information about pituitary function and dynamic pituitary testing, see Chaps. 1 and 5.

17.7 Visual Field Examination Visual field analyses reflect the degree of the compression to the optic nerve that results the structural damage of the nerve. Visual fields can be evaluated by Goldmann and Humphrey perimetry. The Goldmann perimeter is a hollow white spherical bowl positioned at set distance in front of the patient (Fig. 17.4). An examiner presents a test light of variable size and intensity in a variety of visual fields. The Humphrey perimetry is an automated test. The patient is required to fixate at a central point with each eye while a light of variable intensity is flashed in the peripheral field of vision. The patient is required to acknowledge the flashing light by pressing a button.

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Fig. 17.4  Humphrey’s visual field examination

Informal visual field exams by confrontation can also be accomplished in clinic with the practitioner seated 3–4 ft from the patient. With both practitioner and patient facing each other, each cover one eye as the practitioner holds up fingers equidistant between them. Each visual quadrant is tested when the patient correctly perceives the number of digits displayed in each visual field quadrant. Formal testing is indicated with any deficiencies when compared with the examiner’s field of vision. Formal evaluation of visual fields pre- and postoperatively or during long-term follow-up provides a standard quantitative method in assessing the progression of visual field loss (Anik et  al. 2011). Other causes of visual field deficits should be ruled out by the ophthalmologist, such as glaucoma and cataract.

17.8 Therapeutic Options Treatment of non-functioning pituitary adenomas depends on the clinical signs and symptoms, comorbidities and personal circumstances. It is a process of shared decision making of the multidisciplinary team, together with the patient.

17.8.1 Pituitary Surgery In patients harbouring a non-functional pituitary adenoma, pituitary surgery is indicated when the

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pituitary adenoma abuts or compresses the optic chiasm. The goal of pituitary surgery is to prevent patients from incurring bitemporal hemianopsia or to restore visual field deficits and visual field acuity loss. Pituitary surgery can be performed by transsphenoidal approach with a microscope or endoscope. In giant adenomas, a transcranial surgery is usually indicated (See Pituitary Surgery Chap. 12).

17.8.2 Radiotherapy In NFPA radiotherapy is commonly used for postoperative adenoma remnants with invasive character that are not accessible surgically. The timing of radiation for NFPA is a current subject of controversy. Some radiotherapists recommend radiotherapy after initial surgery. Others use radiotherapy only if further growth of the resi­ dual adenoma is observed. Read more about radiotherapy in Chap. 12.

J. P. van Eck and S. J. C. M. M. Neggers

a NFPA macroadenomas. In two small nonrandomized studies it was found that with D2 tumour expression some benefit may be achieved with respect to stabilization of any residual tumour in 61–70% (Greenman et  al. 2005; Pivonello et  al. 2004). There may also be some potential benefit in rare cases in whom radiotherapy and a second surgical intervention are less attractive (Neggers and Lelij van der 2014). However, overall there seems to be a limited role for dopamine agonists in NFPA.

17.8.5 Headaches Assessment and Management

Assessment of pain should be integrated in the diagnostic workup and follow-up of patients with a non-functioning pituitary adenoma. Headaches assessment can be performed by using structured questionnaires, or in a less structured way, as long as pain is not neglected. In a proportion of patients, a referral to a neurologist may be useful. Different treatment strategies are often necessary (optimization of 17.8.3 Expectative Approach endocrinological treatment, pharmaceutical pain management, physiotherapy, behavioural In patients harbouring a non-symptomatic non-­ psychotherapy when appropriate, etc.) functioning pituitary adenoma with no compres- (Dimopoulou et al. 2014). sion to the optic chiasm, one can ‘wait and scan’ or ‘wait and watch’. This approach is to closely monitor the evolution of the adenoma. When, or 17.9 Long-Term Management if, growth of the adenoma occurs and/or visual field deficits are demonstrated, the indication for Patients with a non-functioning pituitary adepituitary surgery needs to be reconsidered. noma, especially when patients have undergone pituitary surgery, in most cases need lifelong follow-up of the adenoma. Radiologic assessment by 17.8.4 Medical Treatment MRI is needed to follow the size of the pituitary adenoma or any residual tumour. When the optic In NFPA, the goal of treatment is tumour reduc- chiasm is involved, repeated perimetry to follow tion or stabilization of tumour size in order to the visual fields and visual acuity is also needed. reduce signs and symptoms caused by compres- Usually this can be discontinued or performed sion of the tumour on surrounding structures (e.g. less frequently during long-term follow-­up after optic chiasm). Currently, no treatment medical pituitary surgery. Regular biochemical assesstreatment modality has been found that has ment is essential to follow up the anterior pituitary de­monstrated reliable reduction in tumour size of functions. Long-term hypopituitarism after surNFPA (Greenman 2007). gery is possible and may be more frequent if the There were attempts to use dopamine agonists patient received additional radiotherapy. However, to address tumour growth after surgical resection of hormonal assessment is essential to optimize hor-

17  Non-functioning Pituitary Adenomas

mone replacement therapy. Treatment of hypopituitarism with hormone replacement therapy is needed to improve symptomatology associated with hypopituitarism, to avoid potentially lifethreatening situations in the case of adrenal insufficiency and to protect patients from the ­ long-term sequela of untreated hypopituitarism such as osteoporosis and cardio-­vascular disease.

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Hormone Health Network and patient support organizations such as the World Alliance of Pituitary Organizations (WAPO) can provide both education and direct patient access to appropriate support. How the information regarding the patient’s tumour is delivered sets the stage for patient trust and subsequent learning, particularly at an initial visit after tumour discovery. Using approaches such as a modification of the SPIKE protocol for 17.10 Nursing Interventions giving ‘bad’ news may be useful (Baile et  al. 2000). This involves setting up the encounter in a At the point of diagnosis, patients often fear this private consultation, making a connection with tumour is cancerous and will spread to other parts the patient, preparing for the discussion and of the body. Patient education may start with avoiding highly emotive wording such as ‘brain reassurance and a description of the characteris- tumour’ or technical jargon. Check the undertics of adenomas versus cancerous tumours (See standing of the patient and family members to Imaging Chap. 5). The prevalence of pituitary critical information given and invite them to ask carcinomas is less than 0.1% and if surgery is questions regarding the information they require. needed, the diagnosis will be confirmed by Provide information as requested by both the pathology (Heaney 2011). Explain that if metas- patient and family and use references, written tasis occurs it is usually related to cancer from materials, etc. that can read in a more relaxed other locations such as lung or breast to the manner at home. Lastly address the patient and pituitary and not from the pituitary to other families emotions and immediate concerns such ­ organs. Patients meeting criteria for MEN-1, as preparation for surgery, work-related issues, however, will need further evaluation and psy- expectations postoperatively such as steroids, chological support as described above. monitoring of blood levels of some hormones for Patients often require multiple tests (as events while inpatient or after discharge such as described above) and if better informed can more diabetes insipidus, syndrome of inappropriate actively participate in and adhere to a plan of antidiuretic hormone and adrenal insufficiency assessment and care. Patient preparation enhances (See Chap. 12). trust, decreases anxiety and achieves a more Patient need to be aware that they will have seamless transition between disciplines such as regular, often lifelong, follow-up, although the neuro-ophthalmologists, neurosurgeons, neuro-­ follow-up interval may vary according to the radiologists, ear-nose and throat (ENT) specia­ patient’s clinical needs, treatment location and lists, dynamic or invasive testing units or genetic patient access to care. It is important for the testing and counsellors. patient to be aware of unexpected signs and Involving the patients’ family or support symptoms occurring in the meantime. Symptoms person(s) in disease-related education efforts such as severe, sudden onset headache (often using multiple educational modalities such as described as the ‘worst headache of my life’), print, audio-visual methods, demonstration and progressive headache, particularly associated verbal instruction is important for understanding with nausea and vomiting, and any new visual and retention of information. It is important to changes should be evaluated by the pituitary take into account learning styles, literacy and cul- team immediately (See Endocrine Emergencies). ture (Marcus 2014). Referral to and/or the use of Given the long-term relationship these patients websites with endorsed patient educational mate- form with their pituitary team, endocrine nurses rial such as provided by the European Society of play a key role in educating patients about signs Endocrinology, the Endocrine Society (USA) and symptoms of changes in pituitary function

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and normal and abnormal symptoms across the life cycle. Nurses support the patient maximizing their functional capacity and quality of life in the context of pituitary diseases.

J. P. van Eck and S. J. C. M. M. Neggers

Comtois R, Beauregard H, Somma M, Serri O, Aris-­ Jilwan N, Hardy J. The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer. 1991;68(4):860–6. Cottier JP, Destrieux C, Brunereau L, Bertrand P, Moreau L, Jan M, et  al. Cavernous sinus invasion by pituitary adenoma: MR imaging. Radiology. 2000;215(2):463–9. References Daly AF, Beckers A. Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor Agustsson TT, Baldvinsdottir T, Jonasson JG, Olafsdottir interacting protein (AIP) gene. Endocrinol Metab Clin E, Steinthorsdottir V, Sigurdsson G, et al. The epidemiN Am. 2015;44(1):19–25. ology of pituitary adenomas in Iceland, 1955–2012: a Daly AF, Rixhon M, Adam C, Dempegioti A, nationwide population-based study. Eur J Endocrinol. Tichomirowa MA, Beckers A.  High prevalence 2015;173(5):655–64. of pituitary adenomas: a cross-sectional study in Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold the province of Liege, Belgium. J Clin Endocrinol A, Klibanski A.  Clinically nonfunctioning pituitary Metabol. 2006;91(12):4769–75. tumors are monoclonal in origin. J Clin Investig. De Laat JM, Dekkers OM, Pieterman CRC, Kluijfhout 1990;86(1):336. WP, Hermus AR, Pereira AM, et  al. Long-term Anik I, Anik Y, Koc K, Ceylan S, Genc H, Altintas O, natural course of pituitary tumors in patients et al. Evaluation of early visual recovery in pituitary with MEN1: results from the DutchMEN1 study macroadenomas after endoscopic endonasal transgroup (DMSG). J Clin Endocrinol Metabol. phenoidal surgery: quantitative assessment with 2015;100(9):3288–96. diffusion tensor imaging (DTI). Acta Neurochir. Dimopoulou C, Athanasoulia AP, Hanisch E, Held S, 2011;153(4):831–42. Sprenger T, Toelle TR, et  al. Clinical characteristics Arafah BM.  Reversible hypopituitarism in patients with of pain in patients with pituitary adenomas. Eur J large nonfunctioning pituitary adenomas. J Clin Endocrinol. 2014;171(5):581–91. Endocrinol Metab. 1986;62(6):1173–9. Ebersold MJ, Quast LM, Laws ER Jr, Scheithauer B, Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, Randall RV.  Long-term results in transsphenoidal Kudelka AP. SPIKES—a six-step protocol for deliverremoval of nonfunctioning pituitary adenomas. J ing bad news: application to the patient with cancer. Neurosurg. 1986;64(5):713–9. Oncologist. 2000;5(4):302–11. Edmonds M, Molitch M, Pierce JG, Odell WD. Secretion Beckers A, Aaltonen LA, Daly AF, Karhu A.  Familial of alpha subunits of luteinizing hormone (LH) by isolated pituitary adenomas (FIPA) and the pituitary the anterior pituitary. J Clin Endocrinol Metabol. adenoma predisposition due to mutations in the aryl 1975;41(3):551–5. hydrocarbon receptor interacting protein (AIP) gene. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Endocr Rev. 2013;34(2):239–77. Vance ML, et  al. The prevalence of pituitary adenoBerg C, Meinel T, Lahner H, Mann K, Petersenn mas. Cancer. 2004;101(3):613–9. S.  Recovery of pituitary function in the late-­ Fatemi N, Dusick JR, Mattozo C, McArthur DL, Cohan postoperative phase after pituitary surgery: results of P, Boscardin J, et  al. Pituitary hormonal loss and dynamic testing in patients with pituitary disease by recovery after transsphenoidal adenoma removal. insulin tolerance test 3 and 12 months after surgery. Neurosurgery. 2008;63(4):709–18. Eur J Endocrinol. 2010;162(5):853–9. Fernandez A, Karavitaki N, Wass JAH. Prevalence of pituBrougham M, Heusner AP, Adams RD. Acute degeneraitary adenomas: a community-based, cross-sectional tive changes in adenomas of the pituitary body—with study in Banbury (Oxfordshire, UK). Clin Endocrinol. special reference to pituitary apoplexy. J Neurosurg. 2010;72(3):377–82. 1950;7(5):421–39. Ferrante E, Ferraroni M, Castrignano T, Menicatti L, Caimari F, Korbonits M.  Novel genetic causes Anagni M, Reimondo G, et al. Non-functioning pituof pituitary adenomas. Clin Cancer Res. itary adenoma database: a useful resource to improve 2016;22(20):5030–42. the clinical management of pituitary tumors. Eur J Cannavò S, Ferraù F, Ragonese M, Curtò L, Torre ML, Endocrinol. 2006;155(6):823–9. Magistri M, et  al. Increased prevalence of acro- Gadelha MR, Trivellin G, Ramírez LCH, Korbonits megaly in a highly polluted area. Eur J Endocrinol. M. Genetics of pituitary adenomas. Endocrine tumor 2010;163(4):509–13. syndromes and their genetics. Front Horm Res. Chahal J, Schlechte J.  Hyperprolactinemia. Pituitary. 2013;41:111–40. Karger Publishers. 2008;11(2):141. Gao R, Isoda H, Tanaka T, Inagawa S, Takeda H, Takehara Chandrasekharappa SC, Guru SC, Manickam P, Olufemi Y, et  al. Dynamic gadolinium-enhanced MR imagS-E, Collins FS, Emmert-Buck MR, et al. Positional ing of pituitary adenomas: usefulness of sequencloning of the gene for multiple endocrine neoplasia-­ tial sagittal and coronal plane images. Eur J Radiol. type 1. Science. 1997;276(5311):404–7. 2001;39(3):139–46.

17  Non-functioning Pituitary Adenomas Gondim JA, de Almeida JP, de Albuquerque LA, Schops M, Gomes E, Ferraz T.  Headache associated with pituitary tumors. J Headache Pain. 2009;10(1):15–20. Greenman Y.  Dopaminergic treatment of nonfunctioning pituitary adenomas. Nat Rev Endocrinol. 2007;3(8):554. Greenman Y, Stern N.  Optimal management of non-­ functioning pituitary adenomas. Endocrine. 2015;50(1):51–5. Greenman Y, Tordjman K, Osher E, Veshchev I, Shenkerman G, Reider-Groswasser II, et  al. Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth. Clin Endocrinol. 2005;63(1):39–44. Gruppetta M, Mercieca C, Vassallo J. Prevalence and incidence of pituitary adenomas: a population based study in Malta. Pituitary. 2013;16(4):545–53. Heaney AP. Clinical review: pituitary carcinoma: difficult diagnosis and treatment. J Clin Endocrinol Metab. 2011;96(12):3649–60. Herder dWW, Feelders RA, Van der Lelij AJ. Clinically non-functioning tumors and gonadotropinomas. In: Wass JAH, editor. Oxford textbook of endocrinology and diabetes. Oxford; 2011. p. 209–18. Jaffe CA.  Clinically non-functioning pituitary adenoma. Pituitary. 2006;9(4):317–21. Jayasena CN, Gadhvi KA, Gohel B, Martin NM, Mendoza N, Meeran K, et  al. A single early morning serum cortisol in the early post operative period following transphenoidal surgery for pituitary tumours accurately predicts hypothalamo-pituitary-adrenal function. Endocr Abstr. 2009;19((Jayasena C.N.; Gadhvi K.A.; Gohel B.; Martin N.M.; Meeran K.; Dhillo W.S.) Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom):P272. Lee IH, Miller NR, Zan E, Tavares F, Blitz AM, Sung H, et al. Visual defects in patients with pituitary adenomas: the myth of bitemporal hemianopsia. AJR Am J Roentgenol. 2015;205(5):W512–8. Marcus C. Strategies for improving the quality of verbal patient and family education: a review of the literature and creation of the EDUCATE model. Health Psychol Behav Med. 2014;2(1):482–95. Marques P, Korbonits M.  Genetic aspects of pituitary adenomas. Endocrinol Metab Clin. 2017;46(2):335–74. Molitch ME, Russell EJ.  The pituitary “incidentaloma”. Ann Intern Med. 1990;112(12):925–31. Müslüman AM, Cansever T, Yılmaz A, Kanat A, Oba E, Çavuşoğlu H, et  al. Surgical results of large and giant pituitary adenomas with special consideration of ophthalmologic outcomes. World Neurosurg. 2011;76(1):141–8.

333 Neggers S, Lelij van der A-J.  Medical approach to pituitary tumors. In: Clinical neuroendocrinology. Elsevier; 2014. Nomikos P, Ladar C, Fahlbusch R, Buchfelder M. Impact of primary surgery on pituitary function in patients with non-functioning pituitary adenomas—a study on 721 patients. Acta Neurochir. 2004;146(1):27–35. Ogra S, Nichols AD, Stylli S, Kaye AH, Savino PJ, Danesh-Meyer HV. Visual acuity and pattern of visual field loss at presentation in pituitary adenoma. J Clin Neurosci. 2014;21(5):735–40. Paschou SA, Vryonidou A, Goulis DG. Pituitary incidentalomas: a guide to assessment, treatment and follow­up. Maturitas. 2016;92:143–9. Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, Cappabianca P, et  al. Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. J Clin Endocrinol Metab. 2004;89(4):1674–83. Pressman BD. Pituitary imaging. Endocrinol Metab Clin N Am. 2017;46(3):713–40. Rajasekaran S, Vanderpump M, Baldeweg S, Drake W, Reddy N, Lanyon M, et  al. UK guidelines for the management of pituitary apoplexy. Clin Endocrinol. 2011;74(1):9–20. Rolih CA, Ober KP. Pituitary apoplexy. Endocrinol Metab Clin N Am. 1993;22(2):291–302. Siegel S, Carneiro RW, Buchfelder M, Kleist B, Grzywotz A, Buslei R, et al. Presence of headache and headache types in patients with tumors of the sellar region—can surgery solve the problem? Results of a prospective single center study. Endocrine. 2017;56(2):325–35. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metabol. 2012;97(9):2990–3011. Vance ML.  Hypopituitarism. N Engl J Med. 1994;330(23):1651–62. Vasilev V, Daly A, Naves L, Zacharieva S, Beckers A.  Clinical and genetic aspects of familial isolated pituitary adenomas. Clinics. 2012;67:37–41. Wolf A, Goncalves S, Salehi F, Bird J, Cooper P, Van Uum S, et  al. Quantitative evaluation of headache severity before and after endoscopic transsphenoidal surgery for pituitary adenoma. J Neurosurg. 2016;124(6):1627–33. Yedinak C, Hameed N, Gassner M, Brzana J, McCartney S, Fleseriu M. Recovery rate of adrenal function after surgery in patients with acromegaly is higher than in those with non-functioning pituitary tumors: a large single center study. Pituitary. 2015;18(5):701–9. Yu B, Ji N, Ma Y, Yang B, Kang P, Luo F. Clinical characteristics and risk factors for headache associated with non-functioning pituitary adenomas. Cephalalgia. 2017;37(4):348–55.

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Key Reading 1. Agustsson TT, Baldvinsdottir T, Jonasson JG, Olafsdottir E, Steinthorsdottir V, Sigurdsson G, et al. The epidemiology of pituitary adenomas in Iceland, 1955–2012: a nationwide population-based study. Eur J Endocrinol. 2015;173(5):655–64. 2. Marques P, Korbonits M.  Genetic aspects of pituitary adenomas. Endocrinol Metab Clin North Am. 2017;46(2):335–74.

J. P. van Eck and S. J. C. M. M. Neggers 3. Dimopoulou C, Athanasoulia AP, Hanisch E, Held S, Sprenger T, Toelle TR, et  al. Clinical characteristics of pain in patients with pituitary adenomas. Eur J Endocrinol. 2014;171(5):581–91. 4. De Laat JM, Dekkers OM, Pieterman CRC, Kluijfhout WP, Hermus AR, Pereira AM, et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 study group (DMSG). J Clin Endocrinol Metabol. 2015;100(9):3288–96.

Thyroid Stimulating Hormone Secreting Adenoma (TSHoma)

18

Christine Yedinak

Contents 18.1 Introduction

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18.2 Definition

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18.3 Epidemiology

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18.4 Hypothalamic–Pituitary–Thyroid (HPT) Axis

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18.5 Pathology

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18.6 Assessment

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18.7 Treatment

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18.8 Nursing Care

 341

18.9 Conclusions

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References

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Abstract

Pituitary thyroid stimulating hormone (TSH) hypersecreting adenomas are rarer than any other hypersecretory pituitary adenoma. The etiology of these tumors is not known. TSHomas cause central hyperthyroidism, with elevation of the thyroid hormones without suppression of TSH.  Although reported to occur at most ages, there is a higher prevalence with increasing age.

C. Yedinak (*) Northwest Pituitary Center, Oregon Health and Sciences University, Portland, OR, USA e-mail: [email protected]

Most patients present with macroadenomas (>1  cm), headaches, and visual changes associated with tumor enlargement and optic nerve pathway compression. Others present with symptoms of thyrotoxicosis. Early diagnosis and treatment is recognized as the best means of avoiding complications such as vision loss, cardiac arrhythmias, or bone loss. New imaging modalities have improved diagnosis and made early treatment possible. Treatment has two goals: normalization of TSH hypersecretion and tumor control. Primary therapy is aimed at tumor removal in order to normalize TSH, but medical therapy may be indicated if hypersecretory tumor remnants remain or

© Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_18

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C. Yedinak

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there is tumor regrowth. There is little data regarding long-term outcomes, late effects, or quality of life. This is likely related to the rarity of the disease.

Key Points

• TSHomas are rare pituitary adenomas, frequently misdiagnosed as hyperthyroidism. • Thyroid levels are regulated by the Keywords Hypothalamic–Pituitary–Thyroid Thyroid stimulating hormone · TSHoma · (HPT) axis feedback loop. Pituitary adenoma · Central hyperthyroidism · • A detectable TSH level when FT4 levels Thyrotoxicosis are high is suggestive of a pituitary source of hyperthyroidism or TSHoma. • Exogenous administration of T3 supAbbreviations presses TSH β transcription and production. ACTH Adrenocorticotrophic hormone • AIP Aryl hydrocarbon receptor-­ There has been a significant increase in the diagnosis of TSHomas, likely related Interacting Protein gene to better imaging and diagnostic testing. CT Computerized tomography • Treatment options are similar to other FSH Follicle stimulating hormone pituitary adenomas with surgery as firstFT4 Free thyroxine line and medical therapy as second-line GSU Glycoprotein hormone subunits therapies. Radiation therapy remains an HPA Hypothalamic–pituitary–adrenal (axis) option in unresponsive tumors. HPT Hypothalamic–pituitary–thyroid axis • Research data is limited, particularly LAR Long acting release with respect to long-term impact on the LH Luteinizing hormone patient and their quality of life. MEN-1 Multiple endocrine neoplasia type 1 MRI Magnetic resonance imaging PET Positron emission tomography SSA Somatostatin analogues (ligands) 18.1 Introduction SSTR Somatostatin receptor TRH Thyroid releasing hormone The diagnosis of TSHoma has increased fivefold TSH Thyroid stimulating hormone in some countries, attributed to better and more TSHoma Thyroid stimulating hormone frequent imaging (Tjörnstrand and Nyström producing pituitary adenoma 2017) and likely more awareness of the disorder. The mean age at presentation is in the fourth Key Terms decade in both genders with age impacting the • Central hyperthyroidism: over production size of the tumor. Younger patients tend to presof thyroid stimulating hormone from the pitu- ent with smaller tumors that are more amenable itary leading to enlargement of the thyroid and to surgical removal and enjoy a higher frequency thyrotoxicosis. of remission (Tjörnstrand and Nyström 2017). • Thyroid ablation: the destruction of the thyEarly treatment requires the recognition that roid gland using radioactive iodine. symptoms and biochemistry are associated with • TSH β subunit: the portion of TSH that deter- central and not primary hyperthyroidism. mines the THS receptor activity in thyroid fol- Historically misdiagnosed, this disorder has been licular cells. associated with inappropriate thyroid ablation and • Thyroid feedback loop: the production and thyroidectomies (Tjörnstrand and Nyström 2017; release of thyroid hormones T3 and T4 act on Greenman 2017). Improved biochemical test accuthe hypothalamus and the pituitary to regulate racy, ultrasound, and newer imaging techniques their own production. such as PET/CT scans with 68Ga-DOTATOC

18  Thyroid Stimulating Hormone Secreting Adenoma (TSHoma)

promise even more accurate tumor location and more specific treatment. Improved histopathology allows the determination of tumor cell receptors that may help predict response to medical therapies and potential ­indicators of tumors more likely to recur (Greenman 2017). Delay in diagnosis continues to be 6–12  years, depending on prior treatment and data regarding long-term outcomes is scarce (Greenman 2017). However, increased incidence has generated more interest in research for future impact.

18.2 Definition Central hyperthyroidism is the result of autonomous secretion of Thyroid Stimulating Hormone (TSH) and may present with symptoms of thyrotoxicosis. First recognized in the 1960s, central hyperthyroidism is caused by a pituitary TSH secreting adenoma that causes excess production of active thyroxine from the thyroid gland, which subsequently fails to suppress the production of TSH (Tjörnstrand and Nyström 2017). TSH cells only represent about 5% of all pituitary cells which may help to explain the lower prevalence of TSHomas.

18.3 Epidemiology Among pituitary adenomas, TSHomas are the most rare and represent about 0.4–3% of all pituitary adenomas based on postsurgical and postmortem reports (Tjörnstrand and Nyström 2017; Beck-Peccoz et al. 2015). However, there has been a significant increase in the incidence, which is likely related to a combination of better and more frequent use of imaging and greater recognition of the disease (Tjörnstrand and Nyström 2017). Prevalence of TSHomas is similar in both genders, with a mean age at presentation of 45  years. However, the reported ages at diagnosis range from 8 to 84  years (Beck-Peccoz et  al. 2013). Familial cases have been reported in MEN-1  in association with AIP mutations (Beck-­ Peccoz et al. 2013).

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18.4 Hypothalamic–Pituitary– Thyroid (HPT) Axis TSH is produced by thyrotropes in the pituitary gland and comprises both α (alpha) and β (beta) subunits (Sarapura and Samuels 2017). These are genetically coded by two different genes on two different chromosomes. The genes are transcribed in the thyrotropes and combined to produce TSH.  The β-subunit determines the downstream activity of TSH.  The TSH α-subunit is a gene promotor important in the regulation of thyroid releasing hormone (TRH). TSH production is regulated by thyroid releasing hormone (TRH) from the hypothalamus which in turn is inhibited after thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) are produced from the thyroid (Sarapura and Samuels 2017) (Fig. 18.1). TRH is transported from the hypothalamus to the pituitary via the hypophyseal portal system (the blood vessels connecting the hypothalamus and the pituitary) where it binds to the surface of thyrotrope cells (Sarapura and Samuels 2017). This starts a cascade of events within the cell to produce TSH.  TSH enters the portal circulation and attaches to the cell surface of the thyroid follicular cells to stimulate iodinated thyroglobulin to release T4 and T3. Although T4 has some independent activity peripherally, it is essentially a prohormone for the more metabolically active T3  in peripheral cells. Some T4 is de-iodinated and converted to T3 in the thyroid itself, but the majority is converted in the liver (Nomura et al. 1975). T3 promotes metabolic activity and numerous life sustaining activities in almost all body cells including myocardial contractility, rate and relaxation, fetal neurologic development, and more (Cooper and Ladenson 2011). T3 production is the main regulator of TSH β transcription (Sarapura and Samuels 2017). Therefore, this activity is inhibited by administration of exogenous forms of T3 (triiodothyronine). The serum measurement of free T4 and T3 (T4 and T3 that are not bound to protein) is a more accurate measurement of the levels of both that are available to exert cellular effects (Sarapura and Samuels 2017) (for more details, see Sect. 4 Chap. 26).

C. Yedinak

338 HPT Axis

matic deiodination, or increased conversion of T4 to inactive reverse T3 (rT3) may also be pathologic mechanisms. Reverse T3 levels have been found to be significantly elevated in the sera of patients with TSHomas (Greenman 2017). There may also be a relationship between Hypothalamus defective TRH suppression and significant ele+ vations in serum levels of free α-subunits TRH (Sarapura and Samuels 2017). – Dopamine and somatostatin both inhibit TSH. TSH tumor cells are also known to express Anterior somatostatin receptor subtypes 1, 2, 3, and 5 pituitary which present a target for medical therapy (Greenman 2017). Detailed postoperative histoTSH pathology reports including this information can + help direct medical therapies if needed. During pituitary cell embryonic developThyroid ment, TSH, Growth Hormone (GH), and prolactin (PRL) are generated from the Prop-1/Pit 1 – lineage. Most TSHomas secrete only excess + TSH, but up to 1/3rd may co-secrete growth hormone (GH), prolactin (PRL) or have pluriT4, T3 hormonal secretion (Greenman 2017; McDermott and Ridgway 1998). Despite cosecretion, few patients appear to present with symptoms associated with co-secreted hormones. Co-secretion may be found clinically Increases metabolism and confirmed on microscopic histopathology of tumor samples taken intraoperatively Fig. 18.1  Thyroid feedback loop. The hormones that make (Tjörnstrand and Nyström 2017). up the HPT axis control the metabolic processes of all cells The majority of TSHomas are macroadenoin the body. The secretion of TRH from the hypothalamus mas (80–90%) that are often found to be invasive. activates the pituitary to release of TSH, which in turn promotes the production and release of T4 and T3 by the thy- Increased mitotic activity has also been reported roid gland. Negative feedback effects of T4 and T3 on both based on positive staining on pathology of >3% the hypothalamus and the pituitary regulate the HPT axis of cells for p53 and Ki67, although reports vary function. Permission: https://embryology.med.unsw.edu. au/embryology/index.php?curid=10638; http://tedct.org.uk in this regard (Tjörnstrand and Nyström 2017; Greenman 2017). Prior to the development of sensitive TSH immunoassays, many patients were misdiagnosed and underwent thyroid abla18.5 Pathology tion, which may have contributed to late diagnosis and increased incidence of large and more Although the cause of these tumors is unknown, invasive tumors (Greenman 2017; McDermott multiple factors such as genetic mutations, over-­ and Ridgway 1998). activation of cell proliferation, and lack of TSH The patient may present with mild, inapprosuppression are suspected (Sarapura and priately mild (given biochemistry), or severe Samuels 2017). Defective negative feedback symptoms of thyrotoxicosis, such as weight with decreased levels of T3, defective enzy- loss, nervousness, irritability, easy fatigability,

18  Thyroid Stimulating Hormone Secreting Adenoma (TSHoma)

muscle spasms, intolerance to hot weather, excessive sweating, shakiness and fine motor tremors, palpitations, increased bowel movements, and muscle weakness with loss of ­muscle mass and bone density. Reports of headaches, changes in vision, and visual field deficits ­ secondary to mass effect as the tumor expands are not uncommon (Greenman 2017) (Fig. 18.2). Symptoms of hyperthyroidism may also be masked by those of co-secreted hormones such as growth hormone or prolactin and include: amenorrhea, galactorrhea, hypogonadism, decreased libido, infertility, breast discomfort or discharge or growth of hand or shoe size, sweating, widening gaps between teeth (Tjörnstrand and Nyström 2017). On physical examination, ophthalmopathy and pretibial myxedema are usually absent or if present orbitopathy may be unilateral (Fig.  18.3). A large goiter is usually present (even after partial thyroidectomy) and skin may be hot, moist, and velvety. Tachycardia and/or atrial fibrillation may be present or symptoms of cardiac failure (Beck-­Peccoz et al. 2013, 2015 Brucker-Davis et al. 1999).

339

18.6 Assessment Assessment includes biochemical assessment, thyroid ultrasound, and MRI.  Both a random serum free T4 (FT4) and TSH should be measured. Serum TSH may be normal or elevated, but free T4 and T3 are significantly elevated and are considered the most sensitive indicator of the presence of a TSHoma (Greenman 2017; Beck-­ Peccoz et  al. 2015). Measurement of glycoprotein hormone subunits (GSU) may reveal an imbalance of α-subunit and β-subunit (GSU) with an elevated α-GSU. This may only be useful in the presence of a macroadenoma (Greenman 2017). An elevated α-subunit/TSH ratio has also been reported as a sensitive indicator of TSHoma in a patient with an intact thyroid (Carmichael 2017). Elevated FT4 and FT3, in the presence of a detectable TSH, rules out Grave’s disease and argues for TSHoma (Beck-Peccoz et al. 2015). In the presence of elevated or detectable TSH with elevated FT4 and FT3 and/or compressive symptoms (headache and visual deficits), a head CT or MRI should be performed to confirm a pituitary tumor. Rare ectopic TSH secretion (usu-

Galactorrhea

Tumor size

Menstrual disorders Invasive Extrasellar Intrasellar

Previous thyroid surgery

Headache

No thyroid surgery

Visual field defects Anti-thyroid Abs Hyperthyroid features Goiter 0

20

Fig. 18.2  Clinical manifestations in patients with TSH-­ secreting adenomas. The presence of goiter is indicative of TSHoma, even in patients after partial thyroidectomy. Hyperthyroid features may be overshadowed by those of

40 60 % of patients

80

100

associated hypersecretion/deficiency of other pituitary hormones. Invasive tumors are seen in about half of the patients with previous thyroidectomy and in 1/4 of untreated patients (permission Beck-Peccoz 2015)

C. Yedinak

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a

b

c

Fig. 18.3 (a) right unilateral orbitopathy. (b) bilateral orbitopathy (c) left orbitopathy. From: Kashkouli MB, et al. Indian J Ophthalmol. 2011 Sep-Oct; 59(5): 363–366. doi: https://doi.

org/10.4103/0301-4738.83612. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported

ally pharyngeal) has been described (Beck-­ Peccoz et al. 2013). If the lesion on CT/MRI is a microadenoma, resistance to thyroid hormone needs to be considered and an incidentaloma ruled out (Beck-Peccoz et  al. 2015). Thyroid ultrasound and fine needle biopsy are recommended for nodular goiter, in consideration of a higher risk of thyroid cancer in TSHomas (4.8% of cases) (Beck-Peccoz et  al. 2015). Guidelines suggest that other biomarkers such as cholesterol, LDL, triglycerides, ferritin, erythrocyte microcytosis, resting energy expenditure, and cardiac function parameters are of limited diagnostic value (Beck-Peccoz et al. 2013). Dynamic testing may be indicated if no defined pituitary or ectopic mass is found or when there is concern for resistance to thyroid hormone. A TRH test and/or T3 suppression test are first-line tests and an octreotide infusion to suppress TSH may be useful. TRH dynamic testing measures the increase in TSH after adminis-

tration of exogenous TRH, with doubling of baseline levels considered a positive test (Tjörnstrand and Nyström 2017). This test is done infrequently and TRH is no longer available in some countries including the USA (Salvatori et al. 2010). Scintigraphy radiolabeled octreotide scans and PET/CT scans with 68Ga-DOTATOC may be useful in  locating a rare ectopic source of TSH (Tjörnstrand and Nyström 2017).

18.7 Treatment First-line treatment is tumor removal in appropriate cases and suppressive therapy if the patient is not a candidate for surgical options. Surgical tumor resection can achieve a remission rate of 60% in patients with macroadenomas in the hands of an experienced surgeon (Beck-Peccoz et  al. 2013, 2015). Although controversial, antithyroid

18  Thyroid Stimulating Hormone Secreting Adenoma (TSHoma)

drugs such as methimazole or propylthiouracil and/or medical suppressive therapies with cabergoline or somatostatin therapy are recommended by some clinicians prior to surgical tumor removal to decrease TSH (Beck-Peccoz et al. 2015). If TSH remains elevated after tumor removal, medical suppressive therapy is indicated. Although TSHomas express several somatostatin receptors (SSTR 1, 2, 3, and 5), SSTR2 is most frequently expressed in subtypes 2A and 2B (Tjörnstrand and Nyström 2017). First-generation somatostatin ligands/analogues (SSAs) such as octreotide LAR®, lanreotide SR®, or lanreotide Autogel® are recommended for suppressive therapy based on their affinity to act on SSTR2 and SSTR5 receptors (Tjörnstrand and Nyström 2017; Beck-Peccoz et al. 2013). All preparations may not be available in some countries. There is evidence that euthyroidism is restored in up to 90% of cases with goiter and tumor shrinkage achieved in 30 and 40% of cases respectively after medical therapy (BeckPeccoz et al. 2013). Patients report side effects of treatment including diarrhea and should be monitored for symptoms of cholelithiasis. Ongoing follow-up is recommended, but data regarding appropriate intervals is scarce (Beck-­ Peccoz et al. 2013). Likewise there are few reports of recurrence rates and even fewer regarding quality of life in patients after treatment of a TSHoma.

18.8 Nursing Care Assessment of patient history with emphasis on their past medical history and family history of pituitary, thyroid, or parathyroid tumors is important. Evaluate the patient’s and families ­understanding of the process of medical evaluation and the path to the anticipated diagnosis. This process may be complex if multiple imaging modalities, fine needle biopsy, cardiac and bone evaluations are required. Preparation for some procedures is essential and must be reviewed with the patient in advance. Determine if the patient/family has adequate resources at their disposal and if further support is required in any functional domain.

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Patient education may be a staged process, as each test is resulted and the diagnosis is confirmed. Disease-related education along with information and coordination of care for any concomitant diseases revealed in the process of assessment may be indicated. Preparation for surgery and pretreatment with an antithyroid medication involves coordination between the patient and the operative team. Further assessment postoperatively may reveal persistent TSH secretion, indicating the need for medical therapy. A detailed explanation of the purpose for treatment and treatment options that demonstrate clear value to the patient both with respect to short-term symptoms and long-­term outcomes will enhance adherence. SSA therapies are currently injectable, some of which have been shown to be safe and effectively administered at home by the patient or family (Salvatori et  al. 2010). Assessment of the patient/family’s capacity and willingness to deliver this treatment as prescribed in the home is required in some countries. Drug administration may also involve coordinating home nursing support and/or in office teaching. The treatment plan should evolve as an interaction between patient, family, and all health care providers. Long-term follow-up will be required. At each visit, assessment of the patient’s understanding of the disease and treatment in the context of their changing symptoms and understanding is advised to facilitate self-care. Regular biochemical testing, including liver function testing, TSH and FT4 are recommended. This may need to be done as frequently at least 2–3 times in the first year postoperatively or until the patient is stable (Beck-Peccoz et  al. 2013). Ophthalmologic and visual field examinations are recommended as a baseline preand postoperatively for patients with a history of large macroadenomas. These may be best obtained in between MRIs that are recommended every 1–2 years at least for the first 5 years ­postoperatively (Beck-Peccoz et al. 2013). Coordination of followup at a location that is convenient for the patient is more likely to result in long-term adherence (Yedinak et al. 2018; Craig et al. 2014).

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18.9 Conclusions Historically, many patients with elevated TSH and symptoms of hyperthyroidism were inappropriately treated with thyroid ablation or thyroidectomy. This may have inadvertently promoted TSHoma growth. With improved ultrasonic techniques and TSH sensitivities and the availability of sophisticated CT/MRI techniques, the incidence and prevalence of the disease has significantly increased but diagnostic accuracy has substantially improved. This has also spurred a substantial increase in research. Despite diagnostic advances, treatment delays are estimated to be over 6  years from the onset of symptoms and over 12 years for patients post thyroid ablation or thyroidectomy. TSHomas are still most often found as macroadenomas and present with symptoms of mass effect and/or thyrotoxicosis. Treatments include surgical and medical approaches, with surgical removal of the TSHoma as the first choice in therapy. Somatostatin ligands remain the next most effective treatment in cases of residual or recurrent disease. There is limited data about the long-term outcomes and quality of life for these patients, but best outcomes are achieved with early diagnosis and treatment of microadenomas. The minimum follow-up recommendations are for monitoring of MRI and serum biochemistries yearly for the first 5 years postoperatively. However, lifelong intermittent follow-up may be indicated.

C. Yedinak Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD.  Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab. 1999;84:476–86. Carmichael JD. Anterior pituitary failure. In: Melmed S, editor. The pituitary. 4th ed. London: Elsevier; 2017. p. p329–63. Cooper DS, Ladenson PW. The thyroid gland. In: Gardner DG, Shoback DM, editors. Greenspan’s basic and clinical endocrinology. 9th ed. The McGraw-Hill Companies, Inc.; 2011. p. 170–89. Craig BM, Reeve BB, Brown PM, et  al. US valuation of health outcomes measured using the PROMIS-29. Value Health. 2014;17(8):846–53. https://doi. org/10.4172/clinical-practice.1000386. Review. Greenman Y.  Thyrotropin-secreting pituitary tumors. In: Melmed S, editor. The pituitary. 4th ed. London: Elsevier; 2017. p. 573–88. McDermott MT, Ridgway C.  Central hyperthyroidism. Endocrinol Metab Clin N Am. 1998;27(10):187–203. Nomura S, Pittman CS, Chambers JB, Buck MW, Shimizu T. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest. 1975;56(3):643–52. Salvatori R, Nachtigall LB, Cook DM, Bonert V, Molitch ME, Blethen S, Chang S, SALSA Study Group. Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naïve patients with acromegaly. Pituitary. 2010;13(2):115–22. Sarapura VD, Samuels MH.  Thyroid-stimulating hormone. In: Melmed S, editor. The pituitary. 4th ed. London: Elsevier; 2017. p. 163–201. Tjörnstrand A, Nyström HF.  Diagnosis of Endocrine Disease: diagnostic approach to TSH-­ producing pituitary adenoma. Eur J Endocrinol. 2017;177(4):R183–97. Yedinak C, Pulaski-Liebert K, Adelman DT, Williams J. Acromegaly: current therapies benefits and burdens. Clin Pract. 2018;15(2):499–511.

References Beck-Peccoz P, Lania A, Beckers A, Chatterjee K, Wemeau Key Reading JL. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting 1. Greenman Y. Thyrotropin-secreting pituitary tumors. pituitary tumors. Eur Thyroid J. 2013;2:76–82. https:// In: Melmed S, editor. The pituitary. 4th ed. London: doi.org/10.1159/000351007. Elsevier; 2017. p. 573–88. Beck-Peccoz P, Lania A, Persani L.  Chapter 24: TSH-­ 2. Beck-Peccoz P, Lania A, Persani L.  Chapter 24: producing adenomas. In: Jameson JL, DeGroot TSH-producing adenomas. In: Jameson JL, DeGroot LJ, editors. Endocrinology. 7th ed. Philadelphia: LJ, editors. Endocrinology. 7th ed. Philadelphia: W.B. Saunders Pub.; 2015. p. 266–74. W.B. Saunders Pub.; 2015. p. 266–74.

Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia

19

Christine Yedinak

Contents 19.1   Introduction

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19.2   Prolactin Physiology 19.2.1  Embryonic Cell Differentiation and Lactotrophs Proliferation 19.2.2  Prolactin Production 19.2.3  Prolactin Variants 19.2.4  Prolactin Receptor Activity

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19.3   Causes of Elevated Prolactin 19.3.1  Physiologic 19.3.2  Pharmacologic 19.3.3  Pathologic

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19.4   Tumor Recurrence

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19.5   Quality of Life (QoL)

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19.6   Nursing Care Summary 19.6.1  Assessment 19.6.2  Diagnosis 19.6.3  Implementation 19.6.4  Evaluation

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References

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Abstract

Prolactinomas (PPAs) are the most common type of secretory pituitary adenomas. The majority of prolactinomas are found in women on evaluation of amenorrhea, infertility, and new onset or persistent lactation after discontinuation of breastfeeding. Although galactor-

C. Yedinak (*) Northwest Pituitary Center, Oregon Health and Sciences University, Portland, OR, USA e-mail: [email protected]

rhea may also be a sentinel symptom in males, this is not as common, and is often preceded by sexual dysfunction. Diagnosis may not occur, particularly in males or postmenopausal women, until midlife when tumor growth impacts the optic chiasm and/or visual deficits are found, prompting ophthalmology review and subsequent imaging. Likewise, pituitary adenomas may be an incidental finding on a head CT or MRI obtained during a workup for headaches, after a head trauma, or other symptoms.

© Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_19

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In addition to a brain MRI to determine tumor size, location, and characteristics, all pituitary hormonal expressions are usually evaluated. Both macroadenomas (MA) and microadenomas (mA) may cause anterior pituitary hormone deficits, and further dynamic testing may be needed. Posterior pituitary hormone deficits are quite rare and would only occur with very large tumors. Prolactin (PRL) assays may vary, so obtaining a diluted PRL level is necessary when levels are high in patients with large tumors (usually >3  cm diameter) to avoid misinterpretation of results secondary to the assay “hook effect.” Evaluation of macroprolactin (biologically inactive PRL) may also be needed in patients without symptoms in order to avoid unnecessary treatment. Treatment may depend on presenting symptoms and deficiencies. However, prolactinomas are most frequently responsive to dopamine agonist (DA) medications that both normalize prolactin levels and can shrink tumors. Normalization of PRL most often restores fertility, resolves galactorrhea, and significantly improves headaches. Likewise, visual deficits will often resolve or significantly improve with tumor shrinkage. Intolerance or resistance to dopamine agonists, tumor growth while on dopamine agonists, co-­secretion with another hormone or a need for a biopsy for histopathology are criteria for transsphenoidal tumor resection. Best postoperative results are achieved by an experienced neurosurgeon. However, treatment with medical therapies (DA), other hormone replacements, or radiation therapy may still be needed postoperatively to control prolactin levels or residual tumor growth.

Keywords

Prolactin · Prolactinoma · Hyperprolactinemia Hypogonadism · Infertility · Galactorrhea

Abbreviations AP DA FSH GH GnRH ICD LH MA mA MRI PA PPA

Anterior pituitary Dopamine agonist Follicle stimulating hormone Growth hormone Gonadotropin releasing hormone Impulse control disorder Luteinizing hormone Macroadenomas/adenomas >1 cm Microadenomas/adenomas 100 kDa) forms of ­prolactin have been found in plasma and in the pituitary gland (Romijn 2014; Bernard et al. 2015; Freeman et al. 2000). These heteromers and PRL complexed with immunoglobulins may cause an accumulation of large prolactin moieties termed “macroprolactin.” These are less biologically active forms of prolactin. Other PRL variants such as 14  kDa, 16  kDa, and 22 kDa are the result of cleavage of the “small” 23 kDa protein which is thought to happen outside the cell. These variants subsequently act at PRL receptor sites to independently or synergistically regulate target tissue activities such as in the retina, myocardium, chondrocytes, and mammary gland in animal studies (Bernard et  al. 2015). Some studies have shown that 16  kDa PRL isoform has potent antiangiogenic and antitumoral effects and several researchers have connected 16 kDa PRL with peripartum cardiomyopathy and impaired cardiac capillary function (Bernard et al. 2015; Horseman and Gregerson 2014; HilfikerKleiner et al. 2006, 2012; Dalzell et al. 2011).

19.2.4 Prolactin Receptor Activity The PRL molecule attaches to receptor sites not only in the mammary glands but in diverse tissues. This attachment recruits and binds to a second receptor which changes the membrane conformation and PRL is transported into the cell. Although some forms of PRL use different cell signaling pathways, monomeric 23 kDa PRL transmits instructions to the cell nucleus for gene transcription, (cell proliferation or inhibition) via what is known as Janis Kinase 2-Signal Transduction and Activator of Transcription 5 (JAK2-STAT5) signaling pathway (Fig.  19.3) (Ignacak et al. 2012; Gorvin 2015). Instructions for both cell and receptor site proliferation are required for mammary gland development and lactation. This requires the cooperative activities of estrogen, progesterone, and other growth factors (Romijn 2014; Gorvin 2015). In the same way, PRL also affects fertility by inhibiting gonadotropin secretion and downstream testosterone production in men and egg development,

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia Fig. 19.3 Signal transduction pathways of the prolactin receptor activation. Prolactin effects target tissue changes by attaching to cell membrane receptors which activates a JAK-2/ STAT cascade. This is transcribed in the cell nucleus to regulate gene expression. Ignacak A, Kasztelnik M, Sliwa T, Korbut RA, Rajda K, Guzik TJ. Prolactin - not only lactotrophin a “new” view of the “old” hormone. J Physiol Pharmacol. 2012 Oct;63(5):435–43. Fig. 2. p437. Reprinted with permission

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PRL

Cell membrane P. JAK-2

BOX BOX 1 1

JAK-2 .P

BOX BOX 2 2

P.

STAT

P.

.P

P.

.P

Cytoplasm Fyn kinase Src kinase GRB2/SOS/Ras/RaF/MAPK cascade

STAT P

P STAT Nucleus P STAT

STAT P

ovulation, and blastocyst implantation in women (Gorvin 2015). PRL receptor site isoforms or mutations in different tissues could potentially affect the downstream signaling and ultimately alter the function(s) of PRL (Ignacak et al. 2012). Increased expression of PRL receptors and/or alterations in the JAK2-STAT5 signaling pathway have been implicated in tumorigenesis or tumor progression and have generated particular research interest with respect to the development of breast cancer (Bernard et  al. 2015; Gorvin 2015). There is also much interest in the association of tumor invasiveness with the interaction between PRL and estrogen receptors.

19.2.4.1 Prolactin Receptors Expression PRL receptors have been found to be expressed in most tissues. In mouse models they are highly expressed in the pancreatic B cell, impacting glucose-­mediated insulin secretion, particularly during pregnancy. It is hypothesized that this mechanism may be associated with gestational diabetes in humans, but current evidence is not convincing (Gorvin 2015). Increased adipose tissues and changes in fat storage distribution,

genes regulation

Transcription factors

leptin and adiponectin levels have also been demonstrated in mice when PRL levels are increased during pregnancy (Gorvin 2015). Likewise, weight gain and insulin resistance have also been demonstrated in hyperprolactinemia in humans (Gillam and Molitch 2011a). PRL receptors expressed on leukocytes in the spleen and thymus suggest a role in the immune system function by enhancing T-cell activation and proliferation (Gorvin 2015). In humans, elevated prolactin levels have been found in patients with immune diseases such as lupus, rheumatoid arthritis, psoriasis, Sjogren’s syndrome, uveitis, and multiple sclerosis, diseases that have been improved with therapy to lower PRL levels (Gillam and Molitch 2011a). Bone mass was also found to be decreased in hyperprolactinemic women that normalized with treatment to lower PRL levels but appears to be mediated primarily by the restoration of normal estrogen levels (Klibanski 2010). In mammals, prolactin has also been shown to reduce Na  +  and K+ renal excretion and adenosine triphosphatase activity, thereby affecting osmoregulation and, in particular, affecting human amniotic fluid transport (Ignacak et al. 2012).

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19.3 Causes of Elevated Prolactin Elevated prolactin (hyperprolactinemia) can be related to physiologic, pharmacologic, or pathologic causes including poor renal prolactin clearance. Hyperprolactinemia is idiopathic in up to 40% of cases (Romijn 2014; Ignacak et al. 2012; Majumdar and Mangal 2013). Normal physiologic causes are adaptive such as pregnancy and lactation (milk production). Other causes, particularly pathologic etiologies, effect biologic change and dysfunction (Grattan 2015) (Table 19.1).

19.3.1 Physiologic Physiologic hyperprolactinemia is a response to pregnancy, nipple stimulation, exercise, and stress (Romijn 2014). The dominant physiologic role of prolactin in women is the development of the mammary glands in pregnancy and lactogenesis (milk production). Estrogen, progesterone, placental lactogen, insulin growth hormone, and cortisol also play a synergistic role (Gillam and Molitch

2011b). Recent studies have shown that the PRL level doubles from pre-pregnancy levels in the first trimester, during which time the size of the pituitary gland itself enlarges. PRL levels continue to climb to over 30 times above baseline with highest levels 24–48 h after delivery (vaginal or cesarean section) (Hu et al. 2017). Levels decrease again to normal in the first week postpartum in the absence of breastfeeding or are maintained throughout breastfeeding (Klibanski 2010; Cocks Eschler et al. 2018). An early study demonstrated that PRL levels in breastfeeding mothers during the first 6  weeks postpartum peak to 8.5 times baseline with suckling. After this time, and at least through to 28  week period of the study, prolactin levels normalized but increased to an average of 6 times baseline with suckling (Noel et al. 1974). Mothers who used a breast pump experienced similar elevated PRL levels after pumping. Current evidence, from animal models, suggests that low maternal PRL levels at the end of pregnancy and high prolactin levels in the early postpartum period may negatively affect maternal nurturing behavior and may also be a factor in

Table 19.1  Etiology of hyperprolactinemia Physiological Coitus Exercise Lactation Pregnancy Sleep Stress Menses Pathological Hypothalamic-pituitary stalk damage Granulomas Infiltrations Irradiation Rathke’s cyst Trauma: pituitary stalk section, suprasellar surgery Tumors: craniopharyngioma, germinoma, hypothalamic Metastases, meningioma

Pituitary Acromegaly Idiopathic Lymphocytic hypophysitis or parasellar mass Macroadenoma (compressive) Macroprolactinemia Plurihormonal adenoma

Other Surgery Trauma Systemic disorders Chest—neurogenic chest wall trauma, surgery, herpes Zoster Chronic renal failure

Prolactinoma Pituitary Acromegaly Idiopathic Lymphocytic hypophysitis or parasellar mass Macroadenoma (compressive) Macroprolactinemia

Cirrhosis Cranial radiation Epileptic seizures Polycystic ovarian disease Surgery

Plurihormonal adenoma

Chest—neurogenic chest wall trauma, surgery, herpes Zoster

Suprasellar pituitary mass extension

Trauma Systemic disorders

Chronic renal failure Ref: Melmed S, Kleinberg D 2008 Anterior pituitary. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR eds. Williams textbook of endocrinology 11th ed. Philadelphia: Saunders Elsevier; 185–261

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia

poor transgenerational nurturing behaviors in offspring (Sairenjia et  al. 2017; Mitani et  al. 2018). Higher levels during pregnancy not only support lactation but play a significant role in inhibiting pregnancy during breastfeeding by suppressing gonadotropin release and thereby, ovulation (Majumdar and Mangal 2013). Vigorous exercise induced elevations of PRL have been reported to briefly increase prolactin levels, especially under the influence of serotonin in depressed subjects (E et al. 2004; Noel et al. 1972). Other studies reported increased core body temperature and not exercise per se significantly increases PRL levels (Chang et al. 1986). Major stress such as surgery and severe illness has been shown to transiently increase prolactin levels up to an average of 2–5 times baseline. Smaller increases were found after minor procedures, such as during colonoscopy and venipuncture (Melmed et al. 2011; Gillam and Molitch 2011b; Noel et al. 1972). With prolonged stress, levels decrease.

19.3.2 Pharmacologic Pharmacologic causes are numerous and must be considered, particularly when the patient presents with no classical clinical symptoms associated with hyperprolactinemia and other causes (pregnancy, renal failure, hypothyroidism, and macroprolactin) have been excluded. Close scrutiny of the patient’s history and concomitant medications is recommended (Table  19.2). To confirm a pharmacologic etiology, if possible, the offending medication should be withdrawn for 3–4  days and PRL rechecked (Molitch 2005). Withdrawal of antipsychotic and anti-depressive therapies requires consultation with the patient’s psychiatric provider. Treatment options include discontinuing or switching from the offending agent to another therapeutic option.

19.3.3 Pathologic Pituitary adenomas producing excess prolactin are the main cause of pathologic hyperprolactinemia. This may be the result of PRL receptor and/or transcription mutations and alterations in

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Table 19.2 Drugs that interfere with dopaminergic function Class Major Tranquillizers

Drug Thiazides Butyrophenones Antipsychotics Phenothiazines Haloperidol Amisulpride Atypical Risperidone Molindone Antidepressants Serotonin Reuptake Inhibitors (SSRIs) (minimal) Tricyclics Amitriptyline Desipramine Clomipramine Monoamine oxidase inhibitors Pargyline Clorgyline Antihypertensives Verapamil Methyldopa Dopamine receptor Reserpine blockers Alcohol Cocaine Heroin Prokinetics (GI motility) Metoclopramide (Reglan) Domperidone Diabeticorum Serotonin 5-HT3 Proton Pump Inhibitors receptor antagonists (PPIs) Omeprazole Estrogens Oral contraceptives Opiates Morphine Ref: Molitch, Molitch (2005); and Chahal and Schlechte (2008)

prolactin stimulating factors that inhibit dopamine tone (Glezer and Bronstein 2015). Systemic diseases such as liver failure, ACTH dependent Cushing’s disease, and hypothyroidism can be contributory. Large sellar masses and inflammatory disorders that impinge on the pituitary stalk can interrupt dopaminergic inhibition of prolactin production causing serum PRL levels to rise (Klibanski 2010; Romijn 2014; Chahal and Schlechte 2008). Poor renal clearance of prolactin causes elevated serum prolactin, particularly in chronic renal failure or related to the presence of large molecular weight prolactin. “Big” prolactin (a covalently bound dimer of prolactin with a molecular weight 48–56  kDa) and “big big”

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(molecular weights >100 kDa) forms of prolactin have been found both in plasma and in the pituitary gland (Romijn 2014; Bernard et  al. 2015; Freeman et  al. 2000). These macroprolactins are aggregate forms of prolactin or complexes of PRL and IgG that are less biologically active and usually do not cause clinical symptoms. However, they can confound clinical diagnosis (Klibanski 2010; Bernard et al. 2015; Freeman et  al. 2000; Gillam and Molitch 2011b). Women with macroprolactinemia may present with menstrual irregularities. Therefore, measurement of the bioactive monomeric prolactin is recommended using subfractionation (polyethylene glycol (PEG) precipitation) to avoid unnecessary treatment (Romijn 2014; Bernard et al. 2015; Gillam and Molitch 2011b; Olukoga and Kane 1999). Approximately 10–20% of patients presenting with hyperprolactinemia are found to have macroprolactinemia (Chahal and Schlechte 2008; Olukoga and Kane 1999; Smith et al. 2007).

19.3.3.1 Prolactinoma Prolactinomas are benign pituitary tumors producing excess prolactin, resulting in hyperprolactinemia. They represent up to 66% of all pituitary adenomas (Grossman and Besser 1985; Cocks Eschler et  al. 2018). Prevalence is estimated at 400–500 cases per million, with higher prevalence in females of childbearing age between 20 and 50 years than in men 10:1 (Ciccarelli et al. 2008; Chanson and Maiter 2017). Postmenopausal prevalence is similar for females and males but males tend to have larger and more aggressive tumors (Cocks Eschler et al. 2018). Prolactinomas are classified by size with microadenomas (mA) being 10 mm. In women with prolactinoma, 60% are found to have mA (Glezer and Bronstein 2015). MA have an estimated prevalence of 100 per million but a ratio of 1:8–9 females to males (Chanson and Maiter 2017). Prolactin levels correlate with tumor size with higher levels associated with larger tumors. Cancerous or malignant PPAs are extremely rare and estimated to represent one-­third of the 0.1– 0.2% occurrence of all malignant pituitary

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a­ denomas (Glezer and Bronstein 2015; Chanson and Maiter 2017). The pathogenesis of prolactinomas is not fully understood, however, as in most pituitary adenomas, PPAs are monoclonal. It is hypothesized that PPAs develop as the result of a cascade of events that include genetic translational mutations, microRNA alterations, and/or epigenetic changes (Chanson and Maiter 2017). Aggressive PPAs may result from disinhibition of proliferation, lack of sensitivity to inhibitory signals, or lack of cell apoptosis (cell death) (Chanson and Maiter 2017). Giant prolactinomas are defined as PPAs with the greatest diameter 40  mm or greater, with suprasellar extension and a baseline PRL level of more than 100 ng/L (Chanson and Maiter 2017). These tumors are more prevalent in adolescent boys and middle aged males. 19.3.3.1.1  Signs and Symptoms of Prolactinoma Most commonly, patients present with symptoms of hypogonadism secondary to the suppression of pulsatile GnRH and subsequent low expression of pituitary gonadotrophs (LH/FSH), testosterone and decreased ovulation (Majumdar and Mangal 2013). Therefore, women present more frequently with oligomenorrhea, amenorrhea, and infertility. Males often present with erectile dysfunction. Both genders present with poor libido, although elevated prolactin may go undiagnosed in males much longer than females. After the age of 50, hypogonadism is often attributed to age and therefore this may further delay the correct diagnosis (Klibanski 2010; Chanson and Maiter 2017). Galactorrhea is more common in women, is not independently diagnostic of a prolactinoma and may not even be present, as estrogen and progesterone are required to prime lactation (Glezer and Bronstein 2015). Conversely, isolated galactorrhea may occur in the context of normal PRL if increased breast sensitivity to lactotrophic stimulation is present, increasing the clinical challenge in diagnosis (Chanson and Maiter 2017). As a result of prolonged hyperprolactinemia resulting in amenorrhea and chronic estrogen suppression, osteopenia and osteoporosis may develop

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia

(Klibanski 2010). Decreased bone mass and anemia also occur in males secondary to low testosterone (Klibanski 2010). Headache is a common presenting symptom regardless of the size of tumor but is more common in men with larger tumors, as are visual changes and visual field deficits (Klibanski 2010). Approximately 10–15% of patients with macroadenomas present with quadratic visual field deficits due to compression of the optic chiasm. Ophthalmoplegia (eye muscle paralysis) with the involvement of cranial nerves III, IV, and VI is present in approximately 10% of MA with cavernous sinus invasion (Chanson and Maiter 2017). Headaches, in clusters, are common in these patients, particularly when the tumor extends into the cavernous sinuses (Chanson and Maiter 2017). 19.3.3.1.2  Diagnosis In the presence of symptoms, a serum prolactin level greater than 100 μg/L is suggestive of prolactinoma, and levels >250 μg/L and in particular >500 μg/L are indicative of a MA (Melmed et al. 2011; Gillam and Molitch 2011b). Levels 200  ng/L (Chanson and Maiter 2017; Kim et al. 2017). Recurrence rates for patients with microadenomas ranges from 10 to 15% postoperatively (Chanson and Maiter 2017). Few patients require radiation treatment for tumor control after failing to respond to DA.

19.5 Quality of Life (QoL) Few studies of QoL in patients with hyperprolactinemia or prolactinomas were found in a review of the literature. Children treated with DA were found to have no difference in survival or functional capacity compared with long-term survivors of different sellar masses (Hoffmann et  al. 2018). Premenopausal women with DA-treated macroprolactinomas had lower physical functioning, physical role and pain scores compared to age matched controls using SF-36 questionnaire (Kim et  al. 2017). In other small studies, social functioning and mental health, vitality, role emotion, and mental summary scores were found to be

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia

lower in patients with prolactinoma even after normalization of PRL levels when compared to unaffected controls (Kim et  al. 2017; Johnson et al. 2003). Patient scores were not differentiated by tumor size in these studies. There remains no substantial evidence that QoL is changed or improved by treatment or normalization of PRL.

19.6 Nursing Care Summary 19.6.1 Assessment Assessment at presentation requires the collection of detailed and often sensitive information. Data collected in referral information and patient completed questionnaires requires verification. Patients require assurance of privacy before being comfortable divulging personal information, particularly regarding hypogonadism and sexual activity. The comfort level of the interviewer will often frame the patient’s response. In many countries, personal medical information is protected by law unless it is medically necessary to be shared with other medical professionals. Full disclosure regarding psychiatric history, all medications (including those purchased “over the counter”), other drug use including illicit drugs used by the patient is vital. Direct inquiry may be necessary by the health care provider regarding more sensitive drug use such as alcohol volumes, marihuana, cocaine, and morphine that may decrease or increase PRL levels (Ranganthan et al. 2009; Torre and Falorni 2007). Again, reassurance of confidentiality and information security is needed in order to obtain accurate information for the provision of appropriate care. Anecdotally, by the time the patient consults in endocrinology, they have many unanswered questions. Initial assessment includes the patients understanding of the reason for the referral and their expectations regarding ongoing evaluation and treatment. Many have little knowledge of the pituitary and its function and may have been told they have a “brain tumor.” Connotations of malignancy serve to increase the anxiety of patient and family. Information regarding the benign nature of prolactinomas in 99.8–99.9% of cases is helpful.

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Health and illness beliefs and practices vary according to cultures and may need to be made explicit in order for the patient to fully understand the etiology of any pathology and their role in self-care. Identify the key symptoms that the patient wishes to address and clarify these based on known data to support and frame realistic expectations. As with headaches, complete resolution may not be achievable but jointly establish symptom remission goals that would be acceptable and improve his/her quality of life. Coordination and consultation with other services is often necessary.

19.6.2 Diagnosis Diagnostic testing may be limited to a simple blood draw or may be more extensive and is based on the patient’s symptoms. In asymptomatic patients, a macroprolactin level may need to be assessed to determine bioactive PRL levels. If the patient has symptoms and prior PRL levels have been normal, ensuring that a diluted assay has been done may change the course of further evaluation and treatment. Patient instructions for blood draws should ensure that all medications and drugs that may affect the PRL level have been withdrawn for at least 3–4  days. The patient may need to hold estrogen-based birth control and use other forms of birth control during evaluation. Avoidance of breast stimulation and vigorous exercise before the draw is recommended (Chang et  al. 1986). Although midday is usually nadir PRL level, there is no clear recommendations for a specific time of day for samples to be obtained. Nadir levels may vary for shift workers. Repeat samples may be needed prior to a final diagnosis. A pregnancy test may need to be performed simultaneously in woman of child bearing age in order to ensure that an elevated level is not related to an unanticipated pregnancy. MRI is recommended in symptomatic patients with elevated diluted PRL levels. If the patient is anxious regarding this procedure, pre-treatment with an anxiolytic may be indicated. In the USA, a prior authorization from the patients insurance

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is usually required prior to the procedure. Interpretation by an experienced neuroradiologist may be needed to evaluate small mA. Patients with MA that impact the optic apparatus require further evaluation with a formal ophthalmologic exam to identify visual changes and deficits. Both the MRI and ophthalmologic exam will serve as baseline evaluations for comparison after treatment. Further evaluation of pituitary functions may be needed such as evaluation of cortisol, ACTH levels, thyroid function (TSH/FT4), LH, FSH, testosterone (males) and in addition, renal function. Bone density scanning is recommended to evaluate bone density in patients with prolonged hypogonadism. Males may need further assessment for CVD.

19.6.3 Implementation With a diagnosis of prolactinoma a detailed patient education is warranted. The goal of patient education is to promote self-care and improve treatment adherence. Visual aids such as the patient’s own MRI images are powerful messages and can frame the patient’s understanding of the disease. The use of media such as vetted online and YouTube videos and resources such as www.pituitarysociety.org /patient education, the European Society of Endocrinology https://www. ese-hormones.org/for-patients/ and Hormone Health https://www.hormone.org/ that can be readily accessed on mobile devices are valuable educational tools. These resources can be used in an office setting and continue to provide a reference for patients after an introductory discussion. It is important to remember that, under stress, information retention is limited and repetition of material with subsequent visits is essential. Treatment planning requires patient involvement in decision making. A clear understanding of the risk, benefits, and side effects of each option includes a discussion of the implications for each individual patient. Patient treatment tolerance and adherence may begin with a discussion of coping strategies and practices to minimize the effects of the most common side effects. High risk side effects such as DA behav-

ioral changes and impulse control disorders must be clearly described to the patient and relatives along with a discussion of an effective management plan should these occur. For treatment planning and management of patient pre and post-surgery, see Chap. 23. Emergency guidelines should be provided in written form and reinforced with each visit. Communicate key events that represent a need for immediate medical intervention and a plan to seek emergency care. These events should include: sudden severe onset of headache, peripheral vision loss, clear nasal drainage usually along with severe headache (cerebrospinal fluid (CSF) leak), and acute psychotic behaviour changes and severe depression with suicidal ideation. Pregnancy may or may not be a desired outcome but is a risk in sexually active child bearing age women once treatment with DA is initiated and PRL is normalized. If pregnancy is not desired, then a form of birth control should be started concomitantly with DA, particularly when using cabergoline, which can normalize PRL levels quickly. At the confirmation of pregnancy, the DA is withdrawn and the patient is monitored every trimester for compressive symptoms and visual field exams are recommended for patients with MA.

19.6.4 Evaluation Follow-up may occur in various settings from a general practitioner office to specialty endocrine or pituitary centers or with endocrine consultants and advance practice providers. This may depend on accessibility and convenience for the patient, the complexity of the patient’s care needs, and/or the comfort level of the provider. However, the key components of follow-up evaluations include: side effects review, particularly the identification of critical side effects; medication review including usage, dosing interval and timing, consistency and continuity of use; desire for or restoration of fertility; symptom changes or improvement; biochemical assessment; and interval review of MRI (every 6–12  months until stable then every 2  years) (Klibanski 2010). All reviews may require adjustment to a management plan.

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia Acknowledgement The author acknowledges Mark Molitch MD who is the Professor of Medicine (Endocrinology), Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, IL USA.

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362 cardiomyopathy. Curr Heat Fail Rep. 2012;9:174–82. https://doi.org/10.1007/s11897-012-0095-7. Hoffmann A, Adelmann S, Lohle K, Claviez C, Müller HL.  Pediatric prolactinoma: initial presentation, treatment, and long-term prognosis. Eur J Pediatr. 2018;177:125–32. https://doi.org/10.1007/ s00431-017-3042-5. Horseman ND, Gregerson KA.  Prolactin actions. J Mol Endocrinol. 2014;52:R95–R106. Hu Y, Ding Y, Yang M, et al. Serum prolactin levels across pregnancy and the establishment of reference intervals. Clin Chem Lab Med. 2017;56(5):803–7. https:// doi.org/10.1515/cclm-2017-0644. Retrieved 19 Jan 2018 Ignacak A, Kasztelnik M, Sliwa T, Korbut RA, Rajda K, Guzik TJ.  Prolactin  - not only lactotrophin a “new” view of the “old” hormone. J Physiol Pharmacol. 2012;63(5):435–43. Ikeda H, Watanabeb K, Tominagac T, Yoshimotoc T.  Transsphenoidal microsurgical results of female patients with prolactinomas. Clin Neurol Neurosurg. 2013;115:1621–5. Jankowski PP, Crawford JR, Khanna P, Malicki DM, Ciacci JD, Levy ML. Pituitary tumor apoplexy in adolescents. World Neurosurg. 2015;83(4):644–51. Jeffcoate SL, Bacon RRA, beastall GH, Diver MJ, Franks S, Seth J. Assays for prolactin: guidelines for the provision of a clinical biochemistry service. Ann Clin Biochem. 1986;23:638–51. Jethwa PR, Patel TD, Hajart AF, Eloy JA, Couldwell WT, Liu JK.  Surgery versus medical therapy in the management of microprolactinoma in the United States. World Neurosurg. 2016;87:65–76. Johnson MD, Woodburn CJ, Vance ML.  Quality of life in patients with a pituitary adenoma. Pituitary. 2003;6(2):81–7. Kars M, Pereira AM, Smit JW, Romijn JA.  Long-term outcome of patients with macroprolactinomas initially treated with dopamine agonists. Eur J Intern Med. 2009;20:387–93. Kiive E, Maaroos J, Shlik J, Tõru I, Harro J.  Growth hormone, cortisol and prolactin responses to physical exercise: higher prolactin response in depressed patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(6):1007–13. Kim Y-M, Seo GH, Kim Y-M, Choi J-H, Yoo H-W. Broad clinical spectrum and diverse outcomes of prolactinoma with pediatric onset: medication-­ resistant and recurrent cases. Endocrine J [Advance publication]. Released December 27, 2017, Online ISSN 1348-4540, Print ISSN 0918-8959. https:// doi.org/10.1507/endocrj.EJ17-0268. https:// www.jstage.jst.go.jp/article/endocrj/advpub/0/ advpub_EJ17-0268/_article/-char/en Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med. 1977;296(11):589–600. Klibanski A.  Prolactinomas. N Engl J Med. 2010;362(13):1219–26.

C. Yedinak Low MJ.  Neuroendocrinology. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams textbook of endocrinology. 13th ed. Philadelphia: ScienceDirect Elsevier; 2016. p. 109–75. Majumdar A, Mangal NS.  Hyperprolactinemia. J Hum Reprod Sci. 2013;6(3):168–75. https://doi. org/10.4103/0974-1208.121400. Marano RJ, Ben-Jonathan N.  Minireview: extrapituitary prolactin: an update on the distribution, regulation, and functions. Mol Endocrinol. 2014;28(5):622–33. https://doi.org/10.1210/me.2013-1349. Medicines and Healthcare Regulatory Agency. WHO International Standard Prolactin, Human. Classification in accordance with Directive 2000/54/ EC, Regulation (EC) No 1272/2008: Not applicable or not classified NIBSC code: 83/573 (Version 5.0, Dated 10/11/2016). http://www.nibsc.org/documents/ ifu/83-573.pdf. Accessed 28 Feb 2018. Melmed S, Felipe F, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, JAH W. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–88. https://doi. org/10.1210/jc.2010-1692. Mitani S, Amano I, Takatsuru Y.  High prolactin concentration during lactation period induced disorders of maternal behavioral in offspring. Psychoneuroendocrinology. 2018;88:129–35. Molitch M.  Medication-induced hyperprolactinemia. Mayo Clin Proc. 2005;80(8):1050–7. Molitch M.  Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516–24. https:// doi.org/10.1001/jama.2016.19699. Noel GL, Suh HK, Stone JG, Frantz AG.  Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab. 1972;35(6):840–51. https://doi.org/10.1210/ jcem-35-6-840. Noel GL, Suh HK, Frantz AG.  Prolactin release during nursing and breast stimulation in postpartum and non postpartum subjects. J Clin Endocrinol Metab. 1974;38(3):413–23. https://doi.org/10.1210/ jcem-38-3-413. Noronha S, Stokes V, Karavitaki N, Grossman A. Treating prolactinomas with dopamine agonists: always worth the gamble? Endocrine. 2016;51:205–10. https://doi. org/10.1007/s12020-015-0727-2. Olukoga AO, Kane JW. Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition. Clin Endocrinol. 1999;51:119. Ranganthan M, Braey G, Pittman B, Cooper T, Perry E, Krystan J, D’Souza DC.  The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology. 2009;203(4):737–944. https:// doi.org/10.1007/s00213-008-1422-2. Rodman EF, Molitch ME, Post KD, Biller BJ, Reichlin S.  Long-term follow-up of transsphenoidal selective adenomectomy for prolactinoma. JAMA.

19  Prolactin Producing Adenomas: Prolactinomas and Hyperprolactinemia 1984;252(7):921–4. https://doi.org/10.1001/ jama.1984.03350070039020. Romijn JA.  Hyperprolactinemia and prolactinoma. Handb Clin Neurol. 2014;124:185–95. https://doi. org/10.1016/B978-0-444-59602-4.00013-7. Review. PMID: 25248588 Sairenjia TJ, Ikezawaa J, Kanekob R, Masudaa S, Uchidac K, Takanashia Y, Masudaa H, Sairenjid T, Amanoa I, Takatsurua Y, Sayamae K, Haglundf K, Dikicg K, et al. Maternal prolactin during late pregnancy is important in generating nurturing behavior in the offspring. Proc Natl Acad Sci U S A. 2017;114(49):13042–7. Salenave S, Ancelle D, Bahougne T, Raverot G, Kamenický P, Bouligand J, Guiochon-Mantel A, Linglart A, Souchon P-F, Nicolino M, Young J, Borson-Chazot F, Delemer B, Chanson P.  Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients. J Clin Endocrinol Metab. 2015;100(3):1177–86. https://doi.org/10.1210/ jc.2014-3670. Sarwar KN, Huda MS, Van de Velde V, Hopkins L, Luck S, Preston R, McGowan BM, Carroll PV, Powrie JK.  The prevalence and natural history of pituitary hemorrhage in prolactinoma. J Clin Endocrinol Metab. 2013;98(6):2362–7. https://doi.org/10.1210/ jc.2013-1249. Epub 2013 Apr 12 Smith TP, Kavanagh L, Healy ML, McKenna TJ.  Technology insight: measuring prolactin in clinical samples. Nat Clin Pract Endocrinol Metab. 2007;3(3):279–89. Spiegel K, Follenius M, Simon C, Saini J, Ehrhart J, Brandenberger G. Prolactin secretion and sleep. Sleep. 1994;17(1):20–7. Stewart JK, Clifton DK, DJ K, Rogol AD, Jaffe T, Goodner CJ. Pulsatile release of growth hormone and prolactin from the primate pituitary in  vitro. Endocrinology. 1985;116(1):1–5. Torre DL, Falorni A. Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag. 2007;3(5):929–51.

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Key Reading 1. Melmed S, Felipe F, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, JAH W.  Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–88. https:// doi.org/10.1210/jc.2010-1692. 2. Gillam M, Molitch M.  Proactin. In: Melmed S, editor. The Pituitary. 3rd ed. London: Elsevier; 2011. p.  119–66. https://doi.org/10.1016/ B978-0-12-380926-1.10015-X. 3. Chanson P, Maiter D.  Prolactinoma. In: Melmed S, editor. The pituitary. fourth ed. London: Elsevier; 2017. p. 467–514. 4. Glezer A, Bronstein MD.  Prolactinoma. Endocrinol Metab Clin N Am. 2015;44:71–8. 5. Romijn JA.  Hyperprolactinemia and prolactinoma. Handb Clin Neurol. 2014;124:185–95. https://doi. org/10.1016/B978-0-444-59602-4.00013-7. Review. PMID: 25248588 6. Torre DL, Falorni A.  Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag. 2007;3(5):929–51.

Growth Hormone Producing Adenomas: Acromegaly

20

Karen J. P. Liebert, Daphne T. Adelman, Elisabeth Rutten, and Christine Yedinak

Contents 20.1

Introduction 

 367

20.2

Epidemiology

 368

20.3

Pathophysiology

 368

20.4

Clinical Symptoms

 371

20.5 Comorbidities 20.5.1   Cardiovascular Comorbidities 20.5.2   Metabolic Comorbidities 20.5.3   Respiratory Comorbidities 20.5.4   Neoplasia and Malignancies 20.5.5   Arthropathies 20.5.6   Other Comorbidities

 373  373  374  374  375  375  376

20.6

Diagnosis

 376

20.7

Treatment Options

 376

K. J. P. Liebert (*) Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA e-mail: [email protected] D. T. Adelman Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA e-mail: [email protected] E. Rutten Department of Endocrinology, Ghent University Hospital, Ghent, Belgium e-mail: [email protected] C. Yedinak Northwest Pituitary Center, Oregon Health and Sciences University, Portland, OR, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_20

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366 20.7.1   Transsphenoidal Surgery 20.7.2   Medical Management 20.7.3   Emerging Therapies 20.7.4   Radiation Therapy

 377  378  380  381

20.8

Quality of Life (QoL)

 381

20.9

Nursing Management Considerations

 382

20.10

Long-Term Management

 383

20.11 20.11.1 20.11.2 20.11.3 20.11.4 20.11.5

Home Care Educational Programme Programme Goals Role of the Specialist Endocrine Nurse in Home Care Method: A Home Care Programme Programme Content Programme Conclusion

 385  385  385  385  386  386

20.12

Conclusions

 386

20.13

Patient Case Studies

 386

20.14

Patient Stories

 387

20.15 20.15.1

 atient Advocacy Groups P Best Practice “Bulgarian Association of Patients with Acromegaly”

 388  389

References

 391

Abstract

Keywords

Acromegaly is a rare disorder characterized by overproduction of growth hormone (GH) predominantly by a pituitary adenoma. Clinical features associated with acromegaly are a result of chronic excess GH and insulinlike growth factor-I (IGF-1) effects on tissue, bone, and other organs. The disease is associated with increased mortality, chiefly from cardiovascular disease, but morbidity from associated comorbidities is also increased. Adequate control of growth hormone excess is paramount to controlling comorbidities. The diagnosis is made by the biochemical confirmation of elevated GH and IGF-1 levels, the presence of clinical features, and evidence of a pituitary tumor based on MRI imaging. Transsphenoidal surgery, medical therapies, and radiation therapy are all options for disease control. Patients with acromegaly require long-term health surveillance, despite the fact that they may have normal GH and IGF-1 levels. Patients are monitored lifelong for disease recurrence, management of comorbidities and treatments to improve quality of life.

Acromegaly · Growth hormone excess · Pituitary · Pituitary tumor · Insulin-like growth factor-1

Abbreviations BMI CHD CSF CVD DI GH GHRH

Body Mass Index Congestive heart disease Cerebrospinal fluid Cardiovascular disease Diabetes insipidus Growth hormone Growth hormone releasing hormone IGF-1 Insulin-like growth factor-1 OGTT Oral glucose tolerance test OSA Obstructive sleep apnea SIADH Syndrome of inappropriate ­antidiuretic hormone SRIF Somatostatin SSA Somatostatin analogue SSRA Somatostatin receptor analogue

20  Growth Hormone Producing Adenomas: Acromegaly

Key Terms • Macroadenoma: pituitary tumour >1.0 cm in any dimension. • Gigantism: growth hormone excess occurring in childhood prior to the fusing of the long bone growth plates. • Somatotroph: growth hormone secreting cell in the anterior pituitary. • Somatostatin: a peptide hormone secreted by the hypothalamus that inhibits the production of growth hormone. • Ectopic Acromegaly: growth hormone-releasing hormone (GHRH) secretion from neoplastic tissue that stimulates pituitary somatotrophs to inappropriately release growth hormone.

Key Points

• Acromegaly is an insidious disease caused by overproduction of growth hormone and insulin-like growth factor-­1 (IGF-1) predominantly from a growth hormone producing adenoma in the pituitary gland. • Hypersecretion of growth hormone may lead to disturbances in the musculoskeletal, cardiovascular, metabolic system as well as have implications for the development of other neoplasms. • Early diagnosis and prompt treatment can prevent development of comorbidities and improve mortality and morbidity outcomes. • Diagnosis is based on clinical and biochemical assessments and should include a screening IGF-1 with confirmation of the disease using an oral glucose tolerance test. • Treatment of acromegaly includes surgery to remove the adenoma, medical therapy, pituitary irradiation, and/or combinations of each therapy. • Quality of life may be adversely affected in chronic conditions like acromegaly and should be addressed by all care providers.

367

20.1 Introduction Acromegaly is a disorder characterized by the overproduction of growth hormone (GH). Acromegaly comes from the Greek words for “extremities” (acro) and “big” (megaly), as one of the hallmark symptoms of this condition is abnormally large hands (Chanson and Salenave 2008). Growth hormone overproduction is usually from a benign tumor found in the pituitary gland. The pituitary gland is located at the base of the brain and directly below the hypothalamus (See Chap. 1). GH-secreting pituitary adenomas are thought to arise from abnormal changes to somatotroph cells whose primarily role is to secrete GH. Although the reason GH producing tumors occur is unknown, most are the result of a genetic mutation in the replication of somatotroph cells. When GH hypersecretion occurs before the fusion of long bone growth plates in late adolescence, pituitary gigantism results, characterized primarily by excessive vertical growth (Chanson and Salenave 2008). GH excess occurring during adulthood does not result in abnormal height, but rather is associated with slow insidious changes to the patient’s physical appearance and alterations in body physiology. Hence, acromegaly often goes unrecognized in adults for many years. Many patients complain of non-specific symptoms for many years, seeking consultation from a number of medical specialties. Early recognition of symptoms and treatment is paramount to limiting the impact of GH excess and subsequent comorbidities. A blood test for IGF-1 is recommended as a screening test when a patient presents with signs and symptoms of acromegaly. If elevated, referral to specialty centers versed in the diagnosis and treatment of pituitary diseases is highly recommended. Comprehensive care and access to health care professionals who are devoted to treating this disease is associated with best patient outcomes.

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20.2 Epidemiology

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more GH than men, and overall GH production decreases with age. Under normal conditions, Acromegaly is a slow, progressive disease. It may growth hormone is secreted in an episodic pulsabe up to 10 years (or more) before clear features tile manner and has a half-life of 11–19  min of the disease emerge and are recognized by (Faria et al. 1989). GH production during the day health care providers, necessitating a referral to is relatively low, but secretion and pulsatility an endocrinologist (Chanson et  al. 2014; increase at night in association with slow wave Nachtigall et al. 2008; Galoiu and Poiana 2015). sleep (Melmed 2017). Approximately 70% of This delay may largely be the result of the rarity GH is produced at night, beginning within 2 h of of the disease. the onset of sleep (Fig. 20.1). This circadian patCurrent population prevalence estimates range tern is shifted in jet lag, but is unchanged in shift from 2.8 to 13.7 cases per 100,000 people with a workers (Fig. 20.1) (Morris et al. 2012). yearly incidence of 0.2–1.1 cases per 100,000 Episodic or pulsatile GH secretion and release population (Chanson et  al. 2014; Gurel et  al. is a complex process influenced by many factors. 2014; Knutzen and Ezzat 2006; Lavrentaki et al. It is primarily under the central neurogenic con2016). This is a significant increase over histori- trol of two hormones released by the hypothalacal reports and may represent a true reflection of mus, growth hormone releasing hormone increased disease, increased awareness of the dis- (GHRH), and somatostatin. GHRH stimulates ease and earlier diagnosis, and/or patients more (positive action) and somatostatin inhibits GH actively seeking medical attention for symptoms, secretion (negative action) (Fig. 20.2). The alterparticularly after internet research (Lavrentaki nating action of these hormones is largely responet al. 2016). sible for GH pulsatility and the regulation of the The median age of diagnosis is reported to be appropriate concentration of growth hormone in in the fifth decade of life, between 40.5 and the body (Bonert and Melmed 2017). Ghrelin is a 47 years of life (men: 36.5–48.5, females: 38–56) peptide secreted from the gastrointestinal tract (Lavrentaki et  al. 2016). Acromegaly generally and stomach that modulates the release of GH at affects both men and women equally. Over 65% the levels of the hypothalamus and pituitary of cases are associated with a pituitary macroad- gland. GH and ghrelin have been found to be enoma at presentation (Nachtigall et al. 2008). If secreted simultaneously in humans with ghrelin left untreated, disease comorbidities contribute amplifying GH pulses (Melmed et  al. 2014). significantly to increased mortality, which is 2–4 Exercise and stress also influences GH secretion times higher than the general population (Melmed et al. 2014). (Beauregard et  al. 2003; Colao et  al. 2014a; GHRH (positive stimulation) from hypothaMelmed 2017; Melmed et al. 2005). lamic neurons is released in response to sex steEpidemiologic data is sparse regarding young-­ roids, neuropeptides, neurotransmitters, and onset acromegaly, or gigantism, mainly due to opiates (Bonert and Melmed 2017). GHRH travthe rarity of the cases. Reports indicate that only els to the pituitary via the infundibulum and 2.4% of all cases of acromegaly were found in attaches to receptors on somatatroph cells. This children between the ages of 0–19  years old process results in the synthesis of GH within (Daly et al. 2006). GH production from an ecto- these cells. GH is then distributed to receptor pic source is very rare. sites on target tissues throughout the body to affect nerves, muscles, bones, and other organ functions. 20.3 Pathophysiology GHRH release and GH synthesis are stimulated by many factors. Leptin regulation of fat Growth hormone is a peptide hormone manufac- mass, food intake, and energy expenditure may tured and secreted by somatotroph cells located provide a metabolic signal in fasting states trigin the anterior pituitary gland. Women secrete gering GH secretion in order to maintain meta-

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20  Growth Hormone Producing Adenomas: Acromegaly 30

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00

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00

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Fig. 20.1  GH circadian pulsatile production. (a) Normal subjects circadian pulsatile GH secretion with highest amplitude and frequency of pulses in slow wave sleep. GH levels are undetectable much of the time during the day. (b) Acromegaly subjects: Dysregulation of circadian

–

Hypothalamus GHRH

SS

+ +

Ghrelin from stomach

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frequency, and amplitude of GH pulses. Elevated baseline GH production. Ref: Chanson P, Salenave S: Acromegaly. Orphanet Journal of Rare Diseases. 3–17 (2008). Reproduced under creative commons license

Growth Hormone

Liver

+ IGF-1

–

Pituitary Growth Hormone

04

–

+ Liver, etc. IGF-1

Fat

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Indirect effect

Fig. 20.2  Growth hormone physiology. Growth hormone (GH) or somatotropin secreted by the pituitary gland. Growth hormone releasing hormone (GHRH) stimulates anterior pituitary gland to release GH.  The target of

growth hormone: adipose tissue, liver, bone, and muscle. GH has direct effects and indirect effects on these targets. Reprinted with permission from http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/gh.html

bolic homeostasis (Bonert and Melmed 2017). Central dopamine and subsequent norepinephrine secretion stimulate GH secretion. Hypoglycemia also increases GH secretion via adrenergic stimulation while cholinergic and serotoninergic neurons have been associated with sleep-induced GH secretion (Bonert and Melmed 2017). Somatostatin (Somatostatin Receptor Inhibiting Factor or SRIF) is a peptide that blocks GH secretion. SRIF can also inhibit adrenocorticotrophic

hormone (ACTH), thyroid stimulating hormone (TSH), insulin, and glucagon secretion. Synthesized in the hypothalamus, SRIF travels down the infundibulum to the anterior pituitary, where it attaches to somatostatin receptors on somatotroph cells, thereby blocking GH secretion. It has similar actions at somatostatin receptors found throughout the body. Somatostatin attaches to five somatostatin subtype membrane receptors (SSTRs), SSTR 1, 2, 3, 4, and 5 (Bonert and

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Melmed 2017). These subtypes have varying affinities for coupling with somatostatin (Bonert and Melmed 2017). SSTR 1, 3, and 5 are found on somatotrophs in the pituitary gland, whereas pituitary tumors express SSTR 1, 2, 3, and 5. These receptors provide a target for treatment of GH excess (Bonert and Melmed 2017). Other adrenergic pathways also inhibit GH release. Once secreted, GH circulates in the blood stream attaching to peripheral receptors inducing specific cellular changes. In the liver, IGF-1 is synthesized via the JAK/STAT signaling pathway (Morris et al. 2012; Burton et al. 2012). IGF-1 is essential for promoting developmental growth activities, but also provides inhibition of GH and GHRH production via negative feedback mechanisms (Melmed et al. 2014). GH and IGF-1 excess induces multiple downstream physiologic changes. Bone metabolism is increased with periosteal new bone formation and skeletal overgrowth (Bonert and Melmed 2017). Simultaneously, bone resorption is accelerated, increasing the risk of fracture in the presence of GH excess. There is an associated increase in soft tissue growth, adipose tissue, lipolysis, increased muscle and liver uptake of triglycerides (Bonert and Melmed 2017). GH excess antagonizes both insulin action and carbohydrate metabolism, resulting in hyperglycemia. Pituitary GH producing adenomas are largely thought to be the result of a genetic mutation leading to autonomous GH secretion and proliferation of somatotroph cells. However, some tumors may also result from GHRH synthesis or secretory dysfunction. Most GH adenomas are monoclonal, leading to abnormal proliferation of cells that only produce GH. However, up to 25% of GH producing tumors contain cells that co-­ secrete GH and prolactin (Melmed et al. 2014). Rare tumors also contain cells that can produce both GH and prolactin from the same cell (Chanson and Salenave 2008). Familial genetic acromegaly syndromes or familial isolated pituitary adenomas (FIPA) associated with acromegaly are rare and include McCune–Albright syndrome, multiple endocrine neoplasia type 1 (MEN-1), and Carney Complex (Melmed et  al. 2014). (See Chap. 9).

Histopathology of GH-secreting tumors demonstrates distinct cell cytoplasmic staining for GH granules and may reflect tumor activity (Melmed 2017). These include: sparsely granulated or rapidly growing tumor cells or densely granulated or slowly growing tumor cells (Melmed 2017). Cell proliferation markers Ki67 (a nuclear protein associated with proliferation) and p53 (a tumour antigen and marker of mitotic activity) are usually quantified are considered of concern if elevated. A Ki67 > 3%, mitotic activity in >10% of cells, and positive nuclear staining for p53 (>10 strongly positive nuclei per 10 high power fields) are indicative of more aggressive tumors (Raverot et al. 2017). Higher expression of SSTR2 and p21 (inhibiting cell proliferation) are associated with lower likelihood of tumor aggression and recurrence (Cuevas-Ramos et al. 2015). Two classification systems have been proposed in an effort for early prediction of treatment response, and/or tumor recurrence or progression. Raverot et al. focused primarily on histopathology and tumor invasion, prospectively evaluating a grading system from 1 to 3 for all pituitary adenomas (Raverot et  al. 2017) (Table 20.1). Tumors graded as 2b were found to have a 3.7 times higher risk of recurrence or progression than grade 1 tumors. Others examined clinical, radiologic, histopathologic, and outcome characteristics in order to develop a system of risk specifically for patients with acromegaly (Cuevas-Ramos et al. 2015) (Table 20.2). In this tool, level 1 is considered to have minimal risk of recurrence and is most likely to respond to monotherapy, whereas level 3 characteristics carry a significant risk of recurrence and poorer outcomes. This tool is pending further validation. Table 20.1  Grading system for prediction of tumour recurrence Grade 1a 1b 2a 2ba 3

Description Non-invasive, no or low proliferative indicators Non-invasive but proliferation Invasive Invasive with proliferation Malignant

2b had a 3.7 times higher risk of recurrence or progression over 1a (Raverot et al. 2017)

a

20  Growth Hormone Producing Adenomas: Acromegaly Table 20.2  Characteristics of aggressive GH producing tumors Type 1

Type 2

Type 3

Older age at diagnosis Longer disease duration before diagnosis (less symptomatology) Nadir GH and IGF-1 lower Smaller tumor volumes but both micro- and macroadenomas Tumors extend toward sphenoid Densely granulated cells on histopathology Ki67  3% p16 low or undetectable High p21 immunoreactivity Lower SSRT2 staining More likely to require 2 or more surgeries Younger age at diagnosis Macroadenomas all invasive Nadir GH and IGF-1 higher than type 1 and 2 Higher prolactin levels (p = 0.01) than Most aggressive tumors Sparsely granulated cells Ki67 > 3% p16 low or undetectable Low expression of p21 and alpha subunit Negative or low SSRT2 staining More likely to require 2 or more surgeries More likely to require radiotherapy More commonly require combination medical therapy or modalities for control More likely to be medication resistant

Adapted from Cuevas-Ramos et al. (2015)

20.4 Clinical Symptoms The presenting manifestations of acromegaly may be a reflection of disease progression and the time to diagnosis. Since the diagnosis is frequently delayed, it may account for the predominance of macroadenomas (tumors >1 cm) found in the majority of patients with acromegaly and the extent of the observed phenotypic changes (Nachtigall et al. 2008).

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The most commonly reported symptoms at presentation are headaches, as well as menstrual disturbances in women and hypogonadism in men (Chanson and Salenave 2008; Chanson et al. 2014). The most prominent physical changes in appearance include acral enlargement (78–85%) and course facial features (70%) (Chanson and Salenave 2008; Melmed 2017). Excess GH and IGF-1 act at multiple receptor sites on body organs, tissues and bone and muscle that ultimately produce the clinical characteristics and morbidity associated with acromegaly. In bone, high levels of IGF-1 increase chondrocyte and osteocyte activity, stimulating excess skeletal bone and cartilage formation (Chanson et  al. 2014). Over time, overgrowth of bone and cartilage results in acral changes (enlargement of the hands and feet) and changes in facial features such as frontal bossing and jaw growth. Joint laxity and remodeling is associated with soft tissue changes and boney overgrowth eventually resulting in arthritis and/or joint deterioration (Chanson et al. 2014). Vertebral fractures occur up to 6.9 times more frequently in patients with acromegaly, particularly in association with hypogonadism (Chanson et al. 2014; Mazziotti et  al. 2013). Increases in facial soft tissues result in changes in features, such as a bulbous nose, thickened lips, and enlarged tongue. Increases in peripheral tissue and edema result in enlargement of hands (leading to symptoms of carpal tunnel syndrome) and feet. Skin changes, including oily skin with large pores, excessive hair growth, excessive sweating, and skin hyperpigmentation are observed (Chanson and Salenave 2008; Chanson et  al. 2014; Melmed 2017; Melmed et  al. 2014). Multiple skin tags may be found under arms and on the trunk (Ben-­Shlomo and Melmed 2006; Capatina and Wass 2015). Elevated GH levels are also associated with organ tissue hypertrophy and enlargement. This can promote the development of a goiter and colon polyps. Airway obstruction results from tongue enlargement and hypertrophy of pharyngeal tissue leading to sleep apnea and poor oxygenation (Capatina and Wass 2015). IGF-1 production overstimu-

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lates myocyte activity, resulting in ventricular hypertrophy, compounding hypertension, cardiomegaly and congestive heart disease (CHD) (Melmed 2017) (Fig. 20.3). Other pituitary hormonal changes in acromegaly are common and include hyperprolactinemia, which is seen in about 25–30% of patients with acromegaly (Abreu et al. 2016). In the presence of a large tumor, this may be associated with pituitary stalk compression, but co-secretion of prolactin, either from a single cell type or two different cell types, is possible and may be confirmed on histopathology (Melmed 2017). Patients frequently

a

b

present with symptoms or a history of hypogonadism, menstrual abnormalities, and infertility (Melmed 2017). Hypopituitarism can be due to mass effect on the pituitary, or damage of the pituitary gland from surgical tumor excision or radiotherapy. On presentation, patient reported symptoms include frontal headaches, increase in ring and shoe size, weight gain, excessive sweating, difficulty with speech, snoring and breathlessness, deepening voice, coarse oily skin, multiple joint pains and carpel tunnel symptoms, hirsutism, fatigue, poor endurance, infertility, plus difficulty

Prominent supraorbital ridges Lower teeth separation

Mental disturbances Enlarged head circumference

Prominent lower jaw Cardiomegaly

Hypertension

Organomegaly

Hyperglycaemia

Large hands Accelerated osteoarthrosis

Increased heel-pad thickness on X-ray

Large feet

Fig. 20.3  Clinical features of acromegaly. (a) Clinical characteristics, (b) common morphological changes and comorbities. (c) Hand swelling and enlargement (right) (d) feet enlargement (left) (e) gaps between teeth particu-

larly on mandible (f) broadening of nose and jaw enlargement (g) frontal bossing and jaw enlargement. Adapted from: Chanson P, Salenave S: Acromegaly. Orphanet J Rare Dis 3, 17 (2008)

20  Growth Hormone Producing Adenomas: Acromegaly

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d

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e

f

Fig. 20.3 (continued)

with cognition and memory. Patients may also have changes in vision, particularly peripheral vision and acuity when large tumors are present (Chanson and Salenave 2008; Chanson et  al. 2014; Melmed 2017).

20.5 Comorbidities National registries have been created in several countries to track comorbidities and mortality rates and also monitor the effects of treatment. Past reports from registries and other studies have indicated that life expectancy for a patient with untreated acromegaly is reduced by about 10  years compared to the general population. Cardiovascular disease is cited as the leading cause of death. However, in a recent analysis of the French Acromegaly Registry Group, better disease control reduced the incidence of comorbidities, bringing life expectancy close to that of the general population (Maione et al. 2017).

20.5.1  Cardiovascular Comorbidities Cardiovascular disease (CVD) is the most prevalent comorbidity affecting people with acromegaly. Arrhythmias and sudden cardiac death represent the most common causes of mortality (Colao et  al. 1999; Sharma et  al. 2017). An increased risk of dilated cardiomyopathy, congestive heart failure (CHF), aortic and mitral valve disease, and coronary artery disease (CAD) are all reported (Sharma et al. 2017). Early studies (published prior to 1995) reported a standardized mortality risk associated with acromegaly of up to 3.31, or over 3 times higher than the general population. However, due to earlier diagnosis and disease control, mortality rates have improved with reported standardized mortality ratio now lower around 2.79 times that of the general population (Esposito et al. 2018). Some studies have found that coronary artery disease (CAD) risk is normalized with disease remission, whereas myocardial fibrosis, valvular dysfunction, and cardiac arrhythmias may be unchanged, despite

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treatment for acromegaly (Sharma et  al. 2017). CAD (stroke and myocardial infarction) risk remains unclear given concomitant risks from diabetes and hyperlipidemia, confounding morbidity and mortality statistics. However, encouraging data from a large German registry study demonstrated no increased risk of myocardial infarction (MI) or stroke in patients with acromegaly (Schöfl et  al. 2017). Regardless, early recognition of CVD, treatment in specialty facilities, and pre-surgical treatment with somatostatin analogues have been shown to improve CVD outcomes (Sharma et  al. 2017; Schöfl et  al. 2017; Colao 2012). Hypertension plays a significant role in development of cardiac hypertrophy or thickened heart chamber walls. It has been estimated that the incidence of hypertension in acromegaly is 18–60% and is associated with a significant increase in mortality (Pivonello et  al. 2017). Pathogenic mechanisms of hypertension are unclear. However, it is postulated that GH and IGF-1 excess also act directly on the kidneys causing antidiuretic and antinatriuretic effects or by indirectly expanding plasma volume, resulting in increased peripheral resistance. Epithelial sodium channels (ENaC) are found in all cells and play a role in extracellular fluid volume and blood pressure. Excess GH stimulates sodium reabsorption in the distal nephrons, resulting in water retention and volume expansion (Kamenicky et  al. 2008). Sleep apnea may also play a role (Sharma et  al. 2017). Additionally, chronic GH exposure causes myocardial inflammation and fibrosis, hence tissue hypertrophy and loss of tissue elasticity. Using echocardiography, it has been reported that up to 85% of patients with acromegaly have left ventricular hypertrophy (Sharma et al. 2017). Thus, hypertension in acromegaly is multifactorial. Cardiomyopathy in acromegaly has been described as occurring in progressive stages (Sharma et  al. 2017). Early stages involve increased myocardial performance and decreased peripheral vascular resistance progressing to cardiac hypertrophy associated with myocardial inflammation and fibrosis. These early changes can progress to congestive heart failure, primarily through severe systolic and diastolic dysfunc-

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tion and increased peripheral vascular resistance (Sharma et  al. 2017). Dysfunctional changes in the cardiac valves, particularly in the mitral and aortic valves, are also a common feature in cardiomyopathy (Sharma et  al. 2017). All patients presenting with acromegaly should be assessed with echocardiography and referred to cardiology as appropriate.

20.5.2  Metabolic Comorbidities Disorders of glucose metabolism are frequently reported in patients with acromegaly. IGF-1 regulates carbohydrate metabolism and insulin sensitivity, manifesting in a range of comorbidities such as heart disease, hypertension, and diabetes (Galoiu and Poiana 2015; Melmed 2017). Studies have reported variable rates of impaired glucose tolerance (16–46%) and overt diabetes mellitus type II (19–56%) in patients with acromegaly (Alexopoulou et al. 2013). Chronic GH excess is known to lead to insulin resistance in the liver and peripheral tissues. Impaired beta cell function has also been implicated in hyperglycemia. Severity of impairment in this patient population is also influenced by IGF-1 levels, age, and increased BMI (Alexopoulou et  al. 2013) (Fig. 20.4). Links have been shown between glucose intolerance, hypertension, and acromegalic cardiomyopathy (Chanson and Salenave 2008).

20.5.3  Respiratory Comorbidities The most notable respiratory comorbidity in acromegaly is obstructive sleep apnea syndrome (OSA). Risk factors include: anatomical changes in the craniofacial bones, posterior pharyngeal soft tissue thickening, and soft palate hypertrophy and tongue enlargement. These changes lead to airway impairment (Guo et al. 2018). Sleep apnea affects up to 80% of patients with acromegaly and is a common cause of daytime sleepiness, snoring, sleep hypoxia, headache, and memory dysfunction (Guo et al. 2018; Attal and Chanson 2018; Grunstein 1991). Obesity, particularly in males over 50 years, is a significant risk factor for OSA. Screening for sleep apnea is

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20  Growth Hormone Producing Adenomas: Acromegaly P 5.83

Fig. 20.4  Relationship of acromegaly: Glucose intolerance. Proportion of patients with NFG/NGT, IFG/IGT and DM within groups subdivided according to IGF-I z-score tertiles T1-T3. NFG normal fasting glucose, NGT normal glucose tolerance, IFG impaired fasting glucose, IGT impaired glu-

cose tolerance, DM diabetes mellitus. Ref: Alexopoulou O, Bex M, Kamenicky P et  al. Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary 17(1):81– 89. Creative commons License with permission

recommended for all patients with active and controlled acromegaly. Lung function changes are also apparent in acromegaly patients, with rib cage remodeling, changes in cartilage and soft tissue that decrease elasticity and shorten inspiratory time (Chanson and Salenave 2008). Although alveolar volume may be increased, subclinical hypoxemia may be present (Chanson and Salenave 2008).

et al. 2016). Thyroid nodules appear to be common and are found in up to 90% of patients with acromegaly. These patients have a greater likelihood of developing multinodular goiter when there is a longer interval between onset of symptoms and diagnosis (Chanson and Salenave 2008). However, some studies report the incidence of thyroid cancer does not appear to be different from the general population. A meta-­ analysis indicated that the overall cancer incidence for acromegaly patients was only slightly higher than the general population particularly for colorectal, breast, urinary, prostate, and hematologic cancers (Dal et al. 2018). No difference was found with respect to lung or gastric cancers. This emphasizes the need for ongoing cancer surveillance in patients diagnosed with acromegaly.

20.5.4  Neoplasia and Malignancies Higher risk of developing neoplasms and some forms of cancers has been reported in patients with acromegaly. In a large Italian study, renal, thyroid, and colon cancer risk was significantly higher than in the general population (Terzolo et al. 2017). Pre-cancerous adenomatous colorectal polyps have been reported in upwards of 28% of acromegaly patients (Chanson and Salenave 2008; Abreu et al. 2016). Overexpression of GH in the colon was shown to increased epithelial cell proliferation and decreased apoptosis rates predisposing the development of polyps (Chesnokova

20.5.5  Arthropathies Arthralgias and myalgias are reportedly experienced by about 70% of patients with acromegaly. Arthropathies develop after an average of 10 years of excess GH exposure, and can affect

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all joints, causing progressive pain and dysfunction (Chanson and Salenave 2008; Melmed 2017; Abreu et  al. 2016). Carpal tunnel syndrome and hip osteoarthropathy are commonly reported. Range of movement may be limited secondary to mechanical, non-inflammatory etiologies and/or hypermobility and tenderness. On radiographic images, joint spaces are seen to be widened (Melmed 2017). Osteocyte formation and uneven chondrocyte formations are thought to cause joint changes and osteoarthritis. In general, joint degeneration has been found to be irreversible and has been reported to impair activities of daily living and quality of life (Melmed 2017). Neurological conditions in the spine are thought to be associated with neural thickening and nerve entrapment, while disc space widening has been implicated in the development of kyphosis and scoliosis seen in these patients (Melmed 2017). Vertebral fractures have been reported in about 10% of patients (Abreu et  al. 2016; Mazziotti et al. 2008).

20.5.6  Other Comorbidities A higher incidence of asymptomatic cholelithiasis and gallbladder polyps is found in patients with untreated acromegaly (Annamalai et  al. 2011; Montini et al. 2010). In addition, the treatment with somatostatins has also been associated with the development of gallstones and gallbladder sludge (Melmed 2017).

20.6 Diagnosis The diagnosis of acromegaly is made through the clinical assessment of features and the measurement of biochemical parameters. Clinical findings unique to acromegaly, such as changes in facial features, enlarged hands (rings no longer fitting), and an increase in shoe size raise suspicions of acromegaly. Old photographs may be useful in determining changes in facial features (such as a driver’s license photograph if taken 5–10 years previously). Other presenting symptoms may include headaches, joint aches or car-

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diovascular findings and hypogonadism (Chanson and Salenave 2008; Melmed 2017). Biochemical confirmation of autonomous GH oversecretion is needed to make the diagnosis of acromegaly (Melmed 2017). A screening IGF-1 level should be performed if acromegaly is suspected. An elevated level should prompt a referral to a pituitary specialist or a general endocrinologist if a pituitary specialist is not available. Due to the pulsatile nature of GH secretion, a random GH level to confirm elevated GH is not useful, and is not recommended for diagnosis (Katznelson et al. 2014). According to internationally recognized guidelines, the gold standard test for confirming acromegaly is an oral glucose tolerance test (OGTT/GH suppression test). In this test, an oral glucose load of 75 g is given to the patient and GH levels are monitored every 30  min for 2  h. GH nadir of 1 cm) and can impinge on the optic nerves, it is also recommended that these patients undergo ophthalmologic and visual field testing as a component of the initial examination (Katznelson et al. 2014).

20.7 Treatment Options Treatment goals are to suppress or normalize GH and IGF-1, manage symptoms, and reduce tumor mass without compromising pituitary function (Melmed 2017; Katznelson et al. 2014). If surgical resection fails to achieve GH control, or if the patient is not a candidate for sur-

20  Growth Hormone Producing Adenomas: Acromegaly

gery, medical therapies and/or radiation therapy may be indicated (See Chapter: Pituitary Radiation) (Fig. 20.5).

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sophisticated intraoperative tumor localizing technologies (See Chap. 22). Post-surgically, new onset hypopituitarism and secondary empty sella may occur (Melmed 2017). Surgical risks and complications include vision loss, cerebral spinal fluid (CSF) leak and epistaxis and hormonal dysfunction. The most common disturbances in hormones following surgery include diabetes insipidus, syndrome of inappropriate antidiuretic hormone (SIADH) and adrenal insufficiency. Recurrence rates of pituitary tumors postoperatively range from 2 to 8% at 5 years post-op, with reports of up to 10% by 10 years postoperatively (Katznelson et  al. 2014; Swearingen et  al. 1998). This may be related to residual tumor from incomplete resection with subsequent growth or true recurrence. Re-operation is indicated for patients who experience visual impairment or if there is a high probability for substantial debulking or completely removing

20.7.1  Transsphenoidal Surgery First-line treatment where a pituitary tumor is evident on MRI is selective transsphenoidal surgical resection. Success in achieving the aforementioned goals is dependent on a variety of factors, such as tumor size and location and presence of the tumor in the cavernous sinuses (Chanson et al. 2014). If the tumor is a microadenoma (2.5 l/24 h) at the first postoperative day after transsphenoidal surgery for a pituitary adenoma. • 5% suffer from polyuria at the fifth postoperative day. • Permanent diabetes insipidus is only found in 1% of cases postoperatively.

J. Honegger

Algorithm for the Management of Diabetes Insipidus: A Single Centre Protocol

Diagnosis • Fluid intake and output exceeds 3500 mL in 24 h. • Urine output exceeds 400 mL within 2 h. • Serum sodium above upper limit of normal. Treatment • Desmopressin 2  μg subcutaneous or intramuscular after transsphenoidal surgery during the first postoperative days (because of reduced nasal uptake following transsphenoidal surgery). • Nasal application of desmopressin spray 1 puff can be commenced from postoperative day 6 onward. • Desmopressin tablets are also recommended for cases of mild or partial diabetes insipidus.

22.2.1.3 Diagnosis and Treatment of Postoperative Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) SIADH usually occurs between postoperative day 3 and day 10 and is a potential life-­ threatening complication. This is reported in up to 30% of cases. SIADH results in hyponatremia. Therefore, our protocol is to regularly measure serum sodium level until postoperative day 10 but protocols may be site specific. Asymptomatic SIADH can be treated with restriction of fluid intake to 1 L per day. In symptomatic SIADH, hyperosmolar sodium infusion is often required in addition to fluid restriction. Recently, the vasopressin antagonist tolvaptan became available. It allows efficient treatment of SIADH without fluid restriction. We start with a single dose of tolvaptan 7.5 mg. Mostly, a second dose is necessary 1–2 days later.

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22  Pituitary Surgery

It is imperative that an unduly rapid correction of hyponatremia is avoided. A rapid correction can cause damage to the myelin sheath of the nerve cells in the brainstem called central pontine myelinolysis which is a severe neurological disorder with poor prognosis.

Signs and Symptoms of SIADH

• • • • • • • •

Headache Malaise Agitation Tiredness Poor Concentration Nausea and vomiting Mental state changes and confusion Epileptic seizure

22.2.1.4 Perioperative Replacement Therapy of Adrenal Insufficiency Replacement therapy for adrenal insufficiency is of vital importance. A higher demand of cortisone is required during the stressful event of an operation. Two principle perioperative strategies can be pursued: (a) Replacement in every patient undergoing pituitary surgery. (b) Replacement only if: • Preoperative adrenal insufficiency exists or • Adrenal function is unknown (for example in emergency cases) or • New adrenal failure is anticipated based on intraoperative findings. Table 22.1 shows our regime if glucocorticoid replacement is required during the perioperative period. Physiological doses are continued at discharge as indicated after assessment of HPA axis (Table 22.1). In some countries, an emergency card is available or provided to the patient if postoperative

Table 22.1  Hydrocortisone Replacement Regime: a single centre protocol Day of surgery

First postop day Second postop day Third postop day Forth postop day From fifth postop day onward

100 mg hydrocortisone intraoperatively (intravenous) 100 mg hydrocortisone until the next morning (intravenous) 50 mg hydrocortisone (oral) 40 mg hydrocortisone (oral) 30 mg hydrocortisone (oral) 30 mg hydrocortisone (oral) 20 mg hydrocortisone (oral) (maintenance dose)

adrenal insufficiency is found or if adrenal function is equivocal.

22.2.1.5 Early Postoperative Assessment of Remission Status In functioning adenomas, postoperative assessment of the oversecreted hormone provides important information about the success of the surgery. Re-assessment should be performed as early as possible because the result is not only important for further treatment but also urgently awaited by the patient. In prolactinomas, prolactin can be assessed on the first postoperative day. In acromegaly, we also assess GH on the first postoperative day. However, IGF-1 decline is delayed. Both prolactin and GH are peptide hormones with a short half-life period. Their measurement at the first postoperative day provides valuable information of surgical success regarding correction of the oversecreted hormone (see specific chapters for more information). In Cushing’s disease, different methods for early assessment of the remission status are in use: Some centres withhold perioperative hydrocortisone replacement and measure cortisol daily after surgery. A drop in serum cortisol into the hypocortisolemic range indicates remission. As soon as remission is documented or the patient shows clinical signs of adrenal insufficiency, hydrocortisone replacement therapy must be c­ ommenced.

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This regimen allows for the earliest possible detection of remission. However, continuous clinical surveillance for symptoms of adrenal insufficiency is paramount to avoid adrenal crisis. Other centres use perioperative hydrocortisone replacement and withdraw hydrocortisone some days after surgery for assessment of the remission status.

J. Honegger

blesome nasal secretion or painful retention of secretion in the paranasal sinuses. Some centres use xylometazoline 0.1% nasal spray or drops. This shrinks the swollen nasal mucosa via vasoconstriction. It is applied after transnasal surgery until there are minimal secretions and free ventilation is restored which is usually the case after 7–14 days. Other centres use sterile saline spray multiple times daily to achieve a similar outcome. 22.2.1.6 Early Postoperative Medication for nasal pain is not routinely adminAssessment of Anterior istered. Nonsteroidal anti-inflammatory drugs can Pituitary Function be given if required. However, acetylsalicylic acid The regimen of postoperative endocrine re-­ should be avoided during the first 10 postoperative assessment of pituitary function differs between days because of the anticoagulant effects. centres. An orienting status of pituitary hormones It may be difficult to differentiate nasal secreprior to discharge should be the minimal standard. tion from cerebro-spinal fluid (CSF) rhinorrhea. No laboratory test is absolutely reliable. Measurement of glucose in nasal fluid is not 22.2.2 Postoperative Care: helpful after transnasal surgery. Mucosal fluid Neurosurgical is a hint for nasal secretion while clear fluid like water is suspicious of CSF. CSF rhinorrhea can 22.2.2.1 Surveillance of Vision be provoked if the patient is brought into a sitting The optic chiasm is in close proximity to the pitu- position and the head bend forward. itary gland. Patients with pituitary tumours may The nasal conditions must be closely supersuffer from chiasmal syndrome preoperatively. vised. If CSF rhinorrhea occurs, lumbar drainage Assessment of visual acuity and visual fields is or operative repair in a timely fashion is indicated mandatory immediately and regularly postopera- to avoid further complications such as meningitis. tively. Visual fields are tested with finger perimetry. Knowledge of preoperative vision and visual fields is important for proper judgement of the 22.2.3 Further Early Postoperative Care postoperative state. Furthermore, the nurse must have information from the surgeon about which patients are at risk for visual deterioration. The timing of discharge from the neurosurgical Visual failure may indicate postoperative unit varies between centres. The postoperative bleeding. The risk of bleeding is particularly high stay is usually between 3 and 6  days. In some during the first postoperative day. On the other centres, the patients are transferred to the endohand, improvement of preoperative visual deficits crine unit during the postoperative hospital stay. can often be detected immediately after surgery Prior to discharge, the patient is given both verbut may also be delayed. Formal ophthalmological bal and written instructions regarding postoperare-assessment can be done 1 week after surgery. tive home care. After transsphenoidal surgery, an Furthermore, optomotor nerves run lateral to increase of intracranial pressure must be avoided the pituitary fossa within the cavernous sinus. for a period of at least 4 weeks (Knappe et al. Postoperative care includes alertness for double 2018). For that time, physical strain, sports activvision and ptosis. ities, steam baths, saunas, and blowing the nose must be avoided. After 4 weeks, physical activi22.2.2.2 Nasal Care After ties can be slowly resumed. Patients are advised Transsphenoidal Surgery to sneeze with an open mouth to avoid Valsalva Regular nasal application of decongestant nose pressure. The use of continuous positive airway drops enhances nasal breathing and avoids trou- pressure (CPAP) devices is not recommended

22  Pituitary Surgery

immediately postoperatively and patients may need supplemental oxygen. Review with the Ear Nose and Throat (ENT) specialist 2–4  weeks postoperatively is recommended. The patient’s case is booked for the tumour board where decisions of further management (for example requirement of postoperative medical treatment or radiotherapy) are made. Most importantly, an appointment with the endocrinologist must be arranged prior to postoperative discharge. An exact date for the appointment is strongly recommended to guarantee an endocrinological follow-up. A first re-assessment by the endocrinologist is usually recommended 2–3 weeks after surgery. Some endocrinologists see their patients as early as 1 day after discharge from the neurosurgical unit. Similarly, a neurosurgical follow-up appointment is mandatory. The first appointment at the neurosurgical outpatient department is usually scheduled 3–6  months postoperatively. The patient is instructed to bring along a recent postoperative MRI or is scheduled the same day for a postoperative MRI.  Postoperative endocrine re-­ assessment may be scheduled simultaneously or independently and these results should be available to the neurosurgery at the time of this appointment. If the adenoma had suprasellar extension or the patient had suffered from chiasmal syndrome, an ophthalmological report should also be presented at the neurosurgical follow-up appointment.

22.3 Transcranial Surgery 22.3.1 Indications for Transcranial Surgery Transcranial surgery is only required if a pituitary adenoma is not sufficiently accessible by a transsphenoidal operation. The decision for the appropriate approach depends on adenoma size and location. A multilobulated suprasellar extension points to a perforated diaphragm sellae. It means that the adenoma has grown out of the confines of the pituitary fossa into the intracranial (intradural) space. Under these circumstances, the risk of trans-

427

sphenoidal surgery might be too high because it does not provide adequate control of intracranial neurovascular structures. Transcranial surgery is necessary in some of these adenomas. A predominant suprasellar adenoma with a small pituitary fossa, an eccentric suprasellar extension or a dumbbell shaped adenoma also hamper transsphenoidal resection and are reasons for transcranial surgery (Buchfelder and Kreutzer 2008). Today, less than 5% of pituitary adenomas require a transcranial operation.

22.3.2 Transcranial Approach and Tumour Removal For a transcranial approach, the skin incision is made fronto-temporal behind the hairline to avoid an externally visible scar. The pterional approach and the fronto-lateral approach are most frequently used. The pterional approach exposes the Sylvian fissure between the frontal and temporal lobes. The arachnoid of the Sylvian fissure is opened for exposure of the adenoma. The adenoma can be visualized and removed through the prechiasmatic space or through the space between the optic nerve and carotid artery (so-called “optico-carotid triangle”). The fronto-­ lateral approach provides a more anterior view. It is less invasive but the lateral view through the optico-carotid triangle is limited.

22.3.3 Risk of Transcranial Surgery The reported morbidity and mortality of transcranial surgery is certainly higher than of transsphenoidal surgery. However, one has to keep in mind a selection bias because the difficult adenomas with major intracranial, suprasellar extension require a transcranial operation. The mortality rate of transcranial surgery is approximately 2% (Buchfelder and Kreutzer 2008). Transcranial operations carry a particularly high risk of re-­ bleeding into the tumour bed. Another specific risk is hypothalamic dysfunction which may be caused by damage to small perforating arteries.

J. Honegger

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The risk of visual deterioration following transcranial surgery is approximately 15–22%. On the other hand, the chance that a pre-existing visual deficit improves after surgery is 50% (Bulters et al. 2009). In large adenomas with eccentric lateral extension, a significant risk of an oculomotor nerve palsy with ptosis and double vision exists. The risk of postoperative hypopituitarism and diabetes insipidus is also higher in transcranial surgery than in transsphenoidal surgery and the chance of postoperative recovery of pre-existing endocrine deficits is low (Buchfelder and Kreutzer 2008). As the adenomas requiring craniotomy are typically large and show invasive character, a gross total resection is mostly not feasible.

22.4

 urgery for Non-­adenomatous S Pituitary Lesions

22.4.1 Other Pathologies The vast majority of surgically treated lesions of the pituitary area are adenomas. However, numerous other pathologies of the pituitary, pituitary stalk and hypothalamus are encountered (see Chap. 14). The appropriate surgical approach for other pituitary pathologies also depends on their location. Among non-adenomatous lesions, tumours of neighbourhood origin that secondarily encroach upon the pituitary such as chordomas, chondosarcomas or perisellar meningiomas must also be considered.

22.4.2 Surgery for Craniopharyngiomas The second most frequent pathology of pituitary or hypothalamic origin is the craniopharyngioma. In contrast to pituitary adenomas, only 30% of craniopharyngiomas show major intrasellar involvement allowing transsphenoidal surgery (Honegger and Tatagiba 2008). Many craniopharyngiomas are not confined to the pituitary fossa and grow in the suprasellar intradural space above the diaphragm

sellae requiring craniotomy. Various transcranial approaches have to be considered as craniopharyngiomas may involve several intracranial compartments. Large craniopharyngioma cysts can be decompressed by stereotactic cyst puncture. Recently, extended transsphenoidal operations have been suggested for purely suprasellar craniopharyngiomas (Kim et  al. 2011) and other suprasellar tumours. The major disadvantage of such extended approaches is the large defect in the skull base and intraoperative CSF leak which is necessary for tumour exposure. It carries a high risk of a postoperative CSF fistula. Whether purely suprasellar tumours should be operated by craniotomy or extended transsphenoidal surgery is still a matter of debate (Jeswani et al. 2016). Gross total resection of craniopharyngiomas offers a high chance of recurrence-free longterm survival. Some neurosurgeons recommend an attempt at total removal so long as there is no risk of hypothalamic damage (Honegger and Tatagiba 2008). Other surgeons recommend conservative resection (biopsy or partial resection) followed by radiotherapy. However, the tumour burden remains with this policy and the therapeutic options in the case of re-growth are limited.

22.5 Recommendations for Radiotherapy Postoperatively 22.5.1 Indications for Radiotherapy in Pituitary Tumours 22.5.1.1 Indications for Radiotherapy in Non-functioning Pituitary Adenomas (NFPA) In NFPA, radiotherapy is indicated for postoperative adenoma remnants with invasive character that are not accessible surgically. The typical indication is a residual adenoma within the cavernous sinus (Fig. 22.7). The timing of radiation for NFPA is a current subject of controversy. Some radiotherapists recommend radiotherapy

22  Pituitary Surgery

a

429

b

d c

Fig. 22.7  Planning for stereotactic radiosurgery (SRS) with Gamma Knife of a left parasellar residual adenoma (arrow in a) within the cavernous sinus following transsphenoidal surgery. (a) Coronal view, (b) axial view, (c) 3D, (d) sagittal view. Yellow: 16 Gy isodose of the target vol-

ume; Green: 10  Gy isodose of the target volume. Blue: Optic chiasm (asterisk in a). Cyan: pituitary stalk and gland. The target volume has a sufficient distance to the optic chiasm to avoid visual compromise. Courtesy by Dr. G.A. Horstmann, Gamma Knife Centre, Krefeld, Germany

after initial surgery. Others use radiotherapy only if further growth of the residual adenoma is observed (Fig. 22.7).

might be required while awaiting the delayed effect of radiotherapy.

22.5.1.2 Indications for Radiotherapy in Cushing’s Disease Radiotherapy (RT) is a second treatment option in CD.  Radiotherapy is indicated if CD persists after pituitary surgery. This can be the case after negative sellar exploration(s) or for non-­ resectable invasive residual adenoma within the cavernous sinus. RT is also an option for recurrent CD (Estrada et al. 1997). Other second-line options are medical treatment or bilateral adrenalectomy. The treatment decision in the second-line therapy is usually made on an individual basis. Medical treatment

22.5.1.3 Indications for Radiotherapy in Acromegaly In acromegaly, RT competes with medical treatment as the second-line treatment. However, medical treatment is favoured in some countries for second-­line treatment and RT is used if GH hypersecretion cannot be controlled by surgery and medical treatment. 22.5.1.4 Indications for Radiotherapy in Prolactinomas In prolactinomas, RT is used if hyperprolactinaemia persists under dopamine-agonist (DA) treatment and surgery is not successful or not

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indicated because of invasive adenoma extension. Radiotherapy is rarely used in prolactinomas because of the high efficacy of DAs.

22.5.1.5 Indications for Radiotherapy in Craniopharyngiomas RT is indicated for residual or recurrent craniopharyngiomas. The ideal timing of RT is yet to be determined. An ongoing study in childhood craniopharyngiomas investigates whether adjunctive RT immediately after incomplete resection or salvage RT upon re-growth is superior.

22.5.2 Tumour Control and Remission Rates with Radiotherapy Radiation techniques are explained in Chapter 24: Radiotherapy.

22.5.2.1 T  umour Control Rates in  Non-functioning Pituitary Adenomas (NFPA) The goal of radiotherapy in NFPA is tumour control which means that the adenoma remains stable in size or shrinks. According to the literature, 80–98% of patients with NFPA are recurrence-free after fRT. The reported studies of SRS for NFPA showed tumour control rates of 83–100% (Sheehan et  al. 2012) (Fig. 22.7). On average, the tumour control rate was 96%. However, long-­term follow-up was not available in most of the studies on SRS.

J. Honegger

22.5.2.3 Remission Rates in Acromegaly In the retrospective data collection of fRT for acromegaly from 14 centres throughout the United Kingdom, normalization of IGF-1 was achieved in 63% of the patients at 10  years (Jenkins et al. 2006). The remission rates of SRS in acromegaly reported in the literature are heterogeneous. On average, a remission was achieved in approximately 50% of the patients (Pollock et al. 2008). Recent studies suggest that higher remission rates can be achieved today (Lee et al. 2015). 22.5.2.4 R  emission and Control Rates in Prolactinomas Both with fRT and with SRS, further tumour growth can be prevented in the vast majority of cases. However, remission with normal prolactin off dopamine-agonist treatment is only achieved in a minority of cases. Evidently, remission in prolactinomas is less frequent than in Cushing’s disease and acromegaly (Tanaka et al. 2010). 22.5.2.5 Control Rates in Craniopharyngiomas In the main published studies on fRT, control rates at 10  years after RT were 56.5–100% (Minniti et  al. 2009). Long-term results of SRS are still sparse. In the main published studies on SRS with mean follow-up periods between 16 months and 17 years, control rates of SRS were 34–88% (Minniti et al. 2009).

22.5.2.2 R  emission Rates in Cushing’s Disease Acknowledgement  The editors acknowledge manuscript With fRT, the reported remission rates with review by Justin Cetas MD who is the Associate Professor of Department of Neurosurgery, Oregon Health & complete reversal of ACTH- and cortisol-­ Sciences University, Portland, Oregon, USA. oversecretion were between 46% and 100% (Estrada et al. 1997). In published series of SRS with more than ten cases, the remission rates were highly vari- References able with a range from 17% to 83%. Recent M, Wei L, Ciric I. Short-term outcome of endostudies provide evidence that remission rates Ammirati scopic versus microscopic pituitary adenoma surof 60–80% can be achieved today (Marek et al. gery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84:843–9. 2015).

22  Pituitary Surgery Buchfelder M, Kreutzer J. Transcranial surgery for pituitary adenomas. Pituitary. 2008;11:375–84. Bulters DO, Shenouda E, Evans BT, et al. Visual recovery following optic nerve decompression for chronic compressive neuropathy. Acta Neurochir. 2009;151:325. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JAH, Giustina A. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol. 2006;65:265–73. Chandler WF, Barkan AL, Hollon T, Sakharova A, Sack J, Brahma B, Schteingart DE. Outcome of transsphenoidal surgery for Cushing disease: a single-center experience over 32 years. Neurosurgery. 2016;78:216–23. Chang EF, Sughrue ME, Zada G, Wilson CB, Blevins LS, Kunwar S. Long term outcome following repeat transsphenoidal surgery for recurrent endocrine-­ inactive pituitary adenomas. Pituitary. 2010;13(3):223–9. https://doi.org/10.1007/s11102-010-0221z. Estrada J, Boronat M, Mielgo M, Magallón R, Millán I, Díez S, Lucas T, Barceló B. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med. 1997;336:172–7. Fatemi N, Dusick JR, de Paiva Neto MA, Kelly DF. The endonasal microscopic approach for pituitary adenomas and other parasellar tumors: a 10-year experience. Neurosurgery. 2008;63(4 Suppl 2):244–56. Griffith HB, Veerapen R.  A direct transnasal approach to the sphenoid sinus. Technical note. J Neurosurg. 1987;66:140–2. Hadad G, Bassagasteguy L, Carrau RL, Mataza JC, Kassam A, Snyderman CH, Mintz A. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope. 2006;116:1882–6. Hardy J.  Transsphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg. 1969;16:185–217. Honegger J, Tatagiba M.  Craniopharyngioma surgery. Pituitary. 2008;11:361–73. Honegger J, Ernemann U, Psaras T, Will B.  Objective criteria for successful transsphenoidal removal of suprasellar nonfunctioning pituitary adenomas. A prospective study. Acta Neurochir. 2007;149:21–9. Jenkins PJ, Bates P, Carson N, Stewart PM, Wass JAH, On behalf of the UK National Acromegaly Register Study Group. Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly. J Clin Endocrinol Metab. 2006;91:1239–45. Jeswani S, Nuno M, Wu A, Bonert V, Carmichael JD, Black KL, Chu R, King W, Mamelak AN.  Comparative analysis of outcomes following craniotomy and expanded endoscopic endonasal transsphenoidal resection of craniopharyngioma and related tumors: a single-­ institution study. J Neurosurg. 2016;124:627–38.

431 Jho HD, Carrau RL, Ko Y, Daly MA.  Endoscopic pituitary surgery: an early experience. Surg Neurol. 1997;47:213–23. Juraschka K, Khan OH, Godoy BL, Monsalves E, Kilian A, Krischek B, Ghare A, Vescan A, Gentili F, Zadeh G.  Endoscopic endonasal transsphenoidal approach to large and giant pituitary adenomas: institutional experience and predictors of extent of resection. J Neurosurg. 2014;121:75–83. Kim EH, Ahn JY, Kim SH.  Technique and outcome of endoscopy-assisted microscopic extended transsphenoidal surgery for suprasellar craniopharyngiomas. J Neurosurg. 2011;114:1138–349. Knappe UJ, Moskopp D, Gerlach R, Conrad J, Flitsch J, Honegger JB. Consensus on postoperative recommendations after transsphenoidal surgery. Exp Clin Endocrinol Diabetes 2018 doi: 10.1055/a-0664-7710. [Epub ahead of print]. Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R, Buchfelder M.  Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol. 2008;158:11–8. Lee CC, Vance ML, Lopes MB, Xu Z, Chen CJ, Sheehan J.  Stereotactic radiosurgery for acromegaly: outcomes by adenoma subtype. Pituitary. 2015;18(3):326–34. https://doi.org/10.1007/ s11102-014-0578-5. Marek J, Jezková J, Hána V, Krsek M, Liscák R, Vladyka V, Pecen L.  Gamma knife radiosurgery for Cushing’s disease and Nelson’s syndrome. Pituitary. 2015;18:376–84. Minniti G, Jaffrain-Rea ML, Esposito V, Santoro A, Tamburrano G, Cantore G. Evolving criteria for post-­ operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature. Endocr Relat Cancer. 2003;10(4):611–9. https://doi. org/10.1677/erc.0.0100611. Minniti G, Esposito V, Amichetti M, Enrici RM. The role of fractionated radiotherapy and radiosurgery in the management of patients with craniopharyngiomas. Neurosurg Rev. 2009;32:125–32. Mortini P, Barzaghi LR, Albano L, Panni P, Losa M.  Microsurgical therapy of pituitary adenomas. Endocrine. 2018;59(1):72–81. https://doi.org/10.1007/ s12020-017-1458-3. Epub 2017 Oct 24. Pollock BE, Brown PD, Nippoldt TB, Young WF. Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery. 2008;62:1271–8. Schloffer H.  Erfolgreiche Operation eines Hypophysentumors auf nasalem Wege. Wien Klin Wochenschr. 1907;20:621–4. Schöfl C, Franz H, Grussendorf M, Honegger J, Jaursch-­ Hancke C, Mayr B, Schopohl J.  Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. Eur J Endocrinol. 2013;168:39–47.

432 Sheehan JP, Xu Z, Lobo MJ. External beam radiation therapy and stereotactic radiosurgery for pituitary adenomas. Neurosurg Clin N Am. 2012;23:571–86. Tanaka S, Link MJ, Brown PD, Stafford SL, Young WF, Pollock BE.  Gamma knife radiosurgery for patients with prolactin-secreting pituitary adenomas. World Neurosurg. 2010;74:147–52.

Key Reading 1. Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84:843–9.

J. Honegger 2. Chandler WF, Barkan AL, Hollon T, Sakharova A, Sack J, Brahma B, Schteingart DE. Outcome of transsphenoidal surgery for Cushing disease: a single-­center experience over 32 years. Neurosurgery. 2016;78:216–23. 3. Honegger J, Tatagiba M. Craniopharyngioma surgery. Pituitary. 2008;11:361–73. 4. Sheehan JP, Xu Z, Lobo MJ.  External beam radiation therapy and stereotactic radiosurgery for pituitary adenomas. Neurosurg Clin N Am. 2012;23:571–86. 5. Schöfl C, Franz H, Grussendorf M, Honegger J, Jaursch-Hancke C, Mayr B, Schopohl J.  Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. Eur J Endocrinol. 2013;168:39–47.

Pituitary Surgery: Nursing Implications

23

Sarah Benzo and Christina Hayes

Contents 23.1   Introduction

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23.2   Review of the Physiology of the Pituitary Gland

 435

23.3   Postoperative Nursing Care Considerations 23.3.1  Surgical Approach

 435  435

23.4   Key Endocrinological and Neurosurgical Nursing Considerations 23.4.1  Perioperative Glucocorticoid Replacement

 435  436

23.5   Monitoring Neurosurgical Complications 23.5.1  Infection 23.5.2  CSF Leak 23.5.3  Lumbar Drainage 23.5.4  Visual Loss 23.5.5  Epistaxis

 440  440  440  441  442  442

23.6   Summary of Patient Education 23.6.1  Perioperative 23.6.2  Discharge

 443  443  444

References

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Keywords

Pituitary surgery · Postoperative complications · Diabetes insipidus (DI) · SIADH · Adrenal insufficiency · Patient education

Abbreviations ACTH ADH AI

Adrenocorticotropic hormone Antidiuretic hormone Adrenal insufficiency

S. Benzo (*) · C. Hayes Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_23

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CD Cushing’s disease CRH Corticotropic releasing hormone CSF Cerebrospinal fluid DDAVP Desmopressin DI Diabetes insipidus HPA axis Hypothalamic-pituitary-adrenal axis IV Intravenous SIADH Syndrome of inappropriate antidiuretic hormone

Key Terms • Hypothalamic-Pituitary-Adrenal (HPA) Axis: Complex hormonal interaction between the hypothalamus, pituitary, and adrenal glands that takes place in order to provide hormonal homeostasis. • Adrenal Insufficiency: Inadequate production of cortisol (steroid hormone) from the adrenal glands to support physiologic needs. • Antidiuretic Hormone (ADH): Hormone secreted by the pituitary gland that works at the level of the kidney to regulate fluid and electrolyte balance to maintain appropriate intravascular hydration. • Diabetes Insipidus (DI): Insufficient secretion of ADH results in excessive urinary secretion of dilute urine resulting in intravascular dehydration characterized by elevated serum sodium and decreased urinary specific gravity. • Desmopressin (DDAVP): Medication consisting of a synthetic form of ADH that may be administered to patients with DI. • Syndrome of Inappropriate Antidiuretic Hormone (SIADH): Oversecretion of ADH resulting in excessive retention of free water despite low serum osmolality resulting in intravascular hyponatremia and increased intravascular circulating volume. • Cerebrospinal Fluid (CSF): A clear fluid that circulates in and around the brain and spinal cord.

• Lumbar Drainage: Catheter inserted into the lumbar subarachnoid space in order to remove CSF from the body. • Transsphenoidal Surgery: Approach to the pituitary gland for surgery by route of the sphenoid sinus, most commonly through the nose or upper lip. • Epistaxis: Bleeding from the nose, most often originates from the nasal mucosa after ­transsphenoidal surgery, however may indicate bleeding from more critical structures.

Key Points

• Nursing considerations in the care of the patient undergoing pituitary surgery include knowledge of patient’s preoperative hormone levels, surgical approach, and postoperative monitoring needs. • Diligent monitoring for disturbances of water and electrolyte balance, and HPA axis dysfunction are essential to the care of pituitary surgery patients. • The nurse caring for the neurosurgical pituitary patient should monitor for the following potential postoperative complications: infection, CSF leak, visual loss, and epistaxis. • Key neurologic components in the care of pituitary surgery patients include visual field testing, monitoring for visual changes, CSF leak monitoring, and lumbar drain management, when applicable. • Thorough patient discharge teaching regarding activity restrictions, prescribed hormone replacement, sign and symptoms of HPA axis dysfunction (with emphasis on signs of adrenal insufficiency), and scheduled follow-up with medical and surgical teams is paramount.

23  Pituitary Surgery: Nursing Implications

23.1 Introduction Pituitary surgery is performed to address a variety of pathologies. Surgical technique will vary based upon surgeon preference, tumor location, and any involvement of surrounding structures. Nursing care of the patient undergoing pituitary surgery is founded in a comprehensive understanding of pituitary physiology and pathophysiology. Expert knowledge of the pituitary gland, the hypothalamic-pituitary-adrenal (HPA) axis, underlying pathology, and surgical risks allows for early identification and intervention of postoperative complications. It is important to be aware of hospital specific protocols regarding the routine care of patients undergoing pituitary surgery, as they may vary from institution to institution. Comprehensive, broad based knowledge empowers the nurse to provide diligent, comprehensive care and identify potentially life-­ threatening complications promptly.

23.2 Review of the Physiology of the Pituitary Gland Review of the role of the pituitary gland in the endocrine system, each hormonal axis function, and the mechanisms of hormonal homeostasis is recommended (Amar and Weiss 2003; Yuan 2013; Greenberg 2016; Ben-Shlomo and Melmed 2011). For details, refer to Chap. 12.

23.3 P  ostoperative Nursing Care Considerations 23.3.1 Surgical Approach The surgical risks for patients undergoing removal of a pituitary adenoma may vary depending on the location of the tumor and the surgical approach as described in Chap. 22. The three standard surgical approaches for pituitary adenomas are transsphenoidal, transethmoidal, and transcranial. Transsphenoidal surgery is often the approach of choice for many surgeons, and this procedure may be performed via a sublabial or trans-nare approach depending upon the tumor

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characteristics and surgeon skill set and preferences. There are specific nursing implications associated with the different surgical approaches.

23.3.1.1 Sublabial Approach Patients who undergo a transsphenoidal procedure with a sublabial approach will have an incision under their lip, and oral care will be essential in preventing infection. Dietary considerations include soft foods and liquid protein supplements until sutures have dissolved. Oral care should be performed after every meal. The use of a straw is usually discouraged (Yuan 2013). 23.3.1.2 Extended Transsphenoidal Skull Base Approach In this approach, additional cranial base bone is removed to provide better exposure to the parasellar and clival region compared with the standard transsphenoidal approach (Zhao et  al. 2010). Both patients who undergo an “extended” ­transsphenoidal skull base approach and those found to have a CSF leak at the conclusion of a transsphenoidal surgery may require a lumbar drain placement postoperatively (Yuan 2013). Thus, it is important for nurses to be trained in proper care of lumbar drains. The key principle is the drainage is gravity dependent so the amount of drainage will change with the position of the patient (Overstreet 2003). Refer to individual facility lumbar drainage guidelines and physician orders regarding clamping versus opening lumbar drains. Patients with lumbar drainage systems and their family members require education pertaining to lumbar drainage, specifically in regards to patient position and mobilization.

23.4 Key Endocrinological and Neurosurgical Nursing Considerations The pituitary gland is essential for normal endocrinologic function (See Chap. 1). It is important to know if your patient experienced endocrine dysfunction prior to surgery, and if so what hormones were impacted to determine their level of perioperative risk (Malenković et  al. 2011). If hormonal oversecretion was evident, which

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hormone(s) were biochemically overactive and what disease symptoms was the patient experiencing. These symptoms will need to be monitored postoperatively. Likewise, if there is a deficiency in one or more hormonal axis, it is important to know if these deficiencies were replaced and if they are currently stable. These will also necessitate a monitoring plan postoperatively. Evidence suggests a multidisciplinary team approach to the care of transsphenoidal surgery patient is most effective, inclusive of neurosurgery, neuroendocrinology, and a pituitary nurse specialist (Carminucci et al. 2016). Length of stay was significantly reduced without compromising patient safety or outcomes (Fig. 23.1).

23.4.1 Perioperative Glucocorticoid Replacement Patients undergoing pituitary surgery are frequently given glucocorticoid replacement therapy during the perioperative period to treat potential cortisol deficiency. However, the practice of glucocorticoid administration post pituitary surgery varies between institutions and remains a controversial practice (Kelly and Domajnko 2013; Glowniak and Loriaux 1997; Pimentel-Filho et al. 2005; Inder and Hunt 2002). There are some data favoring treatment only when the patient is symptomatic of adrenal insufficiency versus protocol driven replacement, and depending on the status of the patient’s HPA axis function on preoperative testing. In the event of adrenal insufficiency in the latter circumstance, glucocorticoids must be replaced and continued until postoperative testing indicates normal HPA axis function. In other patients who have an intact HPA function preoperatively, and whom selective adenomectomy is possible, perioperative glucocorticoids may not be necessary. However, most patients with a large adenoma are at risk for cortisol deficiency following surgery. Therefore a stress dose 40–100 mg of IV steroids is frequently given to patients immediately before, during and/or immediately after surgery (Kelly and Domajnko 2013). The recommended replacement dose of glucocor-

S. Benzo and C. Hayes

ticoid by Endocrine Society Clinical Guidelines is 15–30 mg of oral cortisol daily in divided doses (Nieman et al. 2015). It should be reiterated that the use of glucocorticoid replacement will vary based upon institution protocol, patient pathology, and surgical or endocrine team preference. Postoperative assessment of glucocorticoid requirement is dependent on clinical assessment and diagnosis of the patient. In cases of Cushing’s disease, some centers recommended that all patients in postoperative remission with morning plasma cortisol levels less than 5 μg/dL be treated with glucocorticoids until further testing indicates a normal HPA axis function (Inder and Hunt 2002). Thus, it is important that nurses ensure morning cortisol levels and ACTH levels are drawn postoperatively in order for the physicians to assess HPA axis function and determine if oral hormone replacement after discharge is needed (Yuan 2013). See Box 23.1 for a suggested postoperative glucocorticoid regimen. If the patient is to be discharged on a glucocorticoid regime, it is essential to provide the patient and family with education regarding: symptoms of adrenal insufficiency (AI); symptoms to report urgently to their physician; administration of emergency glucocorticoid injection for symptoms of AI; to report to the nearest hospital emergency room for evaluation of the etiology of AI. Adrenal insufficiency following surgery may be temporary or permanent. Therefore, it is important for the patient to establish ongoing, follow-up care with a local endocrinologist.

23.4.1.1 HPA Axis Function Adrenal insufficiency or HPA axis dysfunction may be evident immediately after a successful surgery to remove an ACTH producing tumor or in remitted Cushing’s disease. However, manipulation or damage to the pituitary during surgery can also impair ACTH secretion, thus disrupting the HPA axis and secretion of cortisol. Lack of cortisol following surgery can result in adrenal insufficiency (AI). AI can be a life-threatening condition if not identified and treated (Yuan 2013; Nieman et  al. 2015) (See clinical indication of AI, Box 23.2).

*dopamine is the man PIF

Lactation

Protein synthesis, Thermogenesis

Somatostatin (SRIH)

+

+

Chondrocyte proliferation

Epiphyses of long bones

Stress response, Homeostatis

Cortisol

Insulin-like growth factor-I (IGF-1) Cell proliferation, Insulin antagonism

Adrenal

+

Corticotropin (adrenocorticotropic hormone) (ACTH)

corticotrophs

+

Corticotropin releasing hormone (CRH)

Liver & other tissues

+

Growth hormone (GH) (somatotropin)

somatotrophs

–

Ghrelin

GI Tract

Growth hormone releasing hormone (GH-RH) parvicellular neurosecretory cells

POSTERIOR PITUITARY

to dural sinus

inferior hypophyseal artery (br.of cavernous ICA)

pituitary stalk

median eminence

magnocellular neurosecretory cells

= hormone secreting gland cells

ANTERIOR PITUITARY

“long” portal veins

superior hypophyseal artery (br. of intracranial ICA)

optic chaism

capillary O:Testosterone, bed O: + Estradiol to cavernous sinus Secondary sex characteristics, Germ cell function

Gonads

+

Follicle stimulating hormone (FSH)

Luteinizing hormone (LH)

gonadotrophs

+

Gonadotropin releasing hormone (GnRH)

Fig. 23.1  Pituitary neuroendocrinology. Used with permission from Greenberg, M. S. (2016). Handbook of neurosurgery, image 8.1 pg153

ACTION

FEEDBACK HORMONE

T3 & T4

Thyroid

O:? O: + Breast

?

+

+

TARGET ORGAN

Thyrotropin (thyroid stimulating hormone) (TSH)

Prolactin (PRL)

–

thyrotrophs

+

PITUITARY HORMONE

+

lactotrophs

–

Thyrotropin releasing hormone (TRH)

PITUITARY CELL

CONTROL

Prolactin release inhibitory factors (PIFs)*

INHIBITORY

HYPOTHALAMIC HORMONE

INHIBITORY

Antidiuretic hormone (ADH)

Water retention, Arteriole constriction

Kidneys

Oxytocin

POSTERIOR PITUITARY

(ADH)

HYPOTHALAMUS

Milk letdown reflex in lactation, Uterine contractions

Breast

(Oxytocin)

ANTERIOR PITUITARY

23  Pituitary Surgery: Nursing Implications 437

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438

Box 23.1 Example of a Postoperative Glucocorticoid Regime

Day 0: 50  mg hydrocortisone (IV or PO) every 8 h Day 1: 25 mg hydrocortisone PO every 8 h Day 2: 20–25 mg hydrocortisone PO at 8 am daily Discharge: as needed (15–30 mg daily in divided doses) (Inder and Hunt (2002))

Box 23.2 Clinical Symptoms of AI

• • • • • • •

Headache Fatigue Weakness Dizziness with standing Nausea and/or vomiting Diarrhea and abdominal discomfort Decreased appetite and anorexia

• • • •

Clinical Signs of AI Hypotension Tachycardia Hyponatremia Hypoglycemia (Yuan (2013))

The patient may initially complain of worsening headache, dizziness, and fatigue before other symptoms become apparent. Depending on the level of deficiency, symptoms may develop slowly over several hours or become quickly apparent with stressful stimuli such as a blood draw, straining with post-op constipation, or with air travel. If an adrenal crisis is evident, parenteral (intravenous or intramuscular) injection of 100 mg (50 mg/m2 for children) hydrocortisone must be administered immediately (Naziat and Grossman 2000; Bornstein et  al. 2016).

Measurement of serum electrolytes (particularly serum sodium) followed by fluid resuscitation is recommended. Glucocorticoids should be continued every 6 h for 24–48 h (half-life of hydrocortisone is 90–120 min) and until follow-up testing indicates normal function or the patient is stable on a physiologic dose of hydrocortisone (15– 30  mg in divided doses daily (Naziat and Grossman 2000; Bornstein et al. 2016)).

23.4.1.2 C  ushing Disease: ACTH Hypersecretion Patients with Cushing Disease have ACTH secreting pituitary adenomas resulting in hypercortisolemia. Oversecretion of ACTH by the pituitary adenoma causes suppression of the normal circadian production of ACTH from surrounding normal corticotrophs and hypersecretion of cortisol from the adrenal glands (Nieman et  al. 2015). There may also be a suppressive effect on hypothalamic CRH production that inhibits normal ACTH production. After the ACTH secreting pituitary adenoma is removed, the normal circadian corticotroph production of ACTH may still be absent or suppressed; therefore, ACTH and cortisol levels may be low in remitted disease. The Endocrine Society Guidelines define remission of Cushing’s disease as: “a morning serum cortisol level  10%); vomiting; persistent jaundice  • Observations: jaundice; hypothermia; tachypnoea; dyspnoea; dehydration (sunken fontanelle, poor skin turgor)  •  Hypovolaemic shock, cardiovascular collapse  • Laboratory abnormalities: hypoglycaemia; hyponatraemia; hyperkalaemia; metabolic acidosis Childhood:  •  History of rapid growth (crossing centiles)  •  Advanced bone with reduced height prediction  • Early pubic hair development or sexual precocity (typically at 2–4 years of age)   • Clitoromegaly  •  Increased body odour  •  Oily skin and hair Adolescence and adulthood:   • Hirsutism  • Hair loss and receding hair line (male-patterned baldness in women)  •  Oily skin and hair   • Excessive acne   • Menstrual irregularities  •  Infertility in both men and women

Nonclassic CAH (late-onset CAH) Nonclassic CAH is usually associated with milder signs and symptoms of androgen excess. Patients can be diagnosed anywhere from early childhood to adulthood. Adolescent girls and adult women can have a clinical picture that is indistinguishable from the polycystic ovarian syndrome. Men are often asymptomatic. Affected females do not have ambiguous genitalia. Late childhood:  • Early pubic hair development or sexual precocity (before the age of 8 years in girls or 9 years in boys)  •  Clitoromegaly (rare, mild)  •  Accelerated growth  •  Advanced bone age  •  Increased body odour Adolescence and adulthood:   • Menstrual irregularities   • Hirsutism  • Hair loss and receding hair line (male-patterned baldness in women)   • Excessive acne Fertility: Subfertility is milder in comparison to classic CAH. Men usually have a normal testicular function.

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

deficiency. If 17OHP is elevated, blood sodium, potassium, and glucose must be checked. The measurement of 17OHP after an ACTH stimulation test can be used to confirm the diagnosis (White 2009). Abnormal results should then be complemented with DNA analysis for CYP21A2 mutations. In females, the diagnosis of classic CAH is most commonly made at birth because of the ambiguity (atypical development) of their genitalia (=46,XX DSD). In males who don’t undergo newborn screening and do not develop a saltwasting crisis in the neonatal period, the diagnosis may be delayed and only present when they develop signs of androgen excess. Most cases of nonclassic CAH are not picked up at neonatal screening (White 2009). The diagnosis of nonclassic CAH can be made at any time from childhood to adulthood, including asymptomatic individuals identified during genetic screening because of affected relatives. The initial assessment is done by measuring early morning 17OHP. Abnormal results should be followed up by an ACTH stimulation test for 17OHP and cortisol (Witchel and Azziz 2010).

35.4.2  Classic Congenital Adrenal Hyperplasia: Medical Treatment Treatment includes glucocorticoid replacement which aims to normalise hormone balance and reduce excess androgen production from the adrenal glands. Treatment is required lifelong, and adherence to treatment is essential for normal growth and development throughout the lifespan (El-Maouche et  al. 2017). It is crucial that families, children, and adult patients with CAH are able to learn the necessary skills to manage the condition and understand why treatment is needed and how it is managed (please refer to Chap. 37 for more information on how to support patients and improve their adherence to treatment in adrenal insufficiency). The mainstay of treatment of classic CAH are glucocorticoids (hydrocortisone [=cortisol] or,

663

if difficult to control in adulthood, long-­acting synthetic glucocorticoids such as prednisolone) and mineralocorticoids (fludrocortisone). Glucocorticoids must be given in sufficient doses to replace cortisol deficiency and downregulate excessive production of ACTH from the pituitary and over-secretion of adrenal androgens. Fludrocortisone is given to keep electrolytes and intravascular fluid volume normal. Table  35.2 reports treatment goals and typical regimens in patients with classic CAH (El-Maouche et  al. 2017; Speiser et al. 2010; Han et al. 2013a; Joint Lecahwg 2002). These should be seen only as a guide; treatment must be individualised after clinical and laboratory assessment. Daily treatment in children includes hydrocortisone three to four times daily and fludrocortisone one to two times daily, with additional salt replacement in the newborns: • For children with CAH, hydrocortisone is the drug of choice. The daily dose per m2 body surface is higher compared to those children who have other causes of adrenal insufficiency because of the need to downregulate excess ACTH production and mitigate the androgen excess. Daily doses must be prepared from tablets when each dose is due, crushed, and administered in a small quantity of water prior to a feed—the use of oral hydrocortisone suspensions is discouraged, as they are not bioequivalent to the tablets (Speiser et al. 2010). The European Medical Agency has recently granted a paediatric use marketing authorisation for Alkindi® (Diurnal Ltd), a formulation of hydrocortisone granules that allows for more accurate and age-appropriate dosing in children and masks the bitter taste of conventional tablets. • Fludrocortisone can be administered together with hydrocortisone. Neonates often require higher doses in the first months of life. Blood pressure should be monitored and doses minimised to prevent hypertension. • Any need to increase treatment to maintain normal sodium and potassium levels can be addressed by the addition of salt (sodium chloride). Solutions of 20% (made by

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664 Table 35.2  Medical treatment of classic congenital adrenal hyperplasia Treatment goals

Neonates and infants

Children

Older adolescents and adults

All patients:  •  Correct cortisol deficiency and prevent adrenal crisis  • In patients with “salt-wasting” CAH: correct aldosterone deficiency to promote normal electrolyte balance  •  Mitigate androgen excess while avoiding iatrogenic glucocorticoid excess Children:  •  Promote normal growth, development, and final height outcome  •  Obtain normal sexual maturation Adolescents and adults:  •  Ameliorate hirsutism, acne, and menstrual irregularities in adolescents and women   • Preserve fertility  •  Achieve positive sexual outcomes for females requiring genital reconstructive surgery Medical treatment needs to be adjusted on an individual basis with frequent clinical and biochemical monitoring over the first months of life. Typical doses are initially:  • Hydrocortisone: starting dose 20–30 mg/m2/day in three divided daily doses. Higher doses may be used for initial reduction of markedly elevated androgens, but it is important to very rapidly reduce the dose when target hormone levels are achieved  •  Fludrocortisone: starting dose 50–100 mcg twice daily  • Salt: starting dose 1–2 g/day of sodium chloride divided into several feedings. Salt supplementation can be discontinued as the child begins to eat table food and the taste for salty food increases  • Fludrocortisone and salt supplements are balanced carefully with monitoring of blood pressure and electrolytes Medical treatment needs to be adjusted on an individual basis with frequent clinical and biochemical monitoring over time. Typical maintenance doses are:  •  Hydrocortisone: maintenance dose 10–15 mg/m2/day in three divided daily doses  •  Fludrocortisone: maintenance dose 50–200 mcg/day  •  Encourage salt intake with exposure to hot weather or with intense exercise  • Glucocorticoids: hydrocortisone is the treatment of choice. However, long-acting glucocorticoids are often used in adults. Typical glucocorticoid regimens include one of the following:    –  Hydrocortisone: 15–25 mg/day in two to three daily doses    –  Prednisolone: 3–7 mg/day in one or two doses    –  Dexamethasone: 0.25–0.5 mg at bedtime  • Fludrocortisone: usual maintenance dose 50–200 mcg/day. It is important to reassess mineralocorticoid requirements when the patient transitions from paediatric to adult care because they can differ significantly between these phases  •  Encourage salt intake with exposure to hot weather or with intense exercise  • Oral contraceptive pills can be considered as an adjunct treatment in women to regularise menses and ameliorate the cosmetic effects of androgen excess (hirsutism and acne). Direct hair removal methods are also an option (e.g. photoepilation, electrolysis, eflornithine cream)

compounding pharmacies for accuracy) can be used to minimise the volume given, with the dose given neat just before a feed or mixed in a small amount of breast milk or formula. Babies adapt fairly quickly to the taste, and simple administration strategies need to be developed to enhance adherence to treatment. Children with classic CAH are salt–losers and therefore have a preference for salty foods. As toddlers, salt should be added to their cooked foods to balance their

intake, with older children having the ability to balance their own by “adding salt”. Long-acting glucocorticoids (prednisolone or dexamethasone) are often used in adults instead of hydrocortisone due to convenience of less frequent dosing (Table 35.2). When possible, hydrocortisone should be favoured because of the lower risk of over-replacement; both prednisolone and in particular dexamethasone are longacting, and activate the glucocorticoid receptor

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

for much longer including evening and night-­ time when circulating cortisol concentrations in healthy individuals are physiologically low. A novel modified-release formulation of hydrocortisone (Chronocort®, Diurnal Ltd) has been designed to mimic physiological cortisol secretion and improve control of the androgen excess (Mallappa et al. 2015). A phase-III clinical trial is currently evaluating its efficacy in adult patients with classic CAH.

35.4.3  Classic Congenital Adrenal Hyperplasia: Treatment and Prevention of Adrenal Crisis Patients with classic CAH have primary adrenal insufficiency and do not have the capacity to secrete extra cortisol in situations of stress. If the dose of glucocorticoids is not increased in these situations, a patient with classic CAH can develop a life-threatening adrenal crisis. If not promptly recognised and treated, an adrenal crisis rapidly leads to systemic collapse, hypovolaemic shock, and death (Table 35.3) (Bornstein et al. 2016). Adrenal crisis is a common occurrence in patients with classic CAH (Hahner et  al. 2015;

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Reisch et al. 2012). Precipitating factors include intercurrent illness, infections (particularly gastroenteritis and respiratory infections), persistent vomiting or diarrhoea, fever, significant pain, trauma (e.g. fractures), emotional distress, and strenuous physical activity (Hahner et al. 2015). Surgery requiring general anaesthesia, preparation for invasive diagnostic procedures (e.g. colonoscopy), and oral surgery (e.g. dental extractions) are further risk factors. Patients with CAH can also become acutely unwell if they do not have good adherence to medical treatment or do not follow the simple sick day rules outlined below (refer to Chap. 62 for more information on prevention and management of adrenal crisis). A patient with a suspected adrenal crisis must be promptly treated with lifesaving injectable hydrocortisone (IM as priority pending IV access). Diagnostic measures should never delay treatment. If an adrenal crisis is suspected, act immediately and refer to hospital emergency management guidelines, if available. As a guide (Joint Lecahwg 2002; Bornstein et al. 2016): • STEP 1: Give hydrocortisone immediately (injection of hydrocortisone IM or IV): 25 mg in those 12 years of age; 200 mg per 24 h in adults. Alternatively, the total daily dose can be split and administered IM or IV every 6 h. STEP 5: Treat the precipitating factor of the crisis, if possible (e.g. infection, trauma). STEP 6: Contact an endocrinologist for urgent review of the patient and advice on further tapering of hydrocortisone.

•

•

•

•

In order to prevent an adrenal crisis, several measures need to be in place (Bornstein et  al. 2016). These are simple and are lifesaving: • • Educate parents, patients, and partners regarding correct adjustment of glucocorticoid replacement in case of stress (“sick day rules”): –– Sick day rule 1: double or triple daily oral glucocorticoid dose during illness that requires bed rest and/or antibiotics or is associated with high fever (>38  °C) until recovery. Children should get hydrocortisone in three to four doses and given sweet drinks and salt supplements if off their food. Double or triple the dose on the day of any minor procedure/surgery that do not require fasting (e.g. procedures requiring local anaesthesia and tooth extraction). –– Sick day rule 2: administer hydrocortisone per IM or IV injection during severe illness, prolonged vomiting or diarrhoea, acute trauma and if the patient is confused, drowsy, or unconscious. Hydrocortisone per IM or IV injection must be given in preparation for surgery/procedures requiring general anaesthesia and during pro-

•

•

•

•

longed fasting (e.g. preparation for colonoscopy). In adults, the recommended dose is 100  mg via bolus injection, followed by 200 mg/24 h. Educate patients, parents, and partners regarding symptom awareness and possible precipitating factors of adrenal crisis. They should be advised that “if in doubt” they should give a hydrocortisone emergency injection and seek medical advice. Ensure patients have an additional supply of tablets so that they can double/triple their dose for at least 7 days, for example, when travelling abroad. If a patient is unable to tolerate tablets, hydrocortisone should be given IM and medical advice promptly sought. Provide patients and caregivers with a hydrocortisone emergency injection kit. Check regularly that their kit is up to date. Educate patients, parents, and partners on how to self-administer and inject hydrocortisone IM (for example: www.pituitary.org.uk/information/ treating-a-pituitary-condition/hydrocortisone/ how-to-give-an-emergency-injection-of-hydrocortisone; www.CAHPepTalk.com). Provide the patient with a steroid emergency card (for example: www.endocrinology.org/ adrenal-crisis) and encourage them to wear medical alert bracelets or necklaces. Patients must keep the steroid emergency card with them at all times and show it to any health professional they are dealing with. Instruct parents of school-aged children affected by CAH to inform school staff about the condition. An emergency letter and response plan can be of use (as an example: www.cah.org.au/products-resources; www. CAHPepTalk.com). Provide patients and caregivers with emergency phone numbers for on-call services and the ambulance service (register with their consent onto the red flagged ambulance emergency service, if available locally). Instruct patients and caregivers to inform the endocrinologist before surgical procedures so that proper advice can be given to the hospital staff. Encourage salt intake with exposure to hot weather or with intense exercise. Before major

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

physical activity (e.g. long distance running, major sports, or competitive dancing), patients might benefit from taking a small dose of extra hydrocortisone. • Regular review of the patient by health professionals to reinforce the sick day rules and adherence to treatment.

35.4.4  Classic Congenital Adrenal Hyperplasia: Monitoring Patients with classic CAH require lifelong care. While the correction of cortisol and aldosterone deficiency and the control of androgen excess are common aims in children and adults, treatment goals do change over time (Table 35.2). In children with CAH prevention of early puberty and achievement of an acceptable final height are paramount. Upon completion of pubertal development and attainment of adult height, continued monitoring of symptoms of androgen excess (menstrual irregularities, hirsutism), quality of life, sexual health, and fertility become increasingly more important. The avoidance of the longterm side effects of excess glucocorticoid treatment is also crucial (e.g. stunted linear growth in children and, in particular in adults, metabolic syndrome, increased cardiovascular risk and osteoporosis) (Reisch et  al. 2011; Arlt and Krone 2007). Medical treatment of CAH can be challenging and is a fine balance between over- and undertreatment (Table 35.3). The goal is achieving the best clinical results with the lowest possible daily glucocorticoid dose. Regular clinical assessment and blood tests are required to monitor the effectiveness of treatment (Table 35.4 and Fig. 35.2) (Escobar-Morreale et  al. 2012). The frequency and modalities of monitoring need to be tailored to the individual patient. Management can be complex and should involve multiple heath care professionals including endocrinologist, endocrine nurse specialist, genetic counsellors, gynaecologists, urologists and surgeons, fertility specialists, mental health providers, and social services. The endocrinologist and the specialist endocrine nurse play a pivotal role in coordinat-

667

ing management to guide the patients and their carers to achieve satisfactory health outcomes.

35.4.5  Classic Congenital Adrenal Hyperplasia: Management in the Neonatal Period A female newborn with 46,XX DSD requires urgent consultation with the paediatric endocrine team and specific management strategies to provide the family with appropriate information and support to manage the shock and grief process until gender is determined. Placating comments and judgements regarding the gender of the baby should not be made. The focus should be on “your baby” who is “well and beautiful” with positivity expressed about the labour and delivery. Parents are advised that specialist endocrine team will be consulted immediately to explain the situation and assist in ascertaining the gender of their baby. The paediatric endocrinologist will direct the plan to determine the diagnosis and gender and develop a treatment strategy to manage the glucocorticoid and mineralocorticoid deficiencies. The initial assessment is made on the physical findings, electrolyte and hormone analysis, radiological investigations, and genetic testing. The severity of genital malformation is assessed according to the Prader scale (Fig. 35.3) (White and Speiser 2000). The surgical management of children born with 46,XX DSD is complex. Patients should be referred to centres with substantial experience and a team of paediatric surgeons, paediatric endocrinologists, mental health professionals, and social work services (Speiser et al. 2010). Boys with classic CAH who did not undergo neonatal screening can present aged 1–3 weeks of life with a salt-wasting adrenal crisis—a state of systemic collapse which can lead to death if not managed quickly (Table  35.1). Because of the serious state of circulatory collapse, intravenous access may be difficult an intraosseous access may be required. A blood gas will give an immediate indication of the blood glucose, electrolytes, and assess for acidosis. At any stage of concern,

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668 Table 35.4  Monitoring of patients with classic congenital adrenal hyperplasia Frequency of monitoring

Clinical assessment

Laboratory assessment

Radiological assessment

 •  At least monthly during the first 3 months of life  •  Every 3 months in the neonate and infant  •  Every 3–6 months in children and adolescents  •  Every 6–12 months in adults on stable medical treatment  •  History taking, including current medications and comorbidities  •  Assess the adherence to medical treatment  •  Monitor growth velocity in children  •  General physical examination  • Vital signs and body measurements: height; weight; waist circumference; blood pressure sitting and standing (to look for hypertension and orthostatic hypotension)  •  Look for signs and symptoms of over- or under-replacement (Table 35.3)  • Examination of the genitalia to look for any signs of virilisation in children (e.g. clitoromegaly and precocious pubic hair development) and assess the outcome of reconstructive surgery in girls. It is imperative that such examinations are discussed with the parents and child and are undertaken discretely, particularly as children become older. Testicular examination should be performed periodically in adolescents and adults, looking for palpable masses or testicular atrophy  •  Assess the menstrual function in adolescents and premenopausal women  • Assess women for hirsutism, using the modified Ferriman–Gallwey score (Fig. 35.2)  • Assess health-related quality of life. Questionnaires can be used in older children and adults (e.g. PedsQL™ Generic Core Scale, PedsQL™ Fatigue Scale, WHOQoL-BREF scale, MAF scale, SF-36®; EQ-5D™). Investigate psychological, social, and sexual health issues, as well as current health concerns  • Ask if the patient had any sick days since the previous visit and needed to increase the dose of glucocorticoids or required hospitalisation  • Reinforce the sick day rules and confirm that measures are in place to prevent and treat promptly adrenal crisis (e.g. hydrocortisone emergency injection kit, steroid emergency card, medical alert bracelet)  • Investigate family plans in patients of reproductive age Hormonal evaluation:  • CHILDREN: morning serum 17-hydroxyprogesterone and androstenedione. Testosterone measurement is sometimes useful in patients whose disease is not well controlled. Adrenal androgen secretion should not be completely suppressed; normal levels of 17-hydroxyprogesterone generally indicate overtreatment  • MEN AND WOMEN: morning serum 17-hydroxyprogesterone and androstenedione. The goal is individualised to achieve patient goals, but androstenedione should not be suppressed  • MEN: morning serum testosterone, sex hormone-binding globulin (SHBG), and gonadotropins (FSH and LH)  • WOMEN: morning follicular-phase progesterone should be checked in those seeking fertility. Testosterone measurement is sometimes useful in patients whose disease is not well controlled Plasma renin activity or direct renin concentration: it is used to monitor fludrocortisone replacement. Reference intervals are based on postural state and age, and data should be evaluated accordingly. A suppressed result reflects overtreatment and increases the risk of hypertension Other tests:  •  Blood sodium, potassium, and kidney function  • Fasting plasma glucose: in neonates and young children glucose must be monitored because of the risk of hypoglycaemia, particularly if the child is unwell or requiring salt replacement. Conversely, adults are at risk of developing diabetes mellitus  •  In adults: lipid panel; glycated haemoglobin (HbA1c); vitamin D  •  Regular bone age assessment in children (X-ray of the hand)  •  Regular testicular ultrasound in males from adolescence onwards  •  Monitor adults periodically for low bone density (DEXA scan)

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

1

1

1

1

1

2

2

2

2

2

3

3

3

3

3

669

4 1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

4

4

4

4

Fig. 35.2  Modified Ferriman–Gallwey score is the gold standard for the evaluation of hirsutism, scoring nine body areas (upper lip, chin, chest, upper and lower abdomen, arm, thigh, upper and lower back). Ferriman–Gallwey total scores that define hirsutism in women of reproductive age are: US and UK black or white women, ≥8;

Mediterranean, Hispanic, and Middle Eastern women, ≥9 to 10; South American women, ≥6; Asian women, a range of ≥2 for Han Chinese women to ≥7 for Southern Chinese women. Reproduced with permission from EscobarMorreale et  al. (2012). Copyright Oxford University Press, 2011

or if there is a delay in obtaining intravenous access, hydrocortisone followed by glucagon should be administered IM for suspected adrenal insufficiency and hypoglycaemia. Once intravenous access is established, IV hydrocortisone, dextrose, and normal saline should be administered to correct hypovolaemia, hypoglycaemia, and the electrolyte abnormalities.

and family members depending greatly on individual coping abilities, and also influenced by social background, cultural and family beliefs (Patterson et al. 1990). A family’s adjustment to a new diagnosis can be greatly enhanced by a health professionals’ approach to the situation through counselling, education, and support (Hatton et al. 1995). By facilitating a process of understanding and adjustment health professionals can increase the likelihood of families having the knowledge, understanding, and confidence to manage difficult situations when they occur, such as a possible adrenal crisis. This education process should be reviewed regularly at clinical follow-up. Psychological support is important for the parents but also for the children as they grow and adapt to living with a complex condition and its physical and emotional consequences. Managing intercurrent illness in order to prevent serious

35.4.6  Classic Congenital Adrenal Hyperplasia: Management During Infancy and Childhood The psychosocial adjustment of the parents to the diagnosis of CAH initially, and later for the child, is critical to achieving a positive outcome for the child and the family in the long term. Having a child with a complex chronic condition is a lifealtering experience, with the impact on parents

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a - Prader scale (cross-sectional view)

Bladder Müllerian duct Müllerian tubercle Primitive urethra

Vaginal plate

Vaginal plate

Undifferentiated stage

Prostatic utricle

Uterus Vagina Normal

1

2

3

4

5

Normal

Perineal urethra

Female

Male

b - Prader scale (external view) Glans Urethral Fold Labial Swelling

Clitoris Labia Minora Labia Majora

Female

Glans Urethral Groove Scrotal Swelling

Tubercle

Genital Fold

Genital Swelling

Urethral Groove Anus

Undifferentiated stage

Urethral Orilice Vaginal Opening Normal

1

2

3

4

5

Normal

Prepuce

Urethral Orifice

Scrotal Raphe

Scrotum

Male

Fig. 35.3  Prader scale. The severity of virilisation is often quantitated using the five-point Prader scale. (a) Normal and abnormal differentiation of the urogenital sinus and external genitalia (cross-sectional view). (b) Normal and

abnormal differentiation of the external genitalia (external view). Reproduced and edited with permission from White et  al. (2000). Copyright The Endocrine Society, 2000

deterioration to a possible life-threatening adrenal crisis is a serious concern for parents and always at the forefront of their minds. They have to adapt their daily routine around their child’s medication plan, attendance for regular medical reviews, and routine investigations. Health professional should aim to help families adapt the care required for these children into their daily lives in order to ensure positive health outcomes in the long term. CAH has an element of androgen exposure in utero, which can affect brain development and function (Webb et al. 2018). Girls can have maletypical childhood play and more interest in maletypical activities during childhood and adolescence (Dittmann et al. 1990). Health professionals need to be aware of parental concerns regarding this variation to the norm and guide

parents appropriately. Counselling with a psychologist will assist in this process for both the parents and the child. Autism, which is more often found in males than females, has been found to be more prevalent in patients with CAH of both sexes (Knickmeyer et al. 2006). Support groups are important for parents and extended families, enabling them to share with others their experiences and difficulties in having a child with a diagnosis of CAH. Not all parents are ready to meet other families and will do so in their own time. Support groups can be invaluable in providing families with a sense of normality, and being able to meet other children who have grown up having the diagnosis of CAH.  It is important that patients themselves are able to share their experiences in confidence with others with the same diagnosis.

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

35.4.7  Classic Congenital Adrenal Hyperplasia: Management During Adolescence Adolescence is the phase of transition from childhood to adulthood. Managing CAH at this stage of development can be challenging, with a rapidly changing body and the impact of the hormonal changes of puberty (Merke and Poppas 2013). Adolescence is also a time of significant emotional change and often adherence to medical treatment is an issue. Adolescent females can struggle with hormonal control at puberty, which often requires an increase in routine hydrocortisone doses. They may also need the addition of an oral contraceptive pill to regulate their monthly cycle and reduce acne and excess body hair. The outcome of reconstructive genital surgery carried out in infancy should be reviewed in adolescence and discussed with an appropriately skilled surgeon. If (additional) surgery is desired, particular expertise is imperative to ensure comprehensive understanding, appropriate consent by the adolescent and parents for adequate surgical outcomes. In adolescent males with classic CAH, ACTH hypersecretion can cause hyperplasia of ACTHsensitive cells present in the testes. This leads to the development of testicular nodules known as “testicular adrenal rest tumours” (TARTs), which can cause infertility (see section on fertility below) (El-Maouche et al. 2017). Poor adherence to hydrocortisone treatment and severe loss-of-function CAH genotypes have been identified as risk factors for the development of TARTs, which should be actively monitored for by ultrasound starting in adolescence, at the latest at the point of transition to adult care.

35.4.8  Classic Congenital Adrenal Hyperplasia: Management in the Adult Care Setting With adolescence, the patient with CAH must gradually assume primary responsibility for his/her care and eventually transition to adult care. The adolescent’s needs and concerns shift to a more adult focus on quality of life, long-term health and eventually

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relationships, fertility, and family planning (Reisch et al. 2011; Han et al. 2013b; Auchus and Arlt 2013). As patients with classic CAH often require higher doses of glucocorticoids to control the androgen excess, they are at increased risk of obesity, diabetes mellitus, dyslipidaemia, cardiovascular disease, and bone loss during adult life (Auchus and Arlt 2013; Arlt et al. 2010; Han et al. 2014). Consequently, a key priority when managing adults with CAH is to minimise long-term consequences of both the condition itself and its treatment. The transition of care from a paediatric to an adult care setting remains a major challenge and many patients are lost to follow up (Gleeson et al. 2013). Ideally, patients should be jointly reviewed by the paediatric endocrinologist, the newly introduced adult endocrinologist, a clinical nurse specialist, and a geneticist on their first appointment. Apart from clinical and laboratory assessment, the initial evaluation should also focus on the following: • Get to know the patient and understand their childhood journey. • Assess the patient’s understanding of the condition, goals of, and adherence to treatment. • If available medical records are incomplete, these few questions are helpful: “At what age were you diagnosed?” “When did you stop growing?” and “Did you have any genital surgeries?” (Auchus and Arlt 2013). • If indicated, an external genital examination may be necessary. Discuss sexual health with the patient and consider referral to a gynaecologist or urologist, if appropriate. • Discuss family plans. Refer the patient to a fertility clinic, if appropriate. • Consider the need for psychological counselling. Ongoing follow-up will depend on this baseline assessment. Patients can have both or alternating appointments with their endocrinologist and the clinical nurse specialist, usually on yearly basis if they are on stable medical treatment (Table  35.4). Establishing a good nurse–patient relationship can enhance continued engagement for ongoing care.

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35.4.9  Classic Congenital Adrenal Hyperplasia: Fertility High rates of infertility can occur in patients with classic CAH (Reichman et  al. 2014). Fertility correlates with the severity of the condition and can be reduced in both sexes. Women have low fertility rates mainly due to androgen excess and menstrual irregularities with anovulatory cycles. 46,XX DSD and related surgical outcomes can also impact on sexual relationships and the chance of a positive pregnancy experience. Women seeking a pregnancy often need to intensify glucocorticoid treatment to obtain a more stringent control of the androgen excess and, consequently, promote their ability to ovulate and conceive. They should also be referred for review of the outcomes of previous genital reconstruction surgery; women with complex genital surgery should deliver by Caesarean section. About 30–50% of men with classic CAH develop TARTs (Auchus and Arlt 2013), hyperplastic adrenal-like tissue, which can compress the surrounding testicular structures and cause oligospermia. Moreover, the adrenal-derived androgens can suppress gonadotropins and cause testicular atrophy. Men should be taught to self-examine their testes and have regular testicular ultrasound examinations to assess atrophy and the presence of TARTs. The term “tumour” should not be interpreted as a neoplasm because these masses actually represent hyperplastic tissue and do not show increased proliferation. It is therefore important not to confuse TARTs with primary testicular tumours when discussing a case with the patient and colleagues from other disciplines (Auchus and Arlt 2013). Poor adherence to glucocorticoid treatment is an important risk factor for the development of TARTs and intensified treatment is sometimes required, but not always effective for decreasing the size of the masses and restore fertility. Adult males with TARTS should be offered semen analysis and counselled on sperm banking.

35.4.10  Classic Congenital Adrenal Hyperplasia: Management of a Genetic Diagnosis Once a child has been diagnosed with CAH, genetic testing will identify the specific muta-

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tion present. This should be arranged following referral for genetic counselling, firstly to determine the mutation in the neonate, and then the carrier status of the family members. This will have an impact on their pregnancy planning in the future. CAH is autosomal recessive. Parents of a baby with CAH both have one of their two 21-hydroxylase DNA alleles affected and thus have a onein-four chance of having another baby with CAH and one-in-eight chance of having a female baby with CAH and 46,XX DSD. Treating the mother with dexamethasone before the major period of fetal sexual differentiation (6–8 weeks post-conception) can help to prevent the 46,XX DSD in the female fetus. However, dexamethasone can have adverse effects on the mother receiving treatment during pregnancy and also possible long-term effects on the baby, which require discussion before starting treatment (Speiser et  al. 2010). Previously, there was also concern of treating unaffected pregnancies as treatment had to be initiated before the sex of the child was known and before there was clarity about whether or not the child was affected, which previously could only be found out after invasive measures. However, nowadays both the chromosomal sex of the fetus and whether it is affected by 21-hdyroxylase deficiency can be readily detected through analysis of fetal cells circulating in maternal blood, offered by specialist genetic units. A pregnancy undergoing dexamethasone treatment requires frequent monitoring by endocrine and obstetric specialists.

35.4.11  Management of Nonclassic Congenital Adrenal Hyperplasia Patients with nonclassic CAH do not need continuous glucocorticoid replacement; however, some patients may require glucocorticoid replacement in major stress, such as surgery, trauma, or ICU treatment. If glucocorticoids are needed to control the detrimental effects of androgen excess, they should be given up to the achievement of the treatment goal and then stopped (Auchus and Arlt 2013). Treatment can be considered in:

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

• Children with progressive signs of virilisation and accelerated growth. • Women with anovulatory infertility. If fertility is not desired, glucocorticoids should be avoided in women with bothersome hirsutism and/or menstrual irregularities. In such cases, treatment with oral contraceptives including an anti-androgenic progestin component (e.g. drospirenone or cyproterone) is preferred (Speiser et al. 2010).

35.4.12  Additional Aspects of Optimal Care Health care professionals have a vital role in assessing and guiding individual and family adjustment to the diagnosis of CAH (Auchus et al. 2010). It is essential that health care professionals understand the need to provide a clear and simple explanation about the diagnosis in a positive way. Information needs to be given in limited amounts at a time, remembering that it may need to be repeated a number of times for it to be retained. Evaluating the information given is understood is an important step in this process. Using a timely approach will ensure that patients and families will acquire the appropriate information they need to manage the condition and assist in allaying any anxieties which may persist (Hatton et  al. 1995). Continuous reinforcement of health information is also key. The nurse–patient relationship is an extremely important factor in achieving effective health education for patients and families (Auchus et al. 2010). The nurse needs to be sensitive to the emotional needs of patients and caregivers, and assess their readiness for learning. For families with a child with a chronic condition such as CAH, the education process takes place over a continuous period of time as the child progresses through the developmental stages of childhood, adolescence, and into adulthood. Finally, consistency and continuity of care by staff are considered one of the most important factors for patients with CAH, with transition from paediatric to adult care carefully planned (Merke and Poppas 2013; Auchus et  al. 2010; Kruse et al. 2004). Adolescence and early adult-

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hood are crucial times in the life of these patients and associated with significant physical and psychological adjustment. It is important to support the young person in making decisions which build confidence to direct their own care over time. Patient education and assumption of responsibility are critical for adherence to treatment, continuity of care, and successful outcomes.

35.5 R  ole of Patient Advocacy Groups in Improving Patient Care and Education in CAH Patient advocacy groups are a highly valuable resource for patients and their families, not just as a clinical and supportive tool, but by also enabling empowerment and enriching the relationship between patients, families, and their health care providers. The advent of social media, with websites and online support groups can add to this, and patients have a reliable and trusted resource for peer support. Most PAGs work very closely with clinical teams to develop evidence-based information and support clinical research; they can form a useful resource and can reach patients and health care teams across the globe especially for rare conditions such as CAH.

35.5.1  The CAH Support Group (Reprinted Permission from CAH Support Group (UK) Patient Advocacy Group) Robin Brett had CAH and was just 18 years old when he sadly died in 2014. He was taken to hospital with vomiting and unable to keep his medication down; this preceded by constipation which was treated by a large dose of enema. Although an IM injection of hydrocortisone was administered on admittance to hospital, no further medication was given on the ward and few checks were made. Just over 16  h after admittance, he went into an adrenal crisis and subsequently a cardiac arrest from which he could not be revived. Robin’s parents had been members of the CAH Support Group since shortly after he was

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born and regularly attended conferences so were knowledgeable about his condition but, despite raising concerns about his treatment, were not listened to. We were very saddened to hear of his death, the cause of which was not originally recorded accurately, which the family found particularly upsetting. However, his brave mother was determined to discover the truth and the support group put her in touch with one of our medical advisors who agreed to view the Coroner’s report. After he read this, he issued his own report categorically stating that death was obviously caused by “acute adrenal insufficiency consequent on a lack of adequate steroid replacement”. His conclusion was then confirmed by another specialist who was instructed by the Coroner’s Office and the death certificate was altered accordingly. Although nothing could bring Robin back, his mother was determined that her son’s death would not be in vain and was keen to work with the support group to try and ensure the mistakes that occurred at the hospital where Robin was admitted would not happen again and cause another family to suffer as they had. We put her in touch with another eminent endocrinologist (who agreed to help) and she tirelessly wrote to the medical director of every hospital trust in the UK, explaining what had happened to her son and asking them to put measures in place to prevent another tragedy. In particular, she asked that a note be added to a patient’s medication, requesting to utilise a note function on the current electronic prescribing system, highlighting the importance of administering steroids and also requesting measures are put in place to ensure patients with adrenal insufficiency receive appropriate care, to prevent any more unnecessary deaths. Mrs. Brett received a fantastic response from these letters, with medical directors promising to make changes as suggested and to better educate staff about adrenal insufficiency/crisis. Robin even featured in a very poignant and moving training video as a result, which we believe helped highlight how fragile life can be for those with CAH and other steroid-dependent conditions. The primary aims of the CAH group are to support all families affected by CAH and to increase awareness of the condition to the public and the

medical profession. We believe the above tragic account of just one of our members is evidence on how we work together with families and the medical profession in order to do this. We provide a variety of information booklets and leaflets, organise conferences, social meetings as well as a regular newsletter to keep our members up to date. We also encourage and contribute to research projects. Please contact us for any information: Sue Elford Chair: CAH Support Group E-mail: [email protected]. uk

Website: www. livingwithcah.com Sallyann Blackett Treasurer: CAH Support Group E-mail: sallyann@ theblacketts.co.uk

35.5.2  The CARES Foundation (Reprinted Permission from CARES Foundation (USA) Patient Advocacy Group) The Leight family founded CARES Foundation in 2001 after their daughter was diagnosed with Congenital Adrenal Hyperplasia (CAH), a rare disorder of the adrenal gland. When attempting to learn more about the disorder, they found that there was no support for families and affected individuals and few resources for information. Today, CARES Foundation serves as a global resource for patients and families affected by CAH. In 2001, only 27 states in the USA were screening newborns for CAH. CARES initiated a grass-roots campaign to advocate for the inclusion of CAH in the newborn screening panel in all 50 states. As of 2008, every state in the USA tests for CAH, saving numerous lives. In 2009, CARES Foundation embarked on another national campaign to establish EMS (emergency medical service) protocols for adrenal crisis which are currently available in nearly 30 states. CARES Foundation has an extensive support network for patients and families that includes one-on-one support; regional and specialised support groups; regularly scheduled teleconference calls with participation from expert providers, and private support groups on social media. CARES provides referrals to expert physicians

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults

and access to online expert via the “Ask the Expert” service. Education is a key component of our mission. Our educational efforts include: • Annual education conferences for patients, families, and health care professionals • A newsletter containing information on new treatments, research studies, and other valuable information • Guides for educating school and camp personnel • A guide for travelling with CAH • Emergency instructions • Educational packet for school nurses • Website containing valuable information Providing patients with access to quality health care is another cornerstone of CARES Foundation. To this end, CARES designated four centres of excellence across the USA where expert care is provided by a multidisciplinary team addressing patient needs throughout their lifecycle. These centres are also conducting research to advance patient care. CARES is also where patients and researchers turn for participation, recruitment, and information on clinical trials. Since 2001, CARES has established itself as a global resource for not only patients with CAH and their families but also for health care professionals. We encourage all health care professionals to offer CARES as a resource for their patients. Professionals are also encouraged to take advantage of our services. For more information about CARES Foundation, contact Dina Matos, Executive Director of CARES Foundation, at [email protected] or Tel: 866-227-3737 (USA). You can also visit our website www.caresfoundation.org

35.6 A  Patient Perspective (Published with Patient Consent) I am a 30-year-old woman who is lucky enough to be in a loving relationship but who does have long-term medical conditions to cope with every day. I recently tried to deal with fertility treat-

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ment and had two unsuccessful rounds of intrauterine insemination (IUI). Dealing with infertility is emotionally and physically draining. It makes you feel inadequate and alienated from life. I can’t express how much I yearn to be called mummy and dream of a future with my own family. I’m having a break from it now and want to share my story with you as this is the most recent in a long series of medical battles in my life. I was diagnosed with CAH at birth and saltwasting CAH a few weeks later when I had a salt crisis which nearly put me in a coma. I will always be under the care of an endocrinologist and managed with steroid replacement therapy. I had surgery at the age of one and then again at four, I remember the later vividly. The surgery for girls with CAH is very painful and sensitive as it involves cosmetic changes to the vagina and clitoris to normalise the genitals. Although cosmetic the extent of these surgeries was enormous and resulted in psychological problems for many years to come, in my case without any professional support. Put simply this isn’t something you can speak about freely or easily. My teens were particularly difficult, not only was I dealing with regular hospital appointments and medication but I also had the underlying problem of knowing I wasn’t “normal” and believing there was absolutely no way I could ever have sex, which in my young mind equated to never being loved (my vaginal entrance was the size of my little finger; need I say more?). I began asking myself if I was asexual and taught myself to avoid all situations which may compromise me and bat away any attention. That way I could ignore the problem and live in denial. I continued with this approach into my early 20s. My periods started a bit late at age 14 (and have gone on to cause me many problems over the years) and I went into hospital again for vaginal stretching under anaesthetic. The aim: to enable me to use a tampon. The timing: it could not have been worse. Can you imagine experiencing this during puberty in addition to all the usual ups and downs? Constantly being asked by kids at school if you’re a lesbian because you’re not interested in boys? If only it were that simple. I have never felt as isolated as I did at secondary school. All I can say is I’m pleased I had a happy

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childhood and loving parents to look back on; it wasn’t all bad but it was very challenging! And the fun didn’t stop there. When I was 16 I was diagnosed with Crohn’s disease and had surgery a few months later; a right hemicolectomy removing my ascending colon and some of my small intestine all of which had become ulcerated and was causing me incredible pain, nausea, and diarrhoea. Again I was managed with yet more steroids which this time brought along the added frustration of unwanted weight gain and associated difficulties as a teenager. I ended up missing most of year 11 but am pleased to say I did really well in my exams, which I took at home and went on to sixth form college, and later to university. I eventually let my hair down, had a LOT of fun forgetting all that I had been through and enjoying being with people who didn’t know me or my past. That said I know now that I was avoiding dealing with my issues by partying all the time rather than seeking help. In 2005, I moved to another city and finally got up the courage to see a gynaecologist. I desperately wanted to have sex and enjoy my sexuality which I had oppressed for so many years. After an initial period of overdoing “it” I met my partner and we are planning to get married next year…as they say, the rest is history! Learning points: • The struggles to live and lead a normal healthy life continue in patients with CAH hence, lifelong monitoring, support, and individualised approach is required. • Education in the prevention and management of adrenal crisis is paramount for everyone involved in the multispecialty care of patients with CAH. • The positive patient-health care engagement, empowerment of patients and their families/ carers in voicing their concerns, and active involvement of patient support groups will improve all aspects of care being received.

35.7 Conclusions Classic CAH is a rare and life-threatening chronic condition that needs lifelong adrenal replacement

therapy. Patients and families are required to have a good knowledge and understanding of the condition and its management needs in both the short and long term. Their involvement with the health system will be lifelong and requires regular review and ongoing treatment and medial management. Health professionals have a crucial role in coordinating the care of patients with CAH. Treatment goals must be agreed with family and, as soon as possible, with the patient. The management plan is individualised and needs to be modulated throughout the patient’s lifetime. For a patient with CAH, a sense of feeling connected and understood within the health system is one of the most important aspects in achieving positive health outcomes and satisfaction with their life’s journey. Aknowledgments With special thanks to Sue Elford, Chair, and Sallyann Blackett, Treasurer, from The CAH Support Group, website: www.livingwithcah.com and Dina Matos, Executive Director, from the CARES Foundation, website www.caresfoundation.org for their contributions with patient case studies and details on information and resources available through their Patient Advocacy Group.

References Arlt W, Krone N. Adult consequences of congenital adrenal hyperplasia. Horm Res. 2007;68(Suppl 5):158–64. https://doi.org/10.1159/000110615. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110–21. https://doi. org/10.1210/jc.2010-0917. Auchus RJ, Arlt W.  Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98(7):2645–55. https://doi.org/10.1210/ jc.2013-1440. Auchus RJ, Witchel SF, Leight KR, Aisenberg J, Azziz R, Bachega TA, et al. Guidelines for the development of comprehensive care centers for congenital adrenal hyperplasia: guidance from the CARES Foundation Initiative. Int J Pediatr Endocrinol. 2010;2010:275213. https://doi.org/10.1155/2010/275213. Bornstein SR, Allolio B, Arlt W, Barthel A, DonWauchope A, Hammer GD, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–89. https://doi.org/10.1210/ jc.2015-1710.

35  Diagnosis and Management of Congenital Adrenal Hyperplasia in Children and Adults Dittmann RW, Kappes MH, Kappes ME, Borger D, Stegner H, Willig RH, et  al. Congenital adrenal hyperplasia. I: gender-related behavior and attitudes in female patients and sisters. Psychoneuroendocrinology. 1990;15(5–6):401–20. El-Maouche D, Arlt W, Merke DP.  Congenital adrenal hyperplasia. Lancet. 2017;390(10108):2194–210. https://doi.org/10.1016/S0140-6736(17)31431-9. Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012;18(2):146–70. https://doi.org/10.1093/humupd/dmr042. Gleeson H, Davis J, Jones J, O’Shea E, Clayton PE. The challenge of delivering endocrine care and successful transition to adult services in adolescents with congenital adrenal hyperplasia: experience in a single centre over 18 years. Clin Endocrinol. 2013;78(1):23–8. https://doi.org/10.1111/cen.12053. Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D, et  al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407–16. https://doi.org/10.1210/ jc.2014-3191. Han TS, Stimson RH, Rees DA, Krone N, Willis DS, Conway GS, et al. Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia. Clin Endocrinol. 2013a;78(2):197–203. https://doi.org/10.1111/cen.12045. Han TS, Krone N, Willis DS, Conway GS, Hahner S, Rees DA, et al. Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Eur J Endocrinol. 2013b;168(6):887–93. https://doi.org/10.1530/EJE-13-0128. Han TS, Conway GS, Willis DS, Krone N, Rees DA, Stimson RH, et al. Relationship between final height and health outcomes in adults with congenital adrenal hyperplasia: United Kingdom congenital adrenal hyperplasia adult study executive (CaHASE). J Clin Endocrinol Metab. 2014;99(8):E1547–55. https://doi. org/10.1210/jc.2014-1486. Hatton DL, Canam C, Thorne S, Hughes AM.  Parents’ perceptions of caring for an infant or toddler with diabetes. J Adv Nurs. 1995;22(3):569–77. Joint Lecahwg. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab. 2002;87(9):4048–53. https://doi.org/10.1210/ jc.2002-020611. Knickmeyer R, Baron-Cohen S, Fane BA, Wheelwright S, Mathews GA, Conway GS, et  al. Androgens and autistic traits: a study of individuals with congenital adrenal hyperplasia. Horm Behav. 2006;50(1):148–53. https://doi.org/10.1016/j. yhbeh.2006.02.006.

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Kruse B, Riepe FG, Krone N, Bosinski HA, Kloehn S, Partsch CJ, et  al. Congenital adrenal hyperplasia—how to improve the transition from adolescence to adult life. Exp Clin Endocrinol Diabetes. 2004;112(7):343–55. https://doi.org/10.105 5/s-2004-821013. Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D, et  al. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015;100(3):1137–45. https://doi.org/10.1210/ jc.2014-3809. Merke DP, Poppas DP.  Management of adolescents with congenital adrenal hyperplasia. Lancet Diabetes Endocrinol. 2013;1(4):341–52. https://doi. org/10.1016/S2213-8587(13)70138-4. Patterson JM, McCubbin HI, Warwick WJ.  The impact of family functioning on health changes in children with cystic fibrosis. Soc Sci Med. 1990;31(2):159–64. Reichman DE, White PC, New MI, Rosenwaks Z. Fertility in patients with congenital adrenal hyperplasia. Fertil Steril. 2014;101(2):301–9. https://doi.org/10.1016/j. fertnstert.2013.11.002. Reisch N, Arlt W, Krone N. Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res Paediatr. 2011;76(2):73–85. https://doi. org/10.1159/000327794. Reisch N, Willige M, Kohn D, Schwarz HP, Allolio B, Reincke M, et al. Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency. Eur J Endocrinol. 2012;167(1):35–42. https:// doi.org/10.1530/EJE-12-0161. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et  al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133–60. https://doi.org/10.1210/ jc.2009-2631. Webb EA, Elliott L, Carlin D, Wilson M, Hall K, Netherton J, et  al. Quantitative brain MRI in congenital adrenal hyperplasia: in vivo assessment of the cognitive and structural impact of steroid hormones. J Clin Endocrinol Metab. 2018;103(4):1330–41. https:// doi.org/10.1210/jc.2017-01481. White PC.  Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol. 2009;5(9):490–8. https://doi.org/10.1038/nrendo.2009.148. White PC, Bachega TA.  Congenital adrenal hyperplasia due to 21 hydroxylase deficiency: from birth to adulthood. Semin Reprod Med. 2012;30(5):400–9. https:// doi.org/10.1055/s-0032-1324724. White PC, Speiser PW.  Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21(3):245–91. https://doi.org/10.1210/ edrv.21.3.0398. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010;2010:625105. https://doi.org/10.1155/2010/625105.

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Key Reading 1. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et  al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133–60. https://doi. org/10.1210/jc.2009-2631. 2. Auchus RJ, Witchel SF, Leight KR, Aisenberg J, Azziz R, Bachega TA, et al. Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative. Int J Pediatr Endocrinol. 2010;2010:275213. https://doi.org/10.1155/2010/275213.

A. Prete et al. 3. Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98(7):2645–55. https://doi.org/10.1210/ jc.2013-1440. 4. Merke DP, Poppas DP.  Management of adolescents with congenital adrenal hyperplasia. Lancet Diabet Endocrinol. 2013;1(4):341–52. https://doi. org/10.1016/S2213-8587(13)70138-4. 5. Kruse B, Riepe FG, Krone N, Bosinski HA, Kloehn S, Partsch CJ, et al. Congenital adrenal hyperplasia—how to improve the transition from adolescence to adult life. Exp Clin Endocrinol Diabet. 2004;112(7):343– 55. https://doi.org/10.1055/s-2004-821013.

Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas, and Adrenocortical Cancer

36

Andrew P. Demidowich, Miriam Asia, and Jérôme Bertherat

Contents 36.1   Part A: Adrenocortical Functioning Adenomas and Adrenal Hyperplasia 36.1.1  Introduction 36.1.2  Primary Aldosteronism 36.1.3  Cushing Syndrome 36.1.4  Adrenal Androgens

 681  681  682  685  687

36.2   Part B: Pheochromocytomas and Paragangliomas 36.2.1  Anatomy and Physiology 36.2.2  Pheochromocytomas and Paragangliomas

 688  688  688

36.3   Part C: Adrenal Incidentaloma and Adrenocortical Cancer (ACC) 36.3.1  Adrenal Incidentaloma 36.3.2  Adrenocortical Cancer (ACC)

 693  693  698

36.4   Conclusions

 701

References

 701

A. P. Demidowich (*) National Institutes of Health, Bethesda, MD, USA e-mail: [email protected] M. Asia Department of Endocrinology, Birmingham University Hospital, Birmingham, UK e-mail: [email protected] J. Bertherat Service d’Endocrinologie, Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France e-mail: [email protected] © Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_36

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Abstract

This chapter will discuss in detail the background, evaluation, and management of adrenal tumours, with an additional focus on the role of endocrine nursing in the care of these patients. It is divided into three parts, each providing a comprehensive outline of: A) Adrenocortical functioning adenomas and adrenal hyperplasia, B) Pheochromocytomas and Paragangliomas, and C) Adrenal incidentaloma and adrenocortical cancer (ACC). Evaluation of adrenal tumours and adenomas requires a thorough history and physical examination. Family history is particularly important as adrenocortical disease can be caused by germline mutations passed down from generation to generation. More commonly, however, sporadic somatic mutations are the cause of spontaneous tumour formation and autonomous hormone secretion. Adrenocortical adenomas, hyperplasia, and incidentalomas are non-cancerous “growths” or proliferation of cells in the adrenal cortex. Adenomas are rare in childhood but become more frequent as humans age. Approximately 20% of adenomas are functional; that is, they produce hormones to some degree in an autonomous or dysregulated manner. Functional adenomas most commonly produce cortisol or aldosterone, whereas androgen-producing tumours are quite rare and may portend a cancerous aetiology. Co-secretion of more than one hormone from adenomas/ hyperplasia is also possible. The biochemical work-up, with screening as well as confirmatory testing, and relevant imaging will be discussed in detail. The treatment, management, and long-term monitoring are also discussed for each of the adrenal tumours, respectively. Discussion in this chapter is illustrated with a rich content of figures, box inserts, and case studies. Keywords

Adrenal adenoma · Adrenal hyperplasia · Cushing syndrome · Primary aldosteronism · Cortisol · Aldosterone · Adrenocortical cancer · Pheochromocytomas and paraganglioma

Abbreviations ACC Adrenocortical cancer ACE Angiotensin-converting enzyme ACTH Adrenocorticotropic hormone APA Aldosterone-producing adenoma ARR Aldosterone-to-renin ratio AVS Adrenal venous sampling BMI Body Mass Index CAH Congenital adrenal hyperplasia CPA Cortisol-producing adenoma CRH Corticotropin releasing hormone DHEA Dehydroepiandrosterone GRA Glucocorticoid-remediable aldosteronism HNPGL Head and neck paraganglioma IV Intravenous l-DOPA l-dihydroxyphenylalanine MRA Mineralocorticoid receptor antagonist PA Primary aldosteronism PAC Plasma aldosterone concentration PCC Pheochromocytomas PCOS Polycystic ovarian syndrome PGL Paraganglioma PMNT Phenylethanolamine N-methyltransferase RAAS Renin-angiotensin-aldosterone system SDHx Succinate dehydrogenase complex Key Terms • Adrenocortical functioning adenomas: hypersecreting tumors of the adrenal cortex • Adrenal hyperplasia: enlargement of the adrenal glands • Adrenal incidentalomas: incidentally found benign adenomas on evaluation of unrelated symptoms • Co-secretion: more than one hormone secreted from adrenal adenomas/hyperplasia • Cushing Syndrome: hypersecretion of cortisol from an adrenal adenoma • Catecholamines: are produced in the adrenal medulla and are essential for the stress response • Pheochromocytomas: are tumors arising from the adrenal medulla that produce excess catecholamines

36  Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas…

• Paraganglioma: are also tumors that produce catecholamines, but they originate in paraganglia along the parasympathetic and sympathetic chains

Key Points

• List the most common hormones produced by adrenal functioning tumours/ hyperplasia • Describe common presenting signs and symptoms of primary aldosteronism, Cushing syndrome, adrenocortical cancer, pheochromocytoma, paraganglioma • Explain the evaluation for suspected adrenal tumours/hyperplasia • Discuss the possible treatment and management options for adrenal tumours • Emphasize and describe the role of the endocrine nurse in the care of these patients

36.1 P  art A: Adrenocortical Functioning Adenomas and Adrenal Hyperplasia 36.1.1 Introduction As described in the anatomy and physiology chapter of this section, the adrenal gland is comprised of two main layers: the cortex and the medulla. The medulla derives from neuroectodermal tissue in early fetal life and is mainly composed of chromaffin cells. The cortex develops from the mesoderm and is organized into three layers: the zona glomerulosa, zona fasciculata, and zona reticularis, responsible for producing the hormones aldosterone, cortisol, and androgens, respectively (Avisse et al. 2000). Part A of this chapter focuses on functional benign adrenal tumours and hyperplasia of the cortex; Part B covers pheochromocytomas and paragangliomas; and Part C covers adrenal incidentalomas and adrenocortical cancer (ACC). Congenital adrenal hyperplasia is covered in a separate chapter in this section. Tumours and hyperplasia can be thought of as two ends of the same spectrum. A tumour is a proliferation of cells derived from a single pro-

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genitor cell. Hyperplasia, in contrast, is a “tissue-­ wide” proliferation of cells. Patients can develop a single discreet nodule, multiple nodules (in one or both adrenals), or hyperplasia. Additionally, nodules can grow in the background of a hyperplastic gland (Fig. 36.1). Adrenal adenomas and hyperplasia can occur secondary to chronic hormonal stimulation (e.g. ACTH stimulation in CAH or Cushing disease), or due to a somatic or germline mutation (Hsiao et al. 2009). The imaging characteristics of adrenal tumours and masses are discussed in greater detail in Part B. Briefly, most (~60–90%) benign adrenocortical adenomas are comprised mainly of lipids and are therefore commonly described as “lipid-rich”. On CT imaging, they have a lower density than surrounding organs, such as the liver, kidneys, or spleen, and therefore appear darker. The Hounsfield Units (HU; a measure of density) of the adenoma on non-contrast CT is typically less than 10  HU.  Additionally, these tumours have a relatively high “washout” of IV contrast, when examined 10–15  min after contrast injection (Zeiger et al. 2009a). “Lipid poor” adrenal masses, on the other hand, have higher density on non-contrast CT and commonly have low washout. Benign adrenocortical tumours (either functional or non-­ functional) can be lipid poor; however, other types of diseases, such as pheochromocytomas, ACC, adrenal haemorrhage, or metastatic lesions from other organs, can also present as “lipid poor” masses on CT (Zeiger et al. 2009a). Benign adrenal tumours are extremely rare in childhood, increase to a prevalence of about 3% by age 50, and 10% in elderly adults (Minnaar et al. 2013; Fassnacht et al. 2016). Although 80% of adenomas are non-functional (Zeiger et  al. 2009b), the signs and symptoms of a functional adrenal adenoma can be subtle and easily missed for many years, so most adenomas should undergo evaluation for functional status upon initial discovery (Fassnacht et al. 2016; Zeiger et al. 2009b). The region in which the functional tumour or hyperplasia is located typically determines the hormone produced. In other words, a functional tumour in the zona glomerulosa will typically cause primary aldosteronism, whereas a functional tumour in the zona fasciculata will lead to

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682 Fig. 36.1 Adrenal adenomas and hyperplasia CRH

CRH

Adenohypophysis

Tumor ACTH

Cortisol

A. Normal hypothalamicpituitary-adrenal axis

B. Cushing’s disease

CRH

CRH

ACTH

Cortisol

ACTH

Cortisol

Ectopic ACTH (or CRH)

Tumor

ACTH

Cortisol

D. Primary pigmented nodular adrenocortical disease (PPNAD)

C. Ectopic ACTH (or CRH) syndrome

CRH

CRH

ACTH Cortisol ACTH

Cortisol

Tumor E. Macronodular hyperplasia with marked adrenal enlargement

cortisol excess and Cushing syndrome. Functional tumours solely producing androgens are rare and often suggest a malignant, rather than benign, pathology. However, co-secretion of multiple hormones (e.g. cortisol and aldosterone) from benign tumours or hyperplasia can occur (Willenberg et al. 2010; Sakai et al. 1993).

F. Adrenal cushing’s syndrome

36.1.2 Primary Aldosteronism Aldosterone, a mineralocorticoid produced by the zona glomerulosa, is a major regulator of blood pressure and intravascular volume status. It exerts its effects primarily by acting on the distal convoluted tubule and collecting

36  Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas…

duct in the kidney. By binding to its intracellular receptor, aldosterone stimulates production of the ENaC sodium channel, which enables increased sodium and water reabsorption from the urine. To counteract this cationic influx, potassium (and to a lesser degree hydrogen) ions are simultaneously excreted into urine. Aldosterone synthesis is regulated by several mechanisms. The primary regulator is intravascular volume status via the renin-angiotensin-­ aldosterone system (RAAS), with hyperkalaemia also being a potent stimulus of aldosterone secretion (please see anatomy and physiology chapter in this section). Adrenocorticotropic hormone (ACTH) can also provoke aldosterone release but plays a minor role overall. Primary aldosteronism (PA, a.k.a. Conn’s syndrome) is the dysregulated hyperproduction of aldosterone from either one or both adrenal glands. Unilateral disease is seen in approximately two-thirds of cases (Mathur et al. 2010) and typically stems from an aldosterone-­ producing adenoma (APA, a.k.a. Conn’s ­adenoma), frequently caused by a somatic mutation (e.g. KCNJ5, ATP1A1, ATP2B3, CACNA1D, or CACNA1H). In contrast, bilateral disease most commonly occurs as a result of bilateral adrenal hyperplasia. Heritable forms of PA make up less than 10% of cases; germline mutations include KCNJ5, CLCN2, ARMC5, or a chimeric CYP11B1/CYP11B2 gene translocation (a.k.a. glucocorticoid-remediable aldosteronism or GRA) (Zilbermint et  al. 2015; Dutta et  al. 2016). The most common presenting sign of PA is uncontrolled hypertension. In fact, PA is the leading secondary cause of hypertension, responsible for 5–10% of cases of “presumed” essential hypertension (Funder et  al. 2016). Patients may commonly present with symptoms of recurring headache, chest pain, or oedema. More severe cardiovascular sequelae, such as myocardial infarctions, strokes, or congestive heart failure, may manifest at an early age (33  nmol/day, 12  μg/24  h), saline infusion test (cut off PAC ≥280 pmol/L, 10 ng/dL), captopril challenge test, and fludrocortisone suppression test (Funder et al. 2016). Once confirmed, the patient should undergo CT imaging with IV contrast to better define the adrenal and associated venous anatomy. Because clinicians may be fooled by a non-functional adenoma on imaging, and the disease in fact may be on the contralateral gland or bilateral disease, it is often recommended that patients who are surgi-

A. P. Demidowich et al.

cal candidates should subsequently undergo adrenal venous sampling (AVS), the current gold standard to confirm the laterality of disease. The rate of success of this technically demanding diagnostic procedure depends on the expertise of the interventional radiologist, so referral to high-­ volume centre is recommended. Patients younger than 35, with profound aldosterone concentrations (>830  pmol/L or 30  ng/dL), spontaneous hypokalaemia, and an obvious solitary lipid-rich nodule on imaging can forgo AVS and proceed directly to unilateral adrenalectomy (Funder et al. 2016). Similarly, if AVS lateralizes to one side, it is recommended that the patient proceed to unilateral adrenalectomy (typically performed laparoscopically). Surgery will, in most cases, cure the patient of hypokalaemia and improve hypertension. Hypertension may not improve immediately but may continue to improve even up to 1  year post-operatively (see Box 36.2). Factors that portend a lower rate of hypertension cure include male sex, longer duration of PA (>6  years), multiple antihypertensive medications preoperatively, and overweight or obesity (BMI >25 kg/m2) (Aronova et al. 2014).

Box 36.2 Important Message for Patients for Post-operative Care for PA

Advise your patient that hypertension may not improve immediately and can continue to improve even up to 1  year post-­ operatively. Lifestyle factors can influence this so encourage weight loss for your overweight patients.

If the disease is determined to be bilateral by AVS, however, surgery is typically not offered, and medical management with a mineralocorticoid receptor antagonist (MRA) is instituted. Spironolactone is typically cheap (as it is generic), may be the most potent MRA, and is commonly the first-line medication. However, it

36  Adrenal Tumours: Adrenocortical Functioning Adenomas, Pheochromocytomas, Incidentalomas…

can have mild off-target anti-androgenic effects leading to gynaecomastia or sexual dysfunction in males. Eplerenone, a newer and more specific MRA, does not cause these side effects and may be a better choice for male patients (Parthasarathy et al. 2011). However, it can also be significantly more costly if not covered by health insurance. If a single medication is unable to control the hypertension, additional agents, such as a calcium channel blocker, ACE inhibitor, or triamterene (ENaC channel blocker) may be added.

36.1.3 Cushing Syndrome Cortisol, a glucocorticoid produced by the zona fasciculata, has many wide-ranging effects on the body, including regulation of blood pressure, glucose, immune function, metabolism, and bone turnover. Its synthesis and secretion are primarily regulated by ACTH, which is produced in the pituitary. Among adrenal adenomas, between 5 and 25% have some degree of autonomous cortisol production (Rossi et al. 2000; Mantero et al. 2000). The vast majority of these cortisol-­producing adenomas (CPA) do so in small quantities and rarely progress (138  nmol/L (>5 μg/dL) is consistent with autonomous cortisol secretion, whereas a cortisol of ≤50 nmol/L (≤1.8 μg/dL) effectively rules out the disease. A cortisol between these two values is a grey zone and represents “possible” autonomous cortisol secretion (Fassnacht et al. 2016). It is important to note that women on oestrogen (e.g. oral contraceptives) may have a false-positive as oestrogen raises the circulating cortisol binding globulin. Also, some advocate to measure a dexamethasone level simultaneously with the morning cortisol to assess if a) the patient is a “hypermetabolizer” or b) if the patient did not actually take the medication, as both could lead to a false-positive result (Meikle 1982; Nieman et al. 2008).

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1 A round and bloated face (moonface).

2

3

Build-up of fatty tissue around the abdomen (central obesity).

3

13 14 8 1

6

9

5

6 7

5 4

‘Stretch marks’ (striae) across the abdomen and buttocks.

12

11

Loss of muscle tone, resulting in thin arms and legs and reduced muscle power.

Build-up of fatty tissue around the neck (buffalo hump).

4

4 11

5

High blood pressure.

2

7 Excess blood-sugar levels (diabetes).

10

11

9 8

9 11

Acne. Excessive hair growth (hirsutism).

11 Brittle bones (reduced bone density).

12 Tiredness and sleeping problems.

Thin and fragile skin, easy bruising.

13 Memory and concentration problems.

10 Menstruation problems, Reduced fertility.

14 Mood problems, such as depression, euphoria, or a psychosis.

Fig. 36.2  Possible manifestations of cortisol excess (Cushing Syndrome). Used with permission from AdrenalNET and accessed via https://adrenals.eu/infographics/cushings-syndrome-infographic/

Patients with signs consistent with overt Cushing syndrome should undergo other screening tests, such as a 24-h urine collection for free cortisol (repeated at least twice), a late-night salivary

cortisol (repeated at least twice), or a 48-h lowdose dexamethasone suppression test. Two positive screening tests in the setting of overt signs is consistent with the diagnosis of Cushing syndrome.

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Box 36.3 Principles of Good Clinical Practice for Overnight Dexamethasone Text

Provide the patient with detailed information on why and how to take dexamethasone. Confirm that the patient has taken the tablet at the required time in order to interpret results accurately. Confirm the patient is not taking oestrogen or oral contraceptive pill (OCP) by asking “are you on the contraceptive pill?” rather than just “do you take other medication?”. Patients often don’t view the OCP as medication.

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individuals who are surgical candidates and who also have related comorbid conditions, such as obesity, hypertension, type 2 diabetes, hypertension, or osteoporosis, may derive benefit (Fassnacht et  al. 2016). For non-surgical candidates, medical therapy such as ketocon­ azole, metyrapone, mitotane, pasireotide, and/or mifepristone can be considered (Sharma and Committee 2017).

36.1.4 Adrenal Androgens

Androgens produced from the zona reticularis include dihydroepiandrostenone (DHEA), It is important to remember that ACTH excess DHEA-sulphate (DHEAS), and androstenedione. (e.g. functional pituitary adenoma) can cause Regulation of adrenal androgens is a complex adrenal hyperplasia ± nodules. A suppressed system, partially under the control of ACTH level (10% of their total body weight. Acute episodes of AI require to be managed immediately, guided by standard emergency protocol guidelines, to prevent otherwise a fatal outcome due to AC (see Chap. 62 for more details).

37.3.1.1 A  cute Clinical Presentation of AI in Children and Neonates In acute presentation of AI, examination will reveal a pale and lethargic child, with progressive signs of deterioration of a listless and floppy demeanour and a reduced level of consciousness due to hypoglycaemia. The child will be cool to touch and has hypothermia due to, hypovolaemia and peripheral shutdown (evident with poor skin turgor, delayed capillary return), dry mucous membranes and a history of minimal urine output indicating significant dehydration. Background history may reveal a period of intercurrent illness, poor oral intake, maybe a period of persistent diarrhoea and/or vomiting. Observations reveal tachycardia, dyspnoea, hypotension, and hypoglycaemia. A blood gas and peripheral blood is needed to confirm or rule out any biochemical cause, and a septic workup to determine a bacterial or viral cause for the presentation (Migeon and Lanes 2009; Miller et al. 2008).

37.4 Diagnosis of Adrenal Insufficiency in Adults The diagnosis of AI is based on the patient’s medical history, clinical sign and symptoms suggestive of AI, adrenal and/or pituitary imaging, and diagnostic biochemistry provocative tests. Figure 37.3 presents the diagnostic algorithm for adults with clinical sign and symptoms suggestive of AI and diagnostic test which can set the differential diagnosis (Bancos et al. 2015). The diagnosis of AI is established by the ACTH stimulation test, also known as the short

37  Diagnosis and Management of Adrenal Insufficiency in Children and Adults

713

Clinical suspicion of adrenal insufficiency

Measure cortisol at baseline and after ACTH (fragment 1-24) injection (30 and 60 min): peak cortisol 2.0 cm/m2 require close cardiovascular

40  Diagnosis and Management of Turner Syndrome in Children and Adults

surveillance. An ASI of >2.0 cm/m2 (>99th percentile) is considered a dilated ascending aorta (Carlson et al. 2012). Surgical intervention is recommended for coarctation of the aorta, and/or if significant aortic dilatation develops. Women with aortic dilation need more frequent echocardiographic/CMR monitoring of change in size, aggressive management of blood pressure, advice regarding exercise, careful assessment if pregnancy is planned, and education regarding the symptoms of aortic dissection and appropriate action to take. Classic signs and symptoms of aortic dissection include sudden onset of chest or back pain and may include shortness of breath, nausea, diaphoresis, and syncope. Wearable medical alert documentation should be worn for those identified with increased risk for dissection or rupture.

40.6.4  Conduction Anomalies Conduction abnormalities such as prolonged QT intervals have been reported in TS including in young children (Bondy et al. 2006a). Prolonged QT intervals may occur at any heart rate and is

779

associated with reduced heart rate variability, resting tachycardia and absence of the normal nocturnal dip in blood pressure, indicating autonomic dysregulation. In those with a prolonged corrected for heart rate (QTc) on ECG, care should be taken when prescribing medication which may further prolong repolarisation. Figure 40.2 presents the protocol for monitoring women aged over 16 years old based on the international guidelines (Gravholt et al. 2017). Thus, cardiovascular screening is essential from the time of diagnosis and continued with regularity throughout childhood and adult life. Evaluation by a cardiologist should include regular echocardiography from childhood. In addition, CMR is recommended in older girls and women as this provides a more accurate assessment and serial measurements, in addition to reducing the error due to the common chest abnormalities in women with TS (Fig.  40.3). Repeat imaging should be performed every 3–5  years and more often if aortic dilatation or other pathology is detected and/or pregnancy or fertility treatment is considered. Blood pressure should be monitored annually and hypertension treated early and vigorously, particularly in the

>16 years: Cardiology Exam, TTE, MRI, ECG

No CoA, BAV, HTN

CoA, BAV, and/or HTN

ASI < 2.0 cm/m2

ASI 2.0 – 2.3 cm/m2

ASI > 2.3 cm/m2

ASI ≤ 2.3 cm/m2

ASI > 2.3 cm/m2

Low Risk

Moderate Risk

Moderate Risk

Moderate Risk

High Risk

Repeat TTE or CMR every 5 – 10 years by cardiologist

Repeat TTE or CMR every 3 – 5 years by cardiologist

Repeat TTE or CMR every 1 year by cardiologist

Repeat TTE or CMR every 2 – 3 years* by cardiologist

Repeat CMR every 6 months – 1 year* by cardiologist

Fig. 40.2  Suggested monitoring protocol for women aged over 16. Used with permission from International guidelines 2017 (Gravholt et  al. 2017). Key: TTE trans-

thoracic echo, CMR cardiac MRI, ECG electrocardiogram, HTN hypertension, CoA coarctation of aorta, BAV bicuspid aortic valve, ASI aortic size index

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Echo and CMR at diagnosis of TS Advice regarding exercise ASI >2 – avoid weight training ASI 2-2.3 – low static/dynamic exercise

Follow-up No structural abnormality; 510y/prepregnancy

Cardiovascular Health ECG (? prolongation of QTC)

ASI >2.5 cm/m2 Elective surgery

Advice regarding symptoms of aortic dissection

Blood pressure monitoring Treatment – betablocker +/ACEI

Fig. 40.3  Suggested investigations and management of cardiovascular parameters in Turner syndrome

presence of other cardiac abnormalities. According to the 2007 American Heart Association (AHA) guidelines, antimicrobial prophylaxis to prevent bacterial endocarditis is not required for valvular heart disease including those with BAV (Wilson et al. 2007).

40.7 S  hort Stature, Growth Failure, and Growth-­ Promoting Therapies Short stature is a major clinical finding associated with 45,X karyotype and is the main phenotypic abnormality present in nearly all patients with TS. It is thought to be primarily due to haploinsufficiency (deficient expression) of the short stature homeobox (SHOX) gene expression in chondrocyte. This region does not undergo X-inactivation and it appears that two active copies of this gene are required for full expression of

the protein and normal linear growth. Specific skeletal anomalies such as cubitus valgus, Madelung deformity, and shortened fourth metacarpals may also be manifestations of SHOX deficiency. Growth hormone insensitivity may also play a role in the development of short stature. Growth failure generally begins prenatally, with eventual poor growth that may be evident within the first 3–5 years of life (Davenport et al. 1999). Final adult height is generally 20  cm below expected average female population norms. This translates to an average height of 143  cm (4′8″). It is important to note that girls and women with TS are generally not growth hormone deficient (GHD) as they have increased insulin binding protein-3 (IGFBP-3) proteolytic activity and normal to lower insulin growth factor-­1 (IGF-1). For monitoring growth, height should be tracked using a TS-specific growth curve. Lyon,

40  Diagnosis and Management of Turner Syndrome in Children and Adults

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Preece, and Grant combined the growth data from four European studies representing a total of 366 patients to create the TS-specific growth chart (Lyon et  al. 1985) that documents the expected growth trajectory of girls with TS on a given centile. The standard TS chart may be used from 2  years of age onward. All girls with TS should be tracked on a TS-specific growth chart which allows for the simultaneous opportunity of tracking the patterns of growth of an individual child relative to both the general female population and to other girls with TS. Of note the 50th centile of growth on the TS curve is below the fifth centile of the standard growth charts for North American females. By 5 years of age, 90% of girls with a 45,X karyotype will be below the fifth centile on non-TS female growth charts. During childhood girls with TS gain, on average, less than 5 cm of linear height each year, and this eventually translates to growth below the fifth centile, though it is not uncommon for those with mosaic and/or isochromosome karyotypes to have normal growth velocity during early childhood. For girls whose growth shows crossing of growth centiles in a downward direction on the TS growth curve consideration may be given to further assessing for growth hormone deficiency (GHD).

3–4 years or more to see a meaningful impact on adult height. Even with GH treatment, adult height remains at least 10 cm below the average height of healthy females thereby correcting up to 50% of the adult height deficit. Final adult height in TS is highest for those with a mosaic karyotype, taller stature at initiation of GH therapy, taller parents, and those that received higher dosing and longer duration of GH therapy (Hughes et  al. 2011; Ranke et al. 2007; Ross et al. 2011a). Cochrane Reviews published in 2003 and 2007 reviewed four randomised control trials (RCT) using recombinant GH and noted that GH increased short-term growth in girls with TS by approximately 3  cm in the first year of treatment and 2 cm in the second year of treatment and noted the final adult height (FAH) was still more than 2 SDS below the normal population mean (Cave et al. 2003; Baxter et al. 2007). Many jurisdictions, health systems, and/or insurance companies require evidence and documentation of growth failure or growth fall off prior to providing financial coverage, and/or initiating financially supported expensive GH therapy in TS.  Subsequently, funding sources may require proof of continued enhanced growth benefit, documented in centimetres or inches over and above the pre-GH therapy growth rate.

40.7.1  Growth Hormone Therapy in Turner Syndrome

40.7.1.1 Additional Benefits of Growth Hormone Treatment The literature suggests that GH treatment may also confer a number of additional benefits such as improving body proportions; contributing to cardiac health by lowering diastolic blood pressure even after GH treatment has been discontinued (Bannink et al. 2009a); as well as lowering of total cholesterol and low-density lipoproteins, elevating high-density lipoproteins (Bannink et al. 2009b), and improving insulin resistance as abdominal adiposity is reduced during treatment.

Use of growth hormone (GH) is an approved indication of GH therapy in Europe, and North America. The optimal age of initiating GH therapy has not been firmly established and generally, treatment with GH is justified as soon as growth failure becomes evident (Davenport et al. 1999). A controlled, randomised study to final adult height of patients with TS showed a gain of 7.2 cm over a mean of 5.6 years of using higher doses of GH as compared to the usual doses used in the United States and Europe (Stephure and Canadian Growth Hormone Advisory Committee 2005). This translates into an expected approximate 1 cm of additional growth for every year on GH therapy. GH is required for a minimum of

40.7.1.2 S  afety of Growth Hormone Treatment The general safety of GH Treatment in the literature has been reassuring; however, observational

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data indicate that when compared with children with idiopathic GHD or idiopathic short statue on GH, girls with TS appear to be at increased risk of intracranial hypertension, slipped capital femoral epiphysis, development and/or progression of scoliosis, and development of pancreatitis during treatment (Allen 1996). Data from large GH registries provide no evidence of an increase in risk of neoplasia in GH-treated patients with TS (Bell et al. 2010; Bolar et al. 2008; Tuffli et al. 1995). The Food and Drug Administration has approved 0.375 mg/kg/week (generally given as 6 or 7 divided doses per week) for the GH treatment of TS. Higher doses of GH do not correlate with much increased height gain but do correlate with elevated insulin growth factor 1 (IGF-1) levels (van Pareren et al. 2003). As girls with TS are not GHD and may in fact be somewhat GH resistant, therapy for this population requires greater doses of GH than those used for children with GHD to impact growth. There is significant and substantial variation in GH treatment response among girls with TS, and there is no way to predict how well an individual child with TS will respond to therapy. Most will likely not achieve their genetic potential based upon mid-parental heights. In childhood, girls with TS tend to grow 2.5–4 cm or a year without GH, thus clinicians need to be mindful of this in their ongoing therapeutic assessments and not to ascribe all future growth to GH therapy if and when it has been instituted. Risks of GH therapy in TS include slipped capital femoral epiphysis and idiopathic intracranial hypertension (with persistent visual defects) that are higher than in those treated with GH for GHD and idiopathic short stature (Noto et al. 2011) and worsening scoliosis (Bell et  al. 2010). Growth should be monitored every 4–6 months while on GH therapy (Gravholt et al. 2017). GH treatment is given by subcutaneous injection generally 6 or 7 days each week. This therapy requires considerable commitment by both children and families. Many families also choose not to pursue GH treatment and this is also appropriate. The previous clinical practice of delaying pubertal development until 15 years of age with the goal of preventing earlier epiphyseal closure, to allow more time for growth to improve final

H. E. Turner and I. R. Hozjan

adult height, is no longer acceptable as it generally failed to recognise the importance of age-­ appropriate pubertal development and maturation for overall general and psychosocial health.

40.7.1.3 V  ery Early Growth Hormone Treatment Somewhat recent studies have reviewed the safety and efficacy of beginning GH treatment in very young girls with TS prior to the expected and eventual fall off in growth velocity. The Toddler Turner Study showed that GH rapidly normalised height standard deviation score (SDS) after 2 years of treatment for those that initiated treatment between 9 months and 4 years of age (Davenport et  al. 2007). In the French Collaborative Young Turner Study Group, 80% of girls with TS who started GH at a mean age of 2.6 years of age achieved height within the normal range within 4  years (Linglart et  al. 2011); however, 75% of this treatment group had elevated IGF-1 levels. The clinical implications and significance of long-term elevated IGF-1 levels in the childhood years in TS is unknown. 40.7.1.4 E  arly Oestrogen and Growth Hormone Treatment Early low dose oestrogen has been studied as a way to supplement GH treatment. Some studies have trialled low dose oestrogen (oral ethinyl oestradiol) as early as 5 years of age and showed a synergistic effect of increasing adult height of 2.1 cm beyond the 5 cm of height gain expected when GH treatment was used alone (Ross et al. 2011b). However, this treatment also reported frequent findings of inappropriate early pubertal development or feminisation of young girls. The long-term consequences of early and prolonged oestrogen exposure and relation to future risk of breast cancer are unknown. At this time, use of early low dose oestrogen as a growth-promoting therapy is not supported by the literature and is not recommended (Gravholt et al. 2017). 40.7.1.5 Oxandrolone Adjuvant Therapy The use of the synthetic anabolic steroid and derivative of testosterone, Oxandrolone, is con-

40  Diagnosis and Management of Turner Syndrome in Children and Adults

sidered to be an adjuvant therapy. Oxandralone has been shown to improve growth by acting directly at the growth plate, and by increasing IGF-I concentrations, and blocking the bone maturation effects of oestrogen which may provide up to 4 cm of growth with the use of GH therapy in TS (Rosenfeld et  al. 1998). Oxandrolone is FDA-approved for treating osteoporosis, aiding weight gain, and counteracting the catabolic effect of long-term corticosteroid treatment; use of it in TS is considered off-label. Caution is required as the use of Oxandrolone may be associated with virilisation (enlargement of clitoris, deepening voice), hypertension, delay or deceleration of breast development, and liver dysfunction (Matura et al. 2007). If girls are experiencing these side effects, the doses of Oxandrolone would require reduction thereby reducing the effectiveness of the treatment. It is unclear if the taller height associated with this adjuvant treatment is due to more time for growth, more time on Oxandrolone, or more time on GH (Sheanon and Backeljauw 2015). Doses range between 0.03 and 0.05  mg/kg/day. Oxandrolone therapy would be discontinued prior to initiating hormone replacement therapy. The long-term beneficial effect of Oxandrolone on adult height in TS women has been debated due to the small sample size of studies, varied results in adult height outcomes, and the concern of virilisation due to this treatment. As it has not demonstrated a real benefit for adult height, it is not considered standard of care.

40.7.1.6 D  iminished Pubertal Growth in Turner Syndrome It is important to note that the absence of, or the generalised diminished pubertal growth spurt, with or without HRT will ultimately reduce FAH, and height predictions in TS.  Ultimately, GH increases linear growth and height in the childhood years with generally rapid plateauing of height in the pubertal years. It is not uncommon to later question how much GH therapy ultimately added to FAH when tracking where a girl started (using height standard deviation scores SDS) on the TS curve, and where she ultimately ended up.

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40.7.1.7 Discontinuing Growth Hormone Therapy Discontinuing of GH therapy in TS is an individualised clinical decision. Though the literature supports the discontinuation of treatment when little growth potential remains (bone age of >/=14  years or growth velocity is less than 2–3  cm/year). Other considerations could and should sway earlier discontinuation decision-­ making. These include increasing body disproportion, particularly enlarged hands and feet; coarsening of facial features (rare); very elevated IGF-1; poor adherence; a voiced desire to end therapy; and contentment with current height. It should be noted that those who discontinue therapy between 14 and 15  years of age will still grow an additional 1–2 or more centimetres over the following years.

40.8 Pubertal Development, Ovarian Failure, and Ovarian Hormone Replacement Therapies (HRT) Up to one-third of girls, especially those with mosaic karyotypes, may have normal spontaneous pubertal development (Pasquino et al. 1997). Ovarian function is generally related to underlying karyotype; those that achieve menarche or very rarely pregnancy are predominately individuals with a mosaic karyotype. Spontaneous thelarche occurs in approximately one-third of girls with TS.  Normal puberty may occur and there have been some numerous reports of precocious puberty in TS underscoring the phenotypic variability that occurs whereby girls with TS may have normal functioning ovarian tissue. If gonadotropins are within the normal range for age, continued observation for the development of spontaneous puberty is appropriate. The majority of girls with TS will have primary hypogonadism and/or primary or secondary amenorrhea related to gonadal dysgenesis. Streak gonads are seen in at least two-thirds of patients. Girls with TS have viable oocytes in foetal life however undergo accelerated oocyte degeneration that may begin as early as 18 weeks

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gestation, when fibrous degeneration/erosion of ovarian follicles begins. Follicular loss continues following birth and will affect pubertal development and spontaneous menarche in a majority of individuals with TS.  Elevated and/or rising gonadotropins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) are associated with progressive ovarian failure. Spontaneous pregnancies are reported to be rare, in the 3–5% range. Most will require exogenous oestrogen therapy for pubertal initiation, sexual maturation and/or maintenance of secondary sexual characteristics, optimising uterine growth, attaining peak bone mass, supporting brain, and cardiovascular health. Current recommendations encourage initiation oestrogen therapy between 11 and 12 years of age (Gravholt et al. 2017). This allows for age-­ appropriate secondary for those that require it here sexual characteristic development and menarche in line with peers without compromising adult height. It also supports normalised uterine and bone mineral development, improved cognitive and hepatic function and quality of life (Bannink et  al. 2009b; Kanaka-­Gantenbein 2006). Prolonged oestrogen deficiency in TS is linked to low BMD (Bondy 2007). Transdermal preparations are preferred as this is more physiological and avoids excessive hepatic exposure to oestrogen (Gravholt et  al. 2017). However, generally staged 17B ethinyl oestradiol use is started with 0.25 oral. 0.5  mg increased to 1.0 mg, increased to 1.5 mg, increased to 2.0 mg every 6 months then medroxyprogesterone 10  mg for 10–12  days each month once breakthrough bleeding occurs or after 2 years of oestrogen treatment (Gravholt et  al. 2017). Unopposed oestrogen therapy causes uterine hyperplasia and increases risks for spontaneous and unexpected spotting and increases uterine cancer risk. Eventual transition is to monophasic oral contraceptive pill packs taken as directed or that may be used in the extended or continuous regime (using 3 or more 21 day packages sequentially before a withdrawal bleed is instituted with a no-pill or sugar-pill week). Newer continuous HRT products may be considered whereby menses occurs every 3 months or more.

H. E. Turner and I. R. Hozjan

Once adult replacement is reached, treatment should generally persist until menopause, around 51  years of age, unless the risk of continuation outweighs the benefits. The use of transdermal oestradiol (TDE) facilitates a more physiologic mode of delivery without hepatic first-pass metabolism effects. TDE has been reported to result in: faster bone accrual in the spine; improved uterine growth; possible increased FAH; and reduced thrombotic risk, when used. Though touted to be amenable to dose modification by cutting of the patches, to customise dosing and dose adjustment, this is not recommended by the manufactures. Transdermal gels are often well tolerated and avoid the difficulty with patches. There will be increased use of TDE in pubertal induction and adult replacement in TS in the coming years once optimal dosing has been further elucidated.

40.8.1  Hormone Replacement Therapies and Cardiac, Thrombosis, Cancer Risk Recent studies have suggested that thrombosis may be more common than previously believed in TS raising concerns for increased thrombosis risk with HRT (Calcaterra et al. 2011). The use of transdermal oestradiol (TDE) may lower the risk of thrombosis when compared with oral oestrogens (Vrablik et al. 2008; Canonico et al. 2007). It is not uncommon for many young women with TS to have poor adherence to treatment and/or have declining use of HRT in general (Bondy et al. 2006b). HRT treatment in TS has not been shown to increase risk for myocardial infarction or cancer risk in women with TS (Bosze et al. 2006). A national cohort study in the UK noted that in addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer. However, they were at a decreased risk for breast cancer. Reasons for these risks might relate to genetic and hormonal factors or to the effects of

40  Diagnosis and Management of Turner Syndrome in Children and Adults

hormonal treatments given to women with Turner syndrome (Schoemaker et al. 2008).

40.9 Breast Development in Turner Syndrome Poor breast development is not uncommon in TS. This is related to the broad shield-like chest with wide spaced nipples that is remnant of foetal lymphedema whereby a tight fibrous mesenchymal layer resists growth in any or all of the breast quadrants, except at the areola which is an area of low resistance resulting in tubular breast development with large areolas for some. A paucity of medial and inferior breast tissue/skin leads to inner quadrant tightness and a tendency for areolas to face medially and inferiorly. Poor breast development may make pubertal breast staging difficult or inaccurate with or without the use of HRT. Poor breast development may have psychosocial implications for adolescents and adult women with TS affecting self-esteem and establishing intimacy. Plastic surgery consultation for breast enhancement should be considered for older teens and women who have experienced this. In many jurisdictions, surgical breast augmentation may be covered by national health systems or insurance by being categorised as a congenital anomaly or defect.

40.10 Fertility and Reproductive Assistive Technologies and Pregnancy As a result of ovarian failure, most women with TS are infertile. The literature has noted this to be a major issue affecting quality of life (QOL). Spontaneous pregnancies occur in 4.8–7.6% of women with TS. Unfortunately, the frequency of foetal loss from miscarriage after spontaneous pregnancy is quite high and reported to be 30.8– 45.1% (Gravholt et al. 2017). Also, pregnancies in TS are complicated by higher rates of foetal malformation (TS and Down syndrome). Women with TS also have higher rates of pregnancy complications including hypertension, pre-eclampsia,

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and aortic dissection. Delivery is frequently via caesarean section due to body habitus and complications, which increases morbidity and mortality for both the mother and foetus. In the past, TS has been categorised as a relative contraindication for pregnancy and absolute contraindication for those with documented cardiac anomaly (surgically repaired cardiovascular defect BAV, evidence of aortic dilatation, systemic hypertension) by the American Heart Association (Hiratzka et al. 2010). More recently, a risk stratification approach is accepted which involves careful assessment by a multidisciplinary team and careful cardiac imaging pre-conception (Gravholt et al. 2017). Most women with TS are infertile due to primary ovarian failure but approximately 5% may achieve spontaneous pregnancy particularly if they have a mosaic karyotype 45X/46XX. Integrity of the long arm of the X chromosome is required for maintaining fertility (Quilter et  al. 2010). Most women will therefore require assisted reproduction with in  vitro fertilisation (IVF) using donor oocytes to attempt pregnancy. It is important to assess and counsel women who have not yet developed ovarian failure in order to plan pregnancy because of the risk of premature ovarian failure. Anti-Mullerian Hormone (AMH) is the best endocrine marker of the size of the population of the reserve pool of small antral follicles within the ovaries (Broer et al. 2014). In the near future, consideration of oocyte, ovarian, or embryo cryopreservation will be important in this group (Oktay et al. 2016). Pregnancy and fertility in a woman with TS requires discussion, assessment, and education a. pre-conceptually, b. during any pregnancy, and c. when planning delivery of the offspring. A multidisciplinary approach with input from cardiology (including echocardiography and CMR before any pregnancy consideration), genetics, fertility, and obstetrics is essential to discuss and optimise the likelihood for safe attempts or successful outcome. Multiple embryo transfer is contraindicated. Particular risks of pregnancy for a woman with TS include progression of aortopathy with 1–3.3% risk of dissection particularly associated with assisted reproduction; due to pregnancy-­associated

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increased haemodynamic strain and also hormonal factors (Bondy 2014; Hadnott et  al. 2011). Complications of the pregnancy itself include higher rates of spontaneous abortion, foetal anomaly, premature birth, low birth weight offspring, and cephalopelvic disproportion. Less than 40% may have an entirely normal pregnancy. While vaginal delivery may be possible delivery needs to be carefully planned with elective or emergency caesarean section anticipated for most (Hewitt et al. 2013).

40.11 Lifelong Screening and Management in Women with Turner Syndrome Girls and women with TS need to be followed for life with regular screening not only for the management of age-appropriate issues, e.g. growth and puberty, fertility and pregnancy, but also for the development of complications, e.g. cardiovascular and autoimmune disorders (Conway et  al. 2010; Culen et al. 2017) (Figs. 40.4 and 40.6).

Audiometry

Autoimmune disease

Women with TS should be seen at an annual visit for physical examination, e.g. blood pressure, body mass index, and for biochemical investigations to assess for glucose intolerance, dyslipidaemia, liver abnormalities, and thyroid function. Education is an essential component to lifelong care with advice regarding weight management, hypertension, diabetes, hepatic steatosis, and osteoporosis.

40.11.1  Autoimmune System and Autoimmune Disorders Many autoimmune conditions are commoner in girls and women (Table 40.6) (Bondy 2007) and their incidence increases with age. It is unclear what the underlying mechanism of the TS-associated increased risks of autoimmunity are. One theory is the higher rate of autoimmunity is related to the haploinsufficiency of immunoregulatory genes on the X chromosome, like FOXP3, which encodes a transcription factor that is critical for natural regulatory T cell control

• Aggressive treatment of otitis media • Every 5 years

• Annual screen for hypothyroidism • Screen for coeliac disease

• Lifelong annual HbA1c from age 10y Metabolic

Bone health

Liver

Renal ultrasound

• Lipid profile if ³ 1 risk factor from age 18

• Screen vitamin D deficiency 9-11y and every 2-3y • DXA after adult HRT commenced

• Monitor LFTS every year from age 10 • Continue HRT if abnormal • Inflammatory bowel disease – increased incidence

• Increased risk horseshoe kidney, duplicate collecting system 5-10%

Fig. 40.4  Screening and lifelong monitoring in Turner syndrome

40  Diagnosis and Management of Turner Syndrome in Children and Adults Table 40.6 Autoimmune conditions associated with Turner syndrome showing those which are commoner than the background female population Increased • Primary hypothyroidism? 3.2% • Graves’

No increase • Addison’s disease • Autoimmune polyglandular syndrome 1 and 2

•  Coeliac disease •  T1 DM •  Alopecia areata •  Rheumatoid arthritis • Uveitis •  Inflammatory bowel disease

(Invernizzi et al. 2005; Pessach and Notarangelo 2009) and thus may play a role in autoimmune conditions (Bakalov et  al. 2012). FOXP3 deletions cause immunodysregulation, polyendocrinopathy, and enteropathy (Bakalov et al. 2012). Currently, there are at least ten genes located on the X chromosome which have been identified with possible immune regulatory functions (Pessach and Notarangelo 2009).

40.11.1.1 Autoimmune Thyroiditis Autoimmune thyroiditis is the most common autoimmune diagnosis in TS and occurs in 10–37% with prevalence increasing with advancing age. It rarely develops in those less than 4 years of age. Hypothyroidism develops in approximately 15% of those under 18 and up to 30% in adulthood and up to 50% of adults will have positive thyroid antibodies (Elsheikh et  al. 2001a). Women with the isochromosome X are at particular risk of developing autoimmune thyroid dysfunction (Elsheikh et  al. 2002). Screening at diagnosis, and regular annual thyroid function screening beginning at 4 years of age, along with thyroid antibodies every 3–5 years to identify those at risk for future thyroid disease is recommended (Bondy 2007). 40.11.1.2 Coeliac Disease Intestinal autoimmunity, such as coeliac disease (CD), is an autoimmune disease prevalent in 1–2% of Western populations. Individuals with TS are at a threefold increased risk of CD and the recommendation of active case finding for CD in

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TS continues to be supported by the literature (Marild et  al. 2016). Regular, every 2–5  years, screening of tissue transglutaminase immunoglobulin A antibodies (tTG-IgA, usually combined with total IgA) should begin in childhood (Bondy 2007). Testing should take place regularly throughout the lifespan as classic overt symptoms of coeliac disease may not be present in TS, though tTG-IgA testing, endoscopy, and intestinal biopsy may confirm active disease.

40.11.1.3 Inflammatory Bowel Disease The prevalence of inflammatory bowel disease (IBD) in TS approximately 3–4% whereby the rate in the general population is less than 0.5%. Onset of inflammatory bowel disease tends to be earlier with more severe symptoms in TS. Crohn’s disease is more frequently diagnosed than ulcerative colitis and isoXq karyotype makes up more than half of those with IBD (Gravholt et al. 2017; Elsheikh et al. 2002). 40.11.1.4 Juvenile Rheumatoid Arthritis An association with juvenile rheumatoid arthritis and psoriatic arthritis has been noted in TS, and it is important to have an underlying suspicion of inflammatory arthritis when there is radiologic evidence and/or clinical joint symptoms (Wihlborg et al. 1999).

40.11.2  Metabolic Issues; Diabetes, Insulin Resistance, and Glucose Intolerance Metabolic issues, diabetes, insulin resistance, and glucose intolerance occur more frequently in TS than in the general population. Epidemiological studies have demonstrated the risk of diabetes mellitus, both type 1 and type 2, is about tenfold and fourfold higher in girls in women with TS.  Annual lifelong monitoring for diabetes is essential in TS, as the risk of both type 1 and type 2 diabetes is significantly increased and occurs at a younger age, when compared to the general population (Gravholt et  al. 2017). Impaired

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g­ lucose tolerance, insulin resistance, and other abnormalities of glucose metabolism are more common and found in up to one-third of women with TS.  Recently presented data suggest that diabetes in TS may be different to that in the general population as TS-associated diabetes has features of both type 1 and type 2 diabetes. The association with autoimmune hypothyroidism suggests an autoimmune pathway may be more prominent than previously thought and that being overweight could compound the autoimmune risk (Cameron-Pimblett et al. 2017) (Fig. 40.5). Overweight, obesity, and growth hormone treatment exacerbate insulin resistance. Monitoring of fasting blood glucose concentrations should be regularly completed on any who are significantly overweight, have a strong family history of type 2 diabetes mellitus, are a member of a higher risk ethnic group have signs of insulin resistance such as acanthosis nigricans and/or are on GH therapy. Annual measurement of HbA1c with or without fasting serum glucose starting at age 10 years or sooner if significant risk factors present is recommended.

40.11.2.1 Obesity While the TS literature frequently mentions obesity associated with this syndrome, there is a paucity of literature. The prevalence of obesity in TS reflects population means in most studies. TS is a high-risk condition for complications related to Age of presentation of Diabetes 100 90 80 70 60 % 50 40 30 20 10 0

T1DM Turner (UCLH) n=46

the development of early cardiovascular disease and hypertension independent of obesity. Supportive active medical management is required to reduce and avoid risk factors that additionally predispose to this increased risk. Obesity increases the risk for insulin resistance in the general population and girls and women with TS should be counselled and encouraged to maintain their weight within an appropriate range for height. Girls and women with TS tend to have increased cholesterol and LDL.  GH treatment and obesity exacerbate insulin resistance. Thus, counselling and guidance regarding weight control and healthy lifestyle behaviours including decreasing intake of problematic foods and fluids and maintaining increased rates of physical activity especially weight bearing exercises (Frias et al. 2003), with referral to weight management programmes if needed, should be strongly encouraged.

40.11.3  Vascular Malformations of Gastrointestinal System Gastrointestinal vascular malformations that may cause bleeding such as haemangiomas, telangiectasias, and venous ectasias may involve the small bowel, large bowel, or mesentery have been described in up to 7% of individuals with TS. As discussed earlier, while gastrointestinal bleeding should initially prompt an evaluation for IBD gastrointestinal vascular malformations may also need to be actively considered and evaluated.

40.11.4  Liver Function Abnormalities and Lipid Disorders T2DM

70 Age

Fig. 40.5  Graph showing age of presentation of diabetes in women with TS compared with non-TS individuals (used with permission from Cameron-Pimblett et  al. (2017))

Liver function abnormalities are a common finding with increasing prevalence with age. Liver enzyme elevations (ALT, AST, GGT) tend to persist and remain stable or increase over time. The risk of cirrhosis is fivefold that of the general population (Bannink et al. 2009a). Persistent elevated liver enzyme tests warrant further investigation and referral as fibronodular disease, portal hypertension, fibrosis, or steatosis may be present. Several studies have documented improve-

40  Diagnosis and Management of Turner Syndrome in Children and Adults

ment or resolution of elevated liver enzymes with HRT regardless of the route of administration (Elsheikh et al. 2001b; Gravholt et al. 2007).

40.11.4.1 Liver Disease Asymptomatic biochemical changes in liver function are common in TS (Fig. 40.4), and while usually benign, may in some progress to structural changes including fibrosis and cirrhosis. While obesity and insulin resistance undoubtedly lead to increased incidence of non-alcoholic fatty liver disease, more rarely vascular abnormalities and autoimmune conditions such as primary biliary cirrhosis and sclerosing cholangitis may develop (Roulot 2013). Liver biochemistry should be monitored throughout life from age 10 years with further investigation and referral to liver specialist if found to be abnormal. 40.11.4.2 Lipids An atherogenic lipid profile is very common in TS. Hypercholesterolaemia may affect up to 50% of women with TS with higher total cholesterol, LDL cholesterol, and triglycerides than the general population. There is evidence that oestrogen modifies lipid concentrations (Taboada et  al. 2011; Torres-Santiago et al. 2013). While some studies show an elevation in cholesterol in up to 50% women with TS, others have shown no increased prevalence compared to the karyotypically normal population. The relationship with increased BMI and obesity make it difficult to establish whether TS is an independent risk for developing hyperlipidaemia. However as part of an assessment and optimisation of the potentially atherogenic metabolic profile in TS it is recommended that a lipid profile should be checked from age 18 years or earlier if there are other metabolic risk factors (Gravholt et al. 2017).

40.11.5  Ear Health Recurrent otitis media is common in the early years in TS and is due to anatomical placement of the eustachian tubes that lie more horizontally and impede drainage. Conductive hearing loss is

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common due to recurrent otitis media and middle ear effusions (Davenport et  al. 2010) in childhood and progressive mid-frequency sensorineural hearing loss development, in the 1500–2000-Hz range often begins in childhood and will affect up to 50% of adult women with TS.  An audiological assessment should take place at diagnosis and regularly thereafter. There is a high prevalence of the development of a cholesteatoma in Turner syndrome particularly with 45X and isochromosome Xq karyotypes (Lim et  al. 2014). Early recognition, otolaryngology referral, and surgical treatment of this destructive erosive and expanding growth that consists of keratinising squamous epithelium in the middle ear and/or mastoid process is required for this persistent disease. A cholesteatoma may result in destruction of middle ear ossicles causing hearing loss and may grow through the base of the skull. These may become infected and result in chronically draining ears and conductive hearing loss, classic signs of this condition.

40.11.6  Skeletal Manifestations in Turner Syndrome Congenital developmental dysplasia of the hip occurs more frequently in TS than in the general population (Saenger et al. 2001) and predisposes individuals to arthritis of the hips. Scoliosis and kyphosis is being increasingly recognised as affecting a larger percentage of children with TS than previously thought. Scoliosis develops in up to 40% and kyphosis in up to 50%. The use of GH in girls with TS and scoliosis may exacerbate single or double curves. While the presence of scoliosis in childhood does not preclude the use of growth-promoting therapies it does warrant close monitoring during therapy (Bondy 2007) and referral to orthopaedic specialists if or when curvature progresses. Other abnormalities of the skeleton include short neck (hypoplasia of the neck vertebrae), Madelung deformity (bayonet deformity), cubitus valgus (increased carrying angles in greater than 50%), and genu valgum (knock-knee) causing an in-toeing gait or genu

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varum (bow leggedness), short fourth metacarpal or metatarsal bones.

40.11.6.1 Osteoporosis Although there may be an element of delayed bone maturation, bone density is lower in TS than the normal population when corrected for height and skeletal maturation (Lanes et  al. 1999). Women with TS have reduced bone mass associated with increased risk of fracture, and assessment of bone density and treatment of osteopenia/ osteoporosis is therefore essential. Clearly, GH and oestrogen replacement during childhood and adolescence are crucial for achieving peak bone mass. Adolescents, who undergo puberty spontaneously and continue with normal pubertal development have been noted to have normal BMD into early adulthood (Carrascosa et  al. 2000). Optimisation of oestrogen replacement through adulthood is essential and is associated with higher bone mineral density (BMD). Regular screening for vitamin D deficiency commencing at age 9–11 and continuing throughout the lifespan with replacement as required is a key recommendation in the recent International guidelines (R 6.14) (Gravholt et  al. 2017; Granger et  al. 2016). Bone densitometry assessment after transition to the adult clinic allows risk assessment, monitoring, and treatment where appropriate.

40.11.7  Renal/Urinary Findings in Turner Syndrome Congenital malformations of the renal/urinary system are 10 times more likely to be present in TS (25–40% of patients) (Flynn et  al. 1996) compared with 3–4% in the general population. Renal function tends to be normal despite the high incidence of renal tract abnormalities in TS (Nathwani et al. 2000). The common abnormalities include collecting system malformations (20%), horseshoe kidneys (10%), mal-rotated kidneys, and other positional abnormalities (5%). Anomalies associated with the obstruction of the ureteropelvic junction can produce clinically significant hydronephrosis and increased risk for pyelonephritis.

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Three primary types of defects are recognised according to the stage of gestational development in which the defect occurs. Defects of the collecting system occur in the first 5 weeks of gestation and these include partial or complete duplications. Generally, renal duplications are of no clinical importance. The second type of defect occurs during the period from 5 to 9  weeks of gestation and relates to the position of the kidneys and includes horseshoe kidney, ectopic, or mal-rotated kidneys. Finally, the third type of defect develops during the end of the first trimester and involves abnormalities of the renal vascular supply. With the renal fusion of a horseshoe kidney, the kidneys lie vertically instead of obliquely and are joined at their lower poles by midline parenchymal tissue (the isthmus). The horseshoe kidney lies lower in the abdomen (at L3 to L4 vertebral level). With a horseshoe kidney the normal rotation of the kidney is also prevented and the renal pelvis lies anteriorly with the ureters also passing anteriorly over the kidneys and isthmus however enter the bladder normally. Patients with horseshoe kidney can be reassured that these kidneys generally function normally however, symptoms such as abdominal or back pain should raise the question of urinary tract obstruction. Also, these patients require information and about the risks of trauma as there is increased risk of renal injury associated with abdominal trauma as the kidney is not protected by the ribcage. For horseshoe kidney, the collecting system of each half is usually normally developed and the renal system is also generally normal. However, because the ureters tend to run anterior to the fused portion of the kidney, urine flow may be impeded and ureteric obstruction or secondary urinary tract infection may develop. If severe or inadequately treated, hydronephrosis or pyelonephritis may result. Patients with structural renal abnormalities are at increased risk for urinary tract infections and vesicoureteric reflux. Renal ultrasonography for examination of renal abnormalities at the time of diagnosis is indicated with referral to a Nephrologist Specialist if needed for consultation and/or management of renal disease.

40  Diagnosis and Management of Turner Syndrome in Children and Adults

40.11.8  Ocular Abnormalities Ocular abnormalities are common in TS and the detection and surveillance of eye abnormalities is necessary in all patients diagnosed with TS. The prevalence of visual disturbances in TS is significant as near-sightedness affects 40%, farsightedness 13%, strabismus 15–30%, amblyopia >15%, epicanthal folds up to 45%, ptosis up to 30% hypertelorism 10%, and red-green colour blindness 8–10% (Chrousos et al. 1984; Wikiera et al. 2015). There is no known association between the presence of eye defects and karyotype. Case reports have also noted keratoconus, glaucoma, cataracts, and retinal detachments in TS. Regular ongoing evaluation by an eye specialist optometrist, ophthalmologist will provide surveillance, prevent irreversible deterioration of eye function and permanent poor vision and is recommended from age 12 to 18 months, at the time of diagnosis, and regularly during paediatric years annually and as indicated in adult years.

40.11.9  Lymphedema and Dermatological Related Issues 40.11.9.1 Lymphedema Abnormal lymphatic development in utero is responsible for many of the traits and physical manifestations in TS. Lymphedema is more common in girls with 45,X karyotype, in the newborn period and tends to regress over time particularly in the first 2 years. Jugular lymphatic obstruction during embryogenesis and early gestation results in nuchal cystic hygroma (Lowenstein et  al. 2004). When collateral lymphatic drainage develops, the cystic hygroma resolves leaving a webbed neck (pterygium coli) and the cystic hygroma is no longer present at birth. Referral to Plastic Surgery may be considered for surgical options for improving neck aesthetics and function if limited range of motion, due to moderate to severe webbed neck is present. Congenital lymphedema of the hands, and feet is present in over 60% of females with TS.

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Lymphedema may recur or occur at any time especially during puberty or with hormonal treatment such as growth hormone or ovarian stimulation therapy (Bondy 2007) and is caused by a failure of the lymph-conducting system that may be due to failure of lymph reabsorption by the initial lymphatic capillaries (Atton et  al. 2015). Lymphedema may be controlled in most cases by support stockings, lymphatic drainage massage therapy, and/or physical therapy. Aggressive therapy should be considered when prolonged swelling leads to pain, skin changes, poor circulation, and/or infections. A four-step intervention with attention to skin and nail care, compressive massage, compression bandaging, and remedial exercise programming may be required (Bondy 2007) to reduce oedema, improve circulation, and reduce risk of infection. Vascular surgery should be avoided when possible. A low posterior hairline or hair that extends onto the back of the neck, occurs in 40% of girls in TS. Bushy eyebrows and low-set ears are also associated with congenital lymphedema. This develops secondarily to lymphedema and cell migration abnormalities and is thought to be affected by stretching of the skin by the underlying cystic hygroma at around 10–12 weeks gestation with hair follicles growing downward into the underlying tissues. The bushy eyebrows and low-set ears have been attributed to the altered tension on the skin during this same period of development.

40.11.9.2 Nail Dysplasia Abnormal nail formation or nail dysplasia is found in approximately 70% of those with TS. Peripheral lymphedema is also implicated in the developmental abnormalities of the nails which may be small, narrow, thin, curved, and deeply inserted (Kaplowitz et al. 1993). Nail dysplasia may be particularly marked in the feet with some individuals having very small or complete absence of toenails. Good foot care and well-­ fitting shoes are important. Individuals with short broad feet may have difficulty purchasing properly fit shoes leading to increased susceptibility to ingrown toenails and other toe, foot, nail, skin problems, and infections. This may lead to

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increased risk of infection and cellulitis especially when coupled with lymphedema.

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40.11.9.3 Moles and Nevi There is an increased number of pigmented nevi seen in TS of which the cause is unknown. These nevi have generally been reported as benign melanocytic nevi in 25–70% of individuals with TS (Becker et al. 1994). As with the general population, nevi often increase in number and size throughout childhood and particularly during puberty and adolescence. While there is increased prevalence of nevi in TS there is not an increase in melanoma, and this has led to theories about a tumour suppressive factor operating in TS (Gibbs et al. 2001). Overall, an increased number of nevi is the strongest established risk factor for melanoma (Lowenstein et al. 2004) and as such individuals with a large number of nevi should learn the ABCDEs of mole assessment and have regular assessment of their nevi by their health care provider (HCP) and/or dermatologist. Studies of GH and OHR have failed to confirm any pathologic or harmful impact of these therapies on the number and density of melanocytic nevi (Zvulunov et al. 1998; Wyatt 1999).

dental age which contrasts with the other conditions of delayed skeletal maturation. Early palatal expansion corrects lateral cross bite. Shortness of dental roots and increased risk for root resorption in TS is problematic for orthodontic movements. Early paediatric specialty dental and orthodontic referral is indicated in TS with regular follow-up and communication regarding any active growth therapies being utilised (GH or anabolic steroid) as these therapies affect craniofacial growth. As growth hormone improves mandibular growth, it may help to improve and/ or normalise retrognathia. Active orthodontic therapy is usually delayed until completion of growth-promoting therapies to avoid the need for re-treatment. As a result of the known craniofacial abnormalities in TS, these patients often benefit from meeting the inclusion criteria for evaluation, surveillance, and active treatment for dental and orthodontic services from various health systems (national, provincial, state) cleft lip and palate programmes funding. Access to these programmes may provide significant financial support for dental and/or orthodontic treatment.

40.11.10  Orthodontic and Dental Manifestations in Turner Syndrome

40.11.11  Intelligence, Psychological, Neurocognitive, and Social Issues

The orthodontic manifestations of TS are well documented and require ongoing evaluation and active management. The mandible in many is positioned posteriorly and is hypoplastic compared with the rest of the face. As a result of this underdevelopment and posterior positioning of the mandible, retrognathia and micrognathia are common. Micrognathia has been reported in more than 50% of TS patients. The palate in TS has been described as high-arched, with either an inverted U-shape or narrow vault. Malocclusion with increased incidence of anterior open bite and lateral cross bite (maxillary teeth are positioned inside the mandibular teeth) when the mouth is closed may be seen. It is not uncommon for girls with TS to have advanced

Intelligence is within the normal population range; however, many with TS are at higher risk for neurocognitive, behavioural and social domain impairments (Frias et al. 2003), and educational deficits. Non-verbal IQ may be lower than verbal IQ.  The learning disability profile associated with TS is unique and may require special accommodations and/or modifications in education in many cases. Verbal abilities or skills are usually quite strong. Many are described as avid early readers and perform well with spelling. There is a high degree of individual variability in the somatic, cognitive, and psychosocial phenotypes (Gravholt et al. 2017). Many are very successful with post-secondary education at colleges or universities.

40  Diagnosis and Management of Turner Syndrome in Children and Adults

Selective impairments include non-verbal or specific neurocognitive deficits or challenges particularly with visuospatial, executive function, and/or a non-verbal learning disorder. Those with a ring chromosome ring X chromosomes may have severe mental retardation because ring chromosomes fail to undergo X-inactivation. Visuospatial deficits tend to be in spatial memory and orientation. Many will also have issues with directional sense, knowing their right and left orientation, extra-personal space perception along with spatial reasoning and visual sequencing (Hart et al. 2006). Visuospatial processing impairments are intensified when tasks require increased working memory. Tasks that involve aspects of driving, finding one’s way around new or familiar places, judging distances or geometric mathematics may pose problems. Executive functioning deficits may include difficulty on tasks of planning, fluency of communication, poor working memory and focusing, which is needed to solve complex problems in a step-by-step fashion. Non-verbal disabilities include issues with being able to understand incoming visual and spatial information such as being able to recognise what and where an object is, and visualising objects changing position. Some may have difficulties with global processing and “seeing the whole picture”. Genomic imprinting may be relevant, as those who have maternally derived X chromosome have been shown in some studies to have deficits or impairments in social competence and in social adjustment and verbal function compared to those with a paternally derived X chromosome (Skuse et al. 1997). This implies that social functioning may be influenced by an imprinted gene on the X chromosome that is switched off when this gene is inherited from the mother. Behavioural issues differ by age, younger girls may be very hyperactive, immature, and not particularly cognisant of social cues, and therefore socially vulnerable. In contrast older girls may exhibit continued immaturity, or be inhibited and shy, and experience anxiety, depression, and difficult or unsatisfactory peer relationships

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and be more socially withdrawn than their peers. There is no evidence of significant psychiatric disorder in TS. Clinicians working with individuals with TS should be attuned to the neuropsychological phenotype in TS which may significantly impact their patients’ ability to successfully navigate social, home, school, personal, and work environments (Hong and Reiss 2012). Any child who is not achieving appropriate developmental or educational milestones deserves assessment, intervention, and regular follow-up from developmental and/or educational specialist services. Neuropsychological and/or educational testing is recommended before enrolment in school or when educational issues become apparent. Re-evaluation will be needed at identified intervals throughout their education. Strengths will be recognised and identified issues and areas for development should be addressed by specific implementation of educational strategies both in the school and home setting. Psychosocial assessment and support addressing home environment, friends and relationships, and employment should be considered at each visit. Discussions regarding ongoing health surveillance and the importance of lifelong follow­up is essential. Population studies show a broad variation in socioeconomic profile, with a reduced prevalence of TS women in relationships with a partner (Stochholm et  al. 2006). While educational attainment does not vary from the background population, employment, and income tend to be lower. A recent 6-year follow-up of women with Turner syndrome showed that women with TS were more likely to live alone and have fewer sexual partners and less sexual confidence compared with controls (Fjermestad et  al. 2016). In addition, they had lower self-­ esteem and life satisfaction. Gender dysphoria is uncommon. Targeted clinic psychology support is beneficial and optimal for the wide-ranging problems that may exist. Support groups can be invaluable in providing peer group support, information, and practical management advice (Fig. 40.6).

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Diagnosis and genetics

Neurocognitive and behavioural aspects

Growth and puberty

Clinical Practice Guidelines

Health surveillance

Transition

Fertility, ART and pregnancy

Cardiovascular health issues

Fig. 40.6  Spectrum of the many aspects of lifelong management in women with Turner syndrome

40.12 Transition to Adulthood Adolescence and the transfer of a young woman with TS from the paediatric service to adult clinics is a critical time when many young women may be lost to the recommended targeted lifelong management and health surveillance. There is a risk of increased morbidity and mortality associated with lack of follow-up in TS. The emphasis to engage adolescents early on and develop their abilities and knowledge to actively plan and participate in their own care is needed. There are many differences between paediatric and adult health care systems. The paediatric clinic is involved in GH administration, introduction of oestrogen and induction of puberty, initiation of screening for cardiovascular health and autoimmune conditions, and management of musculoskeletal challenges all with their supportive and responsible parent(s) by their side. In contrast, the

adult clinic focuses interactions and discussion with the patient themselves rather than the parent and the patient is expected to be a participating partner in her health care, arrive prepared with specific questions for her team and make decisions about treatment by herself. This may be problematic for some young women who still may require parental involvement, due to the intellectual and related functional capabilities and the complexity of number of health issues that may be affecting them. Continued discussion and education surrounding genetic, fertility, and lifestyle issues is essential, along with recognition of potential psychosocial challenges (Culen et  al. 2017). It is crucial that care-givers recognise the importance of creating an open dialogue and willingness to address sensitive issues such as sexual health, risk-taking behaviours, sexuality, romantic relationships, and self-esteem in addition to the specific TS health issues and health surveillance recommendations for each individual patient.

40  Diagnosis and Management of Turner Syndrome in Children and Adults

40.13 Nursing and Team Considerations The endocrine nurse plays a crucial role in all phases of the health care journey for the girls and women with TS, their families, and the health care team by providing the appropriate and recommended education and support across the lifespan. An individualised family-centred, multidisciplinary team approach is required to provide medically complex care and long-term surveillance. The endocrine nurse will be able to provide general, TS specific, and detailed health condition information, anticipatory guidance, education and emotional support, and mobilise psychosocial support. The endocrine nurse will participate in and facilitate the coordination and management of multidisciplinary team-related care and ongoing health surveillance and identify when additional evaluations and early interventions may be appropriate for each individual patient. The nurse will recommend and support appropriate strategies for optimal therapy adherence and reinforce the importance of wearable medical alert documentation when needed. The

Box 40.1 Case Study and Resources Provided by the Turner Syndrome Support Society (TSSS) UK (Published with Consent)

Sadly, one of the most common calls for supporting the Turner Syndrome Support Society [UK] [TSSS] is the late diagnosis of girls with Turner syndrome [TS] many girls are not diagnosed until they are 15–21 years old. This is a very difficult age for any girl to cope with. For girls with TS, a late diagnosis is devastating to be told that you may be infertile and that you need to choose what is most important to you “height or pubertal development” is very difficult. Parents are left feeling frustrated and guilty as many of them sought advices from their GPs and were told that she is just a late developer and thus missed out on vital timely treatment. Parents and health care professionals need to know about normal pubertal development

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nurse will connect individuals and families to external information and support networks including the Turner Syndrome Support Society (TSSS). Education, information, and provision of useful resources when appropriate throughout the lifetime of a woman with TS is invaluable. The key to successful management of a woman with TS is the relationship which continues throughout their life. Continuity of follow-up, adjustment of direction of care according to the particular stage in their life, and the ability to detect and address sensitive issues is essential.

40.14 Working with Patient Advocacy Groups Patient Advocacy Groups play a crucial role in improving education and awareness of rare conditions such as Turner syndrome. In Box 40.1, Arlene Smyth describes how the Turner Syndrome Support Society (TSSS) UK was developed and the invaluable resources they provide for patients and health care professionals.

to act if there are no signs of breast bud development by 12 or 13 at the latest. There is a health reason and they should be referred to a Paediatric Endocrinologist. The vast majority of girls with TS are beautiful normal looking girls who are shorter than their peers and have no signs of puberty or their puberty started and then stopped. Many of the documented features are not seen in all girls, please see “Diagnosing Turner Syndrome” and other information leaflets available www.tss.org.uk. The Turner Syndrome Support [UK] was set up to support those affected by Turner syndrome. When my daughter was diagnosed at birth with TS. I wanted her to have friends and I wanted to meet other families too. Initially, it was just friendship and support, then I started to learn more about Turner syndrome and realise what a complex condition it was. I was lucky and met many amazing girls and women

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with TS. They were kind and opened up to us about how difficult life could be, in turn that allowed us to come up with strategies to help and support each other. The TSSS has grown and developed over the years. We have worked with health care professionals to help inform girls and women with TS so they can access the best possible medical care. Ensuring they understand the reason for taking their treatments and the longterm benefits to them. We produce some of the best information on Turner syndrome all checked and approved by our Clinical Advisory Board for accuracy. We have a wonderful relationship with our members we host Open Days, Social Events, and annual conference. We have a large social media presence and regional friendship groups ran by our volunteers. Being diagnosed with a rare condition in its self is isolating, frightening, and you have so many unanswered questions. Not always about the medical issues but often about behaviour, feelings coping with TS. By helping and supporting families, we provide a service that compliments the excellent care available to those with TS once diagnosed. Together we can help them be the best they

The recently published patient directed advice and guidelines to complement the specialist medical publication is invaluable (https:// tss.org.uk/downloads/patient_family_guidelines.pdf) and the Turner Syndrome Support Society (TSSS) UK and counterparts in other countries provide a very helpful resource and support. Moreover, the TSSS developed in collaboration with the author and other health care professionals a cardiac alert card (Fig. 40.7) for girls and women with TS to carry in their wallet to alert them and the emergency services, doctors, and nurses of the symptoms, investigations, and urgent management if clinical features of heart dissection develop.

can be. This is a quote from one of our teen members who was diagnosed at 12 years old. She was asked what the TSSS meant to her. “The people I have met a long away have changed my life in ways I could not have imagined. I am proud to say I am part of the best family in the world, the TSSS Family a bond so close it can never break. That is what the TSSS means to me”. We are proud to work closely with patients, their families, HCP, and others such as teachers. Our website contains a wealth of information free to download. We have a close bond with other TS groups throughout the world and worked collaboratively on writing guidelines and attending conferences. Arlene Smyth, Executive Officer at the TSSS Office Turner Syndrome Support Society [UK] 12 Simpson Court, 11 South Ave, Clydebank Business Park, Clydebank G81 2NR, West Dunbartonshire Tel 0141 952 8006, Helpline 0300 111 7520 Mobile if urgent 07947 554587 www.tss.org.uk Registered Charity NOS ENG 1080507 SCO 37932

40.15 Conclusion Turner syndrome is the commonest karyotype abnormality affecting women, and associated with a broad spectrum of clinical abnormalities which present different challenges throughout a woman’s life from birth to older age. Successful management requires increased ascertainment and earlier diagnosis of the condition, continuity of follow-up from childhood into and throughout adulthood, lifelong monitoring and the treatment where required of the various complications that arise in addition to the provision of appropriate social and psychological support throughout a woman’s life. In the future,

40  Diagnosis and Management of Turner Syndrome in Children and Adults

Fig. 40.7  Cardiac alert card for girls and women with TS.  Used with permission from the Turner Syndrome Support Society [UK], available from https://tss.org.uk/ information/healthcare

the increased use of a multidisciplinary team approach and developments in genetic understanding may help target appropriate follow-up in those at particular risk. Developments in treatment of fertility such as cryopreservation and improvements in cardiac imaging or treatment may lead to increased options for pregnancy and a reduction in the increased morbidity and mortality in women with TS. Acknowledgments  With special thanks to Arlene Smyth, Executive Officer, Turner Syndrome Support Society [UK] www.tss.org.uk for her contribution to this chapter with a case study and information on the Patient Advocacy Group.

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before the age of 4 years prevents short stature in young girls with Turner syndrome. Eur J Endocrinol. 2011;164(6):891–7. Lowenstein EJ, Kim KH, Glick SA.  Turner’s syndrome in dermatology. J Am Acad Dermatol. 2004;50(5):767–76. Lyon AJ, Preece MA, Grant DB.  Growth curve for girls with Turner syndrome. Arch Dis Child. 1985;60(10):932–5. Maraschio P, Tupler R, Barbierato L, Dainotti E, Larizza D, Bernardi F, et al. An analysis of Xq deletions. Hum Genet. 1996;97(3):375–81. Marild K, Stordal K, Hagman A, Ludvigsson JF. Turner Syndrome and celiac disease: a case-control study. Pediatrics. 2016;137(2):e20152232. Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation. 2007;116(15):1663–70. Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome— integrating cardiology, genetics, and endocrinology. Endocr Rev. 2012;33(5):677–714. Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. The influence of renal and cardiovascular abnormalities on blood pressure in Turner syndrome. Clin Endocrinol. 2000;52(3):371–7. Noto R, Maneatis T, Frane J, Alexander K, Lippe B, Davis DA.  Intracranial hypertension in pediatric patients treated with recombinant human growth hormone: data from 25 years of the Genentech National Cooperative Growth Study. J Pediatr Endocrinol Metab. 2011;24(9–10):627–31. Oktay K, Bedoschi G, Berkowitz K, Bronson R, Kashani B, McGovern P, et al. Fertility preservation in women with Turner Syndrome: a comprehensive review and practical guidelines. J Pediatr Adolesc Gynecol. 2016;29(5):409–16. Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pubertal development in Turner’s syndrome. Italian Study Group for Turner’s Syndrome. J Clin Endocrinol Metab. 1997;82(6):1810–3. Pessach IM, Notarangelo LD.  X-linked primary immunodeficiencies as a bridge to better understanding X-chromosome related autoimmunity. J Autoimmun. 2009;33(1):17–24. Pinsker JE.  Clinical review: Turner syndrome: updating the paradigm of clinical care. J Clin Endocrinol Metab. 2012;97(6):E994–1003. Quilter CR, Karcanias AC, Bagga MR, Duncan S, Murray A, Conway GS, et  al. Analysis of X chromosome genomic DNA sequence copy number variation associated with premature ovarian failure (POF). Hum Reprod. 2010;25(8):2139–50. Ranke MB, Lindberg A, Ferrandez Longas A, Darendeliler F, Albertsson-Wikland K, Dunger D, et  al. Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS. Pediatr Res. 2007;61(1):105–10.

800 Rivkees SA.  Ending the late diagnosis of Turner syndrome through a novel high-throughput assay. Pediatr Endocrinol Rev. 2012;9(Suppl 2):698–700. Rivkees SA, Hager K, Hosono S, Wise A, Li P, Rinder HM, et  al. A highly sensitive, high-throughput assay for the detection of Turner syndrome. J Clin Endocrinol Metab. 2011;96(3):699–705. Rosenfeld RG, Attie KM, Frane J, Brasel JA, Burstein S, Cara JF, et  al. Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr. 1998;132(2):319–24. Ross J, Lee PA, Gut R, Germak J. Impact of age and duration of growth hormone therapy in children with Turner syndrome. Horm Res Paediatr. 2011a;76(6):392–9. Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, et  al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011b;364(13):1230–42. Roulot D.  Liver involvement in Turner syndrome. Liver Int. 2013;33(1):24–30. Sachdev V, Matura LA, Sidenko S, Ho VB, Arai AE, Rosing DR, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol. 2008;51(19):1904–9. Saenger P, Wikland KA, Conway GS, Davenport M, Gravholt CH, Hintz R, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab. 2001;86(7):3061–9. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA, United Kingdom Clinical Cytogenetics Group. Mortality in women with turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93(12):4735–42. Sheanon NM, Backeljauw PF.  Effect of oxandrolone therapy on adult height in Turner syndrome patients treated with growth hormone: a meta-analysis. Int J Pediatr Endocrinol. 2015;2015(1):18. Skuse DH, James RS, Bishop DV, Coppin B, Dalton P, Aamodt-Leeper G, et al. Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature. 1997;387(6634):705–8. Stephure DK, Canadian Growth Hormone Advisory Committee. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005;90(6):3360–6. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006;91(10):3897–902. Sutton EJ, Young J, McInerney-Leo A, Bondy CA, Gollust SE, Biesecker BB.  Truth-telling and Turner Syndrome: the importance of diagnostic disclosure. J Pediatr. 2006;148(1):102–7. Taboada M, Santen R, Lima J, Hossain J, Singh R, Klein KO, et  al. Pharmacokinetics and pharmacodynamics of oral and transdermal 17beta estradiol in girls with Turner syndrome. J Clin Endocrinol Metab. 2011;96(11):3502–10.

H. E. Turner and I. R. Hozjan Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, et  al. Metabolic effects of oral versus transdermal 17beta-estradiol (E(2)): a randomized clinical trial in girls with Turner syndrome. J Clin Endocrinol Metab. 2013;98(7):2716–24. Tuffli GA, Johanson A, Rundle AC, Allen DB.  Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab. 1995;80(4):1416–22. Turner H.  A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology. 1938;23:566–78. Turtle EJ, Sule AA, Webb DJ, Bath LE. Aortic dissection in children and adolescents with Turner syndrome: risk factors and management recommendations. Arch Dis Child. 2015;100(7):662–6. Ullrich O.  Uber typische kombinationsbilder multipler abartungen. Z Kinderheilkunde Berlin. 1930;49: 271–6. van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ, et al. Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab. 2003;88(3): 1119–25. Vrablik M, Fait T, Kovar J, Poledne R, Ceska R. Oral but not transdermal estrogen replacement therapy changes the composition of plasma lipoproteins. Metabolism. 2008;57(8):1088–92. Wihlborg CE, Babyn PS, Schneider R.  The association between Turner’s syndrome and juvenile rheumatoid arthritis. Pediatr Radiol. 1999;29(9):676–81. Wikiera B, Mulak M, Koltowska-Haggstrom M, Noczynska A. The presence of eye defects in patients with Turner syndrome is irrespective of their karyotype. Clin Endocrinol. 2015;83(6):842–8. Wilkins L, Fleischmann W.  Ovarian agenesis: pathology, associated clinical symptoms and the bearing on the theories of sex differentiation. J Clin Endocrinol. 1944;39:204. Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116(15):1736–54. Wyatt D. Melanocytic nevi in children treated with growth hormone. Pediatrics. 1999;104(4 Pt 2):1045–50. Zvulunov A, Wyatt DT, Laud PW, Esterly NB. Influence of genetic and environmental factors on melanocytic naevi: a lesson from Turner’s syndrome. Br J Dermatol. 1998;138(6):993–7.

40  Diagnosis and Management of Turner Syndrome in Children and Adults

Key Reading 1. Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92:10–25. 2. Conway GS, Band M, Doyle J, Davies MC. How do you monitor the patient with Turner’s syndrome in adulthood? Clin Endocrinol (Oxf). 2010;73:696–9. 3. Culen C, Ertl DA, Schubert K, Bartha-Doering L, Haeusler G.  Care of girls and women with Turner syndrome: beyond growth and hormones. Endocr Connect. 2017;6:R39–51. 4. Elsheikh M, Dunger DB, Conway GS, Wass JA.  Turner’s syndrome in adulthood. Endocr Rev. 2002;23:120–40.

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5. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Soderstrom-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF, International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177:G1–G70. 6. Bondy C.  Pregnancy and cardiovascular risk for women with Turner syndrome. Womens Health (Lond). 2014;10:469–76. 7. Hewitt JK, Jayasinghe Y, Amor DJ, Gillam LH, Warne GL, Grover S, Zacharin MR. Fertility in Turner syndrome. Clin Endocrinol (Oxf). 2013;79:606–14.

Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

41

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Contents 41.1   Introduction

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41.2   The Menopause

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41.3   Premature Ovarian Insufficiency 41.3.1  Clinical Evaluation and Diagnosis of POI 41.3.2  Aetiology of POI

 806  806  807

41.4   Hormone Replacement Therapy

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41.5   Fertility Options for Women with POI 41.5.1  Spontaneous Fertility in POI 41.5.2  Ovum Donation 41.5.3  Embryo Cryopreservation 41.5.4  Oocyte Cryopreservation 41.5.5  Ovarian Tissue Cryopreservation

 810  811  811  811  811  812

41.6   Nursing Considerations in the Care of Patients with POI

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41.7   Conclusions

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References

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Abstract

Menopause and the years preceding it are associated with a wide variety of symptoms that are often missed in a routine consultation. Informed choice regarding hormone replacement therapy and lifestyle options can alleviate much of the burden of the menopause when this change in life has a major impact on

well-being. Premature ovarian insufficiency is one of the most difficult conditions in reproductive medicine. It occurs in 1% of women. The impact of the diagnosis can dissipate with time assisted by full evaluation and discussion of the implications of POI.  The role of the nurse includes assessment of symptoms, discussion of implications for fertility as well as

G. S. Conway (*) Institute for Women’s Health, University College London, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_41

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assisted fertility treatment options and then to give guidance through choices of sex steroid replacement. Ongoing education is required in order to adapt the level of information and types of treatment according to life circumstances. Women with ovarian insufficiency frequently feel isolated or that there is insufficient time in a clinic visit for full discussion. Nursing input can overcome some of these limitations. Keywords

Autoimmunity · Oestrogen and androgen treatments · Late effects of cancer · Ovum donation

Abbreviations AMH APS BMI COCP DXA Fra-X FSH HRT LH LOR POI TS

Antimullerian hormone Autoimmune polyglandular syndromes Body mass index Combined oral contraceptive pill Dual X-ray absorptiometry Fragile X Follicle-stimulating hormone Hormone replacement therapy Luteinising hormone Low ovarian reserve Premature ovarian insufficiency Turner Syndrome

Key Terms • Premature ovarian failure: A term describing ovarian insufficiency now considered obsolete. • Primary amenorrhoea: Failure for menstruation to occur in adolescence. • Secondary amenorrhoea: Absence of periods for greater than 6 months occurring after menarche. • Hypergonadotrophic Hypogonadism: The finding of each deficiency in the presence of raised concentrations of LH and FSH.

• Gonadal dysgenesis: Early onset ovarian insufficiency causing primary amenorrhoea usually with a genetic cause such as Turner Syndrome. • Low ovarian reserve: Women with regular cycles but raised FSH and low AMH usually in the context of infertility. • Early menopause: Menopause before the age of 45.

Key Points

• Menopause usually occurs at the age of 51 and premature ovarian insufficiency (POI) is defined as hypergonadotrophic hypogonadism before the age of 40. • Ovarian insufficiency requires consideration of fertility options, sex hormone replacement therapy, and psychological support. Nursing assessment should include an evaluation of the priorities in each of these domains at every clinic visit. • Ovarian insufficiency has wide-ranging effects on quality-of-life and relationships requiring counselling and help with decision-making as well as support at the time of an often traumatic diagnosis. • There are a number of options for sex steroid replacement comprising oestrogen, progestogen, and androgens. Assessment of optimal individualised hormone replacement treatment is based on quality of life taking careful note of details in history including mood and sexual function.

41.1 Introduction The ovary is a unique organ in the body with a defined lifespan of approximately 50 years. The life expectancy of the ovary is determined by optimal germ cell development in utero and factors affecting programmed cell death throughout life. The peak germ cell number occurs at 6 months

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

gestation with >700,000 eggs. Once this maximum number has been achieved, the body is no longer able to make new oocytes and the total number gradually decline. It is estimated that nearly 50% of germ cells have been destroyed by the age of menarche, and by the onset of menopause, only 1000 remain. Throughout life, therefore, germ cell apoptosis takes place at a rate of approximately 25–150 lost per day. As the number of germ cell falls, a critical point is reached when periods stop with subsequent reduction in circulating oestrogen, and thus lesser extent testosterone, concentrations. The menopause is defined by the last menstrual period and occurs at an average age of 50.7 years in the western world (van Noord et al. 1997). Premature Ovarian Insufficiency (POI) is defined as amenorrhoea with raised FSH before the age of 40. POI occurs in approximately 1% of females and becomes increasingly rare in younger age groups. For instance, in presence of normal karyotype, 1:1000 of women at 30 has POI, and 1:10,000 at 20 and 1:100,000 of women will present with gonadal failure and primary amenorrhoea (Fig. 41.1). POI accounts for 20–50% of females presenting with primary amenorrhoea and 10% of those with secondary amenorrhoea (Master-Hunter and Heiman 2006). Fig. 41.1  A graph of the distribution of the age of onset of amenorrhoea according to the lifespan of the ovary

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The term premature ovarian insufficiency is preferred to premature ovarian failure because it is an all-encompassing term that accounts for the variable course and occasional remission (Welt 2008a). The term hypergonadotrophic hypogonadism is also used to emphasise ovarian origin, whereby the raised concentrations of LH and FSH contrast from low gonadotrophins in hypothalamic or pituitary causes of hypogonadism. Gonadal dysgenesis refers to hypergonadotrophic hypogonadism with a known genetic cause such as an abnormal 46XY or 45X karyotype and implies that ovarian development was halted at an early stage of embryonic development. In the case of Turner Syndrome, it is thought that early ovarian development is usually normal, but that the chromosome anomaly leads to rapid germ cell apoptosis (Reynaud et al. 2004).

41.2 The Menopause Menopause describes the end of natural reproductive life when periods stop. The process can be abrupt, but in many cases symptoms precede amenorrhoea by months or even years. The age of menopause varies between 45 and 60 with daughters tending to follow mothers in many

Age of onset of Ovarian Insufficiency 5%

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1% 1:1000

15 1:10,000 10 1:100,000 5

0 0

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families (Davis et  al. 2015). The interval between periods usually shortens as the menopause approaches from an average of 28  days often to 21  days. The diagnosis of menopause may not be obvious in women taking hormone treatments for period control or who have had a hysterectomy. In addition, nonspecific symptoms such as joint and muscle stiffness, loss of memory and concentration, or simply low mood can occur in the absence of classical symptoms. Oestrogen deficiency should be considered as a possibility for anyone experiencing new onset of symptoms after the age of 40. The diagnosis of menopause is mainly based on history and, for the majority of women, no diagnostic test is required. A measurement of FSH can be unreliable as it may not correlate with symptoms of the premenopause. The majority of women experience some symptoms of the menopause which often gradually diminish over several years (Monteleone et al. 2018). In a proportion of women, disabling symptoms can be lifelong requiring indefinite treatment with HRT. Treatment of the menopause is individualised and may include lifestyle, hormone-­ based treatments, counselling, and treatments to improve sexual function. A great deal can be achieved with detailed information and advice. A discussion regarding the spectrum of symptoms that are associated with oestrogen deficiency can be reassuring and will ensure that no hidden symptom is left untreated. Symptoms relating to change of mood, libido, sexual function, and urogenital dysfunction may need to be sought by direct questioning. The risks and benefits of hormone replacement therapy require discussion as this treatment is not essential and nonpharmaceutical alternatives are available. Studies which highlighted the risks of HRT between 2002 and 2004 resulted in a decline in the use of HRT (Sassarini and Lumsden 2015). Subsequent assessments, however, have shown that the risks of HRT may have been overestimated. In addition, the risk of stroke can be eliminated by the use of transdermal oestrogen instead of oral oestrogen, which formed the basis of most of the early HRT studies.

41.3 Premature Ovarian Insufficiency 41.3.1 Clinical Evaluation and Diagnosis of POI The clinical presentation of POI varies depending on the age of presentation (Conway et  al. 1996; Nelson 2009). Very early onset in adolescence leads to pubertal delay puberty and primary amenorrhoea. After menarche, the presentation is with symptoms of oestrogen deficiency and secondary amenorrhoea or as part of a work up for irregular periods or infertility. In addition, POI can be part of clinical syndromes that can be genetic, such as Turner Syndrome, or autoimmune. The formal diagnosis of POI is based on the presentation of amenorrhoea with finding of elevated serum FSH concentrations (FSH > 25 IU/L) on at least two occasions separated by 4  weeks (Webber et  al. 2016). The requirement for two samples takes into account the fact that ovarian function can fluctuate and end raised FSH and can be a transient phenomenon. In addition, because the diagnosis has such severe implications, certainty of the diagnosis is required. While it is the usual expectation that the condition will be permanent, some women follow an unpredictable course of relapse and remission particularly in the first year after diagnosis (Bachelot et  al. 2017). There is a commonly quoted pregnancy rate of approximately 1–5% in women with POI and it is, therefore, important to inform women with POI of this phenomenon so that they use contraception when appropriate. Because of this background fertility, case reports of effective treatment of POI must be viewed with caution. Fluctuating ovarian function probably accounts for many cases where the older term ‘resistant ovary syndrome’ was applied and it is now understood that ovarian biopsy is not predictive of remission and should no longer be included as part of the work up of POI (Webber et al. 2016). Antimullerian hormone has found a place as a diagnostic marker of low ovarian reserve, but once the FSH concentration is raised, AMH offers little extra information (Visser et al. 2012).

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

A careful family history can identify other affected female members in as many as 30% of cases (van Kasteren et al. 1999a), and in this situation, more genetic screening is indicated and genetic counselling for relatives may be appropriate. A karyotype should be performed in anyone with a positive family history because small chromosome deletions can be inherited. Fragile X (Fra-X) premutation analysis should be offered to all women with POI because of its value in detecting a new pedigree for the prevention of fragile X syndrome (Conway 2010; Mila et al. 2018). Oestrogen receptors are widely distributed throughout the body and the effects of oestrogen deficiency are diverse. While the classical symptoms of hot flushes, sleep disturbance, and vagina dryness are obvious, more subtle changes in mood and musculoskeletal pain are often unrecognised as part of this symptom spectrum. A careful history listing any change in well-being, no matter how minor, that coincides or precedes amenorrhoea will provide a useful guide to optimising hormone replacement therapy. The major medical issues for health surveillance in women with POI revolve around the quality of life and bone protection offered by hormone replacement therapy (HRT). Oestrogen deficiency is a risk for osteoporosis and DXA scans should be performed at intervals to assist in the correct dosing of HRT. Options for reproduction include oocyte donation, but adoption should not be overlooked. Women also require personal and emotional support to deal with impact of diagnosis on their health and relationships. Long-­ term follow-up is essential to monitor HRT and to consider emerging associated autoimmune pathology.

41.3.2 Aetiology of POI Ovarian insufficiency is the final outcome of many pathogenic mechanisms. Table 41.1 shows the main categories of pathogenic mechanisms that lead to ovarian insufficiency. Despite diagnostic advances, particularly in the identification of genetic associations, the cause of POI remains unknown in the majority of cases (Nelson 2009).

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Table 41.1  Summary of pathogenic mechanisms causing premature ovarian insufficiency Genetic

Autoimmune

Metabolic

Iatrogenic

Environmental factors

Chromosomal and genetic abnormalities causing abnormal ovarian development or accelerated apoptosis. Single gene defects— mutations in genes vital for ovarian development or function Autoimmune ovarian damage is usually presumed because of the association with other organ-specific autoimmune conditions. Thyroid and adrenal autoimmunity is common. Ovarian autoantibodies are rarely positive In galactosaemia, abnormal metabolites are thought to mediate ovarian damage Ovarian damage following pelvic surgery and radiotherapy of chemotherapy during treatment of cancer Viral infections and toxins such as pesticides are presumed. Smoking results in younger age of natural menopause

41.3.2.1 Genetic Causes of POI A genetic aetiology for POI is suggested not only by a positive family history, but also if there are features of an associated syndrome. Cytogenetic chromosome anomalies occur in about 2% of cases with the majority involving the X chromosome (Davison et  al. 1999; Baronchelli et  al. 2011; Desai and Rajkovic 2017). X chromosome defects and Turner’s Syndrome: Defects of the X chromosome associated with POI include complete or partial deletion of one X (Turner syndrome), trisomy X, or X-autosome translocations. In the case of Turner Syndrome variants, there is a great deal of variability in severity of the condition and this corresponds approximately with genotype and the amount of X chromosome disruption. Ovarian histology can vary from streak ovaries to those with well-­ preserved structure and numerous follicles. Those with monosomy X (45X) tend to be the most severely affected, while those with partial deletions of the X chromosome or mosaic 45X/46XX karyotype often lack the typical phenotypic features of the syndrome, but may present with only ovarian insufficiency and secondary

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amenorrhoea. Among women with Turner Syndrome, the prevalence of ovarian failure is between 80 and 90% with most experiencing primary amenorrhoea and complete pubertal delay (Cameron-Pimblett et al. 2017). X chromosome deletions appear to segregate into two specific regions: POI1 at Xq26-qter and POI2 Xq13.3--Xq21.1 (Baronchelli et al. 2012). There are various proposed mechanisms by which X chromosome defects cause POI. Genes responsible for germ cell development located along the critical region may be interrupted, although break point genes that determine ovarian function have not been convincingly identified. It seems most likely that structural rearrangements of the X chromosome do not affect single genes, but rather disrupt normal pairing at meiosis, leading to meiotic arrest and subsequent atresia. It must also be noted, however, that some X chromosome break points are not associated with POI (Baronchelli et al. 2012). Single gene defects causing POI: A growing number of genes have been linked to ovarian insufficiency, although the strength of evidence linking each anomaly with POI is variable (Desai and Rajkovic 2017; Ferrarini et  al. 2013). The most clinically useful genetic association is that between carriers of the Fra-X premutation and ovarian failure. Fra-X premutations occur in 3% of women with sporadic POI and 15% of those with the familial form and this genetic test is the only one advised in the UK as part of routine work up of POI (Conway et al. 1998). In general, the phenotype of this subgroup of women with POI is indistinguishable from others, although a minority are reported to a progressive intention tremor. The pathway by which Fra-X premutations damage ovarian function is unclear as this type of expansion of exon 1 of the gene is not thought to effect protein transcription, even though the protein is expressed within the ovary.

41.3.2.2 Autoimmune Causes of POI Autoimmune mechanisms may be involved in pathogenesis of up to 30% of cases of POI (Welt 2008b; Wilson 2011). POI has been reported to be associated with various endocrine (thyroid, adrenal, hypoparathyroidism, diabetes mellitus,

G. S. Conway

and hypophysitis) and non-endocrine (chronic candidiasis, idiopathic thrombocytopenic purpura, vitiligo, alopecia, autoimmune haemolytic anaemia, pernicious anaemia, SLE, rheumatoid arthritis, Crohn’s disease, Sjogren’s syndrome, myasthenia gravis, primary biliary cirrhosis, and chronic active hepatitis) autoimmune disorders (La Marca et  al. 2010). In many cases, non-­ ovarian autoimmune involvement exists only at subclinical level (Wilson 2011). POI may be part of the autoimmune polyglandular syndromes (APS) when accompanied by other autoimmune endocrinopathies. POI is more common with APS types I and III than with APS type II. The single most common autoimmune association is with hypothyroidism which occurs in 10% of women with POI. Various pathways of autoimmune ovarian damage have been described, but a reliable ovarian specific autoimmune marker is still lacking. Several putative pathogenic autoantibodies have been explored (Melner and Feltus 1999). Anti-­ ovarian antibodies detected by routine immunofluorescence have been reported in several studies of women with POI, but their specificity and pathogenic roles are questionable. The incidence of anti-ovarian antibodies in POI in different studies has been reported to vary from 4 to 69% (Wheatcroft et al. 1997). Other candidate autoantibodies include those directed against steroidogenic enzymes (such as 3ß-hydroxysteroid dehydrogenase), gonadotropins and their receptors, the corpus luteum, zona pellucida, and oocyte. None of these, however, have been validated as a diagnostic marker of autoimmune ovarian failure. Therefore, in the clinical work up of POI, screening for an autoimmune aetiology is usually only possible by seeking coexisting autoimmune diseases. Women with idiopathic POI show an increased number of activated T cells in peripheral blood. Similar findings have been described in other autoimmune endocrinopathies, such as recent onset Graves’ disease, type 1 diabetes mellitus, and Addison’s disease. However, postmenopausal women also show raised numbers of activated peripheral T cells and oestrogen substitution has been shown to lower the number of activated

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

peripheral T cells in women with POI. Therefore, it is difficult to be certain whether the raised numbers of activated blood T cells is the cause or the result of ovarian failure in this situation (La Marca et al. 2010).

41.3.2.3 P  OI Resulting from Cancer Treatments As the number of survivors of childhood cancer increases across the world, iatrogenic POI develops in a greater proportion of women with this condition. Both chemotherapy, alkylating agents in particular, and radiotherapy used in the treatment of cancer or benign diseases are damaging to the ovary (Wallace et al. 2005; Morgan et al. 2012). The return of ovarian function after cancer treatment is commonly observed although difficult to predict. For women estimated to be at high risk of POI, oophorectomy or oocyte harvesting for cryopreservation may be considered (Wallace et al. 2012). 41.3.2.4 Miscellaneous Causes of POI Viral oophoritis is a possible occult aetiology that could theoretically account for the many cases of idiopathic POI.  There is, however, little direct evidence of viral ovarian damage beyond case reports such as mumps oophoritis (Morrison et  al. 1975). Cigarette smoking is known to be associated with earlier age of natural menopause, but whether environmental effects are sufficiently strong to cause POI is not known. The available data regarding effects of endocrine disruptors, heavy metals, solvents, pesticides, plastics, and industrial chemicals on female reproduction are equivocal (Sharara et al. 1998).

41.4 Hormone Replacement Therapy Box 41.1 presents an overview of the management and treatment of POI.  Physiological replacement of ovarian steroid hormones until the age of normal menopause at 50 is generally accepted as routine for women with POI, although there is little risk/benefit data for this young population. The principle of HRT use in young

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Box 41.1 An Overview of the Management of POI

Education and counselling • Return of ovarian function may occur in 5–10% of women with POI, but it is difficult to predict when and if this may happen. • Adoption and oocyte donation are the only realistic options for fertility, although cryopreservation of ovarian tissue is possible for those at risk of developing POI. • Access to follow-up counselling is important as issues return with life events such as a close friend or family member becoming pregnant. Investigations: • Thyroid function tests, vitamin B12 and ferritin to cover associated autoimmune conditions. • Autoantibody screen including thyroid and adrenal antibodies. • Karyotype for early-onset POI and genetic screen for FRAXA premutation. • Pelvic ultrasound and ovarian biopsy are not recommended. Treatment: • Oestrogen and progesterone replacement is usually indicated as individualised. • Education is required regarding risks and benefits of oestrogen preparations— oral, transdermal, and vaginal. • Inform on media HRT scares and relevance to young women. • Consider vaginal oestrogen and testosterone supplements.

women differs only slightly from that in older women with the main treatment goal being optimal quality of life. Young women may require a higher oestrogen dose than that used in an older age group. Also, expectations for sexual function

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can be higher commonly requiring consideration for vaginal oestrogen and androgen replacement. An HRT regimen should be based on the individual preferences of each patient who should be encouraged to undertake a trial and error approach through the wide variety of product available. Management of oestrogen replacement for young women presenting with primary amenorrhoea requires liaison with paediatric endocrinologists with experience in the induction of puberty in order to optimise breast and uterine development. For instance, a popular strategy is to maximise the time between the introduction of oestrogen and starting progesterone and withdrawal bleeding is thought to benefit breast development. Conversely, the common practice of starting a low dose-combined oral c­ ontraceptive in this circumstance may not offer the best outcome of uterine development. Among oral oestrogen choices, oestradiol esters and 17 beta-oestradiol provide the mainstay of treatments (Lobo 2017). Conjugated equine oestrogens are used less frequently than in the past because of a greater risk of hypertension and thrombosis compared to oestradiol (Swica et  al. 2018; Smith et  al. 2014). Some young women with POF find the combined oral contraceptive pills (COCP) a more acceptable option for oestrogen replacement, but careful assessment of the pill-free week is advised. The pill-­ free week amounts to 3  months of oestrogen deficiency each year, which may coincide with symptoms of oestrogen deficiency or bone loss. In choosing a type of COCP, those with lower dose ethinylestradiol and second-generation progestins have the lowest risk to thrombosis (Hugon-Rodin et al. 2014). Transdermal oestrogen avoids first-pass liver metabolism and involves noninvasive self-administration and attainment of therapeutic hormone levels with low daily doses (Henzl and Loomba 2003). This route of oestrogen administration also appears to be free of an excess risk of thrombosis. Subcutaneous oestrogen replacement involves placement of 25–50 mg oestradiol pellets usually in the lower abdomen or buttocks in a minor office procedure, which is not currently available

G. S. Conway

in some countries including the UK. Topical vaginal oestrogen may be used as an adjunct to systemic oestrogen. Creams, pessaries, tablets, and vaginal ring appear to be equally effective for control of symptoms (Faubion et al. 2017). Once the choice of oestrogen has been made, separate consideration can be given to the progestin in women with an intact uterus. Progestins vary from the more potent such as norethisterone to the weaker such as dydrogesterone. Trial and error will allow the user to find the most suitable progesterone preparation. The route may be oral, transdermal, vaginal, or uterine. With the oral and transdermal routes, there is a choice between continuous or sequential (for 10–14  days each month) delivery. Sequential regimen ensures monthly menstrual bleed. Continuous regimen avoids menstrual flow, but breakthrough bleeding may be more common in young women compared to an older age group in whom there is greater uterine atrophy. Uterine delivery with the levonogestrel intrauterine device (Mirena) has the advantage of avoiding the adverse effects of oral progestins highlighted in the studies of older women (Marjoribanks et al. 2017). Androgen replacement is useful in some instances when fatigue and loss of libido persist despite optimised oestrogen replacement (Wierman et al. 2014). Transdermal testosterone administration and dehydroepiandrosterone treatment are two of the options for androgen replacement in these women.

41.5 F  ertility Options for Women with POI Different fertility options will be appropriate for each individual with POI. It is important that discussions on this topic from a professional with experience in the field are made available not only soon after diagnosis, but at intervals throughout follow-up as the technology and opportunities in this field are continually developing. There are a number of psychological issues and ethical dilemmas that women face when considering fertility treatment options and it is very important to

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

discuss this with a specialist healthcare professional. Please refer to chapters on assisted fertility and psychological considerations in Part VI of this textbook for more details.

41.5.1 Spontaneous Fertility in POI Women with POI have a 5–10% chance of spontaneous conception at some time after diagnosis, as in some cases hormone levels and disease activity fluctuate and return to biochemical normality; this is often transient and the likelihood of recovery of ovulation is not possible to predict. Pregnancy loss in those who conceive is reported at 20%, which is similar to that of the normal population. Several medical therapies have been tried to induce ovulation in women with POI; however, in a systematic review, all were reported to be equally ineffective (van Kasteren et  al. 1999a). In particular, glucocorticoids have been considered for those with autoimmune markers, and although promising in early case reports, a controlled trial failed to show benefit (van Kasteren et al. 1999b).

41.5.2 Ovum Donation Assisted conception with donated oocytes has been used to achieve pregnancy in women with POI for over 20 years and remains the only realistic fertility treatment for the majority of women with established POI (Luisi et  al. 2015). The availability of donated oocytes varies from country to country and this option is not acceptable for some ethnic groups. Donated oocytes, fertilised with partner’s sperm, are observed on the usually way for the integrity of the embryo. The best embryo is chosen for implantation with the recipient having been prepared with increasing doses of oral estradiol. Because of the lack of a corpus luteum, progesterone support is required which can be administered orally, virginally, or by injection. Endometrial preparation is established in earlier dummy cycles.

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41.5.3 Embryo Cryopreservation Cryopreservation of embryos is a long established technique as part of in  vitro fertilization, but it will apply to only a small number of women with normal ovarian function who can anticipate imminent ovarian failure but have sufficient time to allow for controlled ovarian hyperstimulation (Wallace et  al. 2005). This circumstance might arise in some cases of malignancy or in someone who is known to be at risk of ovarian failure such as those with X chromosome anomalies or Fra-X premutation who may wish to delay starting a family for some years. Donor sperm could be used for those without a partner.

41.5.4 Oocyte Cryopreservation Cryopreservation of oocytes has become popular since the advent of vitrification, which improved the freezing process for such a large cell. Vitrification involves rapid cooling in high concentrations of penetrating cryoprotectants, which avoids formation of intracellular ice and resulting damage during cooling and warming. In vitro maturation of oocytes, where immature oocytes are retrieved from unstimulated ovaries, has also emerged as a safe and effective treatment for women with cancer who are undergoing gonadotoxic therapy. Oocyte cryopreservation also requires controlled ovarian stimulation, but in contrast to preservation of embryos, no sperm is required. In practice, this option is only applicable to women with normal ovarian function and who are old enough for oocyte harvesting. The success rate for achieving pregnancy is likely to be lower than that for embryo cryopreservation because oocyte survival and subsequent fertilisation are impaired. This option has been used for women with Turner Syndrome who retain some ovarian function (El-Shawarby et al. 2010), but so far the overall success rate is not known for this subgroup compared to the more common application in women diagnosed with cancer.

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41.5.5 Ovarian Tissue Cryopreservation The use of ovarian tissue cryopreservation for later use has been explored in young women undergoing anticancer treatment. Cryo­ preservation of one ovary or strips of ovarian cortical tissue has resulted in the birth of over 12 children according to a review in 2012 (Wallace et al. 2012). This procedure has the advantage of not requiring sperm and being appropriate for prepubescent girls accepting that a laparoscopy is required. The cryopreserved tissue can be reimplanted into the pelvis with ovulation and pregnancy occurring spontaneously or after IVF. Once again, it is too early to be certain of the overall success rate of this procedure, which is only undertaken in specialist oncology centres.

Box 41.2 Patient Case Study and Key Learning Points

I’m 20  years old and I was diagnosed with Premature Ovarian Insufficiency (POI) at the age of 16 back in December 2014. I was only 16, so it wasn’t something that I thought about when I didn’t progress through puberty. I never even heard of the condition until I was diagnosed! So, what happened with me was that I noticed I had never had a period and thought my body shape was not normal for a girl of my age at the time. My mum and I decided to go to my GP who then referred me to the gynaecological unit where I underwent various tests. Then, a few weeks later, the doctor simply sat us down and told us straight— “Your ovaries are not working.” For me, I wasn’t shocked. To me, it just sounded something unusual that I would clearly have to live with and get on with. My mum, on the other hand, was very concerned as mums would be. She cried when we got home, and I just said to her, “It’s okay mum! It’s not terrible! I’m like Monica from Friends!!” However, for her it was awful because earlier on that year my sis-

G. S. Conway

41.6 Nursing Considerations in the Care of Patients with POI POI can be a devastating condition, especially when women are diagnosed at a very early age. The nurse has a crucial role in providing holistic care and taking into consideration many aspects of patient’s life as well as their treatment and management of their condition. Many women with POI require multidisciplinary approach in their care and nurses are key to coordinating and providing a seamless care across settings and disciplines. The case study in Box 41.2 describes the complexities of the condition and the emotional distress patients with POI have to face at the time of diagnosis and throughout life.

ter lost one of her ovaries due to a cyst, which was such a hard time for her and mum. Looking at it that way, one daughter was potentially at risk of not conceiving, whereas the other daughter couldn’t, so no wonder my mum was in heartache! It all happened in 1 year to both of her girls. 2015 was the toughest year I’ve faced as I struggled immensely with anxiety. To this day, I still struggle a bit about my health, but not as much as I did then. I was doing my A-Levels which brought so much stress, and on top of that, I had many hospital appointments following on from my condition. I do look back at that year and think, “How did I manage?” One bad day, especially, was my 17th birthday and I was coming home from London and I remember getting on a train and just felt so shaky, sweaty, dizzy, and was having a panic attack. I told my mum that we needed to get off the train and I just cried in her arms on a bench at the station. That was the worst it got for me! I had had minor panic attacks in bed where I would sweat and shake, but having one in public made it all more concerning. This was all

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy

brought on mainly because I was worrying about my health every second of everyday! So, I decided to do something about it! I started yoga (today, I just do meditation, I find the physical stuff not that relaxing can I just say?! Dance instead!) which really helped! Massively! I wanted to care for myself and help myself get better in my own way. I didn’t see a therapist because, honestly, I didn’t think I was bad enough and understood that it was just something I needed to tackle myself. But self-help books do put you on the right track! I could natter all day, but I really do hope this little segment of my story and experiences help other teenagers out there. What I want my story to do is raise awareness about teen ovarian failure and the mental health that comes along with that. It is a shock and understandably so and I want other teenagers to know that they are not alone. I want to start meeting other girls and share our experiences together, so we can learn from each other and help each other. That is my main aim for the future. After all, this condition is for life, so why not make a positive out of it?!

Patient advocacy groups play a crucial (Box 41.3) role in raising awareness of the condition and providing peer support for patients. They are also a highly valuable resource of information for

Box 41.3 The Role of Daisy Network, Patient Advocacy Group, in POI

The Daisy Network is the only UK-registered charity dedicated to providing free information and support to women with Premature Ovarian Insufficiency (POI). It is run solely by volunteers. Our aim is to provide up-todate medical information about POI and treatment options available to sufferers and to provide a support network of people to talk to for those newly diagnosed, in addition to continually raising awareness of the con-

813

Key learning points: • Having a life-changing diagnosis of POI during adolescence can be devastating for the patient and requires very careful handling and disclosing of information. • It is important to take into consideration the home environment and other factors that may influence the outcome of accepting and coping with the diagnosis. Parents also need to be supported in this journey and not excluded from care planning and shared decision-making. • Most patients will not require regular visits and follow-ups, but it is crucial to plan for adequate support during transition periods such as going to university or very stressful periods such as taking exams, starting a relationship, or planning for a family. • Patients find peer support exceptionally beneficial at learning about and coping with their condition and improving their self-management and adherence to medication. Providing them with access to peer groups or patient advocacy groups can be very beneficial for patient and their families.

patients and their families and it is important to maintain a close working relationship with the clinical teams.

dition among doctors and the broader medical community.

The Daisy Visit us on: https://www. Network daisynetwork.org.uk/ PO BOX 71432 Contact us on: info@ daisynetwork.org.uk London SW6 Twitter and Instagram: @ 9HJ thedaisynet

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41.7 Conclusions The lifespan of the ovary is occasionally interrupted by pathological processes, some known but many unknown. Premature ovarian insufficiency can be a devastating diagnosis for a teenager or for someone who has yet to start a family. Knowledge of the pathogenesis of the condition as well as treatment options in terms of hormones and assisted fertility is a important skill for a nurse practitioner in endocrinology, paediatrics, and reproductive medicine. Acknowledgments Special thanks to Marie Gerval, Co-Chair, The Daisy Network (www.daisynetwork.org. uk) for the contribution to this chapter with a case study and information on the Patient Advocacy Group.

References Bachelot A, Nicolas C, Bidet M, Dulon J, Leban M, Golmard JL, et  al. Long-term outcome of ovarian function in women with intermittent premature ovarian insufficiency. Clin Endocrinol (Oxf). 2017;86:223–8. Baronchelli S, Conconi D, Panzeri E, Bentivegna A, Redaelli S, Lissoni S, et  al. Cytogenetics of premature ovarian failure: an investigation on 269 affected women. J Biomed Biotechnol. 2011;2011:370195. Baronchelli S, Villa N, Redaelli S, Lissoni S, Saccheri F, Panzeri E, et  al. Investigating the role of X chromosome breakpoints in premature ovarian failure. Mol Cytogenet. 2012;5:32. Cameron-Pimblett A, La Rosa C, King TFJ, Davies MC, Conway GS.  The Turner syndrome life course project: karyotype-phenotype analyses across the lifespan. Clin Endocrinol (Oxf). 2017;87:532–8. Conway GS.  Premature ovarian failure and FMR1 gene mutations: an update. Ann Endocrinol (Paris). 2010;71:215–7. Conway GS, Kaltsas G, Patel A, Davies MC, Jacobs HS. Characterization of idiopathic premature ovarian failure. Fertil Steril. 1996;65:337–41. Conway GS, Payne NN, Webb J, Murray A, Jacobs PA.  Fragile X premutation screening in women with premature ovarian failure. Hum Reprod. 1998;13:1184–7. Davis SR, Lambrinoudaki I, Lumsden M, Mishra GD, Pal L, Rees M, et  al. Menopause. Nat Rev Dis Primers. 2015;1:15004. Davison RM, Davis CJ, Conway GS.  The X chromosome and ovarian failure. Clin Endocrinol (Oxf). 1999;51:673–9. Desai S, Rajkovic A.  Genetics of reproductive aging from gonadal dysgenesis through menopause. Semin Reprod Med. 2017;35:147–59.

G. S. Conway El-Shawarby SA, Sharif F, Conway G, Serhal P, Davies M.  Oocyte cryopreservation after controlled ovarian hyperstimulation in mosaic Turner syndrome: another fertility preservation option in a dedicated UK clinic. BJOG. 2010;117:234–7. Faubion SS, Sood R, Kapoor E. Genitourinary syndrome of menopause: management strategies for the clinician. Mayo Clin Proc. 2017;92:1842–9. Ferrarini E, Russo L, Fruzzetti F, Agretti P, De Marco G, Dimida A, et  al. Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. Maturitas. 2013;74:61–7. Henzl MR, Loomba PK.  Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. J Reprod Med. 2003;48:525–40. Hugon-Rodin J, Gompel A, Plu-Bureau G. Epidemiology of hormonal contraceptives-related venous thromboembolism. Eur J Endocrinol. 2014;171:R221–30. La Marca A, Brozzetti A, Sighinolfi G, Marzotti S, Volpe A, Falorni A.  Primary ovarian insufficiency: autoimmune causes. Curr Opin Obstet Gynecol. 2010;22:277–82. Lobo RA.  Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13:220–31. Luisi S, Orlandini C, Regini C, Pizzo A, Vellucci F, Petraglia F.  Premature ovarian insufficiency: from pathogenesis to clinical management. J Endocrinol Invest. 2015;38:597–603. Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J.  Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1:CD004143. Master-Hunter T, Heiman DL.  Amenorrhea: evaluation and treatment. Am Fam Physician. 2006; 73:1374–82. Melner MH, Feltus FA.  Autoimmune premature ovarian failure—endocrine aspects of a T cell disease. Endocrinology. 1999;140:3401–3. Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L. Fragile X syndrome: an overview and update of the FMR1 gene. Clin Genet. 2018;93:197–205. Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T.  Symptoms of menopause—global prevalence, physiology and implications. Nat Rev Endocrinol. 2018;14:199–215. Morgan S, Anderson RA, Gourley C, Wallace WH, Spears N.  How do chemotherapeutic agents damage the ovary? Hum Reprod Update. 2012;18:525–35. Morrison JC, Givens JR, Wiser WL, Fish SA.  Mumps oophoritis: a cause of premature menopause. Fertil Steril. 1975;26:655–9. Nelson LM.  Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360:606–14. Reynaud K, Cortvrindt R, Verlinde F, De Schepper J, Bourgain C, Smitz J.  Number of ovarian follicles in human fetuses with the 45,X karyotype. Fertil Steril. 2004;81:1112–9. Sassarini J, Lumsden MA. Oestrogen replacement in postmenopausal women. Age Ageing. 2015;44:551–8.

41  Premature Ovarian Insufficiency, Menopause, and Hormone Replacement Therapy Sharara FI, Seifer DB, Flaws JA.  Environmental toxicants and female reproduction. Fertil Steril. 1998;70:613–22. Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174:25–31. Swica Y, Warren MP, Manson JE, Aragaki AK, Bassuk SS, Shimbo D, et  al. Effects of oral conjugated equine estrogens with or without medroxyprogesterone acetate on incident hypertension in the Women’s Health Initiative hormone therapy trials. Menopause. 2018;25(7):753–61. van Kasteren YM, Hundscheid RD, Smits AP, Cremers FP, van Zonneveld P, Braat DD. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod. 1999a;14:2455–9. van Kasteren YM, Braat DD, Hemrika DJ, Lambalk CB, Rekers-Mombarg LT, von Blomberg BM, et  al. Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril. 1999b;71:90–5. van Noord PA, Dubas JS, Dorland M, Boersma H, te Velde E.  Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil Steril. 1997;68:95–102. Visser JA, Schipper I, Laven JS, Themmen AP.  Anti-­ Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol. 2012;8(6):331–41. Wallace WH, Anderson RA, Irvine DS. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol. 2005;6:209–18. Wallace WH, Kelsey TW, Anderson RA.  Ovarian cryopreservation: experimental or established and a cure for the menopause? Reprod Biomed Online. 2012;25:93–5. Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, et  al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31:926–37. Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf). 2008a;68:499–509.

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Welt CK. Autoimmune oophoritis in the adolescent. Ann N Y Acad Sci. 2008b;1135:118–22. Wheatcroft NJ, Salt C, Milford-Ward A, Cooke ID, Weetman AP.  Identification of ovarian antibodies by immunofluorescence, enzyme-linked immunosorbent assay or immunoblotting in premature ovarian failure. Hum Reprod. 1997;12:2617–22. Wierman ME, Arlt W, Basson R, Davis SR, Miller KK, Murad MH, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3489–510. Wilson C.  Autoimmunity: autoimmune Addison disease and premature ovarian failure. Nat Rev Endocrinol. 2011;7:498.

Key Reading 1. Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31:926–37. 2. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et  al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177:G1–G70. 3. Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary ovarian insufficiency. Clin Genet. 2017;91:183–98. 4. Desai S, Rajkovic A. Genetics of reproductive aging from gonadal dysgenesis through menopause. Semin Reprod Med. 2017;35:147–59. 5. Lobo RA.  Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13:220–31. 6. Sullivan SD, Sarrel PM, Nelson LM.  Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril. 2016;106:1588–99. 7. Luisi S, Orlandini C, Regini C, Pizzo A, Vellucci F, Petraglia F.  Premature ovarian insufficiency: from pathogenesis to clinical management. J Endocrinol Invest. 2015;38:597–603.

The Endocrine System and Pregnancy

42

Margaret Eckert-Norton and Saundra Hendricks

Contents 42.1   Introduction

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42.2   Normal Glucose Metabolism During Pregnancy

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42.3   Type 1 Diabetes

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42.4   Type 2 Diabetes

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42.5   Preconception Planning

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42.6   Gestational Diabetes

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42.7   Management of Diabetes During Pregnancy 42.7.1  Additional Surveillance 42.7.2  Medical Nutrition Therapy 42.7.3  Insulin Therapy 42.7.4  Multiple Daily Injections (MDI) 42.7.5  Continuous Subcutaneous Insulin Infusion (CSII) 42.7.6  Intrapartum with CSII 42.7.7  Oral Diabetes Agents

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42.8   Maternal and Foetal Complications of Diabetes in Pregnancy

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42.9   The Thyroid Gland and Pregnancy 42.9.1  Review of Thyroid Physiology 42.9.2  Hypothyroidism 42.9.3  Gestational Transient Thyrotoxicosis 42.9.4  Hyperthyroidism 42.9.5  Post-partum Thyroiditis 42.9.6  Thyroid Nodules in Pregnancy and Thyroid Cancer 42.9.7  Screening for Thyroid Disorders During Pregnancy

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M. Eckert-Norton St. Joseph’s College and SUNY Downstate, Brooklyn, NY, USA e-mail: [email protected]; [email protected] S. Hendricks (*) Department of Medicine, Center of Bioenergetics, Houston Methodist Hospital, Houston, TX, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_42

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M. Eckert-Norton and S. Hendricks

818 42.9.8 

 ummary of Thyroid Disorders During Pregnancy S and Nursing Considerations

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42.10   Other Endocrine Considerations During Pregnancy

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42.11   Hypothalamic-Pituitary-­Adrenal Axis

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42.12   Parathyroids and Maintaining Calcium Balance

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42.13   Placenta as an Endocrine Organ

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42.14   Endocrine Disruptors in Human Reproduction and Health

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42.15   Precautionary Principle and Implications for Nursing Practice

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42.16   Conclusions

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References 

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Abstract

Healthy endocrine function is vital for fertility, normal foetal growth and development, labour and delivery, and postnatal breast feeding. In disease states such as diabetes, attention must be given to preconception planning and management of concomitant issues through a pregnancy. Both hypoglycaemia and hyperglycaemia can be teratogenic, resulting in poor maternal and/or foetal outcomes. Likewise, maternal thyroid function must be maintained in the euthyroid range to avoid significant foetal neural damage from hyperor hypothyroidism. Monitoring and adjustments of thyroid replacement at each trimester are recommended to parallel increasing foetal requirements. Pituitary dysfunction may become apparent during pregnancy as the gland enlarges. Prolactin levels will normally rise in response to rising oestrogen levels, but may also stimulate the growth of a prolactinoma. Hypothalamicpituitary-­adrenal dysfunction is uncommon, but may result for other dysfunctions. Successful pregnancy outcomes require pre-­pregnancy patient counselling, planning, and ongoing monitoring of patient responses. This continues through pregnancy and the post-­partum period. Keywords

Pregnancy · Diabetes type 2 · Thyroid function · HPA axis · Parathyroid disease

Abbreviations CSI

Continuous subcutaneous insulin infusion DM1 Type I diabetes DM2 Type 2 diabetes GDM Gestational diabetes HA1c Haemoglobin A1c hCG Human chorionic gonadotropin MDI Multiple daily injections MM Methimazole Mnt Medical nutrition PPT Post-partum thyroiditis PTU Propylthiouracil RAI Radioactive iodine SMBG Self-monitoring of blood glucose T3 Tri-iodothyronine T4 Thyroxine TRH Thyroid-releasing hormone TSH Thyroid-stimulating hormone TSI Thyroid-stimulating immunoglobin μg Micrograms Key Terms • Pre-gestational Diabetes: Maternal hyperglycaemia secondary to inadequate insulin and/or resistance to insulin action prior to pregnancy. • Gestational Diabetes: Maternal blood glucose elevation of variable degree with onset or recognition during pregnancy. • Teratogen: Any agent that causes an abnormality following foetal exposure during pregnancy.

42  The Endocrine System and Pregnancy

• Human Chorionic Gonadotropin (HCG): A placental hormone that stimulates production of progesterone from the corpus luteum, supporting the placenta during the early stages of pregnancy. • Foetal Immunological Privilege: Physiological condition in pregnancy in which the foetus is protected from attack from the maternal immune system. • Post-partum Thyroiditis (PPT): Inflammation of the maternal thyroid gland occurring during the first few months after the birth of a baby. • Progesterone: A hormone secreted by the corpus luteum and the placenta that triggers the uterine lining to thicken to accept a fertilized egg. Progesterone decreases uterine contractions, stimulates blood supply to the endometrium, and suppresses further ovulation during pregnancy. • Endocrine Disrupting Chemicals (EDCs): These are chemicals and compounds that may interfere with the endocrine system producing adverse developmental, reproductive, neurological, and/or immune effects in humans and other organisms. • Precautionary Principle: A foundational concept of environmental regulation in many countries emphasizing that if threats of serious or irreversible damage to the environment exist, the lack of full scientific certainty should not be used as a reason for postponing costeffective measures to preserve the environment and protect the health of living organisms.

Key Points

• Uncontrolled diabetes pre-pregnancy and during pregnancy can have serious adverse effects on both mother and developing foetus that can be minimized with optimal blood sugar level treatment and control. • Aggressive screening of women at risk for thyroid disorders in the prenatal period and through each trimester of

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pregnancy is essential to ensure normal foetal development. • The pituitary gland enlarges during pregnancy; prolactin level increases and may impact the hypothalamic-pituitary-­ adrenal axis function. • Peptide hormones produced by the placenta, hypothalamus, and the pituitary such as: gonadotropin-releasing hormone, corticotrophin-releasing hormone and growth hormone-releasing hCG, growth hormone, are important for sustaining pregnancy and regulating growth and development. • Endocrine disruptors have been linked to reproductive dysfunction in men and women and the generational development of some diseases.

42.1 Introduction This chapter presents current concepts related to the nursing care of pregnant woman with disorders of the endocrine system. While the emphasis is placed on the most commonly encountered clinical issues, other, less common, though clinically relevant, issues are also discussed. The significant role of the placenta as an active endocrine organ is reviewed. Emerging data regarding exposure to endocrine-­disrupting compounds and the impact of these compounds on maternal-foetal health outcomes is explored. The most commonly occurring forms of diabetes are categorized into three major types: Type 1 diabetes, Type 2 diabetes, and Gestational diabetes. Each of these types of diabetes has distinct clinical presentations and management varies widely. There are potential complications for the pregnant woman and her baby that result from poor control of diabetes of any type. The following section discusses normal glucose metabolism in pregnancy and each of the three common types of diabetes as they relate to the pregnant woman and developing foetus.

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42.2 N  ormal Glucose Metabolism During Pregnancy Glucose is the primary foeto-placental fuel and its transport across the placenta is in proportion to the maternal glucose level. In order to adapt to the challenge of meeting the glucose needs of both the mother and the growing foetus, the maternal metabolism undergoes adaptations throughout pregnancy. The primary purpose of these adaptations is to prepare for the accelerated foetal growth in the last trimester when approximately 70% of foetal growth occurs. During early gestation, maternal nutrient and fat stores increase with minimal changes in insulin sensitivity, in order to prepare for the nutritional demands of late gestation and lactation. By late gestation, insulin sensitivity decreases (increased insulin resistance) with a twofold increase in mean circulating insulin and 30% increase in hepatic glucose production from the maternal liver. The resulting increases in maternal blood glucose and fatty acids provide fuel for the developing foetus. Due to high foeto-­placental fuel demands, maternal fasting glucose falls in spite of the increased hepatic glucose production (Lain and Catalano 2007). If foetal glucose demands cannot be met due to maternal malnutrition or illness, the foetus can utilize alternate fuels from breakdown of maternal fatty acids (FeldtRasmussen and Mathiesen 2011). Because maternal insulin does not cross the placenta, early foetal insulin production is vital for foetal utilization of fuels. Both the ambient maternal glucose level and glucose spikes stimulate foetal insulin production (Feldt-Rasmussen and Mathiesen 2011). Other specific types of diabetes exist due to causes such as cystic fibrosis, HIV/AIDS, medications, and organ transplantation. As these are relatively rare, for the purposes of this chapter, we will focus on the first three classifications: Type 1 diabetes, Type 2 diabetes, and Gestational diabetes.

42.3 Type 1 Diabetes Type 1 diabetes (formally called juvenile diabetes) accounts for 5–10% of individuals with diabetes. It can occur at any age and is caused by

M. Eckert-Norton and S. Hendricks

cellular-mediated autoimmune destruction of pancreatic beta cells, the cells that produce insulin. The destructive process takes months, but eventually results in insulinopenia (the decreased or absent insulin levels). The signs and symptoms can be sudden and dramatic at diagnosis. Signs and symptoms include: extreme thirst, frequent urination, and weight loss. Treatment is aimed at achieving optimal glucose levels by replacing the hormone insulin that the pancreas can no longer produce. People with type 1 diabetes require insulin replacement for survival (Guthrie and Guthrie 2004).

42.4 Type 2 Diabetes Type 2 diabetes is caused by a loss of balance between insulin sensitivity and insulin secretion. Unlike type 1 diabetes, in type 2 diabetes the pancreas produces insulin, but peripheral tissues lose sensitivity to insulin action, a process known as insulin resistance. Early in the disease process, insulin levels are often elevated with normal glucose levels. Over a period of months or years, the beta cells cannot produce enough insulin to maintain normoglycaemia and hyperglycaemia ensues. Predisposing factors for Type 2 diabetes include obesity, sedentary lifestyle, family history, puberty, ethnicity, and advancing age. Unlike Type 1 diabetes, the onset of Type 2 diabetes is insidious and the diagnosis can be delayed for years after the onset of hyperglycaemia, setting the stage for long-term complications. Ninety to ninety-five percent of people with diabetes have Type 2 diabetes (CDC 2011). Type 2 diabetes occurs across a wide range of ages (adolescence through advanced maturity) and disproportionately affects ethnic minorities in the U.S. Worldwide prevalence of 8.5% (WHO 2017). It is currently estimated that 12.7% of adults of African descent have Type 2 diabetes as compared to 7.4% in whites, and prevalence rates have more than doubled over in the 10 years previous to 2011, but has decreased a little in recent years (CDC 2017). Rates of Type 2 diabetes are rapidly increasing in youth who are of Latino, Native American, or Asian/Pacific Island descent. According to the

42  The Endocrine System and Pregnancy

National Institutes of Diabetes and Digestive and Kidney Disease (NIDDK) in 2017, 11.7% of all women age 20 years and older have diabetes. This explosion of type 2 diabetes has resulted in a higher than expected rate of pre-­gestational diabetes in women of childbearing age. In the past, pre-gestational diabetes was usually assumed to be Type 1 diabetes. In recent years, the increasing rate of obesity and Type 2 diabetes in adolescents has resulted in an increase in the number of pregnancies complicated by pre-­ gestational Type 2 diabetes. Over time, as the recommendations for earlier testing are widely adopted, the number of preexisting diabetes pregnancies will climb. In any case, no matter the cause of the maternal hyperglycaemia, the resulting foetal hyperglycaemia is a potent teratogen, an agent that causes foetal malformation.

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pregnancy should begin during puberty and continue into adulthood for women with diabetes or who are in a high-risk population for developing diabetes (ADA 2018). Additionally, maternal risks of developing new or progression of existing eye and renal complications are increased during pregnancy in women with pre-gestational diabetes. Eye and renal examinations should begin prior to conception with close follow-up during pregnancy and for 1  year post-partum. Optimally, treatments for preexisting eye, renal, neuropathic, and cardiovascular disease begin prior to conception (Blumer et al. 2013).

42.6 Gestational Diabetes

It is estimated that 2–10% pregnancies are affected by gestational diabetes (GDM). Hyperglycaemia in pregnancy has been associ42.5 Preconception Planning ated with high birth weight above the 90th percentile, increased rates of caesarean sections, Initiating meticulous metabolic management neonatal hypoglycaemia, and foetal hyperinsuprior to conception is critical to the successful linaemia. Mothers have a higher risk for pre-­ outcome of diabetic pregnancies. The importance eclampsia, preterm delivery. The impact on the of preconception planning and counselling can- neonate could include: shoulder dystocia, hypernot be overstated in this high-risk population of bilirubinaemia, and may trigger the need for neowomen with preexisting diabetes (Type 1 or Type natal intensive care admission. 2). When pregnancy is planned, many non-­insulin GDM has been defined as any degree of glutherapies including blood pressure and cose intolerance first identified during pregnancy cholesterol-­lowering medications may need to be without regard to undetected pre-gestational stopped or changed. The Endocrine Society hyperglycaemia (Expert Committee on the Guidelines recommend that blood pressure con- Diagnosis and Classification of Diabetes Mellitus trol of  30 years 3. Symptoms of thyroid disorder or presence of a goitre (enlarged thyroid gland) 4. Women with known thyroid antibodies 5. Women with Type 1 diabetes or other autoimmune diseases 6. History of miscarriage or preterm delivery 7. History of head or neck radiation 8. Family History of thyroid dysfunction 9. Morbid obesity (BMI ≥ 40 kg/m2) 10. Use of amiodarone, or lithium or recent administration of iodine contrast media 11. Infertility 12. Residing in an area of known moderate to severe iodine insufficiency (Stagnaro-Green et al. 2011)

M. Eckert-Norton and S. Hendricks

42.10 Other Endocrine Considerations During Pregnancy Many endocrine disorders are related to autoimmune responses. Whenever preexisting autoimmune processes are present, endocrine disorders are more likely and must be monitored during pregnancy.

42.11 Hypothalamic-Pituitary-­ Adrenal Axis

The maternal pituitary gland increases markedly in size in response to increased oestrogen levels in pregnancy. A normal pituitary is approximately 6  mm size in non-pregnant women, but may enlarge to 12 mm by 1 week post-partum. This activity correlates with rising prolactin levels (Feldt-Rasmussen and Mathiesen 2011). Typically, the pituitary will return to normal size within 6 months after delivery. Cortisol, secreted from the adrenal glands, increases throughout pregnancy and surges during labour. Both the maternal hypothalamus and the placenta stimulate this increase in cortisol production through increase in adrenocorticotrophic-stimulating 42.9.8 Summary of Thyroid hormone (ACTH) from the pituitary and placenDisorders During Pregnancy tal corticotrophin-releasing hormone (CRH). In and Nursing Considerations the course of normal pregnancy, maternal free cortisol may increase threefold. In response to The goal of nursing care of pregnant women with increased oestrogen, binding proteins are also thyroid disorders is to support optimal thyroid increased, decreasing the amount of free cortisol function throughout the entire gestational period that will cross the placenta (Feldt-Rasmussen and post-partum. Optimal thyroid function is and Mathiesen 2011; Smith et  al. 2011) (See supported by adequate iodine intake, pre-­ Chap. 12). Of all neuroendocrine tumours, prolactinomas gestational counselling and evaluation, aggressive screening of women at risk for thyroid are by far the most common, accounting for disorders, and nursing interventions to facilitate about 40% of all pituitary tumours. The prevaadherence to medically prescribed treatment reg- lence of prolactinomas in the general population imens. Thyroid function is assessed by clinical is estimated to be 100 per million (Mann 2011). presentation and laboratory measurement of thy- Prolactinomas most commonly occur in women roid hormone production. Understanding thyroid of childbearing age. Galactorrhea and amenorphysiology is foundational to professional nurs- rhea are common presenting symptoms. ing care and serves as the basis for advocacy, Treatment can include surgery, radiotherapy, and/ education, and counselling for women with thy- or medication, depending on tumour size and presenting symptoms. The drugs most commonly roid disorders during pregnancy.

42  The Endocrine System and Pregnancy

used for treatment are the dopamine-receptor agonists, bromocriptine and cabergoline. When treated with dopamine-receptor agonists, many women will respond favorably with restored fertility. Treatment may be stopped when pregnancy occurs, although bromocriptine has an excellent safety record during pregnancy and cabergoline data seem promising regarding safety during pregnancy (Molitch 2010) (See Chap. 19).

42.12 Parathyroids and Maintaining Calcium Balance

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p­ reventing rejection of the foetal tissue and conferring foetal immunological privilege. Progesterone is also a potent inhibitor of smooth muscle contractility and prevents contractions of the uterine myometrium until the onset of labour. Additionally, progesterone serves as a substrate for the production of foetal adrenal hormones such as cortisol and aldosterone (Feldt-­Rasmussen and Mathiesen 2011). Examples of placental peptide synthesis include hypothalaminc-like hormones (e.g. Gonandotropin-releasing hormone, corticotrophin-­ releasing hormone, and growth hormone-releasing hormone) and pituitary-like hormones such as hCG, growth hormone, and other growth factors including insulin-like growth factors (e.g. IgF1 and IgF2). These peptide hormones are important for sustaining pregnancy and regulating growth and development. It is of interest that there is no neuronal control of placental peptide hormones and the exact mechanism of feedback to regulate placental peptide hormones is unknown (FeldtRasmussen and Mathiesen 2011).

Maternal parathyroid hormone levels are relatively stable during pregnancy. In the first trimester, maternal absorption of calcitonin (vitamin D3) results in increased calcium absorption. The resulting increase in calcium may be stored in the maternal skeleton in preparation for increased demand for maternal calcium from the developing foetus later in pregnancy. This increase in calcium may also explain in part the increased risk for kidney stone in the pregnant women (Feldt-­ Rasmussen and Mathiesen 2011). 42.14 Endocrine Disruptors

42.13 Placenta as an Endocrine Organ The placenta allows both maternal and foetal circulation to be in close proximity to each, while preventing actual mixing of the two systems. During pregnancy, the respiratory, alimentary, and excretory needs of the developing foetus are addressed by the placenta. Throughout pregnancy, the placenta plays an important role in the synthesis of both steroid hormones (derived from LDL cholesterol) and peptide hormones (derived from protein precursors). An example of placental steroid hormone synthesis is progesterone production. During gestation, progesterone secretion is predominantly associated with placental and decidual production. In conjunction with hCG and cortisol, progesterone inhibits the maternal immune system by diminishing T-lymphocyte activity, thus

in Human Reproduction and Health

Over the last decade, there has been increasing awareness of the hazard posed by substances known as endocrine disruptors or endocrine disrupting chemicals/compounds (EDCs). According to The Endocrine Society’s 2009 scientific statement, EDs are defined from a physiological perspective as “...a compound, either natural or synthetic, which, through environmental or inappropriate developmental exposures, alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to the environment” (Diamanti-­ Kandarakis et al. 2009: 2). EDCs are associated with multiple reproductive and developmental problems including, but not limited to: delayed conception, infertility, spontaneous abortion, still birth/neonatal death, preterm birth, congenital anomalies, low birth weight, developmental delays, and childhood cancers (Andersson et al.

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2012; Chalupka and Chalupka 2010; Diamanti-­ Kandarakis et al. 2009). Sources of EDs are diverse and prevalent including many commonly encountered substances such as some plastic bottles, metal food cans, detergents, computers, cell phones, flame retardants, food, toys, cosmetics, paints, varnishes, perfumes, soil, ground water, and pesticides (Chalupka and Chalupka 2010; Diamanti-Kandarakis et  al. 2009; Gilden et  al. 2010; National Institute of Environmental Health Sciences [NIEHS] Website 2012). Examples of just a few specific compounds that have been linked to endocrine disruption include: • Bisphenol A (BPA) which is found in some food and drink containers, hard plastic bottles, and some baby products • Glycol esters used in some paint, varnishes, and perfumes • Pesticides used to protect food in both residential and commercial settings • Phthalates added to some PVC plastics to soften them (plasticizers); also found in some cosmetics, perfumes, toys, and pharmaceuticals (Chalupka and Chalupka 2010) The Endocrine Society identifies five important issues in endocrine disruption: 1. Age at exposure: periods of foetal and neonatal development increase susceptibility to EDCs. 2. Latency from exposure: repercussions of developmental exposure may not be evident until many years later (e.g. puberty, adulthood, or aging). 3. Importance of mixtures: if a population is exposed to environmental contamination multiple compounds may be involved, some of which will have additive or synergistic impact. 4. Non-traditional dose-response dynamics: very low doses of EDCs may have enormous impact, mid-range doses may have enormous impact in some cases, and in other cases high doses may have enormous impact. In still other cases, the substance may be benign or possibly beneficial in low doses and hazard-

M. Eckert-Norton and S. Hendricks

ous in higher doses (U-shaped dose-response curve). 5. Transgenerational, epigenetic effects: EDCs may have an impact on future generations via alterations in regulation of gene expression (Diamanti-Kandarakis et al. 2009). Naturally occurring substances may also be endocrine disrupters. For example, soy baby formula contains plant-derived oestrogens known as phytoestrogens. Soy formula feeding by infant boys has been variably associated with changes in reproductive hormones, spermatogenesis, sperm capacitation, and fertility (Cederroth et al. 2010; Diamanti-Kandarakis et  al. 2009). Therefore, there may be some link between these naturally occurring compounds and future reproductive issues in men. A dilemma regarding exposure to EDCs is evident in breast and bottle feeding. If a mother has exposure to EDCs, it is possible that her breast milk may contain concentrated amounts of the hazardous compound. For infants who are fed formula, in addition to the soy issue, the cans in which formula is packaged may contain plasticizers, a potential source of EDCs. The implication to be drawn from these observations is that there is a developmental basis for adult disease. This concept is fundamental to our understanding of the impact of EDCs in human health across the life span (Diamanti-­ Kandarakis et al. 2009).

42.15 Precautionary Principle and Implications for Nursing Practice As explicated by the Science and Environmental Health Network (SEHN), the Precautionary Principle implies: “When the health of humans and the environment is at stake, it may not be necessary to wait for scientific certainty to take protective action” (SEHN Website 2012). The SEHN stresses the importance of action prior to deleterious health outcomes becoming widespread. The SEHN website offers four important strategies for implementing the Precautionary Principle. These strategies include:

42  The Endocrine System and Pregnancy “Exploring alternatives to possibly harmful actions, especially clean technologies that eliminate waste and toxic substances; placing the burden of proof on the proponents of an activity rather than on the victims or potential victims of the activity; setting and working toward goals that protect health and the environment; and bringing democracy and transparency to decisions affecting health and the environment” (SEHN 2012, FAQ).

The Endocrine Society 2009 scientific statement endorses the Precautionary Principle in addressing the issues raised by EDCs. Among the recommendations for clinical practice suggested in the scientific statement, several are particularly relevant to nursing practice. Nurses need to advise their clients, particularly women of childbearing age, about potential exposure to EDCs and ways to minimize risks of exposure. All health care professionals need to be educated about the potential impact of EDCs across the lifespan. Health care professionals need to: develop, and have access to, clear concise and accurate health education materials to share with patients. Clinicians need to be vigilant about detecting potential cases of EDCs exposure when documenting client health history (Chalupka and Chalupka 2010; Diamanti-Kandarakis et  al. 2009). Nurses are in a unique professional position to advocate for health policies related to endocrine disruptors, to develop community-­ specific educational tools, provide health counseling, and participate in case finding. The health of future generations may depend on what we as nurses do today.

42.16 Conclusions Endocrine function is both altered by pregnancy and is vital to the developing foetus and successful neonatal outcomes. Optimal endocrine function is vital for fertility and normal foetal growth and development. Successful pregnancy outcomes require pre-pregnancy patient counselling, planning, and ongoing monitoring of patient responses. Counselling continues throughout pregnancy and the post-partum period. Additionally, abnormalities in the endocrine system can impact labour and delivery and postnatal breast feeding. Women with

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diabetes, before and/or during pregnancy, must be given preconception planning and careful management to avoid adverse pregnancy outcomes resulting from hypoglycaemia and hyperglycaemia. Optimal maternal thyroid function must be maintained to avoid significant foetal neural damage from hyper or hypothyroidism. Hypothalamic-­ pituitary-­adrenal dysfunction is uncommon, but may present during gestation or post-partum. All families should be aware of EDCs and their potential impact on human health. Clinical Application Exercise Case Study 1 Sonia is a 32-year-old woman with Type I diabetes. She and her husband are school teachers. They have a daughter who is a healthy 3 year old. After her daughter was born, Sonia developed Grave’s disease for which she is still taking medication. Sonia is now pregnant with their second baby. Diabetes Management 1 unit of rapid-acting insulin is needed for each 15 g of carbohydrate and 1 unit of insulin will drop the glucose 20 mg/dL. Using these ratios, if a woman was planning to consume 45 g of carbohydrates and her glucose was 140 mg/dL and she wanted to drop her glucose to 100 mg/dL: 1. How many units would she need to cover her carbohydrate in her meal? 2. How many additional units would she need to bring her glucose down to 100 mg/dL? 3. What will the total number of units or preprandial insulin that she needs to inject (or program her pump to deliver)? 4. If your patient is using MDI or CSII, how would you prepare her for hypoglycaemia and hyperglycaemia? 5. List the three categories of diabetes that most impact pregnancy. 6. Describe the relative degree of insulin resistance during early vs. late pregnancy. 7. List the IADPSG diagnostic criteria. 8. Discuss the short- and long-term complications to the offspring of pregnancies complicated by gestational diabetes.

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9. Discuss the importance of preconception planning in pre-gestational diabetes for the foetus and for the mother. 10. Describe the components of an intensive insulin regimen. 11. Discuss the pros and cons of oral diabetes agents in pregnancy Thyroid Management 1. Does the region in which you practice have a readily available source of iodine? Read the labels of food you commonly consume. Is your iodine intake about 250 μg? 2. Explain the classic feedback loop between TRH, TSH, T3, and T4 3. Describe the potential threats to healthy pregnancy outcomes that result from hypothyroidism. 4. Describe the potential threats to healthy pregnancy outcomes that result from hyperthyroidism. 5. Discuss the concept of foetal immunological privilege. Other Considerations in Management 1. Explain the significance of endocrine disrupting compounds in human reproduction. 2. Apply the Precautionary Principle to nursing practice with women of childbearing age.

References American Diabetes Association [ADA]. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018. Diabetes Care. 2018a;41(Suppl 1): S13–27. American Diabetes Association [ADA]. Management of diabetes in pregnancy: standards of medical care in diabetes—2018. Diabetes Care. 2018b;41(Suppl 1): S137–43. https://doi.org/10.2337/dc18-S013. American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1086–133. https:// doi.org/10.1089/thy.2011.0087. Andersson A, Bay K, Grigor K, Meyts E, Skakkebæk N. Special issue on the impact of endocrine disrupters on reproductive health. Int J Androl. 2012;35(3):215. https://doi.org/10.1111/j.1365-2605.2012.01274.x.

M. Eckert-Norton and S. Hendricks Bernasko J. Insulin pump therapy for pregnancy: a primer. J Matern Fetal Neonatal Med. 2012;25:552–7. https:// doi.org/10.3109/14767058.2011.598586. Blumer I, Hadar E, Hadden DR, Jovanovič L, Mestman JH, Murad MH, Yogev Y. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metabol. 2013;98(11):4227–49. https:// doi.org/10.1210/jc.2013-2465. Carson M. Assessment and management of patients with hypothyroidism. Nurs Stand. 2009;23(18):48–56. Castorino K, Paband R, Zisser H, Jovanovic L.  Insulin pumps in pregnancy: using technology to achieve normoglycemia in women with diabetes. Curr Diab Rep. 2012;12:53–9. https://doi.org/10.1007/ s11892-011-0242-7. Cederroth CR, Auger J, Zimmermann C, Eustache F, Nef S.  Soy, phyto-oestrogens and male reproductive function: a review. Int J Androl. 2010;33(2):304–16. https://doi.org/10.1111/j.1365-2605.2009.01011.x. Centers for Disease Control [CDC] (2011). National Diabetes Fact Sheet 2017. Revised 2 July 2017. Retrieved 15 July 2018 from https://www.cdc.gov/ media/releases/2017/p0718-diabetes. Chalupka S, Chalupka A.  The impact of environmental and occupational exposures on reproductive health. J Obstet Gynecol Neonatal Nurs. 2010;39(1):84–102. https://doi.org/10.1111/j.1552-6909.2009.01091.x. Cheng YW, Block-Kurbisch I, Inturrisi M, Caughey AB.  Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatal Med. 2012;25:379–84. Chong H, See K, Phua J. Thyroid storm with multiorgan failure. Thyroid. 2010;20(3):333–6. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin R, Eastman C, Lazarus J, Luton D, Mandel S, Mestman J, Rovet J, Sullivan S. Executive summary: management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2543–65. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Thomas Zoeller RT, Gore AC.  Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30(4):293–342. http://www.endo-society.org/ journals/scientificstatements/upload/edc_scientific_ statement.pdf. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–97. Feldt-Rasmussen U, Mathiesen E.  Endocrine disorders in pregnancy: physiological and hormonal aspects of pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25(6):875–84. Fitzpatrick D, Russell M. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin N Am. 2010;37(2):173–93.

42  The Endocrine System and Pregnancy Galofre J, Davies T.  Autoimmune thyroid disease in pregnancy: a review. J Womens Health (Larchmt). 2009;18(11):1847–56. https://doi.org/10.1089/jwh.2008. 1234. Gilden R, Huffling K, Sattler B. Pesticides and health risks. J Obstet Gynecol Neonatal Nurs. 2010;39(1):103–10. https://doi.org/10.1111/j.1552-6909.2009.01092.x. Glinoer D, Spencer C.  Serum TSH determinations in pregnancy: how, when and why? Nat Rev Endocrinol. 2010;6(9):526–9. Guthrie RA, Guthrie DW.  Pathophysiology of diabetes mellitus. Crit Care Nurs Quart. 2004;27(2):113–25. EBSCOhost, ez.sjcny.edu/login? url=http://ez.sjcny. edu:2057/login.aspx?direct=true&db=rzh&AN=1067 66982&site=ehost-live&scope=site. Hoeks LB, Greven WL, de Valk HW.  Real-time continuous glucose monitoring system for treatment of diabetes: a systematic review. Diabetic Med. 2011;28(4):386–94. EBSCOhost. https://doi. org/10.1111/j.1464-5491.2010.03177.x. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycaemia in pregnancy. Diabetes Care. 2010;33:676–82. https://doi.org/10.2337/dc09-1848. Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, et  al. Managing preexisting diabetes for pregnancy. Diabetes Care. 2008;31:1060–79. Knowler WC, Hamman RF. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol. 2007;50:938–48. Lapolla AA, Dalfrà MG, Ragazzi EE, De Cata AP, Fedele DD. New international association of the diabetes and pregnancy study groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: a retrospective study on pregnancy outcome. Diabet Med. 2011;28(9):1074–7. https://doi. org/10.1111/j.1464-5491.2011.03351.x. Lutz C, Przytulski K. Nutrition and diet therapy: evidence-­ based applications. 4th ed. Philadelphia: F.A.  Davis; 2006. Mann W.  Treatment for prolactinomas and hyperprolactinaemia: a lifetime approach. Eur J Clin Investig. 2011;41(3):334–42. https://doi. org/10.1111/j.1365-2362.2010.02399.x. Metzger BE, Buchanan TA, Coustan DR, De Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the fifth international workshop-­conference on gestational diabetes mellitus. Diabetes Care. 2007;30: S251–60. https://doi.org/10.2337/dc07-s225.

835 Metzger BE, Lowe LP, Dyer AR, Trimble ER, Sheridan B, Hod M, et al. Hyperglycaemia and adverse pregnancy outcome (HAPO) study: associations with neonatal anthropometrics. Diabetes. 2009;58(2):453–9. Molitch M.  Prolactinomas and pregnancy. Clin Endocrinol. 2010;73(2):147–8. Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes. Obstet Gynecol. 2010;115:55–9. National Institute of Environmental Health Sciences [NIEHS] Website. 2012. http://www.niehs.nih.gov/ health/topics/agents/endocrine/index.cfm. Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes. Obstet Gynecol. 2009;113:193–205. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM. 2001;94:435–44. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003–15. http://www.NEJM.org Science and Environmental Health Network Website. 2012. Retrieved 9/4 at http://www.sehn.org/ppfaqs. html. Smith AK, Newport D, Ashe MP, Brennan PA, LaPrairie JL, Calamaras M, et  al. Predictors of neonatal hypothalamic-­pituitary-adrenal axis activity at delivery. Clin Endocrinol. 2011;75(1):90–5. https://doi. org/10.1111/j.1365-2265.2011.03998.x. Springer D, Jiskra J, Limanova Z, Zima T, Potlukova E. Thyroid in pregnancy: from physiology to screening. Crit Rev Clin Lab Sci. 2017;54(2):102–16. https:// doi.org/10.1080/10408363.2016.1269309. Epub 2017 Jan 19. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081–125. World Health Organization Fact Sheet Diabetes. Reviewed November 2017. http://www.who.int/news-room/fact-­ sheets/detail/diabetes. Accessed 15 July 2018. Yazbeck C, Sullivan S.  Thyroid disorders during pregnancy. Med Clin North Am. 2012;96(2):235–56. Zimmerman MB.  Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009;89(Suppl):668S–72S.

Part VII Male Endocrinology and Reproduction Andrew A. Dwyer and Sofia Llahana

Anatomy and Physiology of the Hypothalamic-Pituitary-­ Gonadal (HPG) Axis

43

Andrew A. Dwyer and Richard Quinton

Contents 43.1   The Hypothalamic-Pituitary-Gonadal (HPG) Axis  43.1.1  Normal Development and Function of the HPG Axis  43.1.2  Abnormal Development 

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43.2   Hormonal Control of the HPG Axis  43.2.1  Gonadotrophins  43.2.2  Gonadal Sex Steroids  43.2.3  Other Gonadal Peptides 

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43.3   Testicular Function  43.3.1  Seminiferous Tubules  43.3.2  Interstitial Compartment 

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43.4   Endocrine Aspects of Sexual Function  43.4.1  Sexual Desire  43.4.2  Erectile Function  43.4.3  Sexual Dysfunction 

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43.5   Conclusions 

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References 

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Abstract 

A. A. Dwyer (*) William F. Connell School of Nursing, Chesnut Hill, MA, USA Boston College, Chesnut Hill, MA, USA e-mail: [email protected] R. Quinton Newcastle-upon-Tyne Hospitals Foundation NHS Trust (Royal Victoria Infirmary), Institute for Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK e-mail: [email protected]

The hypothalamic-pituitary-gonadal (HPG) axis is central for human reproduction. This axis includes neuroendocrine networks that integrate wide ranging internal and external inputs to coordinate reproductive competence. Gonadotrophin-releasing hormone (GnRH) is the principal regulator of reproduction. GnRH controls gonadotrophin secretion and subsequently, gonadal (testicular) function. The HPG axis is activated during foetal life, neonatally and in puberty through adulthood. This developmental perspective is important as these peri-

© Springer Nature Switzerland AG 2019 S. Llahana et al. (eds.), Advanced Practice in Endocrinology Nursing, https://doi.org/10.1007/978-3-319-99817-6_43

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ods contribute to the proper formation and development of sexual structures in utero as well as the development and function of the system enabling reproductive capacity in adulthood. The HPG axis remains silenced during childhood and neuroendocrine re-activation triggers pubertal onset. In early puberty, nocturnal sleep-entrained GnRH-­induced gonadotrophin secretion stimulates testicular development and the initial rise in sex steroids resulting in the appearance of secondary sexual characteristics. Progressively, this pulsatile neuroendocrine activity extends through the day and is regulated by negative feedback. Puberty culminates in sexual maturation and the reproductive capacity of adult life. Sperm development occurs in the seminiferous tubules of the testes and requires testosterone and other testicular products for normal spermatogenesis. Effective HPG axis function is needed for normal sexual function and fertility and contributes to overall health and well-being. This chapter is a minireview for endocrine nurses providing a summary of HPG axis development, function and regulation. This targeted summary is intended to serve as a basis for understanding key elements relating to male reproductive endocrine disorders such as hypogonadism, sexual dysfunction and infertility. Keywords

Hypothalamus · Pituitary · Gonadotrophins Testes · Spermatogenesis · Testosterone Sexual function

Abbreviations AMH CHH

Anti-Müllerian hormone Congenital hypogonadotrophic hypogonadism DHEA Dehydroepieandrostenedione DHEAS Dehydroepieandrostenedione sulphate DHT Dihydrotestosterone

A. A. Dwyer and R. Quinton

DSD Disorder of sex development ED Erectile dysfunction FSH Follicle stimulating hormone GnRH Gonadotrophin-releasing hormone hCG Human chorionic gonadotrophin HH Hypogonadotrophic hypogonadism HPG Hypothalamic-pituitary-gonadal IB Inhibin B INSL3 Insulin-like peptide 3 KS Kallmann syndrome LH Luteinizing hormone PDE5 Phosphodiesterase type 5 SC Sertoli cell SD Standard deviation SHBG Sex hormone binding globulin ST Seminiferous tubule

Key Terms • Mini-puberty: The postnatal surge in gonadotrophins during the first 6 months of neonatal life. In male infants levels rise following the first week of life, peaking at around 3 months then progressively decline. This surge is thought to be important fertility potential in adulthood. • Cryptorchidism (maldescended testes): This refers to testes that are not descended into the scrotum and may be in the inguinal canal or abdomen. It may occur unilaterally or bilaterally and has negative consequences on fertility. • Orchiopexy (orchidopexy): A surgical procedure to bring maldescended testis/testes into the scrotum. Earlier surgical correction (i.e. in the first year of life) may help improve future fertility potential. • Secondary sexual characteristics: These are features that develop during puberty and are outward signs of the progression towards sexual maturation. In males, these characteristics are stimulated by rising androgen levels and include changes in body habitus (increased musculature), deepening of the voice, and development of body and facial hair.

43  Anatomy and Physiology of the Hypothalamic-Pituitary-Gonadal (HPG) Axis

• Spermatogenesis: The process by which spermatogonia become mature spermatozoa. This includes forming haploid gametes via mitosis and meiosis (spermatocytes) and the maturation process (spermiogenesis). • Mitosis: This is a form of cell division wherein one parent cell is transformed into two cells with a full complement of identical sets of chromosomes—each within their own nucleus. • Meiosis: A form of cell division wherein a parent cell produces four haploid gametes (cells with half of the number of chromosomes as the parent cell). It is an essential process for developing sperm for reproduction. • Tumescence: A state in which the sexual organs become swollen and engorged with blood in response to physical, visual or emotional stimuli. In men, this is known as a penile erection. The reverse (detumescence) is when the erectile tissue returns to its flaccid state.

Key Points

• Reproduction is regulated by the hypothalamic-­pituitary-gonadal (HPG) axis. Understanding how the axis functions is fundamental to identifying the cause(s) of male reproductive endocrine disorders. • The HPG axis functions via stimulatory effects and negative feedback effects. Male reproductive endocrine disorders can occur at the level of the hypothalamus, pituitary and/or the testes. • The HPG axis is active in foetal life, during the mini-puberty and at puberty into adulthood. Circulating LH, FSH and testosterone hormone levels reflect GnRH secretion during these periods. • Early HPG axis activity can have longreaching effects on the reproductive phenotype and fertility. Accordingly, careful history-taking is an essential component of endocrine evaluation.

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43.1 The Hypothalamic-PituitaryGonadal (HPG) Axis Reproductive capacity is central to species survival. In humans and other higher vertebrates, this essential function is regulated by the coordinated endocrine action of the hypothalamic-­ pituitary-­ gonadal (HPG) axis. Secretion of gonadotrophin-releasing hormone (GnRH) by a small population of specialized hypothalamic neurons (20%) in non-vertebral fractures (Bischoff-Ferrari et al. 2009). A pooled analysis of eight RCTs indicated that serum 25(OH)D level >24 ng/mL (60 nmol/L) may be required to decrease fracture risk (Bischoff-Ferrari 2012). Osteoporosis

Vitamin D repletion has been shown to be effective in improving bone mineral density (BMD) as illustrated in a population-based study showing a positive correlation between serum 25(OH)D and BMD (Bischoff-Ferrari et  al. 2004). Another report (Adams et  al. 1999) suggested that there was an increase in BMD in subjects previously with both low BMD and vitamin D deficiency after normalisation of 25(OH)D levels. Similar findings were reported in a small study of 229 subjects given vitamin D repletion of vitamin D2 50,000  IU twice weekly with calcium supplementation for 5 weeks who normalised serum 25(OH)D and showed a significant increase in BMD (Kantorovich et al. 2000).

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falls compared to the placebo group (Broe et al. 2007). 54.1.1.4.2  Extra-Skeletal Benefits With the discoveries of vitamin D receptors (VDRs) and the 1 α-hydroxylase enzyme (CYP27B1) in various tissues, there has been growing research interests in the area of the relationship to immunity, macrophages, colon, pancreas, breast, stomach, and placenta (Plum and DeLuca 2010). Within these tissues, 25(OH)D is converted to 1,25(OH)2D without changing the serum 1,25(OH)2D concentrations while 1,25(OH)2D affects gene expression. VDRs are a critical determinant of the ability of proliferating cells to regulate their response to various stimuli. Many observational studies have shown a reduction in risk of many disorders such as cancer, cardiovascular disease, autoimmune disease, diabetes mellitus, mental illness, and infectious disease, associated with a blood level of 25(OH) D > 28–32 ng/mL (70–80 nmol/L) (Holick et  al. 2011; Nowson et al. 2012; Holick 2007). Many research studies have been published recently in relation to extra-skeletal benefits with some still ongoing; however, the evidence of association and magnitude of the effects of these studies are not as strong as the skeletal benefits. Currently there is no consensus on the 25(OH)D levels that should be maintained for the best non-­ skeletal outcomes (Holick 2007). Diabetes

There is a high prevalence of vitamin D deficiency in people with diabetes (Alam et al. 2012). Fall and Muscle Strength The risk of type 1 and type 2 diabetes may be One of the main features of vitamin D deficiency increased due to vitamin D insufficiency (Holick is proximal muscle weakness (Holick et al. 2011; 2004; Mathieu et al. 2005). Holick 2007). In a systemic review and meta-­ VDRs can be found in pancreatic B cells and analysis study, it has been shown that there is an vitamin D may increase insulin secretion and association between muscle strength and vitamin improve insulin sensitivity. An observational study D supplementation in older adults with signifi- described that subjects taking vitamin D supplecant reduction in postural sway and improved mentation with calcium had a reduced risk of type lower extremity strength (Muir and Montero- 2 diabetes (Pittas et al. 2006). Recently a US study Odasso 2011). Interestingly, a recent study dem- with a sample size of 2877 found a weak positive onstrated that vitamin D supplementation has a association between serum vitamin D levels and small positive effect on muscle strength fasting and 2-h plasma glucose and HbA1c levels (Beaudart et al. 2014). In a nursing home study, and a negative association with beta-cell function the intervention group taking 800 IU of vitamin (Nielsen et  al. 2016). Some small studies found D daily together with calcium supplementation that vitamin D supplementation in adults has for 5 months had a 72% reduction in the risk of shown an improvement of insulin sensitivity

Y. F. Chan et al.

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(Mathieu et  al. 2005); however, this outcome is debatable. In a recently published randomised double-blind placebo-controlled hyperinsulinemic-euglycemic glucose clamp study, taking ergocalciferol 50,000  IU weekly for 8 weeks in subjects with low vitamin D levels improved 25(OH)D levels but did not improve insulin sensitivity (Simha et al. 2012). It is still questionable whether normalisation of serum vitamin D levels with vitamin D supplementation will alter diabetic microvascular complications (Alam et al. 2016). Infection/Autoimmune Disorder

The mechanism of the association between vitamin D deficiency and infection is thought to be due to the pleiotropic effects of 25(OH)D on human immunity with T-cell proliferation, immunoglobulin claws switching, and cytokine release (Mora et al. 2008). Some studies findings suggested that vitamin D plays a potential role in the pathogenesis of some organ-specific autoimmune disorders such as rheumatoid arthritis (RA), Crohn’s disease (CD), multiple sclerosis (MS), and type 1 diabetes. This is likely due to interference with genes, transcription factors, and signalling pathways which mediate inflammatory responses (Szekely and Pataki 2012). A systematic review and meta-­analysis of 647 studies found that vitamin D deficiency (a serum 25(OH)D level