Howard J.A. Carp Editor Progestogens in Obstetrics and Gynecology Progestogens in Obstetrics and Gynecology Howard J.A. Carp Editor Progestogens in Obstetrics and Gynecology Editor Howard J.A. Carp Department of Obstetrics & Gynecology Sheba Medical Center Tel Hashomer, Israel Sackler School of Medicine Tel Aviv University Tel Aviv, Israel ISBN 978-3-319-14384-2 ISBN 978-3-319-14385-9 (eBook) DOI 10.1007/978-3-319-14385-9 Library of Congress Control Number: 2015933380 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2015 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. Printed on acid-free paper Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www. springer.com) Foreword In 1930 WM Allen and GW Corner used the name progestin (later renamed proges- terone in 1935) to describe a hormone which was responsible for implantation and embryo survival. They could not have imagined the profound relevance of the hor- mone and implications for the development of a class of drugs, which are in wide- spread use and affect our daily lives. For many years progesterone was thought of as a hormone only affecting pregnancy, and the wider implications of triggering the progesterone receptor were relatively ignored. In the 1960s the contraceptive pill became available and caused a revolution in the way that women could plan their pregnancies. Progestogens were introduced to modulate the estrogen used to inhibit ovulation in the contraceptive pill. Since then a whole host of synthetic drugs known as progestogens have come into clinical use. The main use of progestogens is in pregnancy. Progestogens are used in luteal support, to prevent miscarriage, and to prevent preterm labor. Progestogens are used outside of pregnancy for abnormal uterine bleeding, cycle control, hormone replacement therapy, and even in the prevention and treatment of endometrial cancer. Today, we know that progesterone is found in nonmammalian vertebrates. Progesterone had a physiological role as an anti-inflammatory agent and neurosteroid long before mammalian pregnancy had evolved. Therefore, it is hardly surprising that progestogens are being used as possible anti-inflammatory agents in endometriosis, and even in the male in traumatic brain injury, and in mul- tiple sclerosis. Just as the early investigators in the 1930s could not realize the implications of their discovery, it is difficult to prophesy the future. A new field of development is receptor modulators. Mifepristone is a progesterone receptor modulator. It was introduced as an abortifacient. However, today new uses are being developed for receptor modulators. Experimental work with uterine fibroids may entirely change the management of fibroids and affect the whole approach to surgery for gyneco- logical conditions. This book brings together all the aspects of progestogens in gynecological (and nongynecological) practice. There are chapters governing basic scientific topics v vi Foreword such as physiology and pharmacology. The major applications of progestogen ­therapy luteal support, miscarriage, preterm labor, contraception, abnormal uterine bleeding, etc. have been described in depth. However, in clinical practice, there are always controversies, leaving the clinician puzzled as how to help the patient. The different progestogens with their overlapping effects on estrogen, androgen, gluco- corticoid, and mineralocorticoid receptors are described in order to allow the clini- cian to make the most appropriate choice of progestogen. This book will be useful for specialists including, gynecologists and endocrinologists, general practitioners, and those of associated disciplines, who wish to keep up to date and gain a compre- hensive view of developments. Andrea R. Genazzani University of Pisa, Pisa, Italy International Society of Gynecological Endocrinology (ISGE), Pisa, Italy European Society of Gynecology (ESG), Prague, Czech Republic International Academy of Human Reproduction (IAHR), Venice, Italy Preface The progestogens are defined as any compound which activates the progesterone receptor. This class of compounds is probably the most widely used class of drug in medical practice. Millions of women use progestogens in the contraceptive pill daily for many years. Women use progestogens widely in infertility treatment and in supporting pregnancy to prevent miscarriage. Progestogens are widely used to protect the endometrium in postmenopausal replacement therapy, cycle regulation, abnormal uterine bleeding, endometriosis, and even in endometrial carcinoma. However, the clinician is often in a quandary, as to which progestogen is most appropriate in any clinical situation. The actions of progestogens overlap with other steroid receptors. Therefore progestogens have estrogenic or antiestrogenic actions, androgenic or antiandrogenic actions, and glucocorticoid or mineralocorticoid actions. Each may have advantages or disadvantages depending on the clinical ­situation. However, progestogens also have side effects including stimulatory effects on the breast, possibly predisposing to breast carcinoma, breakthrough bleeding, acne mood changes, loss of libido, and dryness of the vagina. Therefore, it was thought necessary to bring all the actions of progestogens together in one volume in order to discuss the actions and uses of progestogens in depth. This book tries to summarize some of the controversies and discuss the vii viii Preface ­scientific basis for various uses of progestogens. It is hoped that this book describes the accumulating data in a way which is both scientifically sound and also clinically useful and which may improve the care of the patient. The book is planned for general gynecologists and specialists working in the field. Each contributing author is an authority on a specific area of progestogen use. I would like to thank each author for the time and effort taken in preparing the manuscripts to make the publication of this book possible. Tel Aviv, Israel Howard J.A. Carp Contents 1 Physiology of Progesterone..................................................................... 1 Edi Vaisbuch, Offer Erez, and Roberto Romero 2 Pharmacology of Progestogens............................................................... 33 Adolf E. Schindler 3 Progestogens in Infertility Practice........................................................ 41 Ameet S. Patki and Alok Sharma 4 Progestogens in Threatened Miscarriage.............................................. 53 Howard J.A. Carp 5 Progestogens and Recurrent Miscarriage.............................................. 65 Luciano G. Nardo and Spyridon Chouliaras 6 Progestogens in Preterm Labour............................................................ 79 Gian Carlo Di Renzo, Irene Giardina, Giulia Babucci, Chiara Antonelli, Sandro Gerli, and Graziano Clerici 7 Abnormal Uterine Bleeding.................................................................... 93 Yochai Bar Shavit, Jaron Rabinovici, and Howard J.A. Carp 8 Progestogens in Contraception............................................................... 111 Johannes Bitzer 9 Progestogens and Endometriosis............................................................ 129 Howard. J.A. Carp, David Soriano, and Matityahu Zolti 10 Progestogens and Breast Cancer............................................................ 149 Eitan Pe’er 11 Progestogens in Endometrial Cancer..................................................... 159 Ido Laskov and Walter H. Gotlieb ix x Contents 12 Progestogens and the Menopause........................................................... 177 Eitan Pe’er 13 Progestogens and Autoimmunity............................................................ 183 Abraham Tsur, Grant C. Hughes, and Yehuda Shoenfeld 14 Progestogens in Non-gynecological Indications.................................... 191 Christa Nadjafi-Triebsch Contributors Chiara Antonelli Santa Maria della Misericordia University Hospital, Perugia, Italy Giulia Babucci Santa Maria della Misericordia University Hospital, Perugia, Italy Johannes Bitzer, M.D. Department Obstetrics and Gynecology, University Hospital Basel, Basel, Switzerland Howard J.A. Carp, M.B.B.S., F.R.C.O.G. Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Spyridon Chouliaras, M.D., M.R.C.O.G. Centre for Reproductive Medicine, Kenton