Endometriosis: Advances and Controversies [1 ed.] 0824747771, 9780824747770, 9780824758646

Table of contents :
Foreword......Page 4
Preface......Page 6
Contents......Page 8
Contributors......Page 12
Epidemiology of Endometriosis......Page 16
Pathogenesis of Endometriosis: Peritoneal Endometriosis, Ovarian Endometriosis, and Rectovaginal Adenomyosis......Page 34
Anatomical Sites of Endometriosis......Page 60
Genetics of Endometriosis......Page 70
Research Aspects of Endometriosis......Page 84
Animal Models for Research on Endometriosis*......Page 96
Immunology of Endometriosis and Immunotherapy......Page 114
Serum and Peritoneal Markers for Endometriosis......Page 138
How Does Endometriosis Cause Infertility?......Page 166
Medical Therapy for Endometriosis: An Overview......Page 182
Treatment with Aromatase Inhibitors......Page 204
Endometriosis: Medical Treatment with Progestagens......Page 218
Gonadotropin Releasing Hormone Agonist and Antagonist for Endometriosis......Page 234
Management of Endometriosis After Hysterectomy and Bilateral Salpingo-Oophorectomy......Page 260
Treatment of Ovarian Endometrioma......Page 278
Treatment of Endometriosis-Related Pelvic Pain......Page 288
In Vitro Fertilization or Superovulation? Evidence, Flaws, and Advice......Page 310
Does Endometriosis Affect the Results of In Vitro Fertilization?......Page 330
Index......Page 340

Citation preview

ENDOMETRIOSIS edited by

Togas Tulandi McGill University Montreal, Quebec, Canada

David Redwine St. Charles Medical Center Bend, Oregon, U.S.A.

M A R C E L

MARCELDEKKER, INC. D E K K E R

NEWYORK BASEL

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-4777-1 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG, Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Foreword

Endometriosis is an enigma. The chapters in this book represent the endeavors of several experts in the field to review what is known about endometriosis in an objective manner. Yet what emerges is how little is known about endometriosis in spite of the innumerable studies conducted and the quantity of information that has accumulated. Opinions about endometriosis abound, and this book is filled with diverse opinions. Those opinions serve to raise questions for further research and to emphasize further how enigmatic this disorder remains. Because of the myriad of symptoms that may be associated with endometriosis, practitioners are dedicated to attempting to alleviate the symptoms associated with the disorder even in the absence of an understanding of its pathophysiology. Endometriosis is common. Every health care provider who interacts with women has dealt with many cases. Every woman knows others with the disorder. Everyone has an opinion and advice. Yet treatment remains far from satisfactory for many. The authors have provided their opinions as to the best approaches to therapy in these patients with complex medical problems. iii

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Foreword

Endometriosis engenders emotional responses in patients and health care practitioners alike. To women suffering from endometriosis, the disorder seems ill defined and frequently the cause of considerable pain, infertility, surgical procedures, the need for expensive medications, frustration, and anger. To those who provide care to affected women, endometriosis conjures up images of difficult patients whose treatment is often less than satisfactory. If the purpose of this book is to stimulate discussion and thereby research, it will fulfill that goal admirably. If the purpose is to educate readers, it will succeed at that goal as well. If the purpose is to serve as a resource, it will do so commendably. I would encourage individuals interested in endometriosis to read these chapters carefully, to ponder the ideas contained herein, and to commit themselves to serving their patients and future generations of women with a better understanding of this disorder. Only when basic science and research succeed at providing more complete answers will we be able to conquer this disease. Robert W. Rebar, M.D. Executive Director American Society for Reproductive Medicine Birmingham, Alabama

Preface

The science surrounding endometriosis is rapidly evolving and, in some cases, tenets that are widely accepted one year may not be applicable the next. New inventions and discoveries continue to be added and many controversies surround the management of this condition. This book reflects the latest thinking on endometriosis, thereby addressing new concepts and different treatment modalities. The contributors are physicians and researchers, leaders in the field with many years of experience in their topics. The subjects discussed in the first eight chapters include epidemiology, pathophysiology, distribution of endometriosis, genetics, basic and clinical research aspects, immunology, and possible serum markers for this condition. Chapter 9 deals with the mechanism of endometriosis-related infertility and Chapters 10 through 18 are dedicated to the new developments in medical and surgical management of endometriosis. Aromatase inhibitors are a promising new treatment, and the relationship between endometriosis and the outcome of in vitro fertilization are examples of the many advances and controversies in the management of endometriosis. v

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Preface

This is a book for students, residents, fellows, basic and clinical researchers, and practicing gynecologists. Readers will gain a better understanding of endometriosis and its management, as well as insight into designing new investigations. We are grateful to the contributors for their comprehensive and authoritative reviews. We would also like to acknowledge the staff of Marcel Dekker, Inc., for their support and expertise in publishing medical texts. Togas Tulandi David Redwine

Contents

Foreword Robert W. Rebar Preface Contributors 1. Epidemiology of Endometriosis Philippe R. Koninckx 2. Pathogenesis of Endometriosis: Peritoneal Endometriosis, Ovarian Endometriosis, and Rectovaginal Adenomyosis Jacques Donnez and Jean Squifflet

iii v xi 1

19

3. Anatomical Sites of Endometriosis Haya Al-Fozan and Togas Tulandi

45

4. Genetics of Endometriosis Stephen Kennedy

55 vii

viii

Contents

5.

Research Aspects of Endometriosis Dan C. Martin

69

6.

Animal Models for Research on Endometriosis Thomas M. D’Hooghe, Sophie Debrock, Joseph A. Hill, Daniel C. Chai, and Jason M. Mwenda

81

7.

Immunology of Endometriosis and Immunotherapy Emre Seli, Neal G. Mahutte, Murat Berkkanoglu, and Aydin Arici

99

8.

Serum and Peritoneal Markers for Endometriosis Tommaso Falcone and Mohamed A. Bedaiwy

123

9.

How Does Endometriosis Cause Infertility? Ariane Germeyer and Linda C. Giudice

151

10.

Medical Therapy for Endometriosis: An Overview Eric S. Surrey

167

11.

Treatment with Aromatase Inhibitors Serdar E. Bulun, Bilgin Gurates, Zongjuan Fang, Mitsutoshi Tamura, David Langoi, Gonca Imir, Sanober Amin, Santanu Deb, and Sijun Yang

189

12.

Endometriosis: Medical Treatment with Progestagens Robert Lahoud and Robert F. Harrison

203

13.

Gonadotropin Releasing Hormone Agonist and Antagonist for Endometriosis Robert L. Barbieri

219

Management of Endometriosis After Hysterectomy and Bilateral Salpingo-Oophorectomy David Redwine

245

14.

15.

Treatment of Ovarian Endometrioma Haya Al-Fozan and Togas Tulandi

263

16.

Treatment of Endometriosis-Related Pelvic Pain Kevin Jones and Christopher Sutton

273

Contents

17.

18.

ix

In Vitro Fertilization or Superovulation? Evidence, Flaws, and Advice Ian S. Tummon

295

Does Endometriosis Affect the Results of In Vitro Fertilization? Simon M. Kelly, William M. Buckett, and Seang Lin Tan

315

Index

325

Contributors

Haya Al-Fozan Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Sanober Amin Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Aydin Arici, M.D. Department of Reproductive Endocrinology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Robert L. Barbieri, M.D. Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Mohamed A. Bedaiwy, M.D. Department of Gynecology and Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

xi

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Contributors

Serdar E. Bulun Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Murat Berkkanoglu, M.D. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. William M. Buckett Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Daniel C. Chai U.S.A.

Fertility Center of New England, Reading, Massachusetts,

Santanu Deb Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Sophie Debrock, Ph.D. Department of Gynecology and Obstetrics, Leuven University Fertility Center, Leuven, Belgium Thomas M. D’Hooghe, M.D., Ph.D. Department of Gynecology and Obstetrics, Leuven University Fertility Center, Leuven, Belgium Jacques Donnez, M.D., Ph.D. Department of Gynecology, Catholic University of Louvain, Brussels, Belgium Tommaso Falcone, M.D. Department of Gynecology and Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Zongjuan Fang Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Ariane Germeyer, M.D. Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California, U.S.A., and Department of Reproductive Medicine, University of Heidelberg, Heidelberg, Germany Linda C. Giudice, M.D., Ph.D. Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California, U.S.A. Bilgin Gurates Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A.

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Robert F. Harrison, M.A., M.D., D.Sc., F.R.C.S., F.R.C.O.G., F.R.C.P. Department of Obstetrics and Gynecology, Rotunda Hospital, Dublin, Ireland Joseph A. Hill U.S.A.

Fertility Center of New England, Reading, Massachusetts,

Gonca Imir Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Kevin Jones, M.D., M.B., Ch.B., M.R.C.O.G., M.Sc. Department of Obstetrics and Gynecology, Great Western Hospital, Swindon, Wiltshire, England Stephen Kennedy, M.D., M.A., M.R.C.O.G. Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, England Simon M. Kelly, M.D., F.R.A.N.Z.C.O.G. Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Philippe R. Koninckx, M.D., Ph.D. Department of Obstetrics and Gynecology, Catholic University of Leuven, Leuven, Belgium Robert Lahoud, M.B.B.S., M.Med., F.R.A.N.Z.C.O.G. West, Westmead, Australia

IVF Australia

David Langoi Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Neal G. Mahutte, M.D. Department of Obstetrics and Gynecology, Dartmouth College School of Medicine, Lebanon, New Hampshire, U.S.A. Dan C. Martin, M.D. Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee, U.S.A. Jason M. Mwenda, Ph.D. Department of Reproductive Biology, Institute of Primate Research, Nairobi, Kenya David Redwine, A.B., M.D. Oregon, U.S.A.

Endometriosis Institute of Oregon, Bend,

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Contributors

Emre Seli, M.D. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Jean Squifflet, M.D. Department of Gynecology, Catholic University of Louvain, Brussels, Belgium Eric S. Surrey, M.D. Colorado Center for Reproductive Medicine, Englewood, Colorado, U.S.A. Christopher Sutton, M.A., M.B., B.Ch., F.R.C.O.G. Department of Obstetrics and Gynecology, Royal Surrey County Hospital, Guildford, Surrey, England Mitsutoshi Tamura Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A. Seang Lin Tan, M.B.B.S., F.R.C.O.G., F.R.C.S.(C)., M.MED(O&G) Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Togas Tulandi, M.D., F.R.C.S.C., F.A.C.O.G. Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada Ian S. Tummon, M.D., F.R.C.S.(C). Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, U.S.A. Sijun Yang Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois, U.S.A.

1 Epidemiology of Endometriosis Philippe R. Koninckx Catholic University Leuven Leuven, Belgium

INTRODUCTION Endometriosis is still a poorly understood condition. This is despite the high and still increasing publication of more than 500 articles per year. For example, there were 455, 426, 448, 504, and 534 articles in the past 5 years, respectively. Endometriosis is considered to be one of the most important causes of pelvic pain and infertility. The exact prevalence is unknown, as a laparoscopy is required to make the diagnosis and the recognition varies with the experience and the interest of the laparoscopist. Moreover, the pathophysiology is poorly understood, which makes it difficult to formulate and test simple hypotheses. The definitions of endometriosis have changed over time, contributing to biases in the literature. In the mid-eighties, the concept of nonpigmented or subtle endometriosis was introduced, and from the nineties onwards the recognition of deep endometriosis has progressively increased. The revised American Fertility Society (rAFS) classification is widely used. Yet, it has never been validated as a classification for pain or infertility. 1

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Taken together, the absence of an easy, non invasive diagnosis, the changing definitions, and the absence of a clear understanding of the pathophysiology and the absence of a validated classification system are the reasons why there are still many controversies surrounding endometriosis. We therefore consider it a prerequisite to introduce definitions and biases, and the problems of pathophysiology and classification systems, before discussing epidemiology.

DEFINITIONS AND BIASES IN THE LITERATURE Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. It was described at the turn of the century as severe lesions such as ovarian ‘‘chocolate cysts’’ [1] and as adenomyosis externa [2–7]. In 1899, Russell [8] wrote, ‘‘On the microscopic study of the ovary, we were astonished to find areas which were an exact prototype of the uterine glands and interglandular connective tissue.’’ In the following decades, endometriosis was described as a disorder causing pain and requiring surgery. During that period, other sites [9] were described, and endometriosis was reported as an ‘‘accidental’’ finding during surgery for other gynecological disorders [10–12]. Only after the introduction of endoscopy in the late 1960s, blackpuckered endometriosis lesions were recognized as a frequent observation in women with pain or infertility. Following the description of nonpigmented endometriosis in the mid eighties [13–16], the prevalence of the disease increased [17–25]. In the 90s, the awareness of deep infiltrating endometriosis increased progressively, together with the recognition that this type of endometriosis was not always diagnosed during surgery. Subtle Endometriosis Following the recognition of nonpigmented endometriosis [26] in the mid80s, the race to find smaller implants led to a series of articles describing polypoid lesions [14–16,27,28], white and red vesicles, flamelike lesions, and finally microscopic endometriosis [29–31]. The latter is visible only under the microscope or by scanning electron microscopy [32,33]. This led to the suggestion that microscopic endometriosis could be present in all women, which induced techniques such as peritoneal washings [34] or blood painting [35] to diagnose endometriosis. The interest in nonpigmented endometriosis was further triggered by the observation that these lesions were morphologically very active, leading to the speculation that this activity is due to secretion of ‘‘active’’ substances in peritoneal fluid [36], which could explain infertility and pain. These lesions

Epidemiology

3

can be stimulated to develop by substances in peritoneal fluid and suppressed by medical treatment [37–42]. It has been postulated that the severity of endometriosis is better assessed by its degree of activity, rather than by its extent [43]. We will use the term ‘‘subtle endometriosis’’ throughout the text to refer to these lesions. I prefer to define them as small, superficial, and active lesions without surrounding sclerosis and without the hemosiderin black spots. Subtle lesions contain gland and stroma, and thus fit the definition of endometriosis. However, recognition and definition of these lesions remain controversial. Its recognition increases with the awareness and with experience of the surgeon. Morphologic confirmation of endometriosis rarely exceeds 60 (57%) [44]. This is generally attributed to technical problems of excision of these small lesions and detecting them after processing. Endometriosislike lesions are also well recognized. Their prevalence is unknown. The concept of microscopic endometriosis makes the issue more complicated. According to this concept, all women would have endometriosis. The data to support it have been anecdotal, and a study in baboons showed that the incidence is low [45]. The newest concept is ‘‘nonimplanted endometriosis’’ in peritoneal fluid that has to be distinguished from retrograde menstruation. Typical Endometriosis Typical lesions are described as black puckered lesions surrounded by a sclerotic area and by a typical vascular pattern, suggesting angiogenesis. We may assume that an experienced surgeon can readily recognize these lesions. Yet, at least two problems exist in their detection and reporting. The first is that the exact prevalence of endometriosislike lesions is unknown. The second is endometriosis on the diaphragm. This has been considered rare, but the number of surgeons who systematically inspect the diaphragm in steep Trendelenburg, with a 30-degree scope, is very low. Even for this lesion, the histological confirmation rarely exceeds 80% (76% [44], even 50% [46]). Cystic Ovarian Endometriosis Distinguishing cystic ovarian endometriosis from cystic corpus luteum can be difficult. Women with ultrasound findings of persistent endometriotic cyst of more than 4 months, including those who were treated with GnRHa or OCP, often were found to have only cystic corpus luteum at surgery. These clinical observations do not allow any conclusion about its prevalence, but are consistent with the report that ovarian cysts can develop during ovarian downregulation [47].

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Imaging, such as ultrasound and CT scanning, has a sensitivity of 70% to 80% and a specificity of 90% to 95% [48–52]. This is a valuable method of preoperative diagnosis. Ovarian blood flow measurement does not seem to improve its specificity or sensitivity [48]. Measurement of CA125 in the endometrioma fluid increased the sensitivity and specificity to nearly 100% [53,54]. Unfortunately, a rapid test to assist an intraoperative diagnosis is not yet available. In general, cystic ovarian endometriosis is associated with adhesions [25], whereas a ‘‘chocolate cyst’’ without adhesions is most likely a cystic corpus luteum. The presence of severe adhesions, especially in the fossa ovarica, should raise the suspicion of an endometriotic cyst. Diagnostic accuracy can be further increased by inspection of the inside of the cyst by ovarioscopy [55] or laparoscopy [56]. ‘‘Those with a flattened appearance and red or red and brown mottled ridges generally were endometriosis and those with a dark uniform base, an intracavitary clot, or a yellowish rim generally were corpus lutea or albicans.’’ [57]. A second problem is that the pathology report often reveals ‘‘compatible with endometriosis,’’ without a positive identification of endometrial glands and stroma. This is not unusual, especially for larger cysts. However, it is rarely addressed in the literature, making it difficult to know how accurate the diagnosisis is. Different treatments give different results and recurrence rates. During the microsurgery era, the procedure was done by excising the cyst wall and suturing the ovarian opening [58]. Today, there are several endoscopic techniques. Aspiration and rinsing of cystic ovarian endometriosis has been attempted, but the recurrence rate is high [59–61]. For cysts of less than 5 cm, the method of stripping the cyst from the ovary is rapid and relatively easy [62]. Closure of the ovary can be achieved by tissucol or sutures. The cyst wall can be vaporized [63] or destroyed with unipolar or bipolar coagulation. Another method is focal treatment [64]. To understand the rationale of focal treatment, the rediscovery of the work of Hughesdon [31, 65,66] is important. By serial sections of ovarian endometrioma, it was postulated that it developed from invagination of the ovarian cortex. The difficulty in diagnosis, and the different techniques used for treatment should be taken into account when interpreting results and prevalence of endometriosis [67–70].

Deep Endometriosis In the 90s it was realized that deep endometriosis was a frequent disease, either recognized during laparoscopic surgery [25,71] or by clinical examination during menstruation [72]. The endoscopic excision of endometriosis has

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revealed that endometriosis deeper than 5 to 6 mm is associated with pain and infertility. Three subtypes were described [73]. Type I is characterized by a large area of typical and sometimes subtle endometriotic lesions surrounded by white sclerotic tissue. Only during excision does it become obvious that the endometriosis infiltrates deeper than 5 mm. Typically the endometriotic area becomes progressively smaller and as it grows deeper, the lesion becomes cone shaped. Type II lesions are characterized by retraction of the bowel. Clinically they are recognized as a prominent bowel retraction around a small typical lesion. In some women, however, endometriosis might not be seen by the laparoscope, and the bowel retraction is the only clinical sign. Diagnosis is not difficult, because during the laparoscopy an induration under the bowel can be felt. Otherwise, it is diagnosed only during excision. Type III lesions are spherical endometriotic nodules above or inside the rectovaginal septum. Typically, these lesions are felt as painful nodules. In some women, vaginal examination reveals some dark blue cysts (3–4 mm) in the posterior fornix. Sclerosing endometriosis invading the sigmoid is similar to the rectal endometriosis, but is situated 10 cm above the rectovaginal septum. This is another rare form of deep endometriosis, which we proposed to classify as type IV. The literature on deep endometriosis is confusing and controversial. The diagnosis of deep endometriosis cannot be established by clinical examination. Even during menstruation, high located deep endometriosis cannot be palpated. Large lesions can be diagnosed by contrast enema, transvaginal or transrectal ultrasound, or MRI. The sensitivity of these imaging techniques for detecting smaller lesions is unknown. As my expertise and awareness developed, I realized that a substantial amount of these lesions, especially the smaller rectovaginal lesions or the type IV lesions, have been previously missed at surgery. Biases and Shifts in the Literature In the past 20 years, there has been a gradual evolution in the recognition of the different stages of endometriosis. Subtle endometriosis has been recognized since the mid-80s. This has increased the apparent prevalence of endometriosis. It has also change our perception of ‘‘normal women.’’ Traditionally, women with minimal and mild endometriosis were almost exclusively those with typical lesions, whereas ‘‘normal women’’ have subtle endometriosis only. This evolution alone explains why the association between luteinized unruptured follicle (LUF) syndrome and minimal endometriosis systematically reported before 1985 disappeared from the literature. Luteinized unruptured follicle syndrome has been associated with typical lesions, but not with subtle lesions.

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The awareness of these changes is important in understanding and interpreting the data reported in the literature. This is essential when discussing prevalence, and when comparing older data with more recent observations. The bias of confusing cystic ovarian endometriosis and cystic corpora lutea will have little effect on the reported prevalence, although in some series cystic corpora lutea could be as high as 30%. As surgeons became more aware of deep endometriosis over the years, its reported prevalence increased. The recognition that the small lesions tend to go unnoticed even during laparoscopy, mainly because of lack of performing diagnostic methods, leads to the conclusion that the prevalence of deep endometriosis is underreported. This is especially important in studies concerning pelvic pain. CLASSIFICATION OF ENDOMETRIOSIS Revised AFS classification is a point scoring system. We found that class I consisted of superficial lesions with a total area of less than 3 cm2; class II, superficial lesions with a total area of more than 3 cm2; classes III and IV comprised mainly cystic ovarian endometriosis. The contribution of adhesions to the rAFS classification and its association with cystic ovarian endometriosis easily explains this [25]. It should be stressed that the rAFS has never been validated as a tool to evaluate infertility or pain objectively. As the clinical importance of subtle lesions is questionable, it might be preferable to regroup women with subtle lesions into a separate class. Deep lesions are found in all four rAFS classes, but mainly in classes I and II. When we regrouped these lesions into a separate class, we found that cystic ovarian endometriosis and deep lesions are those that correlate with pain. Without regrouping, these associations disappear. This is because milder endometriosis groups are variably contaminated with deep endometriosis. PATHOPHYSIOLOGY Sampson and Metaplasia Theory Sampson’s retrograde menstruation, implantation, and the metaplasia theory focuses on the implantation/metaplasia of cells. It refers to subtle and small initial lesions that will subsequently grow and develop to more severe disease. It is an attractive theory because of the abundance of data demonstrating retrograde menstruation as a frequent phenomenon in all women and the presence of viable endometrial cells in the peritoneal fluid, which have the capacity to implant, grow, and infiltrate superficially. According to this hypothesis, the development into advanced condition may be influenced

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by a decreased cellular immunity, a lower natural killer (NK) cell activity, peritoneal fluid cytokines and growth factors, or low peritoneal fluid steroid concentrations in the luteal phase. Each step in the pathophysiology has been documented. This theory, however, cannot explain why progression occurs in some women only. It holds that progression of endometriosis, once established, is unavoidable, albeit at a different speed and to a different stage according to modulating factors. This theory considers endometriosis as normal endometrial cells behaving abnormally in an abnormal environment, that is, the peritoneal milieu. However, this theory is not supported by all [74]. The key event in the process is implantation or metaplasia, which has been the subject of many investigations. The early subtle lesions become very important. The Endometriotic Disease Theory The endometriotic disease theory (EDT) [75] considers retrograde menstruation, viable endometrial cells in peritoneal fluid, and occasional implantation of these cells as a normal physiological phenomenon. The non implanted and implanted cells are normally removed by the defense mechanisms of the body, such as macrophages. Attachment and implantation occur when the mesothelial layer is damaged by trauma, infection, or low-grade inflammation, for example, irritation caused by CO2 pneumoperitoneum, or by abundant retrograde menstruation. It seems logical that attachment and implantation must occur more frequently when more viable cells are present in peritoneal fluid. These cells can temporarily grow and develop, depending on the environment. When left alone, they can also disappear spontaneously. This may result in some fibrotic or scar tissue as the remnant of local inflammation. It contains some endometrial cells, shielded from the bloodstream and immunocompetent cells similar to bacteria in an abscess. Endometriosis is caused by cellular modification, such as genetic mutation, as observed in many benign tumors. This cellular modification occurs more frequently in genetically predisposed persons, and it is facilitated by other factors such as total body irradiation, or by chemical pollutants, such as dioxins. The probability that such an event occurs is higher when more cells are present seems logical. The type of cellular modification, together with local factors such as the peritoneal fluid microenvironment or the intraovarian milieu, will determine whether they will develop into typical lesions, deep endometriosis, or cystic ovarian endometriosis, and whether the morphological characteristics will be chocolate cysts, endometrial glands and stroma, or adenomyosis externa. This theory also refers to subtle lesions as a normal physiological condition, occurring intermittently in all women. Typical, cystic, and deep endo-

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metriosis are considered as benign tumors, originating from a cellular modification transforming endometrial cells into endometriotic cells. Endometriotic disease is the presence of abnormal cells in an abnormal environment. Pathophysiology and Prevalence The theories of pathophysiology of endometriosis are essential in discussions of prevalence. Indeed, according to the EDT, subtle endometriosis is a physiological condition, occurring intermittently in all women, and these lesions should not be considered a disease [59]. According to Sampson/metaplasia theory, subtle lesions are the early stages of endometriosis and extremely important because they are very active. Accordingly, it is logical to examine the pelvis for these early and small endometriosis lesions and to treat them to prevent progression. The epidemiology of the four major presentations of endometriosis will be discussed separately.

EPIDEMIOLOGY Although neither the ideal design nor the ideal case and control groups are likely to be achievable in epidemiologic studies of endometriosis, better subject-selection strategies may improve the validity of studies that are obliged to depart from the ideal [76]. Subtle Endometriosis Following the description of non pigmented endometriosis in the eighties [13– 16], the prevalence of the disease increased from 5% to 20% to 60% to 80% in women with infertility or pelvic pain [17–25,77]. The prevalence clearly increases with the awareness and the experience of the surgeon. In all series, the underlying biases of no confirmation or, at best, limited confirmation by pathology should be recognized. The prevalence of subtle lesions decreases with age for unknown reasons [25,78]. No studies have demonstrated an association with any of the variables considered important, such as early menarche, short cycles, abundant or painful periods, infertility, race, dioxin, or total body radiation. Typical Endometriosis Taking into account only typical endometriosis, the prevalence of asymptomatic endometriosis varies from 4% in women undergoing tubal ligation to 50% in teenagers with intractable dysmenorrhea. The prevalence in women

Epidemiology

9

with pain or infertility ranges between 40% and 70% [25,46]. In general, the incidence is estimated to be 1.3 per 1000 women aged 15 to 44 [79]. In a recent large study in Norway, the lifetime risk for endometriosis was 2.2% [80]. In this study, early menarche, frequent menstruations, pelvic pain, infertility, and nulliparity were associated with endometriosis. In a controlled study of women with infertility and a normal partner, compared with women with azoospermic partner, stage I endometriosis is not more common in infertile women than in control women. However, stage II endometriosis was more frequent (3.3% vs 5.7%) in infertile women [81]. There is a non validated clinical impression that endometriosis could vary with race blacks having lower rates of endometriosis and Asians have higher rates than Caucasians. According to the Sampson’s theory, abundant retrograde menstruation is a predisposing factor for endometriosis. This seems to be clinically and experimentally supported by increased prevalence of endometriosis in women and in primates with obstructed uterine outflow. Indeed, women with endometriosis have more abundant periods, and early menarche. However, a recent review failed to demonstrate this association [82]. Endometriosis is clearly associated with dysmenorrhea, but it is unknown whether this is a cause or a consequence. Dioxin has been suggested to be causally related to endometriosis. This hypothesis was formulated in 1994 [83] based on indirect observations that the incidence and severity of endometriosis increased in primates treated with dioxins [84,85]. In the human, final proof is still lacking [86]. The Seveso accident, with massive pollution, suggests a nonsignificant doubling of prevalence [87]. Also, breast-fed infants, possibly exposed to dioxins in milk, have a lower incidence of endometriosis in adult life [88]. Total body radiation is associated with increased prevalence of endometriosis in primates [89]. Little evidence is available to support this in the human. Endometriosis is a hereditary disease [90–98]. The prevalence among first-degree relatives is seven times higher than in control groups. In monozygotic twins the prevalence is up to 15 times higher. The lower natural killer cell activity in plasma and in peritoneal fluid [71,99–106] has fueled speculation about the role of the immune system in endometriosis [107–110]. To date, however, no association has been found between the prevalence of endometriosis and chronic immunosuppression (e.g., in transplant patients), or smoking, caffeine, alcohol, or other lifestyle variable affecting NK activity. Stress could be related to endometriosis. This concept is derived from the association of endometriosis and LUF syndrome, the relationship between a higher trait anxiety and LUF syndrome [111–114], and the hypothesis

10

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that lower steroid hormone concentrations in peritoneal fluid might facilitate the implantation/development of endometriosis [115]. As there is no adequate animal model, this hypothesis cannot be tested. The best animal model is the baboon. It has been shown that baboons in captivity have more endometriosis than in the wild (probably through stress) [116]. Another argument to link endometriosis and stress is the widely held belief that endometriosis is a career women’s disease. This, however, can be explained by the delay of childbearing in this group of women, with the inevitable increase of infertility with age, and a higher prevalence of endometriosis at laparoscopy. Nulliparity could be a consequence of the disease but in a large study in Italy, the prevalence decreased with increasing parity [117]. Oral contraception use has been reported to be associated with a decreased prevalence [17]. Endometriosis was recently suggested to be associated with an increased risk in ovarian cancer (OR = 1.73, 95% CI: 1.10, 2.71) [118], and of nonHodgkin’s lymphoma [119]. Cystic Ovarian Endometriosis Cystic ovarian endometriosis increases with age [25]. Most reports confirmed that cystic ovarian endometriosis is clonal in origin [120–123]. Deep Endometriosis Deep endometriosis increases with age [25]. Rectovaginal endometriosis was known since the beginning of the century, but the high prevalence of deep endometriosis remained unsuspected until recently. The observations from Leuven from 1988 to 1991 [25], a period during which endoscopic surgery has not yet developed, showed that the prevalence of deep endometriosis was 10% to 20%. Referrals were only for infertility and pain and not for deep endometriosis. Assuming that laparoscopies for infertility are performed in 10% to 15% of the population and taking into account that Leuven is a tertiary referral center, the prevalence of deep endometriosis can be estimated to be 1% to 3%. No data are available to link deep endometriosis to a subgroup of women or to a potential causal factor. Endometriosis and Cancer Occasional reports describe cancer in cystic ovarian [124] or severe endometriosis [96,125]. We recently diagnosed an adenocarcinoma in a deep endometriotic lesion. The relationship between endometriosis and a possible increased risk of ovarian cancer, however, remains unclear.

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11

CONCLUSIONS AND DISCUSSION When evaluating reports on epidemiology of endometriosis, it is important to distinguish between subtle, typical, cystic, and deep endometriosis and to take into account the evolution of subtle endometriosis and deep endometriosis. A simple non invasive test of endometriosis is still not available. The prevalence of endometriosis is high, particularly in women with pain and infertility. Subtle endometriosis ranges from 5% to 50% in asymptomatic women to 50% to 80% in women with symptoms. For typical lesions, estimations are less than half of these figures, but the data came from reports before 1985. For severe endometriosis either cystic or deep, the prevalence is between 1% and 10%. A poorly addressed problem is the variability of prevalences by region and country. No systematic studies are available, but in my experience, it seems that the prevalence of very severe deep endometriosis is higher in Belgium than in the United Kingdom or south Italy. In Moscow, the prevalence of severe endometriosis is also high. In Middle Eastern countries, endometriosis seems to be rare. Although the evidence is anecdotal, it could be in agreement with the hypothesis of pollution. Endometriosis is a hereditary disease, particularly the typical and cystic ovarian types. Increased retrograde menstruation, for example, by outflow obstruction, will increase the prevalence of endometriosis. The role of nutrition, lifestyle, personality traits, the immune system, the peritoneal fluid, and other variables in endometriosis is unclear. Indirect evidence strongly suggests a modulating role. The question whether endometriosis represents normal endometrial cells or abnormal-modified endometrial cells remains unanswered. Until then, prevention of implantation, prevention of cellular damage, and the treatment of endometriosis will remain empirical.

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27. Martin DC. Is bloody fluid endometriosis? (II). Fertil Steril 1990; 54:1186–1187. 28. Bancroft K, Vaughan Williams CA, Elstein M. Minimal/mild endometriosis and infertility. A review [see comments]. Br J Obstet Gynaecol 1989; 96:454– 460. 29. Brosens IA, Cornillie FJ. Peritoneal endometriosis. Morphological basis of the laparoscopic diagnosis. Contrib Gynecol Obstet 1987; 16:125–137. 30. Nezhat F, Allan CJ, Nezhat C, Martin DC. Nonvisualized endometriosis at laparoscopy. Int J Fertil 1991; 36:340–343. 31. Brosens I, Puttemans P, Deprest J. Appearances of endometriosis. Baillieres Clin Obstet Gynaecol 1993; 7:741–757. 32. Vasquez G, Cornillie F, Brosens IA. Peritoneal endometriosis: Scanning electron microscopy and histology of minimal pelvic endometriotic lesions. Fertil Steril 1984; 42:696–703. 33. Murphy AA, Green WR, Bobbie D, dela Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986; 46:522–524. 34. Ravinsky E. Cytology of peritoneal washings in gynecologic patients. Diagnostic criteria and pitfalls. Acta Cytol 1986; 30:8–16. 35. Redwine DB. Peritoneal blood painting: An aid in the diagnosis of endometriosis. Am J Obstet Gynecol 1989; 161:865–866. 36. Vernon MW, Beard JS, Graves K, Wilson EA. Classification of endometriotic implants by morphologic appearance and capacity to synthesize prostaglandin F. Fertil Steril 1986; 46:801–806. 37. Cornillie FJ, Vasquez G, Brosens I. The response of human endometriotic implants to the anti-progesterone steroid R 2323: A histologic and ultrastructural study. Pathol Res Pract 1985; 180:647–655. 38. Cornillie FJ, Brosens IA, Vasquez G, Riphagen I. Histologic and ultrastructural changes in human endometriotic implants treated with the antiprogesterone steroid ethylnorgestrienone (gestrinone) during 2 months. Int J Gynecol Pathol 1986; 5:95–109. 39. Brosens IA, Verleyen A, Cornillie F. The morphologic effect of short-term medical therapy of endometriosis. Am J Obstet Gynecol 1987; 157:1215–1221. 40. Cornillie FJ, Puttemans P, Brosens IA. Histology and ultrastructure of human endometriotic tissues treated with dydrogesterone (Duphaston). Eur J Obstet Gynecol Reprod Biol 1987; 26:39–55. 41. Brosens IA. The rationale for endocrine therapy. Acta Obstet Gynecol Scand Suppl 1989; 150:21–25. 42. Shaw RW. Endometriosis : Current evaluation of management and rationale for medical therapy. In: Brosens IA, Donnez J, eds. The Current Status of Endometriosis. New York: Parthenon Publishing, 1993:371–383. 43. Brosens IA, Cornillie F, Koninckx PR, Vasquez G. Evolution of the Revised American Fertility Society Classification of Endometriosis [letter]. Fertil Steril 1985; 44:714–716. 44. Moen MH, Halvorsen TB. Histologic confirmation of endometriosis in different peritoneal lesions. Acta Obstet Gynecol Scand 1992; 71:337–342.

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45. D’Hooghe TM, Bambra CS, DeJonge I, Machai PN, Korir R, Koninckx PR. A serial section study of visually normal posterior pelvic peritoneum from baboons (Papio cynocephalus, Papio anubis) with and without spontaneous minimal endometriosis. Fertil Steril 1995; 63:1322–1325. 46. Walter AJ, Hentz JG, Magtibay PM, Cornella JL, Magrina JF. Endometriosis: Correlation between histologic and visual findings at laparoscopy. Am J Obstet Gynecol 2001; 184:1407–1411. 47. Jenkins JM, Anthony FW, Wood P, Rushen D, Masson GM, Thomas E. The development of functional ovarian cysts during pituitary down-regulation. Hum Reprod 1993; 8:1623–1627. 48. Alcazar JL, Laparte C, Jurado M, Lopez GG. The role of transvaginal ultrasonography combined with color velocity imaging and pulsed Doppler in the diagnosis of endometrioma. Fertil Steril 1997; 67:487–491. 49. Mais V, Guerriero S, Ajossa S, Angiolucci M, Paoletti AM, Melis GB. The efficiency of transvaginal ultrasonography in the diagnosis of endometrioma. Fertil Steril 1993; 60:776–780. 50. Outwater EK, Dunton CJ. Imaging of the ovary and adnexa: Clinical issues and applications of MR imaging. Radiology 1995; 194:1–18. 51. Guerriero S, Ajossa S, Paoletti AM, Mais V, Angiolucci M, Melis GB. Tumor markers and transvaginal ultrasonography in the diagnosis of endometrioma. Obstet Gynecol 1996; 88:403–407. 52. Guerriero S, Mais V, Ajossa S, Paoletti AM, Angiolucci M, Melis GB. Transvaginal ultrasonography combined with CA-125 plasma levels in the diagnosis of endometrioma. Fertil Steril 1996; 65:293–298. 53. Koninckx PR, Muyldermans M, Moerman P, Meuleman C, Deprest J, Cornillie F. CA 125 concentrations in ovarian ’chocolate’ cyst fluid can differentiate an endometriotic cyst from a cystic corpus luteum. Hum Reprod 1992; 7:1314–1317. 54. Koninckx PR. CA 125 in the management of endometriosis. Eur J Obstet Gynecol Reprod Biol 1993; 49:109–113. 55. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 1994; 61:1034– 1038. 56. Martin DC, Demos Berry J. Histology of chocolate cysts. J Gynecol Surg 1990; 6:43–46. 57. Martin DC, Ahmic R, El Zeky FA, Vander Zwaag R, Pickens MT, Cherry K. Increased histologic confirmation of endometriosis. J Gynecol Surg 1990; 6: 275–279. 58. Gordts S, Boeckx W, Brosens I. Microsurgery of endometriosis in infertile patients. Fertil Steril 1984; 42:520–525. 59. Vercellini P, Bocciolone L, Crosignani PG. Is mild endometriosis always a disease? Hum Reprod 1992; 7:627–629. 60. Giorlandino C, Taramanni C, Muzii L, Santillo E, Nanni C, Vizzone A. Ultrasound-guided aspiration of ovarian endometriotic cysts. Int J Gynaecol Obstet 1993; 43:41–44.

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61. Aboulghar MA, Mansour RT, Serour GI, Rizk B. Ultrasonic transvaginal aspiration of endometriotic cysts: An optional line of treatment in selected cases of endometriosis. Hum Reprod 1991; 6:1408–1410. 62. Bruhat MA, Mage G, Chapron C, Pouly JL, Canis M, Wattiez A. Present day endoscopic surgery in gynecology. Eur J Obstet Gynecol Reprod Biol 1991; 41:4–13. 63. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas Roux F. Large ovarian endometriomas. Hum Reprod 1996; 11:641–646. 64. Brosens IA, Van Ballaer P, Puttemans P, Deprest J. Reconstruction of the ovary containing large endometriomas by an extraovarian endosurgical technique. Fertil Steril 1996; 66:517–521. 65. Hughesdon PE. Benign endometrioid tumours of the ovary and the mullerian concept of ovarian epithelial tumours. Histopathology 1984; 8:977–990. 66. Hughesdon PE. The endometrial identity of benign stromatosis of the ovary and its relation to other forms of endometriosis. J Pathol 1976; 119:201–209. 67. Brosens IA. New principles in the management of endometriosis. Acta Obstet Gynecol Scand Suppl 1994; 159:18–21. 68. Wood C. Endoscopy in the management of endometriosis. Baillieres Clin Obstet Gynaecol 1994; 8:735–757. 69. Canis M, Mage G, Wattiez A, Chapron C, Pouly JL, Bassil S. Second-look laparoscopy after laparoscopic cystectomy of large ovarian endometriomas [see comments]. Fertil Steril 1992; 58:617–619. 70. Fayez JA, Vogel MF. Comparison of different treatment methods of endometriomas by laparoscopy [see comments]. Obstet Gynecol 1991; 78:660–665. 71. Cornillie FJ, Oosterlynck D, Lauweryns JM, Koninckx PR. Deeply infiltrating pelvic endometriosis: Histology and clinical significance. Fertil Steril 1990; 53:978–983. 72. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ. Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA125 concentration. Fertil Steril 1996; 65:280–287. 73. Koninckx PR, Martin DC. Deep endometriosis: A consequence of infiltration or retraction or possibly adenomyosis externa? Fertil Steril 1992; 58: 924–928. 74. Redwine D. Was Sampson wrong? Fertil Steril 2002; 78:686. 75. Koninckx PR, Barlow D, Kennedy S. Implantation versus infiltration: The Sampson versus the endometriotic disease theory. Gynecol Obstet Invest 1999; 47(Suppl 1):3–9. 76. Holt VL, Weiss NS. Recommendations for the design of epidemiologic studies of endometriosis. Epidemiology 2000; 11:654–659. 77. Wheeler JM. Epidemiology of endometriosis-associated infertility. J Reprod Med Obstet Gynecol 1989; 34:41–46. 78. Redwine DB. Age-related evolution in color appearance of endometriosis. Fertil Steril 1987; 48:1062–1063. 79. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann NY Acad Sci 2002; 955:11–22.

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80. Moen MH, Schei B. Epidemiology of endometriosis in a Norwegian county. Acta Obstet Gynecol Scand 1997; 76:559–562. 81. Matorras R, Rodriguez F, Pijoan JI, Etxanojauregui A, Neyro JL, Elorriaga MA, Rodriguez-Escodero F. Women who are not exposed to spermatozoa and infertile women have similar rates of stage I endometriosis. Fertil Steril 2001; 76:923–928. 82. D’Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update 2002; 8:84–88. 83. Koninckx PR, Braet P, Kennedy SH, Barlow DH. Dioxin pollution and endometriosis in Belgium [see comments]. Hum Reprod 1994; 9:1001–1002. 84. Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL. Endometriosis in Rhesus monkeys (Macaca-mulatta) following chronic exposure to 2,3,7,8tetrachlorodibenzo-p-dioxin. Fund Appl Toxicol 1993; 21:433–441. 85. Rier SE, Turner WE, Martin DC, Morris R, Lucier GW, Clark GC. Serum levels of TCDD and dioxin-like chemicals in Rhesus monkeys chronically exposed to dioxin: Correlation of increased serum PCB levels with endometriosis. Toxicol Sci 2001; 59:147–159. 86. Koninckx PR. The physiopathology of endometriosis: Pollution and dioxin. Gynecol Obstet Invest 1999; 47(Suppl 1):47–49. 87. Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D. Serum dioxin concentrations and endometriosis: A cohort study in Seveso, Italy. Environ Health Perspect 2002; 110:629–634. 88. Tsutsumi O, Momoeda M, Takai Y, Ono M, Taketani Y. Breast-fed infants, possibly exposed to dioxins in milk, have unexpectedly lower incidence of endometriosis in adult life. Int J Gynaecol Obstet 2000; 68:151–153. 89. Fanton JW, Golden JG. Radiation-induced endometriosis in Macaca mulatta. Radiat Res 1991; 126:141–146. 90. Kennedy SH, Mardon H, Barlow DH. Familial endometriosis. J Assist Reprod Genet 1995; 12:32–34. 91. Hadfield RM, Mardon HJ, Barlow DH, Kennedy SH. Endometriosis in monozygotic twins. Fertil Steril 1997; 68:941–942. 92. Hadfield RM, Manek S, Nakago S, Mukherjee S, Weeks DE, Mardon HJ, Barlow DH, Kennedy SH. Absence of a relationship between endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population. Mol Hum Reprod 1999; 5:990–993. 93. Hadfield RM, Manek S, Weeks DE, Mardon HJ, Barlow DH, Kennedy SH. Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1. Mol Hum Reprod 2001; 7:1073–1078. 94. Zondervan KT, Cardon LR, Kennedy SH. The genetic basis of endometriosis. Curr Opin Obstet Gynecol 2001; 13:309–314. 95. Treloar SA, Kennedy SH. Preliminary results from two combined genomewide scans in endometriosis. Fertil Steril 2002; 77(Suppl 1):S19–S20. 96. Kennedy S, Hadfield R, Mardon H, Barlow D. Age of onset of pain symptoms

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in non-twin sisters concordant for endometriosis. Hum Reprod 1996; 11:403– 405. Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet Gynecol Scand 1993; 72:560–564. Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Scand 1994; 73:59–62. Oosterlynck D. Immunosuppressive activity of peritoneal fluid in women with endometriosis. Obstet Gynecol 1993; 82:206–212. Oosterlynck, D. Natural killer cells and endometriosis. PhD thesis, 1983. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR. Transforming growth factor-beta activity is increased in peritoneal fluid from women with endometriosis. Obstet Gynecol 1994; 83:287–292. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR, Vandeputte M. Immunosuppressive activity of peritoneal fluid in women with endometriosis. Obstet Gynecol 1993; 82:206–212. Oosterlynck DJ, Cornillie FJ, Waer M, Koninckx PR. Immunohistochemical characterization of leucocyte subpopulations in endometriotic lesions. Arch Gynecol Obstet 1993; 253:197–206. Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR. The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil Steril 1992; 58:290–295. Oosterlynck DJ, Cornillie FJ, Waer M, Vandeputte M, Koninckx PR. Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium. Fertil Steril 1991; 56:45–51. Vinatier D, Dufour P, Oosterlynck D. Immunological aspects of endometriosis. Hum Reprod Update 1996; 2:371–384. Braun D, Ding J, Shen J, Rana N, Fernandez B, Dmowski W. Relationship between apoptosis and the number of macrophages in eutopic endometrium from women with and without endometriosis. Fertil Steril 2002; 78:830. Braun D, Ding J, Dmowski W. Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis. Fertil Steril 2002; 78:727. Ding J, Shen J, Braun DP, Rana N, Dmowski WP. Endometrial apoptosis, macrophage content, and TNFalpha expression in endometriosis. Fertil Steril 2002; 77(Suppl 1):S1–S2. Dmowski WP. Immunology of endometriosis. Arq Matern Dr Alfredo Da Costa 1992; 12:40–43. Koninckx PR. Pelvic endometriosis: A consequence of stress? Contrib Gynecol Obstet 1987; 16:56–59. Demyttenaere K, Nijs P, Evers-Kiebooms G, Koninckx PR. Coping and the ineffectiveness of coping influence the outcome of in vitro fertilization through stress responses. Psychoneuroendocrinology 1992; 17:655–665. Demyttenaere K, Nijs P, Evers-Kiebooms G, Koninckx PR. Coping, ineffectiveness of coping and the psychoendocrinological stress responses during invitro fertilization. J Psychosom Res 1991; 35:231–243.

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114. Demyttenaere K, Nijs P, Evers-Kiebooms G, Koninckx PR. The effect of a specific emotional stressor on prolactin, cortisol, and testosterone concentrations in women varies with their trait anxiety. Fertil Steril 1989; 52:942–948. 115. Koninckx PR, Kennedy SH, Barlow DH. Pathogenesis of endometriosis: The role of peritoneal fluid. Gynecol Obstet Invest 1999; 47(Suppl 1):23–33. 116. D’Hooghe TM, Bambra CS, De JI, Lauweryns JM, Koninckx PR. The prevalence of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus) increases with the duration of captivity. Acta Obstet Gynecol Scand 1996; 75:98–101. 117. Parazzini F, Luchini L, Vezzoli F, Mezzanotte C, Vercellini P, Romanini C. Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: Results from a multicentric Italian study. Hum Reprod 1994; 9:1158–1162. 118. Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ. Infertility, fertility drugs, and ovarian cancer: A pooled analysis of casecontrol studies. Am J Epidemiol 2002; 155:217–224. 119. Olson JE, Cerhan JR, Janney CA, Anderson KE, Vachon CM, Sellers TA. Postmenopausal cancer risk after self-reported endometriosis diagnosis in the Iowa Women’s Health Study. Cancer 2002; 94:1612–1618. 120. Yano T, Jimbo H, Yoshikawa H, Tsutsumi O, Taketani Y. Molecular analysis of clonality in ovarian endometrial cysts. Gynecol Obstet Invest 1999; 47(Suppl 1):41–45. 121. Tamura M, Fukaya T, Murakami I, Uehara S, Yajima A. Analysis of clonality in human endometriotic cysts based on evaluation of X chromosome inactivation in archival formalin-fixed, paraffin-embedded tissue. Lab Invest 1998; 78:213–218. 122. Jimbo H, Hitomi Y, Yoshikawa H, Yano T, Momoeda M, Sakamoto A, Tsutsumi O, Taketani Y, Esumi H. Evidence for monoclonal expansion of epithelial cells in ovarian endometrial cysts. Am J Pathol 1997; 150:1173–1178. 123. Fujita M, Enomoto T, Wada H, Inoue M, Okudaira Y, Shroyer KR. Application of clonal analysis. Differential diagnosis for synchronous primary ovarian and endometrial cancers and metastatic cancer. Am J Clin Pathol 1996; 105:350–359. 124. Nishida M, Watanabe K, Sato N, Ichikawa Y. Malignant transformation of ovarian endometriosis. Gynecol Obstet Invest 2000; 50(Suppl 1):18–25. 125. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy in endometriosis: Frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol 2001; 20:133–139.

2 Pathogenesis of Endometriosis: Peritoneal Endometriosis, Ovarian Endometriosis, and Rectovaginal Adenomyosis Jacques Donnez and Jean Squifflet Catholic University of Louvain Brussels, Belgium

Pelvic endometriosis can be categorized into three different forms: peritoneal endometriosis, ovarian endometriosis, and endometriosis of the rectovaginal septum [1].

PERITONEAL ENDOMETRIOSIS Since its first detailed description by von Rokitansky in 1860 [2], several theories relating to the pathogenesis of endometriosis have been proposed. The most widely accepted is the transplantation theory that was proposed in 1927 by Sampson. He observed that endometrial cells regurgitated through the Fallopian tubes during menstruation [3]. Three essential conditions must be met to consider retrograde menstruation as the explanation for the pathogenesis of pelvic endometriosis [4]. First, endometrial cells must enter the peritoneal cavity through the Fallopian tubes. Second, cells within the menstrual debris must be viable and capable of 19

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being transplanted into pelvic structures. Third, the anatomical distribution of endometriosis in the pelvic cavity must correlate with the principles of transplantation for exfoliated cells. To explain the discrepancy between the occurrence of regurgitation and endometriosis, one must consider the volume of regurgitated menstrual debris, which can be determined by anatomic-mechanical predispositions. Ayers and Friedenstab [5] showed that uterotubal junction hypotonia occurred in patients with endometriosis, but not in (infertile) control subjects. Their findings seem to be corroborated by Bartosik et al [6], who found more endometrial cells in the abdominal cavity during flushing of the tubes in patients with endometriosis. Presence, Attachment, Invasion Numerous studies have demonstrated that reflux of endometrial cells into the peritoneal cavity during menstruation is a common physiologic condition in women with patent tubes [7,8]. The viability of endometrial cells was demonstrated by culture of menstrual blood or peritoneal fluid [9,10]. Experimental studies proved that endometriosis could be induced by exposure of the pelvis to increased amounts of menstrual discharge [11,12]. Implantation of endometrial tissue also induced endometriosis in rabbits [13,14]. Integrins are cell-surface glycoproteins that act as receptors for extracellular matrix (ECM) proteins. The expression of some integrins has been described in normal endometrium, where they are important in the interactions between glandular and stromal elements [15–17]. Foidart et al in 1993 first discovered these glycoproteins in endometriotic tissue [15]. Attachment of endometrial tissue fragments to the peritoneum could be explained by the detection of such cell adhesion molecules. After adherence of endometrial cells to the basement membrane (peritoneum), local degradation of the ECM is required. Recently, Marbaix et al [18,19] and Kokorine et al [20] demonstrated that the marked decline in progesterone (P) concentration at the end of the menstrual cycle would initiate the synthesis and activation of matrix metalloproteinases (MMPs), causing ECM breakdown, tissue collapse and menstruation. Thus, the presence of collagenases was proved during the menstrual period, and their probable presence in the peritoneal fluid, together with regurgitated endometrial cells, could be one of the elements in the local degradation of the peritoneal ECM. Kokorine et al [21] detected the presence of MMPs in red peritoneal lesions and ovarian endometriomas independent of the menstrual cycle, suggesting that such lesions could represent shedding independent of the decline in P concentration. This hypothesis was bolstered by the detection of

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the aminoterminal propeptide of type III procollagen in peritoneal fluid, which is a sign of increase in the metabolism of the ECM [22]. In vitro studies demonstrated that the invasion index of endometriotic cells was similar to that of bladder metastatic cell lines, suggesting that the invasiveness of endometriotic cells may contribute to the pathogenesis of endometriosis [23]. The anatomic distribution of endometriosis in the pelvic cavity was described by Jenkins et al [24] and correlated with the principles of transplantation for exfoliated cells. These data suggested that any exposure of the pelvic peritoneum to menstrual reflux would result in an increased risk of endometriosis. Evolution of Red, Black, and White Peritoneal Lesions In red flame-like lesions (Figs. 1 and 2), biopsied together with the surrounding normal peritoneum, we observed an extensive vascular network between the stroma recently implanted onto the peritoneal surface and the peritoneal and subperitoneal layers, demonstrating the importance of angiogenesis in the early stages of development after implantation [25,26]. In our opinion, vascularization of endometriotic implants is probably one of the most important factors of growth and invasion of other tissue by endometrial glands [27,28]. It seems reasonable to say that angiogenic factors present in the peritoneal fluid of 58% of women with endometriosis facilitate the growth of endometriotic implants. Peritoneal macrophages, retrograde endometrial cells, or the ectopic endometriotic lesions could produce these angiogenic factors [29]. Data from our group [21] revealed the presence of MMPs in the stroma of red lesions throughout the menstrual cycle. However, in eutopic endometrium, MMPs are detected only during the marked decline in P. After this partial shedding, the remaining red lesion grows again until the next shedding, but menstrual shedding finally induces an inflammatory reaction, provoking a scarification process that encloses the implant. The enclosed implant becomes a ‘‘black’’ lesion because of the presence of intraluminal debris (Fig. 3). This scarification process is probably responsible for the reduction in vascularization, as proved by the significant decrease in the relative surface areas of the capillaries and stroma [27]. The role of trauma or inflammation of the mesothelium was suggested by van Der Linden et al [30], who cultured endometrial cells on amniotic membranes. Adherence of endometrial cells to the epithelial surface of the amniotic membranes was never observed when the epithelium was intact. These investigators proposed that an intact epithelium could be an important

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FIGURE 1 Evolution of red, black, and white peritoneal lesions. After attachment of endometrial cells to the basement membrane (peritoneum), local degradation of the extracellular matrix is required. Angiogenesis is one of the most important factors of growth and invasion (red lesions). Partial shedding occurs in red lesions, and the remaining red lesions constantly regrow until the next shedding. Menstrual shedding finally induces an inflammatory reaction provoking a scarification process that encloses the implant, which then becomes a ‘‘black’’ lesion because of the presence of intraluminal debris. White lesions are quiescent or inactive lesions with occasional glandular structures on histological examination.

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FIGURE 2 (A) Red, flame-like lesion at laparoscopy. (B) Numerous glands with active epithelium and stroma are found on the peritoneal surface.

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FIGURE 3 Typical black lesion, surrounded by a white area of peritoneal fibrosis (white lesion).

defense mechanism in preventing initial adhesion of shed endometrial fragments to peritoneum. On the contrary, we have demonstrated that menstrual endometrium is able to adhere to normal mesothelium [31]. In agreement with Brosens [32], we regard red lesions as early endometriosis and black lesions as advanced endometriosis [27,33]. White lesions are believed to be healed endometriosis or quiescent or latent lesions [27]. This hypothesis corroborates the clinical findings of Redwine [34] and Goldstein et al [35] that red lesions precede the others and that, with time, their presence decreases, as they are replaced by black and ultimately white lesions. Red petechial lesions are found in adolescents [35]. The shedding and implantation of endometrial cells is a process that occurs during the initial phase of reproductive life. The fact that this period is characterized by anovulatory cycles is in accordance with the hypothesis that anovulation, with a low P concentration in peritoneal fluid, is the favored time for the implantation of endometriosis [36]. Black lesions rarely demonstrate typical progestational changes, although some investigators report that 70% of foci with a cyclic pattern undergo changes that are considered synchronous (F3 days) with eutopic endometrium [25,26,37]. This assumption is based on the observation of basal vacuoles in certain cells (3 cm or developing laterally, patients should undergo preoperative intravenous pyelography (IVP). Intravenous pyelography is abnormal in more than 10% of these cases. It can detect small abnormalities of the ureter, such as medialization, substenosis, lack of distension after decompression, and may reveal the beginning of compression of the ureter by lateral extension of the nodule.

CLASSIFICATION: THE KEY TO PATHOGENESIS Koninckx proposed a classification divided into three types: T1, T2, and T3 that suggests adenomyosis (Fig. 9) [69]. Adamyan’s classification attempted to describe the lesions anatomically [70]. More recently, Vercellini et al [71] proposed that intraperitoneal endometriosis could explain the obliteration of the rectovaginal pouch and the subsequent infiltration of the rectovaginal septum by the lesions. That is why the term ‘‘deep-infiltrating disease’’ is

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FIGURE 9 Classification (from left to right): (a) rectovaginal septum lesion (type I); (b) posterior vaginal fornix lesion (type II); (c) hourglass-shaped lesion (type III).

sometimes used to describe these lesions. This latter hypothesis, however, has neither anatomical nor histopathological support. In our theory, adenomyosis originates in the retrocervical area and involves the retroperitoneal space. We have proposed a classification, which takes into account the precise location of the retroperitoneal lesion, as defined by transvaginal ultrasonography and MRI [67]. 1. Rectovaginal septum These lesions are situated within the rectovaginal septum between the posterior wall of the vaginal mucosa and the anterior wall of the rectal muscularis. 2. Posterior vaginal fornix These lesions develop from the posterior fornix toward the rectovaginal septum. The posterior fornix is retrocervical and corresponds, in the attachment of the vaginal mucosa, to the posterior face of the posterior lip of the cervix. 3. Hourglass-shaped or diabolo-like These lesions occur when posterior fornix lesions extend cranially to the anterior rectal wall. The part of the adenomyotic lesion situated in the anterior rectal wall is the same size as the part of the lesion situated near the posterior fornix. A small but well-observed continuum exists between these two parts of the lesion. That is why we have termed these lesions diabolo-like or ‘‘hourglass’’ shaped. As noted before, these lesions always occur under the peritoneal fold of the recto-uterine pouch of Douglas. Hourglass-type lesions were also found to be large, their average size estimated to be 3 cm by clinical examination. The barium enema showed signs of perivisceritis in nearly all cases. In our experience, the most frequent types are lesions in the posterior vaginal fornix in 60% of cases with extension into the rectovaginal septum

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in 20% of all cases, followed by the hourglass-shaped or diabolo-like lesions in 25% of cases (Fig. 10). The infrequent type is the rectovaginal septum in 15% of cases. Accordingly, it is inappropriate to define all retroperitoneal lesions as rectovaginal septum adenomyosis. We suggest classifying the lesions into three types according to their location, clinical examination, transrectal echography and MRI. These three types are rectovaginal septum lesions, posterior vaginal fornix lesions, and hourglass-shaped or diabololike lesions.

FIGURE 10 Magnetic resonance imaging: hourglass-shaped or diabolo-like lesions. It is obvious that this type of lesion occurs under the peritoneal fold of the recto-uterine pouch of Douglas.

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Smooth Muscle Proliferation At least three hypotheses may explain smooth muscle proliferation (Fig. 11). 1. Endometriotic foci involving smooth muscle are typically associated with prominent proliferation of the smooth muscle, creating an adenomyomatous appearance similar to that of adenomyosis in the endometrium [32]. 2. The endometriotic stroma may exhibit smooth muscle metaplasia, similar to that found within the wall of ovarian endometriotic cysts [72]. 3. It may be due to modified gene expression induced by toxic agents. When endometriotic glands affect the retroperitoneal space, smooth muscle proliferation can take place and a nodule develops. Sometimes, retroperitoneal space invasion provokes perivisceritis. This is not a rectal endometriotic lesion or invasion of the rectal wall by the endometriotic process, as has been suggested by many investigators. We believe it is the result of serosal retraction caused by the inflammatory process and fibrosis on the anterior wall of the rectum. The absence of evolution of the rectal lesion after removal of the nodule supports our hypothesis that it originates from the retroperitoneal space.

FIGURE 11 Smooth muscle proliferation in an adenomyotic nodule.

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This suggests that it is not necessary to excise the anterior wall of the rectum [65,66]. In any event, because of the contact between the endometrial glands and the vagina, excision of the nodule and the adjacent vaginal mucosa is essential. Secretory changes are frequently absent or incomplete during the second half of the menstrual cycle. This suggests that adenomyosis may not respond to physiologic levels of P. Similar histological findings can be seen in the endometriotic rectovaginal nodule. It looks like an adenomyoma with a circumscribed nodular aggregate of smooth muscle, endometrial glands and, often, endometrial stroma [28,65,73]. This lesion originates from the tissue of the retrocervical area or from the rectovaginal septum and consists mainly of smooth muscle with active glandular epithelium and scanty stroma. Invasion of the smooth muscle by active glandular epithelium without stroma proves that stroma is not mandatory for invasion. It also shows that the nodule is different from peritoneal endometriosis, where the epithelial glands are surrounded by endometrial-type stroma [25,26]. Because of the similarity between the endometriotic nodule of the rectovaginal septum and uterine adenomyoma, we agree with Brosens [42] that their origin is similar. Furthermore, the coexpression of vimentin and cytokeratin indicates a close relationship with its mesodermal Mu¨llerian origin [25,26,73]. SUMMARY The different aspects of peritoneal endometriosis (red, black, and white lesions) represent distinctive steps in the evolutionary process that can be explained by the transplantation theory. Red lesions are the most active and highly vascularized lesions and can be considered the early phase of peritoneal endometriosis. Based on our histological findings, celomic metaplasia of invaginated epithelial inclusions could be responsible for the development of ovarian endometriosis. The epithelium covering the ovary derives from the celomic epithelium, has great metaplastic potential, and provokes epithelial inclusion cysts by invagination. Under the influence of unknown growth factors, these inclusions could be transformed into intraovarian endometriosis by metaplasia. Retroperitoneal nodule is an adenomyotic nodule whose histopathogenesis is not related to the implantation of regurgitated endometrial cells but to metaplasia of Mu¨llerian remnants in the retroperitoneal space. Metaplastic changes of Mu¨llerian rests into adenomyotic glands of the rectovaginal septum and the retroperitoneal space are responsible for the striking proliferation of the smooth muscle, creating an adenomyomatous appearance similar to that of adenomyosis in the endometrium.

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We conclude that intraperitoneal and retroperitoneal diseases are two different entities with specific histopathogenesis, evolution, and symptoms.

PRACTICAL POINT 

Intraperitoneal endometriosis and retroperitoneal endometriosis appear to be different entities.

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14. Donnez J, Wayembergh M, Casanas-Roux F, Karaman Y, Willems T, Ferin J. Effect on ovulation of surgically induced endometriosis in rabbits. Gynecol Obstet Invest 1987; 24:131–137. 15. Foidart JM, Beliard A, Donnez J. Endometriosis and invasion. In: Brosens I, Donnez J, eds. The current status of endometriosis research and management. Carnforth: Parthenon Publishing, 1993:35–39. 16. Lessey BA, Damjanovich L, Coutifaris C, Castelbaum A, Albelda SM, Buck CA. Integrin adhesion molecules in the human endometrium: correlation with the normal and abnormal menstrual cycle. J Clin Invest 1992; 90:188–195. 17. Tabibzadeh S, Sun XZ. Cytokine expression in human endometrium throughout the menstrual cycle. Hum Reprod 1992; 7:1214–1221. 18. Marbaix E, Kokorine I, Henriet P, Donnez J, Courtoy PJ, Eeckhout Y. The expression of interstitial collagenase in human endometrium is controlled by progesterone and by estradiol and is related to menstruation. Biochem J 1995; 305:1027–1030. 19. Marbaix E, Kokorine I, Donnez J, Eeckhout Y, Courtoy PJ. Regulation and restricted expression of interstitial collagenase suggest a pivotal role in the initiation of menstruation. Hum Reprod 1996; 11:134–143. 20. Kokorine I, Marbaix E, Henriet P, Okada Y, Donnez J, Eeckhout Y, Courtoy PJ. Focal cellular origin and regulation of interstitial collagenase (matrixmetalloproteinase-1) are related to menstrual breakdown in the human endometrium. J Cell Sci 1996; 109:2151–2160. 21. Kokorine I, Nisolle M, Donnez J, Eeckhout Y, Courtoy PJ, Marbaix E. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril 1997; 68:246–251. 22. Spuijbroek MD, Dunselman GA, Menheere PP, Evers JL. Early endometriosis invades the extracellular matrix. Fertil Steril 1992; 58:929–933. 23. Gaetje R, Kotzian S, Hermann G, Baumann R, Starzinski-Powitz A. Invasiveness of endometriotic cells in vitro. Lancet 1995; 346:1463–1464. 24. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol 1986; 67:335–358. 25. Nisolle M. Peritoneal, ovarian and rectovaginal endometriosis are three distinct entities. The`se d’Agre´gation de l’Enseignement Supe´rieur, Universite´ Catholique de Louvain, 1996. 26. Nisolle M, Donnez J, eds. Peritoneal, ovarian and rectovaginal endometriosis: the identification of three separate diseases. Carnforth: Parthenon Publishing, 1996. 27. Nisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril 1993; 59:681–684. 28. Donnez J, Nisolle M. L’endome´triose pe´ritone´ale, le kyste endometriotique ovarien et le nodule de la lame rectovaginale sont trois pathologies diffe´rentes (e´ditorial). Re´fe´rences en Gyne´cologie Obste´trique 1995; 3:121–123. 29. Halme PR. Angiogenic activity of peritoneal fluid from women with endometriosis. Fertil Steril 1993; 59:778–782.

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30. van der Linden PJ, de Goeij AF, Dunselman GA, Erkens HW, Evers JL. Endometrial cell adhesion in an in vitro model using intact amniotic membranes. Fertil Steril 1996; 65:76–80. 31. van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril 2002; 5:861–870. 32. Brosens IA. Is mild endometriosis a progressive disease? Hum Reprod 1994; 9:2209–2211. 33. Donnez J, Casanas-Roux F, Nisolle M. Peritoneal endometriosis: new histological aspects. In: Brosens I, Donnez J, eds. Current status of endometriosis. Research and Management. Carnforth: Parthenon Publishing, 1993: 75–87. 34. Redwine DB. Age-related evolution in color appearance of endometriosis. Fertil Steril 1987; 48:1062–1063. 35. Goldstein MP, de Cholnoky C, Emans SJ, Leventhal JM. Laparoscopy in the diagnosis and management of pelvic pain in adolescents. J Reprod Med 1980; 44:251–258. 36. Brosens IA, Koninckx PR, Corveleyn PA. A study of plasma progesterone, oestradiol-17 beta, prolactin and LH levels and of the luteal phase appearance of the ovaries in patients with endometriosis and infertility. Br J Obstet Gynaecol 1978; 85:246–250. 37. Bergqvist A, Ljunberg O, Myrhe E. Human endometrium and endometriotic tissue obtained simultaneously: a comparative histologic study. Int J Gynecol Pathol 1984; 3:135–145. 38. Ferenczy A. Anatomy and histology of the uterine corpus. In: Kurman RJ, ed. Blaustein’s pathology of the female genital tract. New-York: Springer-Verlag, 1987:257–291. 39. Mazur T, Kurman RJ. Normal endometrium and infertility evaluation. In: Diagnosis of endometrial biopsies and curettings. A practical approach. New York: Springer-Verlag, 1995:7–32. 40. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease : an overview. Methods Enzymol 1990; 186:1–85. 41. Hippeli S, Elstner EF. Transition metal ion-catalyzed oxygen activation during pathogenic processes. FEBS Lett 1999; 443:1–7. 42. Brosens IA. New Principles in the management of endometriosis. Acta Obstet Gynecol 1994; 159:18–21. 43. Murphy A, Palinski W, Rankin S, Morales AJ, Parthasarathy S. Macrophage scavenger receptor(s) and oxidatively modified proteins in endometriosis. Fertil Steril 1998; 69:1085–1094. 44. Moen MH, Halvorsen TB. Histologic confirmation of endometriosis in different peritoneal lesions. Acta Obstet Gynecol Scand 1992; 71:337–342. 45. Stowell SB, Wiley CM, Perez-Reyes N, Powers CN. Cytologic diagnosis of peritoneal fluids. Applicability to the laparoscopic diagnosis of endometriosis. Acta Cytol 1997; 41:817–822. 46. Ponka P, Beaumont C, Richardson DR. Function and regulations of transferrin and ferritin. Semin Hematol 1998; 35:35–54.

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47. Fischbach FA, Gregory DW, Harrison PM, Hoy TG, Williams JM. On the structure of hemosiderin and its relationship to ferritin. J Ultrastruct Res 1971; 37:495–503. 48. Casanas-Roux F, Van Langendonckt A, Nisolle M, Donnez J. Iron deposits and oxidative stress in the peritoneal cavity of patients with endometriosis (abstract no. 10). In: Abstracts of the Endometriosis 7th Biennial World Congress, London, 2000. 49. Murphy A, Zhou MH, Malkapuram S, Santanam N, Parthasarathy S, Sidell N. RU486-induced growth inhibition of human endometrial cells. Fertil Steril 2000; 74:1014–1019. 50. Gue´rin P, El Mouatassim S, Me´ne´zon Y. Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum Reprod Update 2001; 7:175–189. 51. Sampson JA. Perforating haemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921; 3:245–323. 52. Hughesdon PE. The structure of endometrial cysts of the ovary. J Obstet Gynecol Br Emp 1957; 44:69–84. 53. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 1994; 61:1034–1038. 54. Nezhat F, Nezhat C, Allan CJ, Metzger DA, Sears DL. A clinical and histological classification of endometriomas: implications for a mechanism of pathogenesis. J Reprod Med 1992; 37:771–776. 55. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas-Roux F. Large ovarian endometriomas. Hum Reprod 1996; 11:641–646. 56. Serov SF, Scully RE, Sobin LH. Histological typing of ovarian tumors. In: International Histological Classification of Tumors. No 9. Geneva: World Health Organization, 1973:17–21. 57. Motta PM, Van Blerkom J, Mekabe S. Changes in the surface morphology of ovarian germinal epithelium during the reproductive life and in some pathological conditions. Submicr Cytol 1992; 99:664–667. 58. Rosenfeld DL, Lecher BD. Endometriosis in a patient with Rokitansky-KusterHauser syndrome. Am J Obstet Gynecol 1981; 139:105. 59. Canis M, Wattiez A, Pouly JL, Bassil S, Bouquet J, Chapron C, Manhes H, Mage G, Bruhat MA. Laparoscopic treatment of endometriosis. In: Brosens I, Donnez J, eds. The Current status of endometriosis research and management. Carnforthe: Parthenon Publishing, 1993:407–417. 60. Donnez J. CO2 laser laparoscopy in infertile women with endometriosis and women with adnexal adhesions. Fertil Steril 1987; 48:390–394. 61. Donnez J, Nisolle M, Casanas-Roux F. Classification and endoscopic treatment of ovarian endometriosis. In: Popkin E, ed. Women’s health today. Carnforth: Parthenon Publishing, 1994. 62. Nisolle M, Donnez J. Conservative laparoscopic treatment of ovarian endometriosis. In: Shaw RW, ed. Endometriosis—current understanding and management. London: Blackwell Science, Ltd., 1995:237–247. 63. Brosens IA, Van Ballaer P, Puttemans P, Deprest J. Reconstruction of the ovary

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containing large endometriomas by an extraovarian endosurgical technique. Fertil Steril 1996; 66:517–521. Donnez J, Donnez O, Squifflet J, Nisolle M. The concept of ‘‘adenomyotic disease of the retroperitoneal space’’ is born. Gynaecol Endosc 2001; 10:91–94. Sampson JA. Intestinal adenomas of endometrial type. Arch Surg 1922; 5:21–27. Donnez J, Nisolle M, Casanas-Roux F, Bassil S, Anaf V. Rectovaginal septum, endometriosis or adenomyosis: laparoscopic management in a series of 231 patients. Hum Reprod 1995; 2:230–235. Squifflet J, Feger C, Donnez J. Diagnosis and imaging of adenomyotic disease of the retroperitoneal space. Gynecol Obstet Invest 2002; 54:43–51. Balleyguier C, Chapron C, Duibuisson JB, Kinkel K, Fauconnier A, Vieira M, He´le´non O, Menu Y. Comparison of magnetic resonance imaging and transvaginal ultrasonography in diagnosing bladder endometriosis. J Am Assoc Gynecol Laparosc 2002; 9:15–23. Koninckx PR, Martin D. Deep endometriosis: a consequence of infiltration or retraction or possible adenomyosis externa? Fertil Steril 1992; 58:924–928. Adamyan L. Additional international perspectives. In: Nichols DH, ed. Gynecologic and Obstetrics Surgery. St. Louis: Mosby Year Book, 1993:1167–1182. Vercellini P, Aimi G, Panazza S, Vicentini S, Pisacreta A, Crosignani PG. Deep endometriosis conundrum: evidence in favor of peritoneal origin. Fertil Steril 2000; 73:1043–1046. Scully RE, Richardson GS, Barlow JF. The development of malignancy in endometriosis. Clin Obstet Gynecol 1966; 9:384–411. Donnez J, Nisolle M, Smoes P, Gillet N, Beguin S, Casanas-Roux F. Peritoneal endometriosis and ‘‘endometriotic’’ nodules of the rectovaginal septum are two different entities. Fertil Steril 1996; 66:362–368.

3 Anatomical Sites of Endometriosis Haya Al-Fozan and Togas Tulandi McGill University Montreal, Quebec, Canada

Endometriosis was described for the first time in 1860 by von Rokitansky as the presence of tissue resembling functioning endometrial glands and stroma outside the uterine cavity [1]. The prevalence of endometriosis among women of reproductive age was estimated to be as high as 10% [2]. However, the prevalence is higher in infertile women (38%) and in women suffering from pelvic pain (50%). The most common location of endometriosis is the pelvis. Occasionally, it is found in the skin, lungs, or gastrointestinal tract. PATHOGENESIS The possible etiology of endometriosis is discussed in Chapter 2. However, the exact pathogenesis of endometriosis remains unclear. In 1927, Sampson [3] postulated that endometriosis occurs because of retrograde menstruation, where fragments of endometrium reflux through fallopian tubes into the peritoneal cavity, then attach and grow on the peritoneum. This theory may explain the anatomical distribution of the endometriosis. Endometriosis is most commonly found close to the fimbriae and on the dependent portions of 45

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the pelvis. Extrapelvic endometriosis, such as in the lung or brain, may be the result of lymphatic or hematogenic spread of endometriosis implants.

PELVIC ENDOMETRIOSIS Ovary and Posterior Cul de Sac The common sites of pelvic endometriosis are the ovaries and the posterior cul de sac [4–6]. Jenkins et al [5] reported that endometriosis affects both the ovary and the posterior cul de sac at equal frequency. In their report, the incidence of endometriosis on the posterior cul de sac, the left ovary, and the right ovary was 34%, 44%, and 31.3% respectively. They also found that endometriotic implants are found more frequently in the left hemipelvis. Their incidence of endometriosis on the left and right posterior broad ligaments was 25.2% and 21.4%, respectively. We found that 74.8% of endometriotic implants are in the posterior cul de sac [6]. Of interest, endometriosis is more frequently encountered in the left (64.3%) than in the right hemipelvis (Fig. 1) [6,7]. Similarly ovarian endometrioma is found more commonly in the left than in the right ovary. It is possible that this is related to decreased fluid movement in the left side of the

FIGURE 1 Black and whitish endometriotic implants on the left broad ligament.

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hemipelvis owing to the presence of sigmoid colon. In a study of patients with intraperitoneal malignant seeding using peritoneography, the author found that fluid from the pelvic cavity ascended both paracolic gutters. Compared with the right hemipelvis, the fluid flow in the left hemipelvis was weak and slow [8]. These findings may support the theory that the origin of endometriosis is from the regurgitated endometrial cells. Uterosacral ligaments are affected in 15.3% (right) and 20.8% (left) of the cases respectively [5]. Fallopian Tubes Fallopian tubes are infrequently involved with endometriosis (Fig. 2). The prevalence of tubal endometriosis is approximately 5%. Although endometriosis might not be found on the tube, it appears that tubal function is affected. Lyons et al [9] studied the effects of peritoneal fluid from women with endometriosis on the ciliary beat frequency of human fallopian tube epithelium. Compared to the control group, the ciliary beat frequency was significantly lower in the tube incubated with peritoneal fluid from women with endometriosis. The impairment of ciliary action in women with endometriosis might be one of the reasons for reduced fertility.

FIGURE 2 Bluish-black vesicles of endometriotic implants adjacent to the fallopian tube.

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BOWEL The most common location of the extragenital endometriosis is the intestines [10,11]. It is found mainly in the rectum, sigmoid colon, cecum, appendix, and the terminal ileum [12]. In bowel endometriosis, the implants are usually seen on the serosa, but mural involvement may also occur [13]. Cyclic diarrhea, constipation, diarrhea alternating with constipation, cyclic rectal bleeding, cyclic abdominal distention, and partial or complete intestinal obstruction are symptoms suggestive of bowel involvement. Among all surgically treated endometriosis, intestinal obstruction on the level of ileum and sigmoid colon occurs in 0.8%, and 8% to 12%, respectively. However, complete obstruction of intestinal lumen is rare (37 IU/ml), but it was not elevated in any of the 22 control patients. [20] Serum CA19-9 levels were not elevated in 38 patients with stage I and II endometriosis but elevated in 34 of the 63 patients (54.0%) with stage III and IV endometriosis. On comparing the sensitivities of the CA19-9 and CA-125 tests for the diagnosis of endometriosis, the investigators found that the sensitivity of the CA19-9 test was significantly lower than that of the CA-125 test (0.34 and 0.49, respectively). Thus, the observed sensitivity of 0.34 limits the diagnostic value of the CA19-9 test, especially in the earlystage disease. [20] The same study showed that using a cutoff value of 37 IU/ml, the mean serum CA19-9 levels in patients with endometriosis increased in accordance with the stage of the disease. On the other hand, if a new cutoff value of the serum CA19-9 levels ranging from 20 to 25 IU/ml is used, the sensitivity of the CA19-9 test will be improved without change in specificity or positive and negative predictive values. However, this study concluded that the clinical utility of the CA19-9 measurement is not superior to that of the CA 125. Serum-Soluble Intercellular Adhesion Molecule-1 A soluble form of intercellular-adhesion molecule-1 (sICAM-1) is secreted from the endometrium and the endometriotic implants. [21] Moreover, endometrium from women with endometriosis secretes a higher amount of this molecule when compared with tissue derived from women without the disease. Consequently, a strong correlation exists between levels of sICAM-1 shed by endometrium and the number of endometriotic implants in the pelvis. [21] With this observation in mind, a role of sICAM-1 in the diagnosis of endometriosis has been hypothesized. A significant increase in serum concentration of sICAM-1 in endometriosis has been reported by many investigators. [22–25] In a recent prospective cohort study to evaluate the utility of sICAM-1 as a potential serum marker of endometriosis, Somigliana et al included a series of 120 consecutive women of reproductive age who underwent laparoscopy for benign gynecologic conditions. [26] They found that serum levels of sICAM-1 were slightly but not significantly elevated in women with endometriosis [71 women (stage I to II in 24 cases and stage III to IV in 47 cases)] compared with women without the disease. However, serum concentration of

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sICAM-1 in the 21 women who were found to have deep peritoneal endometriosis was significantly enhanced when compared with both women without the disease and those with superficial endometriosis. The sensitivity and specificity of sICAM-1 in detecting deep peritoneal endometriosis were 0.19 and 0.97, respectively. On comparing that to CA-125, the authors found that the measures of accuracy were 0.14 and 0.92, respectively. When both parameters were used concomitantly, the sensitivity and specificity were 0.28 and 0.92, respectively. They concluded that measurement of CA-125 and sICAM-1 may be helpful in specifically identifying women with deep infiltrating endometriosis. [26] Other Serum Polypeptides Serum placental protein 14 (PP14), currently known as glycodelin-A, [27] was found to be significantly more elevated in endometriosis patients than healthy controls. [28] Such high levels were significantly lowered by conservative surgery as well as by danazol and medroxy progesterone acetate treatment. The reliability of serum PP14 levels for the diagnosis of endometriosis is limited because of low sensitivity (0.59). Typically, the PF concentrations of PP14 are low. The levels are elevated in the luteal phase of endometriosis patients. Whether this is of any diagnostic importance is controversial. [29] Peritoneal Fluid CA 125 Peritoneal fluid is often seen in the vesicouterine cavity or the cul-de-sac during gynecologic surgery and bathes the pelvic cavity, uterus, fallopian tubes, and ovaries. It is believed to be a major factor controlling the peritoneal microenvironment that influences the development and progression of endometriosis and endometriosis-associated infertility. Peritoneal fluid is formed in part by the contribution of the follicular activity, corpus luteum vascularity, and hormonal production. The volume of PF is dynamic and phasedependent, peaking at the time of ovulation. [30] The PF ingredients are variable in normal menstrual cycles and different pathologic entities. [31,32] Women with endometriosis were found to have a greater PF volume than fertile controls, patients with tubal disease, or those with unexplained infertility. Moreover, an increased volume of PF may be commonly associated with endometriosis and with idiopathic infertility. CA-125 has been measured in PF of patients with and without endometriosis by many investigators. [33–35] Although PF levels of CA-125 were almost tenfold higher than the serum ones, no differences were found between women with and without endometriosis. [36] Measurement of CA-125 in other body fluids, such as menstrual discharge [37] and uterine fluid [38] have been tried but not found useful in clinical practice.

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IMMUNOLOGICAL MARKERS A significant role of the immune system in the pathogenesis of endometriosis has been recently documented. [2] Based on these recent findings, the concept of treating endometriosis as an autoimmune disease is emerging. [39] Accumulating evidence suggests that systemic T-cell activity influences the pathogenesis of endometriosis. [40,41] Altered T-helper to T-suppressor ratio and concentration of both cells, respectively, have been reported in serum, PF, [42] and endometriotic tissue [43] in endometriosis patients. Moreover, such differences could be detected between eutopic endometrium from women with and without the disease. There is lack of consistency regarding the alterations in T-cells and their role in the pathophysiology of endometriosis. Natural killer (NK) cells are also altered in endometriosis. Both peripheral and peritoneal fluid NK cells from women with endometriosis showed different characteristics compared with those of the controls. [44] Additionally, NK cell cytotoxicity has been shown to be inversely correlated with the stages of the disease. [45] Consequently, altered NK cytotoxicity to endometrial tissue may be responsible in part for the initiation, propagation, and establishment of pelvic endometriosis. Sera and PF from women with endometriosis have been shown to reduce NK cell activity. [46] This is probably caused by monocyte or macrophage activity through their secretions that modulate immune and nonimmune cells. Besides the alterations of T-cell functions, many recent findings have shown alterations in B-cell function in endometriosis patients as evidenced by abnormal antigen-antibody reaction and increased B-cell function. Decreased C3 deposition in the endometrium and a corresponding reduction in the serum total complement levels has been shown in endometriosis patients. [47] Antiendometrial antibodies particularly IgG and IgA have been detected in sera, and vaginal and cervical secretions of endometriosis patients. [48] The presence of antiphospholipids and antihistones of IgG, IgM, and IgA have been documented by some investigators [49] and questioned by others. [50] The exact correlation between the stage of endometriosis and autoantibodies ranges from positive [51] to negative [4] to no relationship at all. [52] These observations of immune alterations have lead investigators to believe that markers of immune reactivity , particularly cytokines, may be potentially used as a diagnostic aid for endometriosis. Cytokines: Chemistry Cytokines are polypeptides or glycoproteins secreted into the extracellular compartment mainly by leukocytes. Upon secretion, they exert autocrine, paracrine, and sometimes endocrine effects. Moreover, cytokines may exist in cell-membrane-associated forms where they exert juxtacrine activity on

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adjacent cells. They are essential mediators of cell-cell communication in the immune system. They affect a wide variety of target cells exerting proliferative, cytostatic, chemoattractant, or differentiative effects. Their biological activities are mediated by coupling to intracellular signaling and secondmessenger pathways via specific high-affinity receptors on target cell membranes. The cytokine nomenclature reflects the historical description of these biological activities. Cytokines: Sources The main source of cytokines is macrophages, which originate in bone marrow, circulate as monocytes, and migrate to various body cavities. Chemoattractant cytokines, particularly regulated on activation, normal T-cell expressed and secreted (RANTES), and interleukin (IL)-8, facilitate macrophage recruitment into the peritoneal cavity. The second major source of cytokines is T-lymphocytes. Helper T-cells can be classified into two subsets: type 1 (Th1) and type 2 (Th2). Th1 cells produce IL-2, IL-12, and interferon-g, which are potent inducers of cell-mediated immunity. Th2 cells produce mainly IL-4, IL-5, IL-10, and IL-13, which are involved in suppression of cell-mediated immunity. There is alteration of cytokines secreted by Th1 and Th2 in endometriosis patients particularly in the balance of Th1 and Th2 cells toward the Th2. This may, in part, be responsible for the impaired immunological defense in endometriosis. [53] Tsudo et al hypothesized that cytokines are not only produced by immune competent cells but by endometriotic implants as well. [54] They demonstrated that endometriotic cells constitutively express IL-6 messenger RNA and produce IL-6 protein, and that adding TNF-a stimulated IL-6 gene and protein expression in a dose-dependent manner. On comparing IL-6 production by macrophages and endometriotic stromal cells in patients with endometriosis, they found that similar levels of IL-6 were produced in stromal cells derived from an endometrioma and by macrophages under basal- and TNF-a stimulated conditions. This finding supports the hypothesis that endometriotic tissue is another important source of cytokines. [54] Peritoneal Fluid Cytokines Peritoneal fluid is rich with variable cellular components including macrophages, mesothelial cells, lymphocytes, eosinophils, and mast cells. The normal concentration of PF leukocytes is 0.5 to 2.0  106/ml, of which approximately 85% are macrophages. [31,32] It has been hypothesized that peritoneal macrophage activation is a pivotal step in the disease initiation and progression. [55] Activated macrophages in the peritoneal cavity of women with endometriosis are potent producers of cytokines. [3] Thus, PF contains a

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rich mixture of cytokines. Iron overload was also observed in the cellular and PF compartments of the peritoneal cavity of endometriosis patients, suggesting a role in its pathogenesis. [56] Individual Cytokines Tumor Necrosis Factors The tumor necrosis factors (TNF) are pleiotropic cytokines that exert an essential role in the inflammatory process. It is believed to be seminal in many physiological and pathological reproductive processes. The spectrum of its activity is very wide, with both beneficial and hazardous effects. The quantity of TNF produced is the main factor that controls its role in the disease process. The main TNF is TNF-a, which is produced by neutrophils, activated lymphocytes, macrophages, NK cells, and several nonhematopoietic cells. Little is known about TNF-h, which is produced by lymphocytes. The primary function of TNFs is their ability to initiate the cascade of cytokines and other factors associated with inflammatory responses. TNF-a helps to activate helper T-cells. In the human endometrium, TNF- a is a factor in the normal physiology of endometrial proliferation and shedding. Tumor necrosis factor-a is expressed mostly in epithelial cells, particularly in the secretory phase. [57] Stromal cells stain for TNF- a mostly in the proliferative phase of the cycle. These data suggest a hormonal control of this cytokine. [58] Peritoneal fluid TNF- a concentrations are elevated in patients with endometriosis, and some studies show higher concentrations correlate with the stage of the disease [59]. Our study did not observe any relationship between levels of TNF-a and stage of the disease. [3] The source of the elevated TNF-a concentration in the PF of endometriosis patients is variable. Some in vitro studies suggest that peritoneal macrophages [60] and peripheral blood monocytes [61] from these patients have up regulated TNF-a protein secretion. Activated macrophages play a critical role in the pathogenesis of endometriosis. The secreted TNF-a may play an important role in the local and systemic manifestations of the disease. Because of its importance in other inflammatory processes, it is likely that this cytokine plays a central role in the pathogenesis of endometriosis. [62] Moreover, its level in the PF can be used as a foundation for nonsurgical diagnosis of endometriosis. [3] Recently, the concept of using TNF-a blockers in treating endometriosis has been gaining popularity. [39] Interleukin-6 Interleukin-6 is a regulator of inflammation and immunity, which may be a physiological link between the endocrine and immune systems. It also

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modulates secretion of other cytokines, promotes T-cell activation and Bcell differentiation, and inhibits growth of various human cell lines. [39] Monocytes, macrophages, fibroblasts, endothelial cells, vascular smoothmuscle cells, and endometrial epithelial, stromal cells, and several endocrine glands, including the pituitary and the pancreas are all production sites for IL-6. [63] The role of IL-6 in the pathogenesis of endometriosis was extensively studied. Interleukin-6 response in the peritoneal macrophages, [64] endometrial stromal cells, [65] and peripheral macrophages [61] was dysregulated in patients with endometriosis. The level of IL-6 detected in the PF of patients with endometriosis was inconsistent. Some investigators have demonstrated elevated concentrations, [66,67] whereas others have found no elevation. [68] Some studies failed to demonstrate statistically significant differences in IL-6 levels between controls and endometriosis patients. [69] These inconsistent findings likely are related to antibody specificity of the assay. In our recent study, we found significant elevation of IL-6 in the sera of endometriosis patients but not in the PF as compared with patients with unexplained infertility and tubal ligation/reanastomosis. [3] Vascular Endothelial Growth Factor Many studies focused on the proliferation and neovascularization of the endometriotic implants. Vascular endothelial growth factor (VEGF) is one of the most potent and specific angiogenic factors. The main biochemical activity of VEGF when it binds to its targeted receptor is that VEGF-receptor activation leads to a rapid increase in intracellular Ca2+ and inositol triphosphate concentrations in endothelial cells. [70,71] The basic physiological function of VEGF is that VEGF-induced angiogenesis allows repair of the endometrium after menstruation. It also modulates the characters of the newly formed vessels by controlling the microvascular permeability, permitting the formation of a fibrin matrix for endothelial migration and proliferation. [72] This may be responsible for the local endometrial edema, which helps to prepare the endometrium for embryo implantation. [73] In endometriosis patients, VEGF was localized in the epithelium of endometriotic implants, [74] particularly in hemorrhagic red implants. [75] Moreover, there are increased concentrations of VEGF in PF of endometriosis patients. The exact cellular sources of VEGF in PF have not been precisely defined yet. Although evidence exists to suggest that endometriotic lesions themselves produce this factor, [74] activated peritoneal macrophages also have the capacity to synthesize and secrete VEGF. [76] Similar to the concept of using TNF-a blockers, antiangiogenic drugs are potential therapeutic agents in endometriosis.

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RANTES RANTES belongs to the h or ‘‘C-C’’ chemokine family. It attracts monocytes and memory T-cells. RANTES is a secretory product of hematopoietic cells, epithelial and mesenchymal cells, and a mediator in both acute and chronic inflammation. [77] RANTES protein distribution in ectopic endometrium is similar to that found in a eutopic endometrium. [78] However, in vitro secretion of RANTES by endometrioma-derived stromal-cell cultures is significantly greater than in eutopic endometrium. In this way, PF concentrations of RANTES may be increased in patients with endometriosis. [79] Interleukin-1 Interleukin-1 is a key cytokine in the regulation of inflammation and immune responses. I+ affects the activation of T-lymphocytes and the differentiation of B-lymphocytes. There are two receptors for IL-1, namely IL-1a and IL-1h sharing only 18% to 26% amino acid homology. Both receptors are encoded by different genes but have similar biological activities. It was found that successful implantation in mice was blocked by the administration of exogenous IL-1 receptor antagonist. This illustrates their important role in the implantation of the ectopic endometrium. [80] Interleukin-1 has been isolated from the PF of patients with endometriosis. Results have been inconsistent, with some investigators demonstrating elevated concentrations in patients with endometriosis [81] and others finding no elevation. [3,60,82] Other Cytokines Highly sensitive enzyme-linked immunosorbent assay (ELISA) kits have made it easy to measure the entire battery of cytokines in the serum and PF of endometriosis patients. Other cytokines have been identified and include IL-4 [53]; IL-5 [66]; IL-8 [3,83]; IL-10 [84]; IL-12 [3,85]; IL-13 [86]; interferong [68]; monocyte chemotactic protein-1 (MCP-1) [87]; macrophage colony stimulating factor (MCSF), [88] and transforming growth factor (TGF)- h. [89] All these cytokines may regulate the actions of leukocytes or may act directly on ectopic endometrium, where they may play various roles in the pathogenesis and pathophysiology of endometriosis. However, their exact role needs further investigation. Cytokines as a Screening Tool The role of cytokines and growth factors in the pathophysiology of endometriosis is evident, as previously discussed. They are probably responsible for

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endometrial cell proliferation [90,91] and implantation of endometrial cells or tissue. [92] Moreover, cytokines increased tissue remodeling through their influence on the matrix metalloproteinases. [93] Increased angiogenesis of the ectopic endometrial tissue and neovasculariztion of the affected region are probably the most important effects of cytokines on ectopic endometrial tissue. Consequently cytokines play a major role in the initiation, propagation, and regulation of immune and inflammatory responses. Immune cell activation results in a burst and cascade of inflammatory cytokines. Besides their role in the pathogenesis of endometriosis, they might have a diagnostic role as well. To evaluate this hypothesis, we conducted a prospective controlled trial to investigate the ability of a group of serum and PF markers to nonsurgically predict endometriosis. [3] Serum and PF from 130 women were obtained while they underwent laparoscopy for pain, infertility, tubal ligation, or sterilization reversal. We measured the concentrations of six cytokines (IL-1h, IL-6, IL-8, IL-12, IL-13, and TNF-a) in serum and PF and reactive oxygen species (ROS) in PF, and compared the levels among women who were divided into groups according to their postsurgical diagnosis. Fiftysix patients were diagnosed with endometriosis, eight were diagnosed with idiopathic infertility, 27 had undergone tubal ligation or reanastomosis (control group), and 39 were excluded because of bloody PF. Only serum IL-6 and PF TNF-a were able to discriminate between patients with endometriosis and those without the disease with a high degree of sensitivity and specificity. The PF TNF-a had an exceptional 99% area under the curve (95% CI: 97% to 100%), indicating a very high discrimination ability (Fig. 3). A cutoff of 15 pg/ml provided 100% sensitivity and 89% specificity (positive likelihood ratio of 9.1 and negative likelihood ratio of 0). A cutoff of 20 pg/ml yielded 96% sensitivity and 95% specificity (positive likelihood ratio of 19.2 and negative likelihood ratio of 0.04). The serum IL-6 achieved a relatively high diagnostic value with an area under the curve of 87% (95% CI: 75% to 99%) [Fig. 3]. A serum IL-6 cutoff of 2 pg/ml provided a sensitivity of 90% and specificity of 67% (positive likelihood ratio of 2.7 and negative likelihood ratio of 0.14). A cutoff of 4 pg/ml provided sensitivity of 85% and specificity of 80% (positive likelihood ratio of 4.3 and negative likelihood ratio of 0.19), and a cut-off of 7.5 pg/ml provided sensitivity of 80% and specificity of 87% (positive likelihood ratio of 6.2 and negative likelihood ratio of 0.23). The positive and negative likelihood ratios of PF TNF-a are so good that, it is possible that ultrasonographically guided transvaginal aspiration of the PF from the cul-de-sac may serve as a basis for the nonsurgical diagnosis of endometriosis. However, the study had two main limitations. First, there may not be enough serum and PF to measure the cytokines. Second, all bloody PF samples were excluded because cytokine levels may be affected by

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FIGURE 3 Receiver operating characteristic (Roc) curves of the endometriosis versus nonendometriosis groups. The area under the curve (AUC) for the peritoneal fluid TNF-a is 99%, and the AUC for the serum IL-6 is 87%. (From Ref. 3.)

blood contamination. Consequently, the study conclusions are not applicable to patients with blood-contaminated PF. This study showed that serum IL-6 and PF TNF-a might be potential markers for endometriosis, thereby allowing for nonsurgical diagnosis. Autoantibodies A variety of autoantibodies have been detected in endometriosis patients. The most commonly reported types are antiendometrial antibodies [47,94] and autoantibodies against oxidative stress parameters. [95] Antiendometrial Antibodies The antigens used to induce antiendometrial antibodies included sonicated endometrium of women with normal menstrual cycles, endometrial tissue of patients with endometriosis, endometriosis tissue, human endometrial carcinoma cells line, epithelial monolayers or endometrial glands, and stromal cells. The exact antigen is not known; consequently, there is no simple antigen-antibody assay as yet. [4] Serum Antiendometrial Antibodies. —Antiendometrial antibodies have been postulated to be a probable cause of infertility in endometriosis patients as shown by some investigators, [47,94] but not by others. [96] The of the assay techniques used are inconsistent, [97] as is the nature of the antigens used to elicit immune response.

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The sensitivity and the specificity of serum antiendometrial antibodies screening were reported by some investigators to be 0.84 and 1.00, respectively. [48] On comparing infertile women with endometriosis with unexplained infertility, Wild and Shivers, found a sensitivity of 0.71 and a specificity of 1.00. [52] Similarly, Meek et al [50] found a sensitivity of 0.75 and a specificity of 0.90, whereas in another study the values were 0.85 and 0.67, respectively. [98] Although serum antiendometrial antibodies match CA-125 regarding both sensitivity and specificity, it does not satisfy the criteria of an ideal screening test mentioned in Table 1. Despite this limitation, antiendometrial antibody was proposed as both a screening marker and as a follow-up marker of treatment results and recurrence. [99] Peritoneal Fluid Antiendometrial Antibodies. —Although antiendometrial antibodies were found in the PF of endometriosis patients, their sensitivity and specificity are variable. Halme and Mathur found a sensitivity of 0.23 and a specificity of 0.96 using a passive hemagglutination assay, [100] whereas the results were 0.75 and 0.90 using Ouchterlony immune diffusion. [50] Autoantibodies to Markers of Oxidative Stress There is increasing evidence of oxidative stress in the PF of women with endometriosis, and it has been shown that oxidatively modified lipid proteins exist in the PF. [1,3,101] In addition, oxidation-specific epitopes and macrophages are present in the endometrium and in endometriosis. [95] Lipid peroxides interact with proteins, resulting in several types of alterations, and such oxidatively modified proteins are themselves antigenic. Antigenicity is attributed to specific modified epitopes and not to the protein backbone. In a study to measure autoantibodies to oxidatively modified proteins in the sera of women with surgically proven endometriosis, Murphy et al included women undergoing surgery for endometriosis or tubal ligation. [95] They measured serum and PF autoantibody titers to malondialdehydemodified low-density lipoprotein, oxidized low-density lipoprotein, and lipid peroxide-modified rabbit serum albumin determined by enzyme-linked immunosorbent assay (ELISA). They correlated the autoantibody titers with the disease stage, symptoms, and morphological type of endometriosis. They found that autoantibodies to markers of oxidative stress were significantly increased in women with endometriosis without any correlation with the stage, symptoms, or morphological type of the disease. Peritoneal fluid did not contain autoantibodies to any of the three antigens. Given the fact that autoantibodies to Ox-LDL have been long considered as a screening tool for atherosclerosis, [102] a similar role might be claimed in endometriosis.

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GENTIC MARKERS OF ENDOMETRIOSIS Given the fact that the etiology of endometriosis is complex and multifactorial, endometriosis is an ideal target for genome-wide scanning. Familial inheritance plays a role, and multiple candidate genes are involved. [103] Many recent technological approaches can help identify possible genetic markers of endometriosis. A gene-based diagnostic test for endometriosis may be the long-sought ideal screening test. [104] A number of technologies have emerged to facilitate progress in this direction. The potential geneticbased technologies that may be a suitable foundation for genetic markers of the disease include subtractive cDNA hybridization [105,106] and cDNA microarray techniques. [107–110] Based on the recent DNA technologies, an ongoing study in our center is trying to create a cDNA library from normal endometrial tissue as well as endometriotic implants. Based on the refined library, potential specific serum antibodies may be identified and subsequently used as a nonsurgical screening tool for endometriosis. ENDOMETRIAL TISSUE BIOCHEMICAL MARKERS Aromatase P450 Aromatase P450 is a catalyst of the conversion of androstenedione and testosterone to estrone. This enzyme is expressed in both eutopic and ectopic endometrium of endometriosis patients but not in eutopic endometrium of healthy controls. [111] Although endometrial aromatase P450 expression did not correlate with the disease stage, a recent study demonstrated that detection of aromatase P450 transcripts in the endometrium of endometriosis patients may be a potential qualitative marker of endometriosis. [112] Another retrospective, case-controlled study also reported that seven (25%) of 28 women without detectable levels of endometrial aromatase P450 protein, determined by immunohistochemical analysis, had either endometriosis, fibroids, adenomyosis, or a combination of these disorders. [111] The potential use of such markers as a clinically useful diagnostic tool of pelvic disease is limited by the observation that large numbers of women with endometriosis did not express aromatase P450 in their eutopic endometrium. However, the use of aromatase inhibitors as a potential treatment of endometriosis is gaining momentum based on these molecular facts. [113–116] Cytokeratines It has been reported that endometriosis cell lines exhibited an epithelial-like morphology and was immunoreactive for cytokeratins 8, 18, 19, vimentin, and human leukocyte class I antigens in culture. [117] However, the cultured

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cells were negative for a whole set of hematopoietic cell markers, including the lymphoid cell antigens CD3, CD20, and CD45, von Willebrand factor, carcinoembryonic antigen, and CA-125. [117] In another study, endometriotic tissues from various locations were immunostained for estrogen receptor, vimentin, Ber-EP-4, and cytokeratins. [118] Using immunofluorescence with monoclonal antibodies against cytoskeletal components and epithelial mucins, Matthews and associates studied the staining patterns for cytokeratins 18 and 19, vimentin, and three different epithelial mucins in endometriotic cell culture. They found that cytokeratins were located in epithelial cells, and vimentin was expressed in both stromal and epithelial cells. [119] No studies evaluated the potential use of these molecular markers as a potential diagnostic/screening tool in endometriosis. Hormone Receptors Given the fact that endometriosis is an estrogen-dependent condition, the expression of estrogen and progesterone receptors could be potentially useful as a screening marker of the disease. The contents of estrogen and progesterone receptors in eutopic endometrium are phase dependent and cyclic. [120] However, the eutopic endometrium of patients with endometriosis was very different from normal endometrium in apoptosis, [121] cytokines, and other characteristics. [65] Although cyclic changes were also detected in ectopic endometrium, they differed greatly from those of eutopic endometrium. The concentrations of steroid receptors in ectopic endometrium increased gradually as the cycle progressed. Compared with eutopic endometrium, estrogen and progesterone receptor concentrations were significantly lower in the proliferative phase, similar in the early secretory phase, and significantly higher in the late secretory phase. [122] The different patterns of receptor expression suggested different hormonal regulations between eutopic and ectopic endometrium. [120] There are two isoforms for E receptor, E receptor-a and E receptor-h, and two for P receptor, P receptor-A and P receptor-B. These isoforms exist in the endometrium and their function and content are different from each another. [123] The different concentration and biological activities of steroid receptor isoforms might lead to various hormonal responsiveness of ectopic endometrium. High concentrations of E and P receptors in the ectopic endometrium during the secretory phase could explain the high proliferative activity of endometriotic tissue in this phase. Conversely, a decrease in E and P receptor expression in ectopic implants during the secretory phase might lead to diminished proliferation. [122] The expression of estrogen and progesterone receptors may be regarded as an index of differentiation of the endometriotic implant. Consequently, E and P receptors may be used as markers of the activity of all subtypes of endometriotic lesions. [4]

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SUMMARY One of the major challenges facing gynecologists is the inability to diagnose endometriosis because a definitive diagnosis of the disease can only be obtained by laparoscopy or laparotomy. At present, reliable markers of the disease are lacking. Serum concentration of tumor markers—particularly CA-125, the most extensively studied and used serum marker of endometriosis—has a limited diagnostic performance. This poses a problem for investigating the presence of early stages of the disease. The detection of endometriosis is critical in stage I to II in infertile women in whom the laparoscopic treatment of the lesions has been reported to almost double the rate of a spontaneous pregnancy. The high specificity of the CA-125 determination indicates its potential usefulness in disease monitoring and follow-up. Because medical treatment has been associated with temporary suppression of the disease activity, CA-125 may be important only in long-term monitoring of surgical therapy. Randomized clinical trials on the use of surgery for infertility or pain associated with endometriosis have shown a clear benefit. [124] This shows that early detection is critical part of the diagnosis and treatment of the disease. Immunological markers gained importance with the accumulating evidence regarding the immunological changes that occur during the evolution of the disease. The most promising diagnostic test is the use of peritoneal fluid and serum cytokines. [125,126] Large clinical trials will be needed to validate this hypothesis. Autoantibodies aim at detecting circulating antibodies raised against a variety of antigens. Their use as a screening tool is limited by their low sensitivity. A combination of the recent immunological discoveries and the recent advances in DNA technologies may provide the long-sought screening tool with the desirable accuracy for such a puzzling disorder.

PRACTICAL POINT .

CA-125 as a serum marker of endometriosis has a limited diagnosis value. It is only important in long-term monitoring after surgical therapy.

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79. Khorram O, Taylor RN, Ryan IP, Schall TJ, Landers DV. Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis. Am J Obstet Gynecol 1993; 169:1545–1549. 80. Simon C, Frances A, Piquette GN, el Danasouri I, Zurawski G, Dang W, Polan ML. Embryonic implantation in mice is blocked by interleukin-1 receptor antagonist. Endocrinologym 1994; 134:521–528. 81. Fakih H, Baggett B, Holtz G, Tsang KY, Lee JC, Williamson HO. Interleukin1: A possible role in the infertility associated with endometriosis. Fertil Steril 1987; 47:213–217. 82. Taketani Y, Kuo TM, Mizuno M. Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis. Am J Obstet Gynecol 1992; 167:265–270. 83. Iwabe T, Harada T, Tsudo T, Tanikawa M, Onohara Y, Terakawa N. Pathogenetic significance of increased levels of interleukin-8 in the peritoneal fluid of patients with endometriosis. Fertil Steril 1998; 69:924–930. 84. Ho HN, Wu MY, Chao KH, Chen CD, Chen SU, Yang YS. Peritoneal interleukin-10 increases with decrease in activated CD4+ T lymphocytes in women with endometriosis. Hum Reprod 1997; 12:2528–2533. 85. Mazzeo D, Vigano P, Di Blasio AM, Sinigaglia F, Vignali M, Panina-Bordignon P. Interleukin-12 and its free p40 subunit regulate immune recognition of endometrial cells: Potential role in endometriosis. J Clin Endocrinol Metab 1998; 83:911–916. 86. McLaren J, Dealtry G, Prentice A, Charnock-Jones DS, Smith SK. Decreased levels of the potent regulator of monocyte/macrophage activation, interleukin13, in the peritoneal fluid of patients with endometriosis. Hum Reprod 1997; 12:1307–1310. 87. Arici A, Oral E, Attar E, Tazuke SI, Olive DL. Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells. Fertil Steril 1997; 67:1065–1072. 88. Fukaya T, Sugawara J, Yoshida H, Yajima A. The role of macrophage colony stimulating factor in the peritoneal fluid in infertile patients with endometriosis. Tohoku J Exp Med 1994; 172:221–226. 89. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR. Transforming growth factor-beta activity is increased in peritoneal fluid from women with endometriosis. Obstet Gynecol 1994; 83:287–292. 90. Hammond MG, Oh ST, Anners J, Surrey ES, Halme J. The effect of growth factors on the proliferation of human endometrial stromal cells in culture. Am J Obstet Gynecol 1993; 168:1131–1136; discussion 1136-1138. 91. Iwabe T, Harada T, Tsudo T, Nagano Y, Yoshida S, Tanikawa M, Terakawa N. Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab 2000; 85:824–829. 92. Zhang RJ, Wild RA, Ojago JM. Effect of tumor necrosis factor-alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: An in vitro system. Fertil Steril 1993; 59:1196–1201.

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9 How Does Endometriosis Cause Infertility? Ariane Germeyer Stanford University School of Medicine Stanford, California, U.S.A. and University of Heidelberg Heidelberg, Germany

Linda C. Giudice Stanford University School of Medicine Stanford, California, U.S.A.

The association between infertility and endometriosis is well established [1]. However, mechanisms by which endometriosis causes infertility are complex and still largely not well defined [2]. One reason for the controversy surrounding the development of infertility in patients with endometriosis is that variation of disease characteristics and severity make study design more challenging. The fact that not all women with endometriosis experience infertility [3] and up to 50% of women with infertility are diagnosed with endometriosis [4], underscores the complexity of the mechanisms involved in the development of infertility in women with endometriosis. This benign disease, which affects 10% of women of reproductive age, can impair female reproduction in nearly every process during attempted conception. This has been shown in the meta-analysis of 22 studies performed by Barnhart et al, which com151

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pared the reproductive outcome after in vitro fertilization (IVF) of women with endometriosis to women with tubal obstruction from other causes. In this study women with endometriosis were found to have lower implantation, fertilization, and pregnancy rates, as well as fewer oocytes retrieved. The impact on those factors (with the exception of the fertilization rate) was more pronounced in women with severe endometriosis compared to those with mild disease [5]. The study emphasizes the multifactorial character of the underlying infertility problem in patients with endometriosis, including oocyte quality, embryo maturation, and interaction of the embryo with the endometrium. It is important to note that the prevalence of associated infer-

FIGURE 1 Factors with potential influence on reproductive functions in women with endometriosis.

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tility factors in patients with endometriosis is similar to those without the disease [6,7], implying that minimizing endometriosis-related infertility factors may not necessarily lead to a viable pregnancy. It is known that fertility rates decrease with moderate to severe endometriosis, as defined by the revised classification of the American Fertility Society [8], as staging is related to anatomical changes in the pelvis. An observational study showed that advanced endometriosis has a higher incidence of infertility than early-stage endometriosis [9]. However, the pathogenesis of infertility in women with minimal to mild endometriosis is less obvious and remains a source of continued debate. Herein, we review the different factors involved in infertility in patients with endometriosis. These include known anatomical changes that lead to adhesions or tubal obstruction, potential negative effects of peritoneal and follicular fluid on egg maturation and sperm motility, potential oocyte maturational abnormalities and hormonal variations, and the effects of endometriosis on uterine receptivity for embryonic implantation (Fig. 1). ANATOMICAL CHANGES CONTRIBUTING TO INFERTILITY Endometriosis can lead to adhesions within the abdominal cavity caused by inflammatory reactions. In moderate to severe endometriosis [8], these adhesions occur between several intra-abdominal and pelvic structures and are usually visualized easily during laparoscopy or laparotomy. Peritubular and periovarian adhesions [10], as well as tubal wall fibrosis, can lead to decreased tubal motility and decreased access to the ovulated oocyte, interrupting ovum pickup [11]. Minor adhesions that are less obvious include intratubal adhesions that lead to blockage of the Fallopian tubes and the inability to transport oocytes to the uterine cavity. Unfortunately radiographic imaging is unreliable, and anatomical distortions can only be adequately diagnosed at the time of surgery [12]. Endometriomas can be diagnosed by ultrasound or MRI [13], but their associated effects on tubal structure and function are variable and effects on fertility cannot be predicted. IMMUNOLOGIC FACTORS Several components of peritoneal fluid (PF), such as growth factors, hormones, and cytokines, are known to be present at different levels in women with endometriosis compared to women without disease. These components are believed to contribute to development of disease by creating a more favorable environment for the ectopic endometrial tissue to implant on peritoneal and other surfaces [14–17]. The peritoneal environment may also affect sperm motility, oocyte maturation, fertilization, embryo survival, and tubal function (Figs. 1 and 2).

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FIGURE 2 Factors affecting fertility in women with endometriosis at the level of sperm/oocyte interaction and maturation (see text).

Macrophages in the Peritoneal Fluid Beside various proteins and other soluble factors, PF contains endometrial and immune cells, with a predominance of peritoneal macrophages (80% to 98%) and a few lymphocytes [18,19]. Increased macrophages in PF have been observed in endometriosis-associated infertility [20], as well as in unexplained infertility [21], compared to normal controls. One explanation would be the elevated level of macrophage migration inhibitory factor (MIF) in infertile women with endometriosis, as MIF promotes accumulation and activation of macrophages [22]. Therefore, it is not surprising that macrophages from infertile women with mild endometriosis have increased activity of acid phosphatase and neutral protease. This may lead to release of active substrates from enzymatic processing in the PF and may contribute to infertility in these patients [23]. It may also lead to higher phagocytotic activity against sperm [24] and a higher activity of nitric oxide (NO) synthase. The latter has been postulated to increase NO levels in the peritoneal cavity of women with

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endometriosis [25], to contribute to infertility by toxicity to the embryo, inhibiting embryonic implantation (in a mouse model) [26], and to have a negative effect on sperm function [27–29]. Effects on Sperm Motility As with many other underlying factors of subfertility, conflicting data exist on the effect of PF from women with endometriosis on sperm motility. Several factors have been thought to contribute to a decrease in sperm motility after exposure of sperm to PF from patients with endometriosis. For example, high levels of NO decrease sperm motility [27–29]. Soldati et al showed that PF from fertile women increases sperm motility, whereas PF from endometriosis patients had less capability of enhancing sperm motility [30]. Transferrin and HS-glycoprotein and their autoantibodies are significantly elevated in serum and PF of women with endometriosis. These autoantibodies decrease sperm motility in vitro [16,31]. Elevated levels of iron have also been found in the PF of affected women, most likely as a result of compromised iron transport resulting from transferrin antibodies in the PF. This may lead to tissue damage and, therefore, de novo adhesions in the peritoneal cavity [32]. Studies have not been able to identify direct antisperm antibodies in PF [33] or a consistent effect of PF from endometriosis patients on sperm motility when fertile endometriosis patients were tested [34]. Sperm-Oocyte Interaction The peritoneal environment may also influence sperm-oocyte interactions. Studies in hamsters and mice have shown that PF from affected women decreases sperm-oocyte interaction in a dose-dependent and disease stagespecific manner [35–37]. It remains unclear which factors are responsible for decreased sperm binding to the oocyte. Nevertheless factors such as nitric oxide produced by macrophages [38] and endometrial glycodelin [39] have been proposed as mediators. Effect on Oocyte Maturation and Toxicity Transferrin affects follicle-stimulating hormone (FSH)-induced differentiation of granulosa cells. It can potentially contribute to ovarian dysfunction, including anovulation or inadequate luteal phase [16]. Women with severe endometriosis also have decreased vascular endothelial growth factor (VEGF) levels in granulosa cells. As VEGF is an angiogenic and mitogenic factor, its decreased levels in affected women can potentially contribute to a decreased oocyte maturation [40].

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Furthermore, in women with endometriosis, TNFa levels, which are elevated in ovarian granulosa cells, may affect fertilization capacity of the oocyte, perhaps by its activation of cytokine production, ovulation regulation and through metabolic and apoptotic pathways [41]. The action is at least partially mediated by the TNFa type II receptor, which was found in human cumulus cells and oocytes [42]. Effect on Endometrium Implantation Infertile women with stage I and II endometriosis have been reported to have higher antiphospholipid antibodies in their PF than women with stage III and IV endometriosis, potentially reflecting the activity of the lesions. It has been proposed that these antiphospholipid antibodies contribute to nidation defects in those women in whom anatomical anomalies are minimal [43]. Embryo Toxicity In a mouse model, PF has been shown to be embryotoxic in several studies. Barroso et al found a negative effect of nitric oxide on the development of the mouse embryo [26], whereas another group attributes the embryotoxic effect of the peritoneal fluid to elevated IL-6 levels found in women with endometriosis [44]. Fakih et al [45] demonstrated that PF from infertile patients with minimal or mild endometriosis has disease stage-dependent elevated levels of IL-1, a protein produced by macrophages, compared with fertile controls, in whom the protein was undetectable. In cultured macrophages, similar trends of the levels of protein were observed. An embryotoxic effect of IL-1 was proven on mouse embryos in an in vitro culture system, as degenerated embryos were observed after 24 hours of incubation with levels of IL-1 similar to the concentrations found in the PF during the follicular phase of affected women [45]. This is of major significance, as increased numbers of activated macrophages were found in tubal fluid—the physiologic environment for early embryo cleavage—of patients with endometriosis [46]. Exposure to this ‘‘toxic’’ environment can be minimized through assisted reproductive technologies.

ENDOCRINE DYSREGULATION Oocyte Development In patients with severe endometriosis undergoing IVF treatment, a decreased ovarian response to gonadotropins, with fewer developing follicles (and therefore lower E2 levels), has been reported. Granulosa cells from women with endometriosis express lower levels of VEGF and unchanged levels of

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IL-6 compared with cells from unaffected women [40]. On the other hand, elevated IL-6 production in granulosa cells was noted by Pellicer et al [40a] and by Carlberg et al, although it did not reach statistical significance [41]. Vascular endothelial growth factor is thought to be important in the development of the oocyte due to increased angiogenesis, suggesting that patients with severe endometriosis experience compromised oocyte maturation [47]. This may also explain the observed decrease in ovarian reserve in patients with moderate to severe endometriosis [48], although other causes also may be operational, including oocyte toxicity by peritoneal fluid components. Harlow et al also demonstrated a decreased level of granulosa cell steroidogenesis in patients with endometriosis [49], presumably contributing to decreased oocyte maturation and, therefore, ovarian reserve. The effect of delayed follicular growth leading to asynchrony of oocyte maturation and ovulation was also observed by Doody et al [50]. Luteal Defect Hormonal abnormalities in patients with endometriosis, with a major emphasis on progesterone levels, are well documented. Early studies postulated a luteal defect in women with mild endometriosis [51]. Apart from abnormalities in luteal phase progesterone levels and corpus luteum development, Ayers et al found elevated progesterone to estradiol ratios in the follicular phase of the cycle of women with endometriosis to be a potential indicator for a defect in luteolysis [52]. Contributing to this change in the hormone ratio was an elevated level of progesterone compared to normal patients, as well as a decreased estradiol level, when the ratio in ovarian veins was examined. It has been suggested that this effect may contribute to asynchrony of endometrial development and folliculogenesis in affected women, despite normal basal body temperatures (BBT) of the subjects in this study [52]. However, luteal phase deficiency in the endometrium is not a consistent finding in women with endometriosis. Ayers et al also observed remnants of several corpora lutea on both ovaries in the early follicular phase in patients with endometriosis during laparotomy [52]. This finding is supported by an earlier study in which, during laparoscopy, fewer ovulation stigmata were noted in women with mild to severe endometriosis, compared with controls. In these patients, normal BBTs were observed. Nevertheless, hormonal dysregulation was noted, including a delayed increase of progesterone rise after the LH peak, and delayed estradiol decline after the LH surge in women with moderate to severe disease. A somewhat shorter and more variable luteal phase was also noted. The authors concluded a disturbance or failure of ovum release and in situ luteinization [53]. However, unruptured follicle syndrome is a controversial entity, and current assisted reproductive

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technologies would bypass such abnormalities. In concordance with this work, another study looking at ovarian dysfunction found a prolonged follicular phase in women with mild endometriosis, whereas normal LH levels arose. Only the LH level within the follicle appeared to be reduced, and affected women showed a significantly lower fecundability rate in unstimulated cycles [54]. IMPLANTATION DEFECT For women with minimal to mild endometriosis and infertility, the reasons for infertility are not as obvious, as the anatomical variations discussed above are not present. One possible reason for infertility in these patients is an abnormality during the attachment, intrusion, and invasive phases of implantation including decidualizing of the endometrium, as well as survival of the embryo proper. Even in the setting of minimal endometriosis, patent Fallopian tubes, regular cycles, and normal male fertility, a lower fertility rate is observed [5,55], potentially due to occult biochemical abnormalities in the endometrium. Despite normal histology of the endometrium, several investigators have identified molecular differences in the eutopic endometrium of women with endometriosis (Fig. 1). Bartosik et al found the expression of C3 complement in eutopic endometrium to be a negative predictor for a subsequent pregnancy, with a more pronounced expression of C3 complement in the endometrium of women with mild endometriosis compared to severe endometriosis [56]. It has been reported that HOX-A10 and HOX-A11, which are normally upregulated in secretory phase endometrium in women without disease, are not upregulated in women with endometriosis [57]. This decreased expression of HOX genes in eutopic endometrium during the secretory phase, which is not correlated to the stage of the disease, has been correlated with lower pregnancy/implantation rates in mice [58]. As HOX genes are transcription factors, it is not surprising that they regulate other genes as well. For example, a recent study has shown that HOXA10 directly regulates the h3-integrin subunit [59]. As avh3 integrin, a cell adhesion molecule of the endometrium expressed at the apical surface of the luminal epithelium, is important for embryonic attachment, its downregulation would negatively impact implantation [60,61]. In fertile women without endometriosis, both avh3 integrin and its ligand, osteopontin, are upregulated specifically during a brief period of uterine receptivity. In patients with endometriosis and patients with other infertility conditions, avh3 integrin is expressed to a lesser extent, whereas osteopontin expression is unchanged [62]. In a mouse model, Illera et al demonstrated subfertility after blocking the binding site of avh3 integrin [63]. Therefore, it seems reasonable to assume that changed levels of this integrin

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during the window of implantation (WOI) have a negative impact on fertility in patients with endometriosis. Increased free radicals in the endometrium may also decrease the oocyte and embryo quality by creating a toxic environment for the developing embryo [64]. Glutathione peroxidase and catalase have been shown to be aberrantly expressed and to lose their typical fluctuation during the menstrual cycle in women with endometriosis [64,65]. This may affect the environment of the endometrium by changing the levels of free radicals. Other factors negatively affecting the free radical concentration in the uterine environment for the developing embryo are elevated levels of manganese and copper superoxide dismutase (SOD) within the endometrium of affected women [66]. On a protein level, changes in the endometrium of women with endometriosis were found for CA125 [67], soluble urokinase-type plasminogen activator receptor (suPA-R) [68], as well as the apoptosis related protooncogene B-cell lymphoma/leukemia-2 (Bcl-2) [69], potentially affecting uterine receptivity. Several genes are dysregulated in affected women. Gene expression studies have shown the following to be differentially regulated in eutopic endometrium of women with endometriosis: aromatase [70], endometrial bleeding-associated factor (EBAF) [71], hepatocyte growth factor and cMET receptor [72], thrombospondin-1 and VEGF [73], and endothelial nitric oxide synthase (eNOS) [74]. In addition in stromal cell cultures of affected women compared with women without disease, a downregulation of transducer of ErbB (Tob-1), a cell-cycle inhibitor, after IL-1h stimulation has been noted [75]. Using a global gene expression approach through microarray analysis, Kao et al detected more than 100 aberrantly regulated genes in eutopic endometrium of women with versus without endometriosis during the window of implantation that may contribute to implantation failure in women with this disorder on the level of embryonic attachment, survival and embryodecidua signaling. These changes affect cell adhesion molecules, endometrial epithelial secreted proteins, transporters, and immune modulators, etc. [76]. In particular, candidate genes like N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) were found, which are thought to be important in the embryo-decidua crosstalk during the attachment phase of human implantation [77]. Which of all the genes, discovered in such studies, contribute(s) to the underlying pathogenesis of endometrial-based infertility in women with endometriosis remains to be determined. It is also possible that a combination of factors may be responsible for the underlying subfertility. Interestingly, some of the better characterized biochemical markers for uterine receptivity are dysregulated in women with endometriosis compared with those without endometriosis. For example, the expression of glycodelin,

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which is upregulated during the WOI in the normal menstrual cycle [78], is lower in affected patients during this phase [76]. In contrast, some studies have shown no difference in implantation rates when oocytes are donated from healthy controls [79], indicating that normal implantation rates can be achieved in these women during artificial cycles or that the oocyte characteristics can overcome deficiencies in the endometrium of affected women [80,81]. A minor change in the receptivity of the endometrium, together with decreased oocyte quality, may have an additive effect on infertility [82], reflected in decreased fertility rates in natural cycles [83]. SUMMARY Endometriosis is a multifactorial disease with several entities affecting fertility. In addition to the obvious and well-established anatomical abnormalities in severe endometriosis, changes in the local environment of the abdominal cavity affecting sperm-oocyte interaction and oocyte maturation/ survival, hormonal changes, as well as abnormalities at the implantation site, contribute to subfertility in patients with minimal to mild disease. With new genomic and proteomic approaches, diagnosis, and perhaps, predicting fertility in women with endometriosis are soon to be realized. It is hoped that further investigation of these markers will lead to new treatment options to overcome the underlying infertility in women with endometriosis to realize their goals of having a family. PRACTICAL POINT 

New genomic and proteomic approaches might lead to easier diagnosis and new treatment of endometriosis-related infertility.

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10 Medical Therapy for Endometriosis: An Overview Eric S. Surrey Colorado Center for Reproductive Medicine Englewood, Colorado, U.S.A.

INTRODUCTION The medical management of endometriosis represents a critical portion of the treatment used to attack this debilitating disorder. The primary goal of this approach is to eradicate the painful symptoms and to enhance fecundity. Reduction of the extent of endometriotic implants is a secondary goal. Medical therapy clearly represents a less invasive approach than surgical management of endometriosis. The majority of controlled trials evaluate the relative benefits of different medical interventions or of a medical intervention in comparison to placebo. Others evaluate the benefit of combined surgical and medical therapy in comparison to surgical therapy alone. Interestingly, there are no studies comparing primary surgical to primary medical therapy alone. One of the difficulties in evaluating these therapies is the great degree of variation among investigative designs. The absence of control groups in any study evaluating the effect of an intervention on either pelvic pain or infertility is clearly problematic given the subjective nature of pain and potential for placebo effect, as well as the very real although compromised potential for 167

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spontaneous conception. Outcome parameters also vary dramatically. Some investigators have assessed efficacy based on reduction of visible implants, which is an inherently flawed approach, given the lack of consistency in visual diagnosis of endometriosis and well-documented lack of correlation between extent of disease and symptoms. Similarly, the lack of a uniform instrument to evaluate painful symptoms makes interpretation of subjective improvement difficult. Lastly, few studies evaluate recurrence rates with long-term follow-up. Similarities in short-term pain relief resulting from several medical interventions may provide very different outcomes when long-term symptom recurrence is evaluated. In this chapter, we endeavor to provide an evidence-based overview of historic, current, and experimental modalities for the medical management of both symptomatic endometriosis and endometriosis-associated infertility (Table 1). Steroidal Manipulation of Endometriosis The theoretic basis for hormonal therapy of endometriosis has been the longheld assumption that endometriotic implants and the endometrium respond in a similar fashion to sex steroid hormone manipulation. Estrogens are believed to stimulate the disease and endometrium, whereas estrogen deficiency should theoretically result in atrophy of both tissue types [1]. However, there is conflicting evidence as to whether this assumption is truly valid. In a large series evaluating 443 implants in 196 patients, Metzger TABLE 1

Evaluated Medical Therapy for Endometriosis

Methyltestosterone Oral contraceptives (pseudopregnancy) Progestins Gestrinone Danazol GnRH agonists GnRH antagonistsa Aromatase inhibitorsa Mifepristonea Progesterone receptor modulatorsa Estrogen receptor modulatorsa Angiogenesis inhibitorsa Cytokine inhibitorsa Immunomodulatorsa a

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and colleagues demonstrated that histologic concordance between endometrium and endometriotic implants could be demonstrated in only 13% of cases [2]. Others have shown that the concentration of steroid receptors is significantly lower in endometriotic implants and that cyclic patterns could not be demonstrated in hormonally dependent secretory products of such lesions in culture [3–5]. In addition, these assumptions do not explain why hormonal manipulation would have an effect on the complex local peritoneal immunological changes, including enhanced cytokine concentrations, macrophage activation, and mesothelial proliferation associated with this disease (see Chaps. 2 and 7). Pseudo Pregnancy and Oral Contraceptives Pregnancy has been shown to have a beneficial effect on the symptoms associated with endometriosis, although long-term disease suppression is somewhat variable after delivery [6–8]. This concept led to the first hormonally induced ‘‘pseudo pregnancy regimens’’ proposed in 1958 by Kistner [9]. Highdose oral contraceptives were administered with the thought that elimination of cyclic changes in ovarian steroid secretion would inhibit development of endometriotic implants. In a comparative trial, Noble and Letchworth reported a 30% symptom improvement rate with this approach, with an extremely high incidence of side effects including mastalgia, abnormal distension, nausea, vomiting, and phlebitis [10]. Only 59% could complete more than 5 months of therapy and 41% required additional major surgery because of persistent symptoms. More recently, Vercellini and colleagues evaluated the effect of a lower dose cyclic oral contraceptive agent (ethinyl estradiol 20-30 mcg+ desogestrel 0.15 mg) [11]. Significant symptom relief with regard to dyspareunia, dysmenorrhea, and nonmenstrual pain was appreciated. Nevertheless, mean pain scores were not significantly different from baseline 6 months after completion of therapy. Oral contraceptive therapy has been associated with decidualization, necrobiosis, and enhanced apoptosis of endometriotic tissue [12,13]. There is little evidence to suggest that continuous oral contraceptive therapy is more beneficial than cyclic therapy, although the former may have an advantage in patients who present primarily with dysmenorrhea. Similarly, switching from one pill formulation to another is rarely beneficial. Progestins A variety of progestational agents (progestins) alone have been used in the medical management of endometriosis in an effort to reduce side effects associated with the estrogenic component of oral contraceptives (Table 2). As

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TABLE 2

Progestins Used in the Management of Symptomatic Endometriosis Medroxyprogesterone acetate (MPA) Megestrol acetate Dydrogestone Lynestrol Norethindrone acetate Levonorgestrel

previously described, it has been proposed that progestins inhibit endometriotic implants by causing an initial decidual reaction, which would presumably result in eventual atrophy. An inhibitory effect of medroxyprogesterone acetate (MPA) on in vitro endometrial stromal cell proliferation when used in therapeutic doses has been demonstrated [14]. More recently, Bruner et al demonstrated that progesterone may affect the expression of endometrial matrix metallproteinases, which may play a role in the establishment of endometriotic implants [15]. A relatively small number of randomized controlled trials have been reported with use of progestins alone. The majority of studies have been retrospective or observational in nature. In a placebo-controlled 6-month trial, Overton et al evaluated the effect of dydrogesterone 40 to 60 mg daily during the luteal phase for 12 days of each cycle [16]. Pain was significantly reduced with a 60-mg dose during treatment and up to 12 months thereafter. Vercellini et al compared MPA administered in an intramuscular depot preparation (150 mg every 90 days) for 12 months to a control group treated with low-dose danazol combined with an oral contraceptive and noted significant and equivalent improvement in symptom scores in both groups [17]. Dysmenorrhea was suppressed in the MPA group up to 1 year after therapy. One of the problems with MPA in depot preparations is the extremely slow return of menses and ovulation, which could have a negative impact on conception. The effect of high-dose oral MPA 100 mg daily was evaluated by Telimaa and coworkers in a 6-month trial with good efficacy noted up to 6 months after completion of therapy [18]. In an analysis of 14 trials using various progestins of which only four investigations were randomized, Vercellini reported that only 9% of symptomatic patients failed to respond [19]. The pooled incidence of recurrent pain was 50% (95% confidence interval [CI] 37.8–67.2%). It is important to note that, in general, rather high doses of progestins must be used to achieve beneficial effects. Medroxyprogesterone acetate and

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megestrol acetate have been used in doses of 30 mg to 100 mg and 40 mg daily, respectively, to achieve efficacy [20–22]. Similarly, norethindrone acetate has been used in doses as high as 20 mg daily [23]. As a result, the incidence of side effects is not insignificant. Vercellini et al reported that approximately one third of patients experienced abnormal bleeding [19]. Other side effects reported in at least 10% of patients included weight gain, bloating, and edema. High progestin doses may also cause untoward changes in highdensity lipoprotein (HDL)-cholesterol and apolipoprotein A-1 [24]. In an effort to minimize side effects, Vercellini et al have reported the results of an uncontrolled prospective trial of a levonorgestrel-releasing intrauterine device [25]. A significant reduction in endometriosis-associated dysmenorrhea and menstrual flow was reported. A more detailed discussion of the role of progestins is presented in Chapter 12. Gestrinone Gestrinone is a 19-norsteroid derivative, that was originally designed as a weekly oral contraceptive, but has been used to treat estrogen-dependent disorders such as endometriosis. This agent acts in a somewhat complex fashion. It blocks follicular development and estradiol production, binds to androgen receptors as an agonist, and exhibits both agonistic and antagonistic effects after binding to the progesterone receptors [26,27]. This agent is administered orally in doses ranging from 1.25 mg to 2.5 mg twice weekly. Thomas and Cooke demonstrated that gestrinone 2.5 mg twice weekly for 6 months resulted in a significant improvement in visible endometriotic implants in comparison to placebo [28]. Hornstein et al reported equal efficacy when 2.5 mg was compared to 1.25 mg twice weekly [29], although others have suggested that the higher dose was more effective [30]. Fedele et al reported that gestrinone 2.5 mg was as effective as danazol with a similar recurrence rate [31]. Others have shown that this agent is as effective as a gonadotropin releasing hormone (GnRH) agonist with regard to pain relief and demonstrated a tendency toward decreased relative pain recurrence rates [32]. The primary side effects for this agent are decreases in HDLcholesterol, increases in low-density lipoprotein (LDL)-cholesterol, weight gain, hirsutism, seborrhea, and acne. This agent is not currently approved for use in the United States. Danazol Danazol is an isoxazol derivative of 17-a-ethinyl testosterone and had been the primary medication for the treatment of symptomatic endometriosis until the more recent general acceptance of GnRH agonists. This agent acts on many levels. From an endocrine viewpoint, it suppresses gonadotropin

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surges, lowers circulating estradiol and progesterone levels by steroidogenic enzyme inhibition, and interacts with both androgen and progesterone receptors to induce endometrial atrophy [33]. Danazol has been shown at therapeutic levels to directly inhibit endometrial stromal cell proliferation in vitro [14]. The agent also appears to act on the altered immunological state associated with endometriosis. Danazol has been shown to have an immunomodulatory effect on T-cell subsets and other immunocompetent cells in eutopic endometrium [34]. Danazol may also exhibit immunosuppressive activity. One investigative team has demonstrated that therapeutic doses of this agent suppress autoantibodies in endometriosis patients [35]. Peritoneal cytokine levels (interleukin-1 and tumor necrosis factor) are significantly suppressed after danazol therapy [36]. Elevated serum soluble C23 levels were also suppressed with this agent [37]. Danazol is typically administered in doses ranging from 400 mg to 800 mg daily in an effort to achieve amenorrhea. In a summary of 16 uncontrolled clinical trials involving 1,035 patients, Metzger and Luciano reported 88% symptomatic improvement and 77% clinical improvement [33]. The efficacy of danazol appears to vary with the dose. In a classic double-blind, 6-month trial, Dmowski et al compared the effects of daily doses ranging from 100 to 600 mg [38]. The improvement in clinical symptoms was 56% in patients receiving 100-mg daily doses and 83% in those receiving 600-mg daily doses. The greatest improvement was in those who developed amenorrhea during therapy. Similarly, the most regression of visible disease at follow-up laparoscopy was noted in patients receiving higher doses (74%) versus those receiving 100 mg to 200 mg daily doses (39%–42%). In a separate trial, Biberoglu and Behrman reported that symptom recurrence rates were also lowest in those receiving higher danazol doses [39]. In addition, recurrence rates seem to be highest in those with stage III to IV as opposed to stage I to II disease [40]. One of the greatest drawbacks of danazol is its side effect profile. The primary adverse effects are caused by the androgenic action of this agent and, at 800-mg daily doses, include relatively high incidences of weight gain (79%), muscle cramps (52%), atrophic breast changes (48%), vasomotor symptoms (42%), oily skin (37%), acne (27%), hirsutism (21%), and voice changes (7%) [41]. Adverse lipoprotein and lipid changes have been reported [24]. Should a patient ovulate and conceive while taking this drug, the potential for masculinization of a female fetus is of concern [42]. Several tactics have been taken to minimize side effects. Vercellini and colleagues treated 42 patients with a 50-mg daily dose of danazol for 9 months alone or for 6 months after an initial 3-month course of a GnRH agonist [43]. Although symptoms were similarly suppressed and side effects decreased in both groups, a significant incidence of ovulatory cycles was also noted in both

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groups (55% and 45% of patients, respectively). It was recommended, therefore, that low-dose danazol be combined with an oral contraceptive to avoid inadvertent conception. Other small trials have minimized side effects while demonstrating efficacy with the use of either danazol suppositories or vaginal rings [44,45]. Needless to say, the side effect profile of this agent, and not its efficacy, has limited its usefulness in the face of newer and equally effective agents. Gonadotropin Suppression: GnRH Agonists Gonadotropin releasing hormone agonists have emerged as the primary medication for the medical treatment of endometriosis. These agents represent modifications of the native hypothalamic hormone GnRH, which stimulates pituitary gonadotropin follish stimulating hormone [FSH] and luteinizing hormone [LH] release in a pulsatile fashion. These agonists are more resistant to enzymatic breakdown and remain bound to pituitary GnRH receptors for prolonged times. The net agonistic effect is an initial stimulation and then suppression of gonadotropin, and subsequently, ovarian estrogen release. This hypoestrogenic state should lead to regression of endometriotic lesions. These agents may also act by altering other mechanisms that have been purported to enhance the development of endometriotic implants. Gonadotropin releasing hormone agonists have been shown to decrease peritoneal fluid leukocyte protease inhibitors [46], enhance apoptic change in endometrial culture [47], suppress cytokine expression in endometrial culture and peritoneal fluid [8,36,47], normalize aberrant expression of tissue inhibitors of metalloproteinase-1 [48], and suppress serum soluble CD 23 levels [37]. The efficacy of these agents has been well demonstrated with regard to both suppression of symptoms and regression of visible disease. The majority of prospective randomized trials are of 6 months’ duration, compare GnRH agonists to danazol, and demonstrate general equivalence in efficacy. Other studies compare the agents to placebo, gestrinone, or oral contraceptives (Table 3). These studies evaluated laparoscopically diagnosed endometriosis in the absence of surgical reduction. Waller and Shaw reported a cumulative recurrence rate of 53% after 5 years of an initial treatment course [58]. Interestingly, the incidence of recurrence was lower in those with minimal (36.9%) as opposed to severe (74.4%) disease at laparoscopy performed before initiation of therapy. Currently these agents are administered intranasally, subcutaneously, or intramuscularly. Dosing varies with the specific agonist and route of administration. One placebo-controlled trial evaluated the efficacy of a 3-month course of GnRH agonist therapy in patients with chronic pelvic pain and a diagnosis

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TABLE 3

Prospective Randomized Trials of GnRH Agonists as Therapy for Symptomatic Endometriosis Author [Ref]

Agonist

Patients

Dlugi [49] Henzl [50] Dmowski [51] Kennedy [52] Shaw [53] NEET [54] Wheeler [55] Rock [56] Wright [57] Berquist [58] Vercellini [11]

Leuprolide Nafarelin Buserelin Nafarelin Goserelin Nafarelin Leuprolide Goserelin Leuprolide Triptorelin Goserelin

28 143 19 50 204 206 128 208 22 24 29

Gestrinone Italian Study Group [32]

Leuprolide

28

Duration 6 6 6 6 6 6 6 6 3 6 6

months months months months months months months months months months months

6 months

Control Placebo Danazol 800 mg Danazol 800 mg Danazol 600 mg Danazol 600 mg Danazol 600 mg Danazol 800 mg Danazol 800 mg Danazol 800 mg Placebo Ethinyl Estradiol 0.02 mg + Desogestrel 0.15 mg Gestrinone

of clinically suspected endometriosis in the absence of surgical documentation [59]. Significantly greater pain reduction was noted in the group of 49 receiving the agonist in comparison to 46 receiving placebo ( P < 0.001). Endometriosis was appreciated at post-therapy laparoscopy in 82% of patients. The authors proposed that this agent can be safely and effectively used empirically in patients with chronic pelvic pain with clinically suspected disease without diagnostic laparoscopy after appropriate evaluation. The primary side effects associated with GnRH agonists are those that are secondary to the induced hypoestrogenic state. These include vasomotor symptoms, reduction in bone mineral density, vaginal dryness, decreased libido, depression, joint pain, mood swings, and fatigue. These symptoms may not only decrease the potential for long-term use of these agents, but can have a major impact on patient compliance. A variety of ‘‘add-back’’ regimens have been used in an effort to maintain the inherent efficacy of the GnRH agonists while minimizing side effects [60]. In patients treated for a standard 6-month therapeutic course, low-dose hormone replacement regimens using either conjugated equine estrogens (0.3– 0.625 mg) + MPA 5 mg or 17 h-estradiol 2 mg + norethindrone 1 mg daily have been shown to be beneficial [61,62]. An alternative approach that avoids administration of estrogens entirely is the use of norethindrone in a 2.5-mg daily dose [63]. In each of these studies, vasomotor and painful symptoms were suppressed, but some degree of reversible bone loss was appreciated.

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Therefore, a different approach to add-back would be appropriate if treatment is to be extended beyond 6 months or retreatment considered. In a prospective, multi center, 12-month trial, Hornstein and colleagues demonstrated that pelvic pain and vasomotor symptoms remained suppressed and bone mineral density loss was prevented when the depot preparation of leuprolide acetate was combined with oral norethindrone acetate 5-mg daily [64]. (Fig. 1) Pelvic pain was suppressed for at least 12 months after completion of therapy [65]. Mean bone loss, which was noted to be progressive in patients receiving the agonist alone, did not return to baseline for 16 months after completion of therapy. This would suggest that a GnRH agonist can potentially be used for up to 12 months or for retreatment, but only so long as an appropriate add-back is administered. A more detailed discussion of GnRH agonists is provided in Chapter 13. Gonadotropin Suppression: GnRH Antagonists GnRH antagonists are a class of drug that binds to GnRH receptors, inhibits gonadotropin secretion, and creates a hypoestrogenic state. Their mechanism

FIGURE 1 Mean changes from baseline in bone mineral density (BMD) of the lumbar spine as measured by dual x-ray absorptiometry in endometriosis patients receiving a 12-month course of a depot preparation of the GnRH agonist leuprolide acetate alone or with add-back. Group A: GnRHa alone. Group B: GnRHa + norethindrone acetate (NEt) 5 mg daily. Group C: GnRHa + NEt 5 mg daily + conjugated equine estrogens (CEE) 0.625 mg daily. Group D: GnRHa + NEt 5 mg daily + CEE 1.25 mg daily. (From Ref. 64. Adapted with permission from the American College of Obstreticians and Gynecologists. Obstet Gynecol 1998; 91:61–24.)

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of action is different than the GnRH agonists in that they competitively inhibit GnRH binding to its own receptor. As a result, the initial flare associated with GnRH agonist is eliminated [66]. Whether this is of great clinical significance has not been clearly demonstrated. These agents have been shown to inhibit the growth of endometriosis in an animal model [67]. There are currently a series of ongoing trials evaluating the efficacy of these agents in treating endometriosis. It is logical that the long-term efficacy and side effect profile would at least be similar to that of the agonists. The need for add-back therapy or perhaps the intermittent use of shorter acting agents may be necessary to overcome side-effects [68]. GnRH antagonists are reviewed in detail in Chapter 13. Antiprogesterone, Antiestrogens, and Selective Progesterone and Estrogen Receptor Modulators Mifepristone (RU-486) is an antiprogesterone agent with antiestrogenic and antiglucocorticoid properties. Initial data had suggested efficacy on shrinking surgically induced endometriosis in an animal model [69,70]. Limited clinical data suggest a dose-dependent efficacy in humans, although large scale studies have not been performed [71]. Selective progesterone receptor modulators are agents that exhibit both progesterone agonistic and antagonistic effects based on the target tissue. Initial clinical trials suggest efficacy in suppressing pelvic pain associated with endometriosis with few side effects [72]. Phase III trials are currently ongoing. The antiestrogenic agent, raloxifene, has also been shown to reduce the severity of endometriosis in a monkey model [73]. Human trials have not been reported. Aromatase Inhibitors Traditional medical approaches to endometriosis have focused on suppression of ovarian hormones. However, recent evidence has suggested that endometriotic implants may synthesize estrogen locally as a result of inappropriate local expression of the enzyme aromatase [74]. Various aromatase inhibitors have been used in small series with success in treating severe and postmenopausal endometriosis [75–77]. This approach is reviewed in detail in Chapter 11. Immunomodulation Given the increasing evidence that the pathophysiology of endometriosis may be intimately related to alterations in immune factors, it is logical that immunomodulators may play some beneficial role in the treatment of this

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disorder. A limited body of evidence primarily in animal models has been recently reported. Keenan et al documented regression of explants in rats with experimentally induced endometriosis administered through intraperitoneal loxoribine, an immunomodulatory agent that, among other actions, enhances the activity of a host of cytokines [78]. Interferon a 2b has been shown to inhibit endometrioma cell growth in culture [79]. In a prospective randomized trial, D’Hooghe and colleagues demonstrated that administration of recombinant human tumor necrosis factor binding protein-1 inhibited the development of experimentally induced endometriosis in the baboon model [80]. Inhibition of endometriosis symptoms was demonstrated in women with relapsing disease treated with thalidomide, an antiangiogenesis agent, in a small pilot study [81]. None of these agents has been evaluated in appropriately controlled human trials but all represent promising approaches for the future management of the disease.

MEDICAL MANAGEMENT OF ENDOMETRIOSIS-RELATED INFERTILITY As previously discussed, the efficacy of a variety of medications on the suppression of symptomatic endometriosis has been well established. In contrast, the efficacy of progestins, danazol, or GnRH agonists when used as primary therapy to enhance patients with endometriosis-associated infertility has not been demonstrated. Hughes et al evaluated data from nine trials comparing ovulation suppression with either danazol, gestrinone, or medroxyprogesterone acetate to no treatment or placebo which all failed to show any beneficial effect on enhancing pregnancy rates (common OR 0.85; 95% CI 0.95–1.22) [82]. In the same study, an additional six randomized trials comparing a GnRH agonist, gestrinone, or an oral contraceptive to danazol also failed to demonstrate any differences (common OR 1.07; 95% CI 0.71– 1.61). These findings were confirmed by Adamson and Pasta in a separate meta-analysis [83]. These investigators recommended that medical therapies should not be used as a treatment of infertility associated with asymptomatic endometriosis. There are several possible explanations for these findings. One could propose that minimal to mild endometriosis has no impact on fertility at all, given the proven efficacy of these agents in treating the underlying disease, but lack of efficacy in improving conception. A second explanation is that the mechanism of infertility associated with endometriosis is different from that associated with pelvic pain and is unaffected by these medications. Neither of these explanations can be supported by data. A third, and perhaps more

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plausible explanation, may be that by the time a patient resumes normal ovulatory patterns, which may be months after completion of therapy, the deleterious effects of the disease process on fertility that were initially suppressed by medications recur even if the patient remains asymptomatic. Thus, if a patient could attempt conception when the disease process is maximally suppressed, pregnancy rates would be heightened. This could only occur with the use of the assisted reproductive technologies. In a prospective randomized trial, Surrey et al have recently evaluated the effect of a 3-month course of a GnRH agonist administered immediately before in vitro fertilization (IVF) in patients with surgically confirmed endometriosis [84]. Significantly higher ongoing pregnancy rates with a trend toward higher implantation rates were appreciated in this group of 25 patients in comparison to 26 controls with endometriosis treated with standard controlled ovarian hyperstimulation techniques before oocyte aspiration in the absence of prolonged GnRH agonist (Fig. 2). These findings have been confirmed by others [85–88].

FIGURE 2 In vitro fertilization cycle outcomes for endometriosis patients pretreated with a GnRH agonist for 3 months (Group I) immediately prior to controlled ovarian hyperstimulation (COH) or undergoing standard COH (Group II). a: P < 0.05 versus Group I. (From Ref. 84. Reprinted with permission by the American Society for Reproductive Medicine. Fertil Steril 2002; 78:699–704.)

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This effect may be a result of a beneficial effect of these agents on either peritoneal cytokine levels or endometrial markers of implantation [35,89].

COMBINED SURGICAL AND MEDICAL MANAGEMENT There are a limited number of prospective, randomized, placebo-controlled studies that evaluate the efficacy of medical therapy administered in conjunction with surgical management of symptomatic endometriosis. Telimaa et al evaluated the effects of a 6-month course of danazol (600 mg daily), MPA 100 mg daily, or placebo after surgical excision of endometriosis at laparoscopy [90]. A greater degree of postoperative pain relief and reduction of disease at follow-up laparoscopy were noted in both the danazol and MPA groups in comparison to placebo. Hornstein et al noted that the median time to initiation of alternative therapy was more than 24 months in patients receiving a 6-month postoperative course of GnRH agonist in comparison to 11.7 months in those randomized to receive post operative placebo [91] (Fig. 3). These findings were confirmed by Vercellini and coworkers [92]. Interestingly, other investigative teams did not demonstrate any difference in comparison to placebo when GnRH agonist or danazol was used post operatively [93–95]. These latter studies included only stage III–IV endometriosis and treated patients with a 3-month as opposed to a 6-month post

FIGURE 3 Time to initiation of alternative treatment for patients treated with the GnRH agonist nafarelin or placebo for 6 months post-laparoscopic ablation of endometriosis. Reprinted with permission by the American Society for Reproductive Medicine, Fertil Steril 1997, Vol. 68, p. 860–864.

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operative course of the GnRH agonist, which may be insufficient to achieve full efficacy. A 6-month preoperative course of GnRH agonists was compared to a 6-month postoperative course in a randomized trial [96]. Similar improvement in pelvic pain symptoms was appreciated, although endometriosis scores were more extensively suppressed when the agonist was given pre operatively. Shaw et al demonstrated that GnRH agonist therapy administered after endometrioma drainage resulted in less extensive recurrence and extent of endometriotic implants at follow-up laparoscopy [97]. In addition, postoperative adhesion formation and reformation after adhesiolysis were reduced in rats with surgically induced endometriosis and adhesions that had been treated preoperatively and postoperatively with a GnRH agonist [98]. The impact on conception of combining surgical resection or ablation with medical therapy administered either pre-or postoperatively has been evaluated. Unfortunately, the majority of studies are nonrandomized, which creates a high degree of selection and inclusion bias. Hughes et al evaluated five older cohort studies comparing laparoscopic surgery plus danazol to danazol alone [82]. The common odds ratio for this group was 1.42 (95% CI 0.94–2.14), suggesting no benefit of adjunctive danazol therapy. A similar finding was noted in patients undergoing laparotomy. Telimaa and colleagues reported the results of a placebo-controlled trial comparing post operative medroxyprogesterone acetate to danazol after conservative surgery [90]. Although only a small subset of patients in each group was attempting pregnancy, the conception rates were similar among the three treatment groups. Donnez et al prospectively evaluated 126 infertile women with ovarian endometriosis resected microsurgically at laparotomy who were treated with preoperative danazol, gestrinone, or the GnRH agonist buserelin, in a non randomized trial [99]. The cumulative pregnancy rates after 18 months of follow-up in patients treated with buserelin (58%) were significantly higher than those treated with danazol (45%) or gestrinone (47%) [ P < 0.05]. In the subsets of patients attempting conception in two randomized placebo-controlled trials that evaluated the effect of either 3 or 6 months of post operative GnRH agonist therapy, no difference in pregnancy rates was appreciated in either study [88,90]. It is important to note that the primary endpoint in these studies was symptom recurrence and not fertility, which may have created a degree of selection bias. Nevertheless, the preponderance of data would suggest that pre-or postoperative adjunctive medical therapy adds little to the benefit achieved with surgical intervention alone in overcoming endometriosis-associated infertility in the asymptomatic patient. In contrast, these approaches appear to be highly advantageous as an adjunct to the surgical management of symptomatic disease.

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SUMMARY The medical management of endometriosis has evolved dramatically over the last 40 years and has greatly benefited from the result of well-designed trials. Nevertheless, the absence of a uniform instrument for evaluating outcomes makes comparisons between studies somewhat difficult. Although a host of medications have demonstrated efficacy in the management of symptomatic endometriosis, none appears to be valuable in the management of endometriosis-associated infertility. The administration of a prolonged course of a GnRH agonist prior to in vitro fertilization represents a possible exception. The use of adjunctive medical therapy appears to enhance surgical outcomes when administered for an appropriate time. Currently, GnRH agonists appear to represent the standard for medical management of endometriosis. However, new classes of agents, which attack the source of this disease and not solely its endocrine stimulation represent, exciting pursuits for the future.

PRACTICAL POINTS  

GnRHa is the standard medical treatment of endometriosis. Administration of a prolonged course of a GnRHa prior to in vitro fertilization may be beneficial.

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24. Telimaa S, Penttila I, Puolakka J, Ronnberg L, Kauppila A. Circulating lipid and lipoprotein concentrations during danazol and high dose medroxyprogesterone acetate therapy of endometriosis. Fertil Steril 1989; 52:31–35. 25. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crossignani PM. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999; 72:505– 508. 26. Moguilewsky M, Philibert D. Dynamics of receptor interaction of danazol and gestrinone in the rat: Correlations with biologic activities. In: Raynard JP ed. Medical Management of Endometriosis. New York: Raven Press, 1984:163–181. 27. Chalbos D, Bardon S, Vignon F, Rocheford H. Use of hormone responsive cell lines to study the mechanism of action of progestins and antiprogestins. In: Raynaud J, ed. Medical Management of Endometriosis. New York: Raven Press 1984:53–71. 28. Thomas E, Cooke I. Impact of gestrinone on the course of asymptomatic endometriosis. BMJ 1987; 294:272–274. 29. Hornstein M, Gleason R, Barbieri R. A randomized double-blind trial of two doses of gestrinone in the treatment of endometriosis. Fertil Steril 1990; 53:237– 241. 30. Dawood M, Obasiolu C, Ramos J, Khan-Dawood F. Clinical, endocrine, and metabolic effects of two doses of gestrinone in treatment of pelvic endometriosis. Am J Obstet Gynecol 1997; 176:387–394. 31. Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani G. Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril 1989; 51:781–785. 32. The Gestrinone Italian Study Group. Gestrinone versus a gonadotropin-releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: A multicenter, randomized, double-blind study. Fertil Steril 1996; 66:911–919. 33. Metzger D, Luciano A. Hormonal therapy of endometriosis. Obstet Gynecol Clin (N.A.) 1989; 16:105–122. 34. Ota H, Igarashi S, Hayakawa M, Matsui T, Tanaka H, Tanaka T. Effect of danazol on the immunocompetent cell in the eutopic endometrium in patients with endometriosis: A multicenter cooperative study. Fertil Steril 1996; 65:545– 551. 35. El-Roeiy A, Dmowski W, Gleicher N, Radwanska E, Harlow L, Binor Z, Tummon I, Rawlins RG. Danazol but not gonadotropin-releasing hormone agonists suppressed autoantibodies in endometriosis. Fertil Steril 1988; 50:864– 871. 36. Taketani Y, Kuo T-M, Mizuno M. Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis. Am J Obstet Gynecol 1992; 167:265–270. 37. Matalliotakis I, Neonalis M, Koumantaki Y, Goumeiou A, Kyriakou D, Koumantakis E. A randomized comparison of danazol and leuprolide acetate suppression of serum-soluble CD23 levels in endometriosis. Obstet Gynecol 2000; 95:810–813.

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38. Dmowski W, Kapetanakis E, Scommegna A. Variable effects of danazol on endometriosis at 4 low-dose levels. Obstet Gynecol 1982; 59:408–415. 39. Biberoglu K, Behrman S. Dosage aspects of danazol therapy in endometriosis: Short-term and long-term effectiveness. Am J Obstet Gynecol 1981; 139:645–654. 40. Barbieri R, Evans S, Kistner R. Danazol in the treatment of endoemtriosis: Analysis of 100 cases with a 4-year follow-up. Fertil Steril 1982; 37:737–746. 41. Buttram V, Reiter R, Ward S. Treatment of endometriosis with danazol: Report of a 6-year prospective study. Fertil Steril 1985; 43:353–360. 42. Kingsbury A. Danazol and fetal masculinization: A warning. Med J Aust 1985; 143:410–413. 43. Vercellini D, Trespidi L, Panazza S, Bramante T, Mauro F, Crosignani PG. Very low dose danazol for relief of endometriosis-associated pelvic pain: A pilot study. Fertil Steril 1994; 62:1136–1142. 44. Igarashi M, Cizuka M, Abe Y, Ibuki Y. Novel vaginal danazol ring therapy for pelvic endometriosis in particular deeply infiltrating endometriosis. Hum Reprod 1998; 13:1952–1956. 45. Janicki T. Treatment of the pelvic pain associated with endometriosis using danazol vaginal suppositories: Two year follow-up. Fertil Steril 2002; 77:S52. 46. Suzumori N, Sato M, Ikuta K, Suzumori K. Secretory leukocyte protease inhibitor in ovarian endometriomas following GnRH agonist therapy. Obstet Gynecol 2001; 97:561–566. 47. Meresman G, Bilotas M Jr, Lombardi E, Tesone M, Sueldo C. Effect of gonadotropin-releasing hormone analog on the apoptosis and release of Il-1 and VEGF in endometrial cultures from patients with endometriosis. Fertil Steril 2002; 78:S202–S203. 48. Sharpe-Timms K, Keisler L, McIntush E, Keisler D. Tissue inhibitor of metalloproteinase-1 concentrations are attenuated in peritoneal fluid and sera of women with endometriosis and restored in sera by gonadotropin-releasing hormone agonist therapy. Fertil Steril 1998; 69:1128–1134. 49. Dlugi A, Miller J, Knittle JLupron Study GroupLupron depot (leuprolide acetate in depot suspension) in the treatment of endometriosis: A randomized, placebo-controlled, double-blind study. Fertil Steril 1990; 54:419–427. 50. Henzl M, Corson S, Moghissi K, Buttram D, Berquist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis: A multicenter double-blind comparative clinical trial. N Engl J Med 1988; 318: 485–489. 51. Dmowski WP, Radwanska E, Binor Z, Tummon I, Pepping P. Ovarian suppression induced with Buserelin or danazol in the management of endometriosis: A randomized, comparative study. Fertil Steril 1989; 51:395–400. 52. Kennedy S, Williams I, Brodribb J, Barlow D, Shaw R. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertil Steril 1990; 53:998–1003. 53. Shaw RZoladex Endometriosis Study TeamAn open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Fertil Steril 1992; 58:265–272.

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54. The Nafarelin European Endometriosis Trial Group. Nafarelin for endometriosis: A large-scale, danazol-controlled trial of efficacy and safety, with 1-year follow-up. Fertil Steril 1992; 57:514–522. 55. Wheeler J, Knittle J, Miller J. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. Am J Obstet Gynecol 1992; 167:1367–1371. 56. Rock J, Truglia J, Caplan R, Zoladex Endometriosis Study Group. Zoladex (goserelin acetate implant) in the treatment of endometriosis: A randomized comparison with danazol. Obstet Gynecol 1993; 82:198–205. 57. Wright S, Valdes C, Dunn R, Franklin R. Short-term Lupron or danazol therapy for pelvic endometriosis. Fertil Steril 1995; 63:504–507. 58. Waller K, Shaw R. Gonadotropin-releasing hormone analogues for the treatment of endometriosis: Long-term follow-up. Fertil Steril 1993; 59:511–515. 59. Ling F, Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol 1999; 93:50–51. 60. Surrey E, Add-back Consensus Working Group. Add-back therapy and gonadotropin releasing hormone agonists in the treatment of patients with endometriosis: Can a consensus be reached? Fertil Steril 1999; 71:420–424. 61. Moghissi K, Schlaff W, Olive D, Skinner M, Yin H. Goserelin acetate (Zoladex) with or without hormone replacement therapy for the treatment of endometriosis. Fertil Steril 1998; 69:1056–1062. 62. Kiiholma P, Korhonen M, Tiumala R, Korhonen M, Hayman E. Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen progestagen add-back therapy in the treatment of endometriosis. Fertil Steril 1995; 64:903–908. 63. Surrey E, Gambone J, Lu J, Judd H. The effects of combining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis. Fertil Steril 1990; 53:620–626. 64. Hornstein M, Surrey E, Weisberg G, Casino L. Leuprolide acetate depot and hormonal add-back in endometriosis: A 12-month study. Obstet Gynecol 1998; 91:16–24. 65. Surrey E, Hornstein M. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: Long-term follow-up. Obstet Gynecol 2002; 99: 709–719. 66. Martha P, Gray M, Campion M, Kuca B, Garnick M. Prolonged suppression of circulating estrogen levels without an initial hormonal flare using abarelixdepot, a pure GnRH antagonist, in women with endometriosis. Fertil Steril 1999; 72:S210–S211. 67. Jones RC. The effect of a luteinizing hormone-releasing hormone antagonist on experimental endometriosis in the rat. Acta Endocrinol 1987; 114:379–383. 68. Kupker W, Felberbaum R, Krapp M, Schill T, Malik E, Diedrich K. Oestradiol-threshold therapy using the GnRH antagonist, cetrorelix in women with endometriosis. Abstract O-O96. 16th Annual Meeting of the European Society for Human Reproduction and Embryology. Bologna, Italy 2000.

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69. Tjaden B, Galetto D, Woodruff J, Rock J. Time-related effects of RU486 treatment in experimentally induced endometriosis in the rat. Fertil Steril 1993; 59:437–440. 70. Grow D, Williams R, Hsiu J, Hodgen G. Antiprogestin and/or gonadotropinreleasing hormone agonist for endometriosis treatment and bone maintenance: A 1-year primate study. J Clin Endocrinol Metab 1996; 81:1933–1939. 71. Kettel L, Murphy A, Morales A, Ulmann A, Baulieu E, Yen S. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril 1996; 65:23–28. 72. Olive D. Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 2002; 57:S55– S63. 73. Fanning P, Kuehl T, Lee R, Pearson S, Wincek T, Pliego J, Spiekerman A, Bryant H, Rippy M. Video mapping to assess efficacy of an antiestrogen (raloxifene) on spontaneous endometriosis in the rhesus monkey. Fertil Steril 1997; 68:S38–S39. 74. Zeitoun K, Bulun S. Aromatase: A key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril 1999; 72:961–969. 75. Scarpelini F, Sbracia M. Aromatase inhibitiors in the treatment of low responder women with severe endometriosis. Fertil Steril 1999; 72:S213. 76. Fang Z, Yang S, Tamura M, Gurates B, Bulun S. Treatment with aromatase inhibitor letrozole significantly reduced the size of endometriotic implants. Fertil Steril 2001; 76:S46. 77. Takayama K, Zeitoun K, Gumby R, Sasano H, Carr B, Bulun S. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril 1998; 69:709–713. 78. Keenan J, Williams-Boyle P, Massey P, Chen T, Candle M, Bukovsky A. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril 1999; 721:135– 141. 79. Badawy S, Etman A, Cuenca V, Montante A, Kaufman L. Effect of interferon a-2b on endometrioma cells in vitro. Obstet Gynecol 2001; 98:417–420. 80. D’Hooghe T, Cuneo S, Nugent N, Chai D, Deer F, Mwenda J. Recombinant human TNF binding protein-1 (r-hTBP-1) inhibits the development of endometriosis in baboons: A prospective, randomized, placebo-and drug-controlled study. Fertil Steril 2001; 76:S1. 81. Scarpellini F, Sbracia M, Lecchini S, Scarpellini L. Anti-angiogenesis treatment with thalidomide in endometriosis: A pilot study. Fertil Steril 2002; 78: S87. 82. Hughes EG, Fedorkow DM, Collins JA. A quantitative overview of controlled trials in endometriosis-associated infertility. Fertil Steril 1993; 59:963–970. 83. Adamson GD, Pasta D. Surgical treatment of endometriosis-associated infertility: Meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994; 171:1488–1505. 84. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. The effect of pro-

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11 Treatment with Aromatase Inhibitors Serdar E. Bulun, Bilgin Gurates, Zongjuan Fang, Mitsutoshi Tamura, David Langoi, Gonca Imir, Sanober Amin, Santanu Deb, and Sijun Yang University of Illinois at Chicago Chicago, Illinois, U.S.A.

INTRODUCTION Estrogen causes proliferation of endometrial tissue. Aromatase P450 (P450arom) is the key enzyme for estrogen biosynthesis. Aromatase activity is not detectable in normal endometrium. In contrast, P450arom is expressed aberrantly in endometriosis and is stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor. We will discuss the molecular mechanisms that give rise to aromatase overexpression in endometriosis tissue. Endometriosis is the leading cause of pelvic pain [1,2]. Endometriosis is characterized by the presence of endometrial glands and stroma within the pelvic peritoneum and other extrauterine sites and is linked to pelvic pain 189

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and infertility. It is estimated to affect 5% of women in the reproductive age group [1,2]. Endometriosis is a polygenically inherited disease of complex multifactorial etiology [3]. Sampson’s theory of transplantation of endometrial tissue on the pelvic peritoneum by retrograde menstruation is the most widely accepted explanation for the development of pelvic endometriosis because of convincing circumstantial and experimental evidence [4]. Because retrograde menstruation is observed in almost all cycling women, endometriosis is postulated to develop as a result of the coexistence of a defect in clearance of the menstrual efflux from pelvic peritoneal surfaces, possibly involving the immune system [5]. Alternatively, intrinsic molecular aberrations in pelvic endometriotic implants were proposed to contribute significantly to development of endometriosis. Aberrant expression of aromatase, certain cytokines and tissue metalloproteinases, deficiency of 17h-hydroxysteroid dehydrogenase (17h-HSD) type 2, and resistance to the protective action of progesterone are some of these molecular abnormalities [6–12]. Because endometriosis is an estrogen-dependent disorder, aromatase expression and 17h-HSD type 2 deficiency are of paramount importance in the pathophysiology of endometriosis. In this article, aberrant mechanisms of estrogen biosynthesis and metabolism in women with endometriosis are reviewed with emphasis on identifying targets for new treatment strategies. Estrogen Biosynthesis and Metabolism in Humans The conversion of androstenedione and testosterone to estrone and estradiol is catalyzed by aromatase, which is expressed in a number of human tissues and cells, such as ovarian granulosa cells, placental syncytiotrophoblast, adipose tissue and skin fibroblasts, and the brain. In the reproductive-age woman, the ovary is the most important site of estrogen biosynthesis, and this takes place in a cyclic fashion. Upon binding of follicle-stimulating hormone (FSH) to its G-protein-coupled receptor in the granulosa cell membrane, intracellular cyclic adenosine monophosphate (cAMP) levels rise and enhance binding of two critical transcription factors, that is, steroidogenic factor-1 (SF-1) and cAMP response element binding protein (CREB), to the classically located proximal promoter II of the aromatase gene [13,14]. This, in turn, activates aromatase expression and estrogen secretion from the preovulatory follicle [14,15]. On the other hand, in postmenopausal women, estrogen formation takes place in extraglandular tissues, such as the adipose tissue and skin [16– 18] (Fig. 1). In contrast to cAMP regulation of aromatase expression in the ovary, this is controlled primarily by cytokines (interleukin [IL]-6, IL-11, tumor necrosis factor [TNF]a) and glucocorticoids by the alternative use of promoter I.4 in adipose tissue and skin fibroblasts [15]. The major substrate

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FIGURE 1 Extraovarian estrogen synthesis in women. Estradiol in women is either directly secreted by the ovary or produced in extraglandular sites (adipose tissue and skin). The principal substrate for extraglandular aromatase activity in ovulatory women is androstenedione of adrenal and ovarian origins. In women receiving GnRH agonists or postmenopausal women, however, the adrenal remains as the primary source of androstenedione. Androstenedione is converted by aromatase to estrone in adipose tissue and skin fibroblasts. Estrone is further converted to estradiol by 17h-HSD type 1 activity in these peripheral tissues. Thus, peripheral aromatization is the major source for circulating estradiol in the postmenopausal period or during ovarian suppression.

for aromatase in adipose tissue and skin is androstenedione of adrenal origin. In postmenopausal women, approximately 2% of circulating androstenedione is converted to estrone, which is further converted to estradiol in these peripheral tissues. This may give rise to significant serum levels of estradiol capable of causing endometrial hyperplasia or even carcinoma [17,18]. Aromatase Expression in Normal and Abnormal Uterine Tissues Mu¨llerian tissues are known targets of estrogen action. Until recently, estrogen action has been classically viewed to occur only by an ‘‘endocrine’’ mechanism: in other words, it was thought that only circulating estradiol, whether secreted by the ovary or formed in the adipose tissue, could exert an estrogenic effect after delivery to target tissues through the bloodstream. Studies on aromatase expression in breast cancer demonstrated that paracrine mechanisms play an important role in estrogen action in this tissue [19]. Estrogen

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produced by aromatase activity in breast adipose tissue fibroblasts was demonstrated to promote the growth of adjacent malignant breast epithelial cells [20]. Finally, we demonstrated an ‘‘intracrine’’ effect of estrogen in uterine leiomyomas and endometriosis: estrogen produced by aromatase activity in the cytoplasm of leiomyoma smooth muscle cells or endometriotic stromal cells can exert its effects by readily binding to its nuclear receptor within the same cell [6,21,22]. Disease-free endometrium and myometrium, on the other hand, lack aromatase expression [21,22]. Aromatase Expression in Endometriosis Among estrogen-responsive pelvic disorders, aromatase expression was studied in greatest detail in endometriosis [6,7,22,23]. First, extremely high levels of aromatase mRNA were found in extraovarian endometriotic implants and endometriomas. Second, endometriosis-derived stromal cells in culture incubated with a cAMP analog displayed extraordinarily high levels of aromatase activity comparable to that in placental syncytiotrophoblast [22]. These exciting findings led us to test a battery of growth factors, cytokines, and other substances that might induce aromatase activity via a cAMPdependent pathway in endometriosis. Prostaglandin E2 (PGE2) was found to be the most potent known inducer of aromatase activity in endometriotic stromal cells [22]. In fact, this PGE2 effect was found to be mediated through the cAMP-inducing EP2 receptor subtype (our unpublished observations). Moreover, estrogen was reported to increase PGE2 formation by stimulating cyclo-oxygenase type 2 (COX-2) enzyme in endometrial stromal cells in culture [24]. Thus, a positive feedback loop for continuous local productions of estrogen and PGs is established, favoring the proliferative and inflammatory characteristics of endometriosis (Fig. 2). Additionally, aromatase mRNA was also detected in the eutopic endometrial samples of women with moderate to severe endometriosis (but not in those of disease-free women), albeit in much smaller quantities compared with endometriotic implants [6]. This may be suggestive of a genetic defect in women with endometriosis, which is manifested by this subtle finding in the eutopic endometrium. We propose that when defective endometrium with low levels of aberrant aromatase expression reaches the pelvic peritoneum by retrograde menstruation, it causes an inflammatory reaction that exponentially increases local aromatase activity, for example, estrogen formation, induced directly or indirectly by PGs and cytokines [22]. It would be rather naive to propose that aberrant aromatase expression is the only important molecular mechanism in the development and growth of pelvic endometriosis. There may be many other molecular mechanisms that favor the development of endometriosis: abnormal expression of proteinase-type enzymes that remodel tissues or their inhibitors

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FIGURE 2 Origin of estrogen in endometriotic lesions. Estradiol in an endometriotic lesion arises from several body sites. In an ovulatory woman, estradiol is secreted directly from the ovary in a cyclic fashion. In the early follicular phase and after menopause, peripheral tissues (adipose and skin) are the most important sources to account for the circulating estradiol. Estradiol is also produced locally in the endometriotic implant itself in both ovulatory and postmenopausal women. The most important precursor, androstenedione of adrenal origin, becomes converted to estrone that is, in turn, reduced to estradiol in the peripheral tissues and endometriotic implants. We demonstrated significant levels of 17h-hydroxysteroid dehydrogenase type 1 expression in endometriosis, which catalyzes the conversion of estrone to estradiol [12]. Estradiol both directly and indirectly (through cytokines) induces COX-2 which gives rise to elevated concentrations of PGE2 in endometriosis [24]. Prostaglandin E2 is the most potent known stimulator of aromatase in endometriotic stromal cells [22]. This establishes a positive feedback loop in favor of continuous estrogen formation in endometriosis.

(matrix metalloproteinases, tissue inhibitor of metalloproteinase-1), certain cytokines (IL-6, RANTES), and growth factors (EGF) represent some of mechanisms [8–11]. Alternatively, a defective immune system that fails to clear peritoneal surfaces of the retrograde menstrual efflux has been proposed in the development of endometriosis [5,25]. The development of endometriosis in an individual woman probably requires the coexistence of a thresh-

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old number of these aberrations. Nonetheless, aberrant aromatase expression is clinically relevant, as aromatase inhibitors suppress postmenopausal endometriosis [26]. Regulation of Aromatase Expression in Endometriotic Stromal Cells As emphasized earlier, PGE2 was found to be the most potent known inducer of aromatase activity by increasing cAMP levels in endometriotic stromal cells [22]. On the other hand, neither cAMP analogs nor PGE2 were capable of stimulating any detectable aromatase activity in eutopic endometrial stromal cells in culture. The obvious question became what are the molecular differences that give rise to aromatase expression in endometriosis and its inhibition in eutopic endometrium? To address this, we first determined that the cAMP-inducible promoter II was used for in vivo aromatase expression in endometriotic tissue [7]. Then, a stimulatory transcription factor, SF-1, and an inhibitory factor, chicken ovalbumin upstream promoter transcription factor (COUP-TF), were found to compete for the same binding site in aromatase promoter II. The COUP-TF was ubiquitously expressed in both eutopic endometrium and endometriosis, whereas SF-1 was expressed specifically in endometriosis but not in eutopic endometrium and binds to aromatase promoter more avidly than COUP-TF [7]. Thus, SF-1 and other transcription factors (e.g., CREB) activate transcription in endometriosis, whereas COUPTF, which occupies the same DNA site in eutopic endometrium, inhibits this process [7] (Fig. 3). In summary, one of the molecular alterations leading to local aromatase expression in endometriosis, but not in normal endometrium, is the aberrant production of SF-1 in endometriotic stromal cells,

Œ

FIGURE 3 Proposed mechanism of regulation of aromatase (P450arom) expression by SF-1 and COUP-TF in eutopic endometrium and endometriosis. (A) Binding of COUP-TF (dimer) to a specific DNA site (nuclear receptor half-site) upstream of aromatase promoter II in eutopic endometrial stromal cells. In the eutopic endometrium, COUP-TF binds to nuclear receptor half-site practically in the absence of any competition by SF-1, as SF-1 expression is not detected in the majority of eutopic endometrial samples. Thus, COUP-TF exerts its inhibitory effect on the complex of general transcription factors (GTFs) that bind to TATA box. (B) In the endometriotic stromal cell, where SF-1 is also present, SF-1 binds as a monomer to the nuclear receptor half-site with a higher affinity compared with that of COUP-TF, which binds to this site relatively loosely as a dimer. Upon replacing COUP-TF, SF-1 synergizes with cAMP response element binding protein (CREB, bound to upstream CRE) and other factors to activate transcription of the aromatase gene in response to cAMP [7].

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which overcomes the protective inhibition maintained normally by COUPTF in the eutopic endometrium. Inactivation of Estradiol in Endometrium and Endometriosis The primary substrate for aromatase activity in endometriosis is androstenedione of adrenal and ovarian origins in premenopausal women and adrenal androstenedione in postmenopausal women. The major product of aromatase activity in endometriosis, namely estrone, is only weakly estrogenic and must be converted to the potent estrogen estradiol to exert a full estrogenic effect. We demonstrated that the enzyme 17h-HSD type 1, which catalyzes the conversion of estrone to estradiol, is expressed in endometriosis [12,27]. In contrast, the enzyme 17h-HSD type 2 (encoded by a separate gene) inactivates estradiol by catalyzing its conversion to estrone in eutopic endometrial glandular cells during the luteal phase [27]. Progesterone actually induces the activity of this enzyme in endometrial glandular cells in culture, making inactivation of estradiol to estrone one of the antiestrogenic properties of progesterone [28]. The expression of 17h-HSD type 2 is absent from endometriotic glandular cells, as demonstrated in paired samples of eutopic endometrium and pelvic endometriosis obtained simultaneously during the luteal phase [12]. Consequently, this protective mechanism that lowers estradiol levels is lost in endometriotic tissue [12]. The aberrant expression of aromatase, the presence of 17h-HSD type 1, and the absence of 17h-HSD type 2 from endometriosis collectively give rise to elevated local levels of estradiol compared with eutopic endometrium. Additionally, 17h-HSD type 2 deficiency may also be viewed as a defective action of progesterone, which fails to induce this enzyme in endometriotic tissue (Fig. 4). Clinical Basis for Using Aromatase Inhibitors to Treat Endometriosis Endometriosis is successfully suppressed by estrogen deprivation with GnRH analogs or the induction of surgical menopause. Control of pelvic pain with GnRH agonists is usually successful during and immediately after the treatment, whereas pain associated with endometriosis returns in up to 75% of these women [29,30]. There may be multiple reasons for the failure of GnRH agonist treatment of endometriosis. One likely explanation is the presence of significant estradiol production that continues in the adipose tissue, skin, and endometriotic implant per se during the GnRH agonist treatment (Fig. 5). Therefore, blockage of aromatase activity in these extraovarian sites with an aromatase inhibitor may keep larger number of patients in remission for longer periods. The most striking evidence for the significance of extraovarian estrogen production is the recurrence of endometriosis after successfully

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FIGURE 4 Defective inactivation of estradiol in endometriosis. Estradiol (E2) reaches the endometriotic lesions via bloodstream (and possibly peritoneal fluid). Additionally, aromatase (P450arom) in the stromal cell catalyzes the conversion of androstenedione (A) to estrone (E1), which is further reduced to E2 by 17h-HSD type 1 in the endometriotic tissue. (At this time, the cell type that expresses 17h-HSD type 1 in endometriotic lesions is not known.) Estradiol is normally inactivated by conversion to E1 by 17h-HSD type 2 in epithelial cells of the eutopic endometrium during the secretory phase. In endometriotic tissue, however, E2 is not metabolized owing to the lack of 17h-HSD type 2 giving rise to increased local concentration of this potent estrogen. Elevated E2, in turn, will promote the growth of endometriotic tissue and local PGE2 formation in stromal cells [24]. Because PGE2 is the most potent known inducer of aromatase in endometriosis, this will complete the positive feedback cycle that favors increased levels of E2 in endometriosis through enhanced biosynthesis and deficient metabolism.

completed hysterectomy and bilateral salpingo-oophorectomy in a number of women [26,31]. Endometriotic tissue in one such aggressive case was found to express much higher levels of aromatase mRNA compared with premenopausal endometriosis [26]. We recently reported the treatment of a 57-year-old overweight woman who had recurrence of severe endometriosis after hysterectomy and bilateral salpingo-oophorectomy. Two additional laparotomies were performed owing to persistent severe pelvic pain and bilateral ureteral obstruction leading to left renal atrophy and right hydronephrosis. Treatment with megestrol acetate was ineffective. A large (3 cm) vaginal endometriotic lesion contained unusually high levels of aromatase mRNA. The patient was

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FIGURE 5 Site of action of GnRH agonists and aromatase inhibitors to treat endometriosis. This figure depicts the origin of estrogen in women with endometriosis: (i) delivery from the ovary and adipose tissue/skin via circulation and (ii) local biosynthesis in endometriosis. GnRH agonists will eliminate estradiol secreted by the ovary by downregulating the pituitary hypothalamic unit. In cases resistant to treatment with GnRH agonists or in postmenopausal endometriosis, the use of aromatase inhibitors to block estrogen formation in the skin and adipose tissue as well as in endometriotic stromal cells may be critical in controlling the growth of endometriotic tissue. Recurrent endometriosis, especially after surgical removal of the ovaries, may represent lesions that are sensitive to extremely low levels of estradiol, thus suppression of estradiol production in the periphery (adipose tissue/skin) and in endometriotic tissue may be mandatory for successful treatment of endometriosis.

given anastrozole (an aromatase inhibitor) for 9 months. Despite the addition of calcium and alendronate (a nonsteroidal inhibitor of bone resorption), bone density in the lumbar spine decreased by 6.2%. The occurrence of significant bone loss in this particular case should be studied further. Dramatic relief of the pain and regression of the vaginal endometriotic lesion were observed within the first month of treatment. At the same time, circulating estradiol levels were reduced to 50% of the baseline value. Markedly high pretreatment levels of aromatase mRNA in the endometriotic tissue became undetectable in a repeat biopsy 6 months later, and the lesion nearly disappeared after 9 months of therapy. Two potential mechanisms may have accounted for this strikingly successful result. Firstly, there was evidence of suppression of peripheral (skin and adipose tissue) aromatase activity, giving

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rise to a significant decrease in serum estradiol level. Secondly, unusually high levels of aromatase expression in the endometriotic lesion disappeared after treatment with the aromatase inhibitor, anastrozole. Besides the expected direct inhibition of aromatase activity in endometriosis by anastrozole, the disappearance of aromatase mRNA expression in the lesion may be explicable by denial of estrogen that is known to stimulate local biosynthesis of PGE2, which, in turn, stimulates aromatase expression (Fig. 2). SUMMARY Endometriosis is an estrogen-dependent disease. The mechanisms and effectiveness of hormonal treatments for endometriosis should be re-evaluated in view of the new advances that increased our understanding of the body sites of estrogen production in a woman with endometriosis. In addition to ovarian secretion, estradiol is produced in peripheral sites such as skin, adipose tissue, and endometriotic lesions. We suggest that the intracrine and paracrine effects of estradiol produced in the target tissue amplify the estrogenic action of steroid hormones delivered through the circulation. Additionally, defective inactivation of estradiol in endometriosis in contrast to eutopic endometrium may further enhance this local effect. Aberrant aromatase activity and defective estradiol metabolism in endometriosis are consequences of specific molecular aberrations, such as inappropriate expression of a stimulatory transcription factor or progesterone resistance in this tissue. The clinical relevance of these findings was recently exemplified by the successful treatment of a severe case of recurrent postmenopausal endometriosis with an aromatase inhibitor. Understanding the unique transcriptional mechanisms responsible for aromatase expression will enable us to define specific targets and design treatments that will target only local estrogen biosynthesis in endometriosis. It remains to be seen whether such high-precision strategies will give rise to clinically successful treatments. The recently developed potent aromatase inhibitors are candidate drugs in the treatment of endometriosis resistant to standard regimens. In fact, the use of aromatase inhibitors may be the only available treatment for aggressive postmenopausal endometriosis. It remains to be seen whether aromatase inhibitors alone or together with present lines of therapy in premenopausal women will increase the pain-free interval and time to recurrence after discontinuation (Fig. 5). Studies are under way to address these questions. ACKNOWLEDGMENTS The preparation of this article was supported, in part, by NIH grants HD38691 and TW01339.

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PRACTICAL POINT .

Aromatase inhibitors could be new drugs for treating endometriosis.

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28. Satyaswaroop PG, Wartell DJ, Mortel R. Distribution of progesterone receptor, estradiol dehydrogenase, and 20a-dihydroprogesterone dehydrogenase activities in human endometrial glands and stroma: Progestin induction of steroid dehydrogenase activities in vitro is restricted to the glandular epithelium. Endocrinology 1982; 111:743–749. 29. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 1988; 318:485–489. 30. Waller KG, Shaw RW. Gonadotropin-releasing hormone analogues for the treatment of endometriosis: Long-term follow-up. Fertil Steril 1993; 59:511– 515. 31. Metzger DA, Lessey BA, Soper JT, McCart KS Jr, Haney AF. Hormoneresistant endometriosis following total abdominal hysterectomy and bilateral salpingo-oophorectomy: Correlation with histology and steroid receptor content. Obstet Gynecol 1991; 78:946–950.

12 Endometriosis: Medical Treatment with Progestagens Robert Lahoud IVF Australia West, Westmead, Australia

Robert F. Harrison Rotunda Hospital, Dublin, Ireland

INTRODUCTION Endometriosis is a disorder defined by the presence of ectopic endometrial tissue. It is common and affects 1 in 7 of the female population of reproductive age [1]. It is more frequent in females presenting with chronic pelvic pain (70%) and in the subfertile population (30%–50%) [2]. The diagnosis is usually made at laparoscopy, hence, accurate prevalence estimates are difficult to obtain. Furthermore, the correlation between symptoms and visible disease is not linear [3]. In 25% of peritoneal biopsies of normal-appearing peritoneum, endometriosis was discovered [4]. Even though described by Rokitanski in 1860, it was only since the advent of laparoscopy that the large prevalence of this disorder was recognized. Endometrium is a tissue characterized by its regenerative potential, angiogenic properties, and hormone responsiveness. The hormones that particularly act on the endometrium include estrogen and progesterone. Medical treatments using danazol, progestagens, antiprogestagens and combined 203

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estrogen/progesterone preparations act on these hormones and have been used for many decades. Since the advent of the gonadotropin releasing hormone (GnRH) agonists, a new dimension of treatment choice has become available. The choice of medical treatment will depend on efficacy but is particularly based on the side effect profile, as long-term compliance with treatment is essential. Danazol, which was a particularly popular treatment for endometriosisrelated pain, has some very undesirable androgenic side effects (Table 1); hirsutism, mood changes, and adverse effects on the lipid profile as well as irreversible deepening of the voice [5,6]. These side effects have made clinicians and patients shy away from this treatment. On the other hand, danazol is effective in improving endometriosis-related pain [7] and is still a viable treatment option today. Progestional agents have been widely used to treat endometriosis. The decidualization and atrophy effect seen in endometriosis when using these agents also leads to irregular menstrual bleeding, which is one of the main reasons for noncompliance with this form of treatment (Table 1). Other side effects such as nausea, breast tenderness, fluid retention, and depression have been encountered [8,9]. High doses of medroxyprogesterone acetate (MPA) can adversely affect the lipoprotein profiles and may also cause suppression of gonadotropin production, leading to relative hypoestrogenism. Any shortterm loss in spinal bone mineral density is restored with time [10]. The commonly used dosages of MPA are 30-mg to 100 mg orally per day. It can also be administered parenterally using a 150-mg intramuscular depot preparation every 90 days. The advantages of progestagen treatment include its relative safety, wide availability, and low cost. Gestrinone is an antiprogestional steroid that causes a reduction in serum estradiol and sex hormone-binding globulin levels and reduces both estrogen and progesterone receptor concentrations in target tissues [11,12]. Like danazol, it is an effective treatment for the pain caused by endometriosis [13]. The androgenic side effects of gestrinone occur less frequently than with danazol. These include deepening of the voice and hirsutism. Another advantage of gestrinone is that it can be given as a once- or twice-weekly dose as compared with daily doses with Danazol. The combined estrogen/progestagen oral contraceptive (COC) has been used in the treatment of endometriosis for more then 40 years [14]. Many of the short-term side effects, such as weight gain and abnormal bleeding, and the more serious long-term effects, such as venous thrombosis, are well documented. However, COC is generally well tolerated [15], widely available, and inexpensive. Combined oral contraceptive treatment can be safely used for long-term treatment. The GnRH agonists induce a state of hypogonadotropic hypogonadism and the resultant hypoestrogenism is very effective in treating the pain of

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TABLE 1 Medication Danazol

ProgestagensMedroxyprogesterone acetate Dydrogesterone Gestrinone

Combined oral contraceptive GnRH analoguesLeuprorelin acetate Goserelin Nafarelin acetate

GnRH analogues with add-back

Administration 200–800 mg/day orally for 6 months

30 to 100 mg/day (oral) 10 to 20 mg/day (oral) 2.5 mg twice a week

Various preparations in cyclical or continuous regimen 1 mg/day sc 3.6 mg sc per month 400–800 Ag/day intranasal

Side Effects Acne, weight gain, seborrhea, hirsutism, edema, hair loss, voice change, hot flushes and sweats, irregular uterine bleeding, muscle cramps, decrease in HDL cholesterol, increased insulin requirement in diabetic patients Irregular uterine bleeding, insomnia, depression, headache, nausea, acne, hirsutism, thromboembolism. Acne, seborrhea, hirsutism, voice change, weight increase, hot flashes, headaches, irritability, depression, nausea, irregular uterine bleeding Side effects estrogenic and progestagenic. Hot flashes, change in libido, vaginal dryness, headaches, emotional lability, acne, myalgia, decreased breast size, bone mineral density loss, functional ovarian cysts. Reduces hypoestrogenic symptoms associated with GnRH analogue use.

endometriosis. The menopause-like symptoms such as hot flushes, vaginal dryness, decreased libido, insomnia, depression, and irritability are a major drawback to this type of treatment (Table 1). All these effects are reversible. The long-term risk of GnRH agonist treatment reducing bone mineral density (BMD) and increasing the risk of osteoporosis is a major concern. It appears that the bone loss associated with treatment for no longer than 6 months does not have a long-term detrimental effect [16]. The concept of ‘‘add back’’ therapy (using estrogens, progestagens, or both) in conjunction with GnRH agonists can overcome many of these side effects and does not appear to reduce the efficacy of the treatment [17–22]. Gonadotropin releasing hormone analogs have the advantage that they can be administered as long-acting depot preparations and safety is now well established. The cost of this class of drug is greater than that of progestagens.

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One of the major adverse effects of all these treatments is that they all act as contraceptive agents. As fertility is not infrequently desired, it limits their use to patients not desiring fertility. In this chapter the concept of progesterone receptors, their agonists, and antagonists are discussed. The clinical evidence for the use of progestagens and antiprogestagens in the treatment of endometriosis-related pain and infertility is critically reviewed. Finally the concept of selective progesterone receptor modulators is described.

PATHOPHYSIOLOGY Receptor Talk By definition, a progestagen is a hormone that binds to progesterone receptors to give a progesterone-like action. There are two major forms of progesterone receptors, A and B. These receptors are expressed by a single gene. As a consequence of transcription from different promoters, the two isotypes exist. Each form of progesterone receptor is associated with additional proteins that make it unique. In the absence of hormone binding, the C terminal region exerts an inhibitory effect on transcription [23]. Receptor agonists induce a conformational change that overcomes this inhibitory function. On the other hand, receptor antagonists allow this inhibitory action to be maintained. As a general rule, the progesterone receptor B acts as a positive regulator. However, progesterone receptor A appears to inhibit the activity of the B receptor [24]. The progesterone receptor A (PRA) also inhibits estrogen, glucocorticoid, mineralocorticoid, and androgen receptor activity. The relative levels of the two receptors in the endometrium differ during the menstrual cycle. This also may be due partly to the fact that progesterone receptors are induced by estrogens at the transcriptional level and decreased by progesterones at both the transcriptional and translational level [25]. Furthermore predominant PRA expression in endometriotic tissue may play a role in the pathogenesis of endometriosis and may explain treatment failure in certain cases [26]. Hormones and Endometriosis Eutopic and ectopic endometrium (endometriosis) display some histological and biochemical differences. Furthermore differences in receptor levels have been noted. As a general rule, estrogen stimulates the growth of endometriotic implants. It has been observed that endometriosis usually regresses after menopause. Hence, inducing a hypoestrogenic state (pseudomenopause) should result in the reduction of endometriotic tissue. This is essentially the mode of action of GnRH agonists.

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It is widely accepted that pregnancy, a state of high progesterone levels, is associated with an improvement in endometriosis. Progesterones are thought to cause decidualization and subsequent atrophy of endometrial tissue [27]. The pseudopregnancy concept was described as early as the 1950s [28]. The most commonly studied progesterone in the treatment of endometriosis is MPA. Progestagens for Endometriosis-Related Pain The pelvic pain of endometriosis commonly manifests as dysmenorrhea and dyspareunia. It can be extremely debilitating. The treatment options include surgery, analgesics (nonsteroidal anti-inflammatory drugs, for example) and medical therapy to suppress endometriosis. Many controversies remain in the field of endometriosis research. Progestagen use for endometriosis pain also remains somewhat controversial. The little evidence from placebo-controlled trials is often limited by low power studies and biases related to patient selection and cointerventions. Exploring some of this evidence, we evaluated several randomized controlled trials (RCTs). In 1987 a trial was performed [30] that evaluated the efficacy of continuous MPA in the treatment of endometriosis. Medroxyprogesterone acetate (100 mg orally) was compared to danazol at a dosage of 200 mg orally three times a day. A placebo group was included. Fifty-nine participants aged 26 to 38 with mild to moderate endometriosis diagnosed by laparoscopy were included. Twenty-seven percent of the patients had electrocoagulation of endometriotic implants at the initial diagnostic laparoscopy. Nine participants were lost to follow-up. A second-look laparoscopy was performed 6 months after completion of the treatment. The outcome measures included a change in the AFS (American Fertility Society) scores for endometriosis and a change in the reported patient pain symptoms. Medroxyprogesterone acetate was found to significantly reduce pelvic pain when compared with placebo. When compared to danazol, MPA showed no significant difference with regard to improvement in the pelvic pain score at 6-month’s follow-up. With regard to a change in AFS score at the secondlook laparoscopy, MPA did not show a significant improvement when compared with placebo, but there was certainly a trend toward an improvement in AFS score. When MPA was compared to danazol, no difference with regard to the AFS scores was noted. Overton published the results of a double-blind, randomized, multi center study in 1994 looking at the use of cyclical progestagen [31]. Sixty-two British women with minimal to mild endometriosis diagnosed at laparoscopy were followed up. Three intervention groups were created: first, 40 mg dydrogesterone (Duphaston) for 12 days starting 2 days after luteinizing hormone

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(LH) surge, second, 60 mg dydrogesterone given as above, third, placebo given as above. The duration of treatment was 6 months. The outcome measures included a change in AFS score and pain scores. At 12 months, the second-look laparoscopy was performed, 23 patients were lost to follow-up, and the remaining treatment groups were small. Dydrogesterone at a dose of 40 mg was not found to be efficacious in reducing pain as compared with placebo. This also held true for the higher dose of 60 mg. Furthermore, AFS scores were not significantly improved compared to placebo. In 1996, Vercellini performed a randomized trial comparing depot MPA (150 mg every 90 days) and a combination of the combined oral contraceptive pill and danazol (50 mg daily for 21 of 28 days) [32]. The outcome measures included pain scores. This study reported a significant improvement in pain scores from the baseline for both treatments. An increased reduction in dysmenorrhea was seen with the progesterone treatment. On the other hand, progesterinic therapy experienced a higher incidence of bloating and spotting. From the limited data, it would appear that continuous progestagens are no less effective in the treatment of endometriosis-related pain than other medical treatments, such as danazol, which has been shown to be effective [33]. On the other hand some questions about the overall efficacy of progestagens remain unanswered. The only study that used progesterone in a cyclical fashion (luteal phase) did use dydrogesterone, and this did not show significant improvement. From these results it is difficult to conclude whether continuous therapy is more effective than cyclical therapy. It is also interesting to note that the reduction in AFS scores seen at a second laparoscopy was not significant. This highlights the discrepancy between macroscopic disease and symptomatology and questions the validity of performing a second-look laparoscopy in patients treated for endometriosis unless further surgical treatment is warranted. Further research is required to evaluate the use of progestagens in the treatment of pain in patients with endometriosis. Larger RCTs are needed that look specifically at patients with chronic pain. Another area of interest would to investigate the use of progestagen-releasing intrauterine contraceptive devices in the treatment of this disorder. Progestagens and Infertility Treatment Medical treatment for endometriosis-related infertility has been accepted for many years. The concept that suppression of ovulation and resultant hypoestrogenism would result in regression of endometriosis, leading to increasing fecundability after the cessation of the treatment, was widely held. In the late 1980s and 1990s, several randomized trials demonstrated a significant lack of effectiveness for many of the medical treatments, such as danazol, progestagens, and GnRH analogues.

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Telimaa [34] performed an RCT comparing MPA 100 mg/day for 6 months, danazol 600 mg per day, and placebo in cases of endometriosis. Seventeen patients were randomized to MPA treatment, 18 to danazol, and 14 to placebo. The outcome measure was pregnancy and the follow-up was up to 30 months. Some of the patients received cointerventions with surgery and clomiphene. The odds ratio for clinical pregnancy was 0.7 (0.2–2.8) for treatment with MPA compared with placebo and 1.1 (0.2–4.8) comparing danazol to placebo. This trial showed no benefit of using either MPA or danazol over using placebo in treating infertility in cases of endometriosis. Harrison performed a randomized, double-blind, placebo-controlled trial in Ireland [29]. One hundred women were randomized into either 3 months of treatment with MPA 50 mg/day or placebo. The diagnosis was made at diagnostic laparoscopy. Three months after the medical treatment, a second laparoscopy was performed during which surgical treatment was instituted for some patients. The main outcome measures were revised AFS scores, with symptomatic improvement and natural pregnancy forming secondary outcome measures. Of the 100 patients, 10 did not have a follow-up laparoscopy. With regard to rAFS scores, this study did not detect a benefit from using MPA over placebo. Also no significant improvement in pain symptoms was recorded. This may be in part because of the low incidence of pelvic pain in the MPA group at baseline. Overall well being was improved with MPA treatment. Pregnancies were achieved in both groups, with MPA showing no benefit. Further randomized trials compared medical treatments (danazol, GnRH agonist, and gestrinone) with either placebo or no treatment [33– 36]. The odds ratios for clinical pregnancy ranged from 0.6 to 1.1, with neither study showing statistical significance. Several other trials have compared danazol with GnRH agonists and have found neither medication to be more efficacious in achieving clinical pregnancies in cases of endometriosis [37–42]. Combining the results, one has to conclude that medical treatment for infertility in cases of endometriosis confers no notable benefit. No specific medical treatment is more effective than others. Hughes concludes that medical treatments for endometriosis related infertility could not be recommended, as there appears to be a lack of efficacy and as these treatments are associated with a significant period of amenorrhea [43]. Combined Medical and Surgical Treatment Studies have shown the effectiveness of surgical treatment of endometriosisrelated pain. Sutton performed a randomized trail comparing laparoscopic treatment of endometriosis with diagnostic laparoscopy and found a significant decrease in pain reported in the treatment group (62.5% vs 22.6%) [44]. This effect was still detectable at 12 months’ follow-up [45].

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The combination of surgical ablation or excision of endometriosis followed by medical treatment has been investigated. Sixty women with advanced endometriosis were given either danazol, MPA, or placebo [30]. Pain scores were significantly lower in the treatment groups as compared to placebo. A further trial compared 6 months’ postoperative GnRH analogue treatment with placebo in 109 women [46]. The percentage of patients requiring retreatment was lower in the GnRH analogue group (31% vs 57%). On the other hand, this same study found no difference in pain scores. In 1994 Parrazini reported similar findings, again showing no improvement in pain scores when postoperative GnRH agonist treatment was compared with placebo [47]. More recently Regidor reported the findings of a randomized trail comparing the postsurgical use of the GnRH agonist leuprorelin acetate (LAD) with the gestagen lynestrenol (LYN, 5 mg orally) [48]. Both groups were treated for 6 months and contained 26 and 22 patients, respectively. Improvements in dysmenorrhea and dyspareunia were more significant in the LAD group after 6 months of treatment, but significant improvements were noted in both groups. Again the data regarding post-surgical treatment of endometriosis is somewhat difficult to interpret. On balance there certainly may be a benefit to using medical treatment as long as fertility is not desired. Obviously treatment side effects may ultimately decide whether medical treatment is utilised.

RECURRENCE AFTER TREATMENT One of the major difficulties with treatment of endometriosis is recurrence of the disease. Follow-up studies of endometriosis have reported recurrence rates of 40% to 50% up to 4 years after danazol treatment [49], and 33% rates in another study [6]. With this in mind, many authorities would describe medical treatments as only suppressive and not curative. Whether endometriosis is a progressive disorder remains controversial. This leads us to the next dilemma—that of long-term treatment. Many of the side effects related to progestagen and antiprogestagen-only therapy make it difficult to achieve long-term compliance. The combined estrogen-progestagen contraceptive and GnRH agonists with add-back therapy offer the most viable long-term strategies. Antiprogesterones in the Treatment of Endometriosis Gestrinone (ethylnorgestrinone) is an antiprogestional steroid that causes a reduction in serum estradiol and sex hormone-binding globulin levels and

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reduces both estrogen and progesterone receptor concentrations in target tissues [11,12]. Gestrinone can be given at a dose of 5 mg to 10 mg twice weekly and does have some androgenic and antiestrogenic side effects. Gestrinone was compared with danazol in two randomized controlled trials [50,51]. Fedele treated 39 patients with laparoscopic-diagnosed endometriosis with either 2.5 mg of gestrinone twice weekly or danazol 600–800 mg daily. The dosages of both drugs were increased if amenorrhea was not achieved at the low dose. Only 16 patients had a follow-up laparoscopy. The primary endpoint was infertility, but pain was also evaluated. The results of these studies showed no significant difference in improvement in dysmenorrhea or dyspareunia. The AFS scores were similar for both the gestrinone and danazol groups. The main differences observed are restricted to the side effect profile with androgenic side effects such as greasy skin and hirsutism being more common in the gestrinone group, and decreased breast size, muscle cramps, and hunger being more common in the danazol group. Bromham reports the findings of a randomized, double-blind, multicenter study comparing gestrinone 2.5 mg twice weekly for 6 months with danazol 200 mg twice daily for 6 months [51]. Two hundred sixty-nine British women with endometriosis were randomized into the two treatment arms. A follow-up laparoscopy was performed after the treatment. The outcome measures were AFS scores and pain scores during treatment and after 12 months. A large percentage of patients were lost to follow-up. The results of this study also show equivalent efficacy in improvement of dysmenorrhea or dyspareunia when comparing the two treatments. One further study compared gestrinone with the GnRH analogue leuproreline [52]. This randomized double-blind multicenter study included 55 Italian women aged 18 to 40 who had chronic pelvic pain and a laparoscopic diagnosis of endometriosis. The two intervention arms included gestrinone 2.5 mg twice weekly and placebo injections as well as leuproreline intramuscularly 3.75 mg once a month plus placebo tablets. Six patients withdrew from the treatment group, seven were lost to follow-up, and eight patients conceived. The conclusions of this study were that there appeared to be a small benefit with respect to dysmenorrhea when using the GnRH analogue. However by the end of the follow-up, this advantage was now with gestrinone. Both treatment arms showed significant reductions in pain scores from the baseline and appeared to be very similar in effectiveness. The side effect profile was again very similar apart from hot flashes being more significant than in the GnRH analogue group. A further study by Hornstein in 1990 compared two doses of gestrinone (1.25 mg and 2.5 mg twice weekly) [53]. No difference in efficacy was noted with regard to pain scores. The lower dose resulted in fewer side effects. Hence gestrinone appears to be as effective in the medical treatment of endome-

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triosis-related pain as danazol or GnRH analogues [54]. Gestrinone has also been studied in the treatment of endometriosis-related infertility and has not been found to be more effective than placebo or danazol [36,50]. RU486 (Mifepristone) is a synthetic steroid with antiprogesterone and antiglucocorticoid activity [55]. It has been used as an abortifacient and may have applications in the treatment of leiomyoma, breast cancer, and meningioma [56]. As this drug has been shown to inhibit ovulation and disrupt endometrial integrity, it was utilized by Kettel in six normally cycling women to treat endometriosis [55]. RU486 at a dose of 100 mg/day for 3 months resulted in amenorrhea in all patients. After cessation of treatment, regular menstruation resumed in all cases within 3 to 6 weeks. All patients treated with RU486 experienced an improvement in pelvic pain, with only one patient reporting a recurrence over the 12 to 24 months’ follow-up (two patients conceived after treatment). Symptoms such as hot flashes, anorexia, nausea, and fatigue were noted. Kettel performed a further trial using RU486 (50 mg/day) in nine women with endometriosis. Pelvic pain and uterine cramping decreased in all patients [57]. The endometriosis regressed by 55% in the absence of significant side effects. Randomized, controlled placebo trials will be required to further assess the use of RU486 in the treatment of endometriosis. Selective Progesterone Receptor Modulators The term ‘‘selective receptor modulators’’ excites most reproductive endocrinologists. The concept that hormonal receptors exist in more than one form within the same tissue, modulating each other’s actions, has raised the prospect of designing drugs with specific actions and side effect profiles. Selective estrogen receptor modulators, such as tamoxifen and raloxifene, are commonly used in clinical practice. Tamoxifen was used to treat recurrent endometriosis in two patients with good effect [58]. As discussed earlier, two types of progesterone receptors exist in differing concentrations in different tissues. These receptors modulate each other’s actions. Selective progesterone receptor modulators (SPRM) are a new class of progesterone receptor ligands that exhibit both agonistic and antagonistic actions [59]. There exists a spectrum of progesterone receptor ligands with pure agonistic actions such as those of progesterone and with the strongest antagonists being onapristone and ZK230211. Selective progesterone receptor modulators are situated in the middle of the spectrum. Most of the experience of these drugs comes from animal models. The best known SPRMs are J867, J956, J912, and J1042 [59]. They exhibit a high binding affinity for progesterone receptors (PR). It appears that in the absence of progesterone, the SPRMs act as weak progestins. In the presence of progesterone, they have weak progesterone antagonist actions, espe-

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cially in the endometrium. In the pregnant guinea pig model, they have only minimal labor-inducing ability as compared to the strong action of PR antagonists [59]. With regard to other steroid hormone receptors, SPRMs have reduced glucocorticoid receptor-binding affinity when compared to RU486. In vivo, SPRMs show minimal binding to estrogen receptors and, in the rat at high doses, may display a mixed androgenic/antiandrogenic activity [59]. Studies using a monkey model showed the potential of SPRMs to suppress estrogen-dependent endometrial growth and to induce reversible amenorrhea [60]. This suppression appeared to be confined to the endometrium and may prevent the side effects of estrogen deprivation [61]. Breakthrough bleeding commonly seen with progestagen treatment is largely explained by progesterone-induced fragility of the endometrial blood vessels. Selective progesterone receptor modulators seem to have the spiral arterioles as a target and cause stabilization of the endometrial blood vessels [59]. These properties make SPRMs an exciting prospect in the treatment of endometriosis with the potential for effective treatment with an improved side effect profile. Clinical trials of these drugs are needed.

SUMMARY Progestagens have been used in the treatment of endometriosis for several decades. They appear to be effective in improving the pain related to endometriosis and as effective as other medical treatments, such as danazol and GnRH analogues. In the treatment of endometriosis-related infertility, medical therapy with progestagens plays no role. Antiprogestagens, such as gestrinone, also have been shown to be as effective as progestagens. Antiprogesterones such as RU486 and SPRMs need further clinical research before they can be recommended as mainstream medical therapy for endometriosis. The future must lie in the development of medications that effectively treat the pain of endometriosis and increase fertility while exhibiting a favorable side effect profile. PRACTICAL POINTS 

Progestagens can be used for endometriosis-related pain. It is as effective as danazol and GnRHa.  Progestagens have no role for endometriosis-related infertility. REFERENCES 1.

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34. Telimaa S. Danazol and medroxyprogesterone acetate inefficacious in the treatment of infertility in endometriosis. Fertil Steril 1988; 50:872–875. 35. Fedele L, Parazzini F, Radici E, Boccoiolone L, Bianchi S, Bianchi C, Candiani GB. Buserelin acetate versus expectant management in the treatment of infertility associated with minimal or mild endometriosis: a randomized clinical trial. Am J Obstet Gynecol 1992; 166:1345–1350. 36. Thomas E., Cooke I. Successful treatment of asymptomatic endometriosis: Does it benefit infertile women? BMJ 1987; 294:1117–1119. 37. The Nafarelin European Endometriosis Trial Group (NEET)Nafarelin for endometriosis: A large-scale, danazol-controlled trial for efficacy and safety, with 1-year follow-up. Fertil Steril 1992; 57:514–522. 38. Dmowski WP, Tummon I, Pepping P, Radwanska E, Binor Z. Ovarian suppression induced with buserelin or danazol in the management of endometriosis: A randomized comparative study. Fertil Steril 1989; 51:395–400. 39. Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. Buserelin versus danazol in the treatment of endometriosis-associated infertility. Am J Obstet Gynecol 1989; 161:871–876. 40. Fraser IS, Shearman RP, Jansen RPS, Sutherland PD. A comparative treatment trial of endometriosis using the gonadotropin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol. Aust N Z J Obstet Gynaecol 1991; 31:158–163. 41. Henzl M, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobsen J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med 1988; 318:485– 489. 42. Shaw RW. Zoladex Endometriosis Study Team. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Fertil Steril 1992; 58:265–272. 43. Hughes E, Fedorkow D, Collins J, et al. Ovulation suppression for endometriosis (Cochrane Review), Cochrane library, Issue 3, 2002. 44. Sutton CJG, Ewen SP, Whitelaw N, Hanines P. Prospective, randomised, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994; 62:696–700. 45. Sutton CJ, Pooley AS, Ewen SP, Hanines P. Follow-up report on a randomised controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril 1997; 68:1070–1074. 46. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril 1997; 68:860–864. 47. Parazzini F, Fedele L, Busacca M, Falsetti L, Pellegrini S, Venturini PL, Stella M. Postsurgical medical treatment of advanced endometriosis: Results of a randomised clinical trial. Am J Obstet Gynecol 1994; 171:1205–1207. 48. Regidor PA, Regidor M, Schmidt M, Ruwe B, Lubben G, Fortig P, Kienle E, Schindler AE. Prospective randomized study comparing the GnRH-agonist

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13 Gonadotropin Releasing Hormone Agonist and Antagonist for Endometriosis Robert L. Barbieri Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.

CLINICAL BIOLOGY OF GONADOTROPIN RELEASING HORMONE The menstrual cycle is dependent on the integrated action of the hypothalamus, pituitary gland, ovarian follicle, and endometrium. The hypothalamus is a neuroendocrine transducer that integrates neural inputs from the cortex, amygdala, other hypothalamic nuclei, cranial nerves (light), and peripheral endocrine signals and transduces them into an endocrine output of pulsatile gonadotropin releasing hormone (GnRH). Like a metronome, the hypothalamus sets the beat for the menstrual cycle by the pulsatile release of GnRH. Gonadotropin releasing hormone pulses occur every 1 to 1.5 hours in the follicular phase of the cycle and every 2 to 4 hours in the luteal phase of the cycle. Pulsatile GnRH secretion stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The pituitary gland translates the tempo set by the hypothalamus to a signal, LH and FSH secretion, that can be understood by the ovarian follicle. In the ovarian follicle, LH stimulates the thecal cells to produce androstenedione, 219

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and FSH stimulates granulosa cells to convert the androstenedione to estradiol. After ovulation, the follicle is transformed into the corpus luteum that secretes progesterone when stimulated by LH or human chorionic gonadotropin (hCG). Estradiol stimulates the endometrial epithelial cells to proliferate. Estradiol plus progesterone causes the endometrium to become differentiated into a secretory endometrium. During the midluteal phase of the menstrual cycle, when progesterone production is at its peak, the secretory endometrium is optimally prepared for the implantation of a pre-embryo. Native GnRH is a decapeptide with a short half-life of approximately 5 minutes (Fig. 1). The short half-life of GnRH results from the rapid degradation of the peptide by tissue and plasma endopeptidases, which cleave the 6–7 and 9–10 peptide bonds. Gonadotropin releasing hormone is secreted in a pulsatile fashion, and information is contained in the pulse interval and the pulse amplitude. The release of GnRH in neurosecretory bursts and the short half-life of GnRH ensure that each pulse is sharp and crisp. During the follicular phase of the cycle, GnRH pulses are characterized by high frequency, every 60 to 90 minutes, and low amplitude. During the luteal phase of the cycle, GnRH pulses are characterized by low frequency, every 120 to 240 minutes, and high amplitude. In classic experiments on the rhesus monkey, Knobil [1] demonstrated that if the arcuate nucleus is destroyed (loss of GnRH), the pituitary gland can no longer secrete gonadotropins, and amenorrhea ensues. Exogenous administration of hourly pulses of GnRH was demonstrated to restart the system and cause menstrual cycles. If GnRH was administered with abnormally low interpulse intervals, normal menstrual cycles were not re-established. These

FIGURE 1 The native decapeptide, GnRH, is secreted in pulses and the interpulse interval is much greater than the half-life of GnRH. This ensures that each pulse is clear and crisp. The short half-life of GnRH is caused by degradation of the peptide bonds 6–7 and 5–6 by endopeptidases.

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studies demonstrate the primacy of GnRH in regulating menstrual cycles in the primate. Early investigators hypothesized that if GnRH was given as a continuous infusion, superovulation could be achieved. Surprisingly, continuous infusion of GnRH resulted in the cessation of gonadotropin secretion and amenorrhea. The basis for this effect is that continuous stimulation of the GnRH receptor causes both downregulation and desensitization of the receptor resulting in the paradoxical suppression of LH and FSH secretion. This unexpected finding has been exploited by the creation of GnRH agonist analogues, which paradoxically initially stimulate LH and FSH secretion, but with prolonged administration (5 to 10 days) profoundly suppresses LH and FSH secretion. PHARMACOLOGY OF GNRH AGONISTS GnRH agonists are analogues of the native decapeptide with chemical changes in amino acids 6 and 10 (Table 1). The introduction of D-amino acids at position 6 of native GnRH results in analogues that are resistant to degradation by endopeptidases and have long half-lives, and high affinity for the pituitary GnRH receptor [2]. Paradoxically, initial treatment with a GnRH analogue stimulates pituitary secretion of LH and FSH, but prolonged treatment suppresses both LH and FSH secretion. The paradoxical suppression of LH and FSH observed with chronic GnRH agonist treatment is due to both downregulation and desensitization of the pituitary GnRH receptor. With GnRH agonist analogues, suppression of LH is greater than suppression of FSH. In turn, the decrease in LH and FSH secretion results in the suppression of ovarian follicular growth and ovulation resulting in low levels of circulating estradiol and progesterone secretion. In women chroni-

TABLE 1 Amino Acid Substitutions in Commonly Used GnRH Agonist Analogues GnRH agonist Leuprolide Nafarelin Goserelin Buserelin Histrelin Decapeptyl

Amino acid substitution D-Leu6-Pro9 D-Na1(2)6 D-Ser(tBu)6, (Aza-Gly-NH)10 D-Ser(tBu)6, Pro9 Imbzl-D-His6-Pro9 D-Trp6

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cally treated with standard doses of parenteral GnRH agonists, the circulating estradiol concentration is in the range of menopausal women, approximately 15 pg/mL. THE CENTRAL DOGMA OF ENDOCRINE TREATMENT OF ENDOMETRIOSIS The central dogma that guides the hormonal therapy of endometriosis is the idea that sex steroid hormones, such as estrogen, progesterone, and androgen, are major regulators of the growth and function of the endometrium and endometriosis lesions. Both laboratory and clinical findings support this central dogma. Endometriosis lesions contain estradiol, progesterone, and androgen receptors and these sex steroids regulate cell function in both eutopic endometrium and endometriosis lesions. Using an immunohistochemistry technique, Bergqvist and colleagues [3] demonstrated that all eutopic endometrium and endometriosis lesions contained both estradiol and progesterone receptors. In endometriosis lesions, the concentration of estrogen and progesterone receptors tend to be approximately 50% to 70% lower than those observed in matched specimens of endometrium. Androgen receptors are present in similar concentrations in endometriosis lesions and matched endometrial specimens. Many laboratory findings support the central dogma that sex steroids regulate function of ectopic endometrial tissue. Bergqvist and colleagues [4] implanted human endometriosis lesions in the abdominal wall of nude mice. In a hypoestrogenic state, the implanted human endometriosis lesions atrophied. If estradiol was given to the mice, the endometriosis implants grew and retained their histological appearance. Sharpe and colleagues [5] autotransplanted rat endometrium to the intestinal mesentery. In animals with intact ovarian function, the autotransplanted endometrium grew into cystic structures lined with endometrial epithelium. In castrated animals, these lesions underwent regression. If either estradiol or progesterone was administered to castrated animals, the experimental endometriosis lesions continued to grow. The administration of estradiol plus progesterone was additive in supporting the growth of the transplanted endometrium compared to either hormone individually. Clinical observations that support the central dogma include: (1) endometriosis lesions rarely occur prior to menarche, (2) menopause, either surgical or natural, usually produces regression of endometriosis lesions, and (3) new cases of endometriosis occur very rarely after menopause unless estrogen is administered. Many investigators have reported the benefits of creating a hypoestrogenic effect resulting in a surgical menopause with bilateral salpingo-oophorectomy [6–8]. Interestingly, after bilateral salpingo-

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oophorectomy, replacement therapy with low-dose estrogen does not appear to be associated with recurrence of the disease. In contrast to estrogen, much less data are available concerning the effects of androgens on endometriosis lesions. Androgens are antiestrogenic in the endometrium and tend to cause atrophy of both eutopic endometrium and endometriosis lesions. The administration of the androgens testosterone proprionate, methyltestosterone, or danazol to women with endometriosis produces atrophy of both the eutopic endometrium and the endometriosis lesions [9,10]. Both low doses of danazol and methyltestosterone can cause regression of endometriosis lesions and atrophy of eutopic endometrium even without interrupting ovulation. This suggests that androgens can produce regression of endometriosis lesions in the presence of relatively normal concentrations of both estradiol and progesterone. Unfortunately, androgens are associated with significant side effects including weight gain from an increase in muscle mass, deepening of the voice, and adverse changes in lipids and liver function tests. Some synthetic progestins are derivatives of the androgen ethinyl testosterone. At high doses, these synthetic progestins have both progestational and androgenic effects, which can be effective in the treatment of endometriosis by suppressing LH and FSH secretion, estradiol secretion, and by a direct antiestrogenic effect in the endometrium and endometriosis lesions. At high doses, C-21 progestins also appear to be effective in the treatment of endometriosis [11]. These progestins probably act as antiestrogens directly in the endometrium by blocking the synthesis and action of the estrogen receptor. In addition, they may suppress LH and FSH, thereby reducing ovarian estrogen synthesis. In the most simplified terms, estrogen and physiological concentrations of progesterone support growth of endometriosis lesions. Androgens and pharmacological concentrations of androgenic progestins cause atrophy in endometriosis lesions. The polarity of the response of endometriosis lesions to androgens and estrogens is the ‘‘yin and yang’’ upon which most hormone therapy of endometriosis is based (Table 2). Gonadotropin releasing hormone agonists, such as leuprolide, nafarelin, and goserelin, are effective in the treatment of endometriosis because they produce low circulating concentrations of estradiol and progesterone.

PRESENTING PROBLEMS FOR WOMEN WITH ENDOMETRIOSIS Women with endometriosis typically present for treatment with one of three problems: (1) an adnexal mass (endometrioma), (2) infertility, or (3) pelvic pain. For women with an adnexal mass resulting from endometriosis, surgery

Danazol Methyltestosterone

Medroxyprogesterone Norethindrone Gestrinone

Hyperandrogenism

Synthetic Progestins

From Refs. 9 and 14.

Oophorectomy GnRH analogues

Hypoestrogenism

Methods available to produce hormonal state 80%

75%

85%

45%

50%

68%

Danazol 200 mg bid (Barbieri 1981)

Medroxyprogesterone acetate, 30 to 50 mg daily (Luciano 1988)

Nafarelin 200 Ag bid (Henzl 1988)

Typical regimen

Percent of patients with improvement in pain symptoms

Percent reduction in AFS endometriosis score

Steroid Hormone Manipulations Effective in the Treatment of Endometriosis

Hormonal state

TABLE 2

Vasomotor symptoms, bone loss, headache, dry vagina, decreased libido Increased body muscle mass, weight gain, hirsutism, oily skin, deepening of the voice Moliminal symptoms, bloating, mood changes, irregular uterine bleeding

Side effects

224 Barbieri

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is indicated to remove the mass [12]. Endometriomas are monoclonal tumors that arise from a somatic mutation in the DNA of a precursor cell. Monoclonal tumors are not likely to regress spontaneously. Surgery also allows for definitive determination of the histology of the adnexal mass, ensuring that cancer is not present. The approach to the treatment of infertility in women with endometriosis is dealt with in Chapters 9, 17, and 18. The remainder of this review will focus on the treatment of pelvic pain caused by endometriosis. GNRH AGONISTS FOR THE TREATMENT OF ENDOMETRIOSIS: THE KEY CLINICAL TRIALS Estrogen-dependent diseases often regress when estrogen production is reduced. Endometriosis is an estrogen-responsive disease, and the pelvic pain associated with it improves when estrogen production is reduced with bilateral oophorectomy or GnRH agonist treatment. Gonadotropin releasing hormone agonist treatment is the most reliable, widely available, nonsurgical method for suppressing ovarian estrogen production. Multiple clinical trials demonstrate that GnRH agonists: (1) suppress circulating estradiol concentration by suppressing pituitary secretion of LH and FSH, (2) reduce endometriosis disease activity as objectively measured by pretreatment and posttreatment surgical staging, and (3) decrease pelvic pain caused by endometriosis lesions. The GnRH agonists are the ‘‘gold standard’’ medical treatment of pelvic pain caused by endometriosis against which all other hormonal treatments are measured. In one randomized, placebo-controlled clinical trial, women with surgically proven endometriosis and pelvic pain were randomized to receive leuprolide acetate 3.75 mg IM every 4 weeks or a placebo injection every 4 weeks for 6 months. Of the women treated with leuprolide acetate, 85% reported a significant decrease in dysmenorrhea, pelvic pain, and dyspareunia. Of the women treated with placebo, 95% left the clinical trial because of continuing pelvic pain. Of the women treated with leuprolide, 82% completed the clinical trial. Women in the leuprolide group reported side effects such as vasomotor symptoms, headaches, and decreased libido [13]. In another clinical trial, Henzl and colleagues randomized women with endometriosis to one of two doses of nasal nafarelin (400 Ag or 800 Ag daily) or danazol (800 mg daily) [14]. Drug therapy was continued for 6 months. More than 80% of the patients treated with either dose of nafarelin or danazol had symptomatic relief of their pelvic pain and objective improvement of their endometriosis lesions as documented by pre-and posttreatment surgical staging. Nafarelin and danazol were observed to be similar in their efficacy. However the side effects of the two drugs differed greatly. The women receiving danazol reported weight gain, edema, and myalgia and had increased

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circulating levels of serum aspartate aminotransferase and alanine aminotransferase and decreased levels of high-density lipoprotein cholesterol. In contrast, the principle side effects reported by women receiving nafarelin were hot flashes, decreased libido, and vaginal dryness. The women treated with nafarelin did not have notable decreases in high-density lipoprotein cholesterol or increases in serum aspartate aminotransferase and alanine aminotransferase. Bone density was not measured in this clinical trial. Many other clinical trials support the conclusion that GnRH agonists have similar efficacy to danazol in the treatment of pelvic pain caused by endometriosis, but the side effect profiles differ greatly between the two classes of hormone [15–19]. An important question that remains to be completely answered is, ‘‘What precise estradiol concentration is required to suppress the activity of endometriosis lesions?’’ A review of multiple studies suggest that GnRH agonist regimens that suppress estradiol concentrations to either 15 pg/ml or 30 pg/ml are both effective in the treatment of endometriosis (Table 3). However, suppressing estradiol to 15 pg/ml is associated with more symptoms of hypoestrogenism, such as vasomotor symptoms and increased bone loss. These observations form the basis for ‘‘add-back’’ regimens that contain estrogen.

GNRH AGONISTS PLUS STEROID ADD-BACK FOR THE TREATMENT OF ENDOMETRIOSIS An important concept in gynecology is that tissues vary in their sensitivity to estradiol. At very low estradiol concentrations (5 to 15 pg/ml), many estrogen responsive tissues are in a quiescent or atrophic state (e.g., the endometrium). In some tissues, an estradiol concentration in the range of 20 to 60 pg/ml will induce a significant tissue response (suppression of urinary calcium excretion, suppression of osteoclasts activity, suppression of vasomotor symptoms) [20– 22]. In other tissues, the estradiol concentration must be more than 80 pg/ml to induce a significant tissue response (stimulation of liver production of lipoproteins). The hierarchy of tissue response to various estradiol concentration is presented in Figure 2. In a manner that parallels the estradiol doseresponse relationships in normal tissues, different disease processes display different responsiveness to estradiol. For example, some breast cancer cell lines may be stimulated by estradiol concentrations as low as 1 to 10 pg/ml. Fibroids are stimulated by estradiol concentrations in the range of 15 to 25 pg/ ml. In contrast to breast cancer and fibroids, endometriosis lesions appear to require estradiol concentrations in the range of 20 to 40 pg/ml to begin to grow [23,24]. These considerations suggest that in the treatment of endometriosis, it is possible to find an estradiol target, in the range of 20 to 40 pg/ml,

Acetate leuprolide Goserelin

Nafarelin

Nafarelin

Buserelin

GnRH agonist 300 ug intranasal 3 times per day 200 Ag nasal spray bid 400 Ag nasal spray bid 3.75 mg depot IM every 4 weeks 3.6 mg implant for 6 months

Dose

15 13

40

15

28

28

Estradiol concentration (pg/ml)

52

79

77

40

Number of subjects studied

Low

Low

Moderate

High

High

Variability of patient response to treatment

Reference

Shaw 1990

Dlugi 1990

Henzl 1988

Henzl 1988

Cirkel 1986

TABLE 3 Effects of Gonadotropin Releasing Hormone Agonists on Serum Estradiol Concentration in Women with Endometriosis

GnRH Agonist and Antagonist 227

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FIGURE 2 Estrogen dose-response hierarchy. Normal tissues vary in their sensitivity to estradiol stimulation. Menopause is associated with an estradiol concentration in the range of 5 to 20 pg/ml. Vasomotor symptoms are significantly suppressed by estradiol in the range of 30 pg/ml. Bone metabolism begins to respond to estrogen stimulation at low concentrations of estradiol (30 to 60 pg/ml). Estrogen stimulation of the synthesis of liver proteins, such as thyroxine-binding globulins, may require estradiol concentrations greater than 80 pg/ml. Estrogendependent disease processes also vary in their sensitivity to estradiol. Breast cancer cells may be stimulated to grow at estradiol concentration in the range of 1 to 10 pg/ml. Endometriosis lesions may require estradiol concentrations in the range of 20 to 40 pg/ml to grow. From Ref. 26.

that provides the best balance of treatment of endometriosis lesions while at the same time reducing hypoestrogenic side effects, such as vasomotor symptoms and bone loss [25–27]. In a seminal study, women with endometriosis and pelvic pain were randomized to receive either a GnRH agonist alone or a GnRH agonist plus low-dose estradiol (transdermal estradiol 25 Ag per day) plus low-dose

GnRH Agonist and Antagonist

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progestin (oral medroxyprogesterone acetate 2.5 mg daily) [28]. The women who received the GnRH agonist alone had a circulating estradiol of approximately 15 pg/ml. The women who received the GnRH agonist plus the estrogen-progestin add-back had circulating estradiol levels of approximately 25 pg/ml. All the women underwent pretreatment and posttreatment surgical staging and bone density measurement. In both groups there was an equivalent reduction in pelvic pain symptom scores. In addition there was an equivalent reduction in endometriosis lesion activity as determined by surgical staging. The women who received the GnRH agonist alone reported more vasomotor symptoms and greater bone loss as measured by dual energy x-ray absorptiometry of the spine. This study suggests that an optimal balance of control of symptoms and disease activity versus induction of hypoestrogenic side effects can be achieved by administering a parenteral GnRH agonist plus steroid hormone add-back. Numerous clinical trials have demonstrated that add-back is a valid clinical treatment strategy [29]. Many trials have extended the concept to explore the relative efficacy of estrogen-progestin versus progestin-only addback and different doses of estrogen. For example, Hornstein and colleagues randomized women with pelvic pain and endometriosis to one of four treatment groups: (1) GnRH agonist alone (leuprolide acetate depot 3.75 mg IM every 4 weeks), (2) GnRH agonist plus progestin-only (norethindrone acetate 5 mg orally daily), (3) GnRH agonist plus low-dose estrogen (conjugated equine estrogen 0.625 mg orally daily) plus progestin (norethindrone acetate 5 mg orally daily), or (4) highdose estrogen (conjugated equine estrogen 1.25 mg orally daily) plus norethindrone acetate 5 mg orally daily [30]. Treatment was planned to continue for 1 year. The study demonstrated that add-back with high-dose estrogen was not as effective as add-back with low-dose estrogen. This conclusion was based on the observation that the group receiving GnRH agonist plus highdose estrogen had a significantly higher rate of treatment discontinuation due to pelvic pain than did any of the other treatment groups. The high-dose estrogen add-back probably stimulated the continued functioning and growth of the endometriosis implants. Consequently GnRH agonist plus high-dose estrogen add back is not recommended as a primary treatment option. The women in the other three groups had a similar decrease in their pelvic pain. Bone density decreased significantly in the women who received the GnRH agonist alone. Bone density was preserved in both the group that received low-dose estrogen plus progestin add-back and the group that received progestin only add-back (Fig. 3). Vasomotor symptoms were significantly reduced in the groups that received the steroid add-back. In longterm follow-up, at 12 and 24 months posttreatment, women in all treatment groups continued to have symptom scores that were below baseline for at least 8 months after completion of active therapy [31].

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FIGURE 3 Effects of GnRH agonist on bone density in women with endometriosis and pelvic pain, who were treated with the GnRH agonist leuprolide depot for 52 weeks. Group A received GnRH agonist plus placebo pills. Group B received GnRH agonist plus norethindrone acetate 5 mg daily. Group C received GnRH agonist plus conjugated estrogen (0.625 mg) plus norethindrone (5 mg). Group D received GnRH agonist plus conjugated estrogen (1.25 mg) plus norethindrone (5 mg). No significant bone density loss occurred in the groups that received the GnRH agonist plus low dose steroid add-back. From Ref. 30.

This study and many others demonstrate that the optimal long-term treatment of pelvic pain caused by endometriosis may involve the use of GnRH agonists to suppress ovarian estrogen and progesterone production followed by the add-back low doses of estrogen plus progestin or progestin only [32,33]. Recent studies have suggested that GnRH agonist plus steroid add-back is clinically effective and safe for long-term use. For example, in one study women with pelvic pain and endometriosis were treated with a GnRH agonist plus estrogen-progestin add-back for up to a mean of 31 months. Pelvic pain was markedly reduced, compared to baseline, throughout the course of treatment. Bone mineral density was stable for the entire add-back treatment period [34]. Table 4 lists three add-back regimens that have been demonstrated to be effective in combination with a GnRH agonist for the treatment of pelvic pain caused by endometriosis.

GNRH AGONISTS: DOSE TITRATION In the treatment of pelvic pain caused by endometriosis, suppression of estrogen production reliably produces pain relief. However, low estrogen levels

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231

TABLE 4

GnRH Agonist Treatment Combined with Low-Dose Steroid ‘‘AddBack’’ Hormone Regimens Low-dose steroid hormone regimen Transdermal estradiol patch 25 Ag/day, plus medroxyprogesterone acetate 2.5 mg daily

Norethindrone acetate 5 mg/day

Conjugated equine estrogen 0.625 mg/day, norethindrone acetate 5 mg/day

Comments This regimen does not completely prevent bone loss. The estradiol concentration achieved is in the range of 30 pg/ml. This is a very high dose of progestin. This dose of progestin is associated with a decrease in HDL-cholesterol This regimen prevents bone loss and markedly reduces the vasomotor symptoms reported. Pain relief was excellent

Investigator Howell 1995

Hornstein 1997

Hornstein 1997

are associated with significant side effects, such as vasomotor symptoms and bone loss. One approach to this problem is to prescribe a GnRH agonist to suppress estrogen secretion and then add-back low doses of estrogen-progestin or progestin only. An alternative approach is to decrease the dose of GnRH agonist to reduce the magnitude of suppression of LH and FSH and allow some ovarian estrogen secretion. One method for decreasing the dose of the GnRH agonist is to initiate therapy with a standard dose of a daily GnRH agonist, such as nafarelin at a dose of 200 Ag bid. After 1 or 3 months, suppression of ovarian estrogen secretion and amenorrhea will have been achieved and pelvic pain should be improved. At that time, the dose of nafarelin can be decreased to two nasal sprays on the even calendar days and one nasal spray on the odd calendar days of the month. This will reduce the dose of GnRH agonist by about 25%. With this regimen, many women will note a decrease in vasomotor symptoms and continued amenorrhea and pelvic pain relief. If the patient remains amenorrheic on this dose, a small number of women can decrease the dose to nafarelin 200 Ag once daily. If menses or pain recurs, the dose can be increased to achieve more complete suppression of pituitary LH and FSH secretion, and in turn, ovarian estrogen secretion [35–37]. An alternative approach is to increase the time interval between depot injections of a GnRH agonist. For example, Tse and colleagues randomized

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women with endometriosis and pelvic pain to triptorelin depot 3.75 mg IM every 4 weeks (standard therapy) or every 6 weeks (extended interval dosing) [38]. Women in both groups had similar improvement in pelvic pain. The extended interval dosing is also less expensive than the standard interval dosing. Body mass index is probably an important variable in predicting whether dose reduction or extended interval dosing will be effective. Women with body mass index (BMI) greater than 30 kg/m2 are less likely to achieve amenorrhea with reduced doses of GnRH agonists. Women with a BMI less than 25 kg/m2 who also exercise intensively are the most likely to reliably respond to reduced doses of GnRH agonist.

GNRH AGONIST ANALOGUES VERSUS THE ORAL CONTRACEPTIVE IN THE TREATMENT OF ENDOMETRIOSIS In 1959, Kistner, working at the Boston Free Hospital for Women (now the Brigham and Women’s Hospital) reported that the combination estrogenprogestin birth control pill, when used in a continuous (pseudopregnancy) fashion, was effective in the treatment of pelvic pain endometriosis [39]. Many clinicians have noted that some women with endometriosis and pelvic pain have improvement in their dysmenorrhea and pelvic pain when treated with combination estrogen-progestin pills. However, few randomized clinical trials have been completed that use oral contraceptives for the treatment of endometriosis. One randomized clinical trial compared the effects of continuous (pseudopregnancy) combination estrogen progestin oral contraceptive versus danazol in the treatment of pelvic pain caused by endometriosis [40]. The oral contraceptive regimen resulted in symptomatic improvement in 30% of the women. Danazol treatment resulted in symptomatic improvement in 86% of the women. Improvement in physical examination findings was demonstrated in 84% of the women treated with danazol and 18% of the women treated with continuous oral contraceptive. In this study, danazol was demonstrated to be superior to the oral contraceptive in the treatment of pain caused by endometriosis. In another randomized trial, an oral contraceptive was compared to a GnRH agonist in the treatment of pelvic pain caused by endometriosis. In this trial, the oral contraceptive and the GnRH agonist were not directly compared for their efficacy in relieving dysmenorrhea, because it was assumed that the GnRH agonist would be more effective in relieving dysmenorrhea. However, the GnRH agonist was superior to the oral contraceptive in the treatment of dyspareunia. A weakness of this study is that laparoscopy was not performed to assess the response of the endometriosis lesions to the hormonal treatment [41].

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233

In a recent clinical trial, women with endometriosis were treated with a GnRH agonist (3.75 mg leuprolide acetate depot) or a GnRH agonist plus a low-dose oral estrogen-progestin contraceptive(20 Ag ethinyl estradiol plus 0.15 mg desogestrel orally for 21 days every 4 weeks). The addition of the lowdose contraceptive reduced the efficacy of the GnRH agonist in the treatment of endometriosis [42]. Pre-and posttherapy surgical staging of the endometriosis lesions demonstrated that the GnRH agonist plus oral contraceptive treatment resulted in a 32% decrease (improvement) in the surgical staging score. In contrast, the GnRH agonist alone produced a superior, 76% decrease (improvement) in the surgical staging score. Both treatment regimens produced a similar improvement in dysmenorrhea. However, the GnRH agonist produced better relief of dyspareunia than the combination GnRH agonist plus oral contraceptives. These randomized studies suggest that oral contraceptives are probably not as effective as GnRH agonists or danazol in the treatment of pelvic pain caused by endometriosis. However, given the low cost of oral contraceptives, most clinicians treat women with pelvic pain with up to 3 months of oral contraceptives, either in a cyclic or pseudopregnancy manner before initiating treatment with a GnRH agonist or performing a laparoscopy. If oral contraceptive treatment is associated with a significant improvement in pain, the treatment can be continued for 6 to 12 months. If the patient has minimal improvement in pain, she is usually offered laparoscopy to definitively diagnose the cause of her chronic pelvic pain, or she is treated empirically with a GnRH agonist analogue based on a clinical diagnosis of endometriosis. It is important for the clinician to abandon oral contraceptive therapy if it is not effective in the treatment of pelvic pain. GNRH AGONISTS VERSUS PROGESTINS FOR THE TREATMENT OF PELVIC PAIN Prospective randomized clinical trials have suggested that GnRH agonists are boht superior to progestin treatment of pelvic pain caused by endometriosis and that the two therapies are similar in their efficacy. The reasons for the discrepancies are not clear. In one randomized clinical trial, women with surgically treated endometriosis and pelvic pain were randomized postoperatively to leuprolide acetate 3.75 mg IM every 4 weeks or lynestrenol, 5 mg orally twice daily for 6 months [43]. After 6 months of hormone treatment, the women underwent laparoscopy to measure the extent of the disease. The women treated with leuprolide had significantly better pain relief than the women treated with lynestrenol. In addition, at second look laparoscopy, the women treated with leuprolide had significantly more resolution of endometriosis lesions than the

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women treated with lynestrenol. This study indicates that the GnRH agonist, leuprolide, is superior to the progestin, lynestrenol, for the treatment of endometriosis.

GNRH AGONISTS AS A SURGICAL ADJUVANT FOR THE TREATMENT OF ENDOMETRIOSIS Winkel and Bray [44] reported the results of a 24 month follow-up of 240 women with endometriosis and pelvic pain who had three different therapeutic interventions: (1) excision of lesions with the Nd:YAG laser, (2) laser ablation alone, or (3) laser ablation plus postoperative leuprolide treatment for 3 to 6 months. This was not a randomized trial. Ninety six percent and 69% of the women who had surgical excision of the lesions were pain-free at 12 and 24 months of follow-up, respectively. Sixty nine percent and 23% of the women who had laser ablation alone were pain-free at 12 and 24 months of follow-up, respectively. Ninety one percent and 70% of the women who had laser ablation plus postoperative leuprolide acetate were pain-free at 12 and 24 months of follow-up, respectively. These observations support the idea that surgical excision of endometriosis lesions is superior to ablation. In addition these data suggest that surgical ablation plus postoperative treatment with a GnRH agonist is as effective as the complete surgical excision of all lesions. Surgical ablation of lesions is technically easier to accomplish for the average gynecologic surgeon. These data suggest that for the average gynecologic surgeon who is most comfortable with ablation techniques, the use of postoperative GnRH agonist therapy can enhance the efficacy of the surgical procedure. Hornstein and colleagues have also reported that postoperative treatment with a GnRH agonist enhances the efficacy of surgical treatment of pelvic pain caused by endometriosis [45]. Other investigators have reported that postoperative treatment with a GnRH agonist for only 3 months did not result in long-term improvement in pelvic pain compared to postoperative expectant management [46]. Taken together, these studies suggest that for a postoperative GnRH agonist to be effective, it may need to be given for longer than 3 months.

GNRH AGONISTS: EMPIRICAL TREATMENT OF PELVIC PAIN Most authorities believe that the best approach to the evaluation and treatment of chronic pelvic pain that has not responded adequately to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives is to perform a laparoscopy. Conceptually, laparoscopy has the advant-

GnRH Agonist and Antagonist

235

age of providing a definitive diagnosis of the disease causing the pain and an opportunity to surgically treat the disease causing the pain. However, evidence suggests that laparoscopy often fails to identify cases of endometriosis caused by atypical and subperitoneal disease, and surgical treatment of visualized endometriosis is often suboptimal. An alternative approach to the treatment of chronic pelvic pain is to consider making a clinical diagnosis of endometriosis based on history, physical examination, and noninvasive laboratory testing [47,48]. Once a clinical diagnosis of endometriosis is made, treatment with a GnRH agonist could be initiated without the need for a laparoscopy after NSAIDs and oral contraceptive treatment have failed to treat the pain [49]. In a high quality, randomized, placebo-controlled trial, Ling and colleagues demonstrated the efficacy of this treatment algorithm [50]. The investigators randomized 100 women with chronic pelvic pain who had not had adequate relief of their pain with NSAIDs and doxycycline to receive either depot leuprolide acetate 3.75 mg IM every 4 weeks for 12 weeks or a placebo injection every 4 weeks for 12 weeks. At the completion of the 3month treatment regimen, all the women had a laparoscopy with videotaping of the findings and review of the videotapes by a single investigator. The study was completed by 49 women in the leuprolide group and 45 women in the placebo group. At the laparoscopy at the completion of the study, 78 of 95 women (82%) were demonstrated to have endometriosis lesions. This demonstrates the high frequency of endometriosis in women with chronic pelvic pain. The women treated with depot leuprolide had significantly more improvement in self-reported dysmenorrhea, pelvic pain, and dyspareunia than the women treated with placebo. The women treated with depot leuprolide had significantly more improvement in pelvic tenderness and pelvic induration than the women treated with placebo. Ling and colleagues emphasize that an extensive but non invasive pretreatment diagnostic workup, followed by the initiation of a treatment plan based on the test results, is important. The workup includes history, physical examination, pelvic ultrasound, complete blood count, urinalysis, and endocervical cultures for gonococci and Chlamydia organisms. Critical to the effectiveness of the protocol is the history of moderate to severe chronic pelvic pain unrelated to menstruation, lasting for at least 6 months and nonresponsive to nonsteroidal anti-inflammatory drugs or oral contraceptives. Gynecological causes of chronic pelvic pain such as pelvic inflammatory disease, leiomyomata uteri, and ovarian cysts should be have been identified by medical history, physical examination, and pelvic ultrasound. Health maintenance organizations that have implanted clinical protocols that use primary empiric hormonal treatment of pelvic pain have noted

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reduced resource utilization compared with protocols that use a primary surgical approach to the diagnosis and treatment of pelvic pain [51]. GNRH ANTAGONISTS: THE FUTURE OF ENDOMETRIOSIS TREATMENT Gonadotropin releasing hormone agonist analogues have one serious problem; when first administered, they cause an increase in LH and FSH secretion and an increase in estradiol production. For women with pelvic pain, the increase in ovarian estrogen production is associated with increased pelvic pain and decreased quality of life [52]. However, the agonist phase is typically limited to the first 5 to 10 days of treatment. The GnRH antagonist analogues may be superior to GnRH agonists because they produce immediate suppression of LH and FSH secretion and avoid the agonist phase of GnRH agonist therapy. The GnRH analogues that possess antagonist properties can be generated by substitution of D-amino acids for native L-amino acids at positions 1, 2, and 3 (Table 5). The main mechanism of action of the GnRH antagonists is competitive receptor occupancy, which results in the blockade of GnRH receptor dimerization, a biochemical process that is required for receptor activation. Native GnRH elicits a gonadotrope response when only 1% to 10% of gonadotrope GnRH receptors are occupied. Consequently, an effective GnRH antagonist must possess high affinity for the receptor, have a prolonged duration of action, and be given in doses large enough to block almost all the pituitary GnRH receptors. A major challenge to the development of GnRH antagonists for general medical use is the cost inherent to manufacturing and administering large quantities of complex synthetic peptides. In addition, first generation GnRH antagonists were associated with histamine release from eosinophils, causing local skin reactions and in some cases systemic anaphylaxis [53]. Significant progress has been made in developing efficient processes for large scale peptide synthesis and GnRH antagonists with low allergic properties have been developed. In preliminary research studies, GnRH antagonists have been demonstrated to be effective in the treatment of endometriosis [54], uterine leiomyomata [55], premenstrual syndrome, polycystic ovary syndrome [56], ovulation induction for in vitro fertilization (IVF), and prostate cancer [57]. Gonadotropin rereasing hormone antagonists are currently approved and widely used to block premature LH surges during ovarian hyperstimulation for IVF. In many centers, GnRH antagonists are replacing GnRH agonists to block premature LH surges. In IVF, a major problem with the GnRH agonist analogues is that LH secretion is stimulated at the initiation of treatment. In some women, prolonged daily use of a GnRH agonist may

His D-Phe D-Phe D-Phe D-Phe

D-Nal D-Nal D-Nal D-Nal

2

pGlu

1

D-Pal D-Pal D-Pal D-Pal

Trp

3

Ser Ser Ser Ser

Ser

4

Tyr Tyr D-Glu Phe

Tyr

5

D-Cit D-hArg D-Glu D-hCit

Gly

6

Leu Leu Leu Leu

Leu

7

8

Arg hArg Arg Lys(iPr)

Arg

Amino Acid Composition of Native GnRH and Third Generation GnRH Antagonists

Pro Pro Pro Pro

Pro

9

D-Ala D-Ala D-Ala D-Ala

Gly-NH2

10

All the Antagonists Have Amino Acid Substitutions at Positions, 1, 2, 3, 6, and 10. In Contrast, the GnRH Agonists Typically Have Substitutions at Positions 6 and 10

GnRH Analogue Cetrorelix Ganirelix Nal-Glu Abarelix

Amino acid position

TABLE 5

GnRH Agonist and Antagonist 237

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cause a small increase in LH secretion directly after the daily administration of the GnRH agonist. In turn, residual pituitary LH secretion stimulates ovarian androgen production, which may have detrimental effects on follicular development and endometrial function [58]. The GnRH antagonists offer the possibility of acutely suppressing LH secretion without an initial increase in LH secretion [59,60]. The GnRH antagonists have been used either as small daily doses (cetrorelix 0.25 mg daily subcutaneous injection) during the early or midfollicular phases of the stimulation cycle [61], or as a single dose (cetrorelix 3 mg subcutaneous) on approximately cycle day 8 [62]. Both regimens block the occurrence of spontaneous LH surges. The GnRH antagonists suppress LH secretion in a dose-dependent manner. At small doses, the suppression of LH is minimal. At large doses, near-complete suppression of LH can be achieved. In one study, the impact of six doses of the GnRH antagonist ganirelix on LH secretion and IVF outcomes was studied [63]. Ganirelix produced a dose-dependent suppression of LH. Ganirelix also produced a dose-dependent suppression of both androstenedione and estradiol. The larger doses of ganirelix were associated with a markedly reduced pregnancy rate. These data support the importance of both FSH and LH in the development of the ovarian follicle. Ovarian estradiol production requires the coordinated action of LH on the ovarian theca to stimulate the production of androstenedione and FSH on the granulosa cells to stimulate the aromatization of the androstenedione to estrogen. Large doses of GnRH antagonists can nearly ablate LH secretion, resulting in a reduction in follicular androstenedione and estradiol production. When LH secretion is completely blocked, pregnancy rates appear to be reduced. These findings support the hypothesis that both high LH levels (premature LH surge) and very low LH levels can be associated with low pregnancy rates in IVF-embryo transfer. The GnRH antagonists, because of their rapid onset of action and quick reversibility offer the opportunity to precisely target LH and FSH levels during ovarian stimulation for IVF-ET. It is likely that in the near future, GnRH antagonists will be approved for the treatment of prostate cancer. However, as of the date of writing this chapter, no GnRH antagonist has been approved for the treatment of endometriosis. In one preliminary study, women with endometriosis and pelvic pain were treated with the GnRH antagonist, cetrorelix 3 mg subcutaneous injection once weekly [64]. With cetrorelix treatment, circulating estradiol was suppressed to a mean of 50 pg/ml. Pelvic pain decreased and endometriosis lesions regressed as demonstrated by pre-and posttreatment surgical staging. Another GnRH antagonist, abarelix, has been demonstrated to be effective in the treatment of pelvic pain caused by endometriosis [54]. However, side effects may have slowed the progress of the development of this antagonist for treatment of endometriosis.

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SUMMARY The GnRH agonist analogues are the most reliable hormonal method of suppressing ovarian estrogen production. In turn, suppression of ovarian estrogen production is the most reliable method for improving the pelvic pain associated with endometriosis. Chronic suppression of ovarian estrogen production is associated with adverse side effects, such as vasomotor symptoms and accelerated bone loss. Low-dose steroid add-back has been demonstrated to avoid the adverse side effects of chronic GnRH agonist treatment without causing a recurrence of pelvic pain in most women with endometriosis.

PRACTICAL POINTS 

GnRHa is the most reliable method for improving the pelvic pain associated with endometriosis.  Low-dose steroid add-back avoids the adverse side effects of chronic GnRHa without causing recurrence of pelvic pain.

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4. 5.

6. 7. 8.

9.

Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Hormone Res 1980; 36:53. Conn PM, Crowley WF Jr. Gonadotropin releasing hormone and its analogues. N Engl J Med 1991; 324:93. Bergqvist A, Feno M. Steroid receptors in endometriotic tissue and endometrium assay with monoclonal antibodies. In: Genazzani AR, ed. Recent Research in Gynecologic Endocrinology. Vol. 1. Carnforth, U.K.: Panthenon, 1989:394. Bergqvist A, Jepsson S. Kullander. Human uterine and endometriotic tissue transplanted into nude mice. Am J Pathol 1985; 121:337. Sharpe K, Bertero MC, Muse KN. Spontaneous and steroid-induced recurrence of endometriosis after suppression by a gonadotropin releasing hormone antagonist in the rat. Am J Obstet Gynecol 1991; 164:187. Ranney B. Endometriosis III. Complete operations: reason, sequelae and treatment. Am J Obstet Gynecol 1971; 109:1137–1144. Gray LA. Endometriosis of the bowel. Ann Surg 1973; 177:580–587. Hammond CB, Rick JA, Parker RT. Conservative treatment of endometriosis: The effects of limited surgery and hormonal pseudopregnancy. Fertil Steril 1976; 27:756–766. Barbieri RL, Ryan KJ. Danazol: Endocrine pharmacology and therapeutic applications. Am J Obstet Gynecol 1981; 141:453.

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10. Hammond MG, Hammond CB, Parker RT. Conservative treatment of endometriosis externa. The effects of methyltestosterone therapy. Fertil Steril 1978; 29:651. 11. Luciano AA, Turksoy RN, Carleo J. Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol 1988; 72:323. 12. Ahmed MS, Barbieri RL. Reoperation rates for recurrent ovarian endometriomas after surgical excision. Gynecol Obstet Invest 1997; 43:53–54. 13. Dlugi AM, Miller JS, Knittle J. Lupron study group. Lupron depot in the treatment of endometriosis: a randomized placebo controlled double blind study. Fertil Steril 1990; 54:419–426. 14. Henzl MR, Corson SL, Moghissi K, Buttram VC, Bergqvist C, Jacobson J, for the Nafarelin Study Group. Administration of nasal nafarelin as compared with oral danazol for endometriosis: A multicenter double-blind comparative clinical trial. N Engl J Med 1988; 318:485–489. 15. Barbieri RL. New therapy for endometriosis. N Engl J Med 1988; 318:512–514. 16. Barbieri RL. Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol 1990; 162:581–855. 17. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotropin releasing hormone analogues for pain associated with endometriosis. Cochrane Database of Systemic Reviews, CD000346. 18. Shaw RW. Goserelin depot preparation of LHRH analogue used in the treatment of endometriosis. In: Chadha DR, Buttram VC, eds. Current Concepts in Endometriosis. New York: Alan R. Liss, 1990:323–383. 19. Cirkel U, Schweppe KW, Ochs H. Effects of LHRH agonist therapy in the treatment of endometriosis. Chadha DR, Willemsen WNP, eds. Gonadotropin Down-regulation in Gynecological Practice, Vol 225. New York: Alan R. Liss, 1986:189. 20. Naessen T, Berglund L, Ulmsten U. Bone loss in elderly women prevented by ultra low doses of parenteral 17-estradiol. Am J Obstet Gynecol 1997; 177:115– 119. 21. Mizunuma H, Okano H, Soda M, Kagami I, Miyamoto S, Tokizawa T. Prevention of post-menopausal bone loss with minimal uterine bleeding using low dose continuous estrogen-progestin therapy: A 2-year prospective study. Maturitas 1997; 27:69–76. 22. Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biological effects of transdermal estradiol. N Engl J Med 1986; 314:1615–1620. 23. Barbieri RL, Gordon AMC. Hormonal therapy of endometriosis: The estradiol target. Fertil Steril 1991; 56:820–822. 24. Barbieri RL. Hormonal therapy of endometriosis. Infertil Reprod Med Clin North Am 1992; 3:187–200. 25. Barbieri RL. Gonadotropin releasing hormone agonists and estrogen-progestogen replacement therapy. Am J Obstet Gynecol 1990; 162:593–595. 26. Barbieri RL. Hormone treatment of endometriosis: The estrogen threshold hypothesis. Am J Obstet Gynecol 1992; 166:740–745.

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27. Barbieri RL. Endometriosis and the estrogen threshold theory. Relation to surgical and medical treatment. J Reprod Med 1998; 43(S):287–292. 28. Howell R, Edmonds D, Dowsett M. Gonadotropin releasing hormone analogue plus hormone replacement therapy for the treatment of endometriosis: A randomized clinical trial. Fertil Steril 1995; 64:474. 29. Surrey ES. Add-back therapy and gonadotropin releasing hormone agonists in the treatment of patients with endometriosis: Can a consensus be reached. Fertil Steril 1999; 71:420–424. 30. Hornstein MD, Surrey ES, Weinberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: A 12-month study. Lupron Add-Back Study Group. Obstet Gynecol 1998; 91:16. 31. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: Long-term follow-up. Obstet Gynecol 2002; 99: 709–719. 32. Ihahara M, Uemara H, Yasui T, Kinoshita H, Yamada M, Tezuka M, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecol Obstet Invest 2001; 52:217–222. 33. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin releasing hormone analogs and hormone replacement therapy in the management of endometriosis: A randomized trial with a 6-year follow-up. Fertil Steril 2000; 74:964–968. 34. Mitwally MF, Gotlieb L, Casper RF. Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH agonist down-regulated patients with endometriosis and premenstrual syndrome. Menopause 2002; 9:236–241. 35. Hull ME, Barbieri RL. Nafarelin in the treatment of endometriosis: Dose management. Gynecol Obstet Invest 1994; 37:263–264. 36. Tahara M, Matsouka T, Yokoi T, Tasaka K, Kurachi H, Murata Y. Treatment of endometriosis with a decreasing dosage of a gonadotropin releasing hormone agonist (nafarelin): A pilot study with low-dose agonist therapy. Fertil Steril 2000; 73:799–804. 37. Uemura T, Shirasu K, Katagiri N, Asukai K, Suzuki T, Suzuki N. Low-dose GnRH agonist therapy for the management of endometriosis. J Obstet Gynecol Res 1999; 25:295–301. 38. Tse CY, Chow AM, Chan SC. Effects of extended-interval dosing regimen of triptorelin depot on the hormonal profile of patients with endometriosis: prospective observational study. Hong Kong Med J 2000; 6:260–264. 39. Kistner RW. The treatment of endometriosis by inducing pseudopregnancy with ovarian hormones: A report of 58 cases. Fertil Steril 1959; 10:539. 40. Noble AD, Letchworth AT. Medical treatment of endometriosis: A comparative trial. Postgrad Med J 1979; 55(suppl 5):37–41. 41. Vercellini P, Trespidi L, Colombo A. A gonadotropin releasing hormone agonist versus a low dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril 1993; 60:75–79.

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42. Freundl G, Godtke K, Gnoth C, Godehart E, Kienle E. Steroidal ‘‘add-back’’ therapy in patients treated with GnRH agonists. Gynecol Obstet Invest 1998; 45(suppl 1):22–30. 43. Regidor PA, Regidor M, Schmidt M, Ruwe B, Lubben G, Fortig P, Kienle E, Schindler AE. Prospective randomized study comparing the GnRH agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis. Gynecol Endocrinol 2001; 15:202–209. 44. Winkel CA, Bray M. Treatment of women with endometriosis using excision alone, ablation alone or ablation in combination with leuprolide acetate. In: Proceedings of the 4th World Congress on Endometriosis, Yokahama, 1996: 55. 45. Hornstein MS, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril 1997; 68:860–864. 46. Busacca M, Somigliana E, Bianchi S, De Marinis S, Calia C, Candiani M, Vignali M. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III–IV: A randomized controlled trial. Hum Reprod 2001; 16:2399–2402. 47. Barbieri RL, Niloff JM, Bast RC, Shaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986; 45:630–634. 48. Hornstein MD, Thomas PP, Gleason RE, Barbieri RL. Menstrual Cyclicity of CA-125 in patients with endometriosis. Fertil Steril 1992; 58:279–283. 49. Barbieri RL. Primary gonadotropin releasing hormone agonist therapy for suspected endometriosis: A nonsurgical approach to the diagnosis and treatment of chronic pelvic pain. Am J Managed Care 1997; 3:285–290. 50. Ling FW, for the Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol 1999; 93:51–58. 51. Kephart W. Evaluation of Lovelace Health Systems chronic pelvic pain protocol. Am J Managed Care 1999; 5S:S309–S315. 52. Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin releasing hormone agonist therapy: A double-blind, randomized placebo controlled trial. Am J Obstet Gynecol 2000; 182:1483–1488. 53. Karten MJ. An overview of GnRH antagonist development: Two decades of progress. In: Crowley WF Jr, Conn PM, eds. Modes of actions of GnRH and GnRH analogs. Amsterdam: Elsevier, 1992:277–297. 54. Martha PM, Gray ME, Campion M, Kuca B, Garnick MS. Initial safety profile and hormonal dose-response characteristics of the pure GnRH antagonist, abarelix-depot in women with endometriosis [abstract]. Gynecol Endocrinol 1999; 13(S):104. 55. Gonzalez-Barcena D, Alvarez RB, Ochoa EP, Cornejo IC, Comaru-Schally AM, Schally AV, Engel J, Resisman T, Riethmuller-Winzen H. Treatment of uterine leiomyomas with luteinizing hormone releasing hormone antagonist, cetrorelix. Hum Reprod 1997; 12:2028–2035.

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56. Hayes FJ, Taylor AE, Martin KA, Hall JE. Use of a gonadotropin releasing hormone antagonist as a physiological probe in polycystic ovary syndrome: Assessment of neuroendocrine and androgen dynamics. J Clin Endocrinol Metab 1998; 83:23443–23449. 57. Behre HM, Kliesch S, Puhse G, Reissman T, Nieschlag E. High loading and low maintenance doses of a gonadotropin releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle stimulating hormone and testosterone in men. J Clin Endocrinol Metab 1997; 82:1403–1408. 58. Martin KA, Hornstein MD, Taylor AE, Hall JE, Barbieri RL. Exogenous gonadotropin stimulation is associated with increases in serum androgens in IVF-ET cycles. Fertil Steril 1997; 68:1011–1016. 59. Frydman R, Cornel C, de Ziegler D, Taieb J, Spitz IM, Bouchard P. Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation. Fertil Steril 1991; 56:923–927. 60. Diedrich K, Diedrich C, Santos E, Zoll C, Al-Hasani S, Reissmann T, Krebs D, Klingmuller D. Suppression of the endogenous luteinizing hormone surge by the gonadotropin releasing hormone antagonist cetrorelix during ovarian stimulation. Human Reprod 1994; 9:788–791. 61. Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van Steirteghem A, Devroey P. Comparison of different doses of gonadotropin releasing hormone antagonist cetrorelix during controlled ovarian hyperstimulation. Fertil Steril 1997; 67:917–922. 62. Olivennes F, Alvarez S, Bouchard P, Franchin R, Salat-Baroux J, Frydman R. The use of a GnRH antagonist (cetrorelix) in a single dose protocol in IVFembryo transfer: A dose finding study of 3 versus 2 mg. Human Reprod 1998; 13:2411–2414. 63. The Ganirelix Dose Finding Study Group. A double-blind randomized dose finding study to assess the efficacy of the gonadotropin releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Human Reprod 1998; 13:3023–3031. 64. Kupker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002; 5:12–16.

14 Management of Endometriosis After Hysterectomy and Bilateral Salpingo-Oophorectomy David Redwine Endometriosis Institute of Oregon Bend, Oregon, U.S.A.

INTRODUCTION For over a century, endometriosis has been a misunderstood disease. Evidence of this misunderstanding is easy to find in the medical literature, where countless authors have called it an enigmatic, mysterious disease, among other things. The intellectual confusion and contradictions that accompany the disease occur simply and only because much of what is accepted as conventional wisdom regarding the disease is not supported by evidence. Yet conventional wisdom is exceedingly slow to change, and so rational therapy for women with endometriosis lags even further behind. Why does change occur so slowly regarding endometriosis, whereas change occurs and is accepted so rapidly in unrelated fields such as astronomy or physics? One reason appears to be that many leaders in endometriosis are not actually experts in the study or treatment of endometriosis, but are merely parroting what others have said before, not believing that these echoes from the past may propagate ideas that are completely wrong. Worse, it is clear that 245

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pharmaceutical companies promoting medical treatment for endometriosis have tremendously influenced modern thought on the matter. Through an orchestrated approach using studies funded by drug companies, paid traveling speakers, and kickbacks to physicians for using medicines, the effort has been successful to popularize medical therapy given indefinitely for any undiagnosed pelvic pain syndrome. It should be obvious that the ship of endometriosis therapy is off course because its steerage is in the hands of a rogue crew using a distorted compass. However, these are just two of the latest problems in understanding endometriosis. One of the many long-standing errors of thought and therapy regarding endometriosis is that hysterectomy and bilateral salpingo-oophorectomy are ‘‘definitive’’ treatment for the disease. Women with ‘‘resistant’’ endometriosis undergo castration for cure. In this one preceding short sentence are crystallized many layers of identifiable misunderstanding that reach back into the last millennium, so this sentence will be examined sequentially and in detail to expose the multiple fallacies contained within it. THE CONCEPT OF ‘‘ ‘‘RESISTANT’’ ’’ ENDOMETRIOSIS There are only two treatment options for surgically diagnosed endometriosis: medicine or surgery. Observation alone would rarely, if ever, be a good choice for surgically diagnosed endometriosis, as this would put the clinician in the logically indefensible position of having to say to a patient, ‘‘I operated on you because I thought I might find a cause of your problem. I found something that might be the cause of your problem, but I chose not to treat it because it might not be the cause of your problem.’’ Medical therapy is based on hormonal suppression of ovarian function or of endometriosis itself. Although medical treatment can produce temporary reduction or relief of symptoms during therapy, it is clear that medical therapy does not eradicate endometriosis of any stage or disease site [1]. Ovarian suppression may relieve pain due to uterine fibroids, uterine adenomyosis, ovulation pain, dysmenorrhea, endometriosis, and some cases of idiopathic pelvic pain. The pain, which is reduced, may not be caused by endometriosis, and recurrent pain appears in most treated patients within a few weeks after the medicine wears off. If ‘‘treatment’’ is defined as something that destroys the origin of a disease process, like antibiotics destroy diseaseproducing bacteria, then medicines do not treat endometriosis. Because medicines do not treat endometriosis, experts agree that surgery is its only treatment. It thus becomes simply a matter of determining which type of surgical treatment destroys the disease most completely. First, though, we must consider what type of disease endometriosis is. It has long been known that endometriosis can be invasive for several centimeters be-

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neath the visible surface [2]. It can occur in any pelvic location and can invade the bowel, bladder, ureter, or diaphragm. With this in mind, it immediately becomes clear that for a surgical technique to have a chance of completely destroying the disease, it must simultaneously be able to penetrate tissue up to several centimeters and allow for identification and repair of surgical defects left during treatment of endometriosis invading vital organs. Fortunately, it does not require a randomized controlled trial to complete this type of thought experiment and arrive at the correct conclusion, as common sense alone is sufficient. It is impossible to imagine that laser vaporization, electrocoagulation, harmonic scalpel coagulation, or endocoagulation would ever be able to destroy endometriosis completely. As well, none of these techniques has been validated in a sufficient number of reoperated patients as being effective in the eradication or reduction of disease extent. Although laser vaporization has been described in the literature in some detail, there is insufficient description of the other thermal ablation methods to allow their consistent application in human females. ‘‘Resistance’’ in medicine implies that a disease does not respond, either completely or at all, to any therapy. Resistance is a product of both the virulence of a disease as well as the efficacy of the applied therapy. The virulence of endometriosis can be manifest by impressive invasion or involvement of multiple vital organs. Regarding efficacy of surgical therapies, our thought experiment of the preceding paragraph has disqualified thermal ablation techniques from having much chance of complete eradication of disease. Thus, excision of endometriosis emerges as the only truly logical treatment for endometriosis of any stage, any location, and any symptomatology, in a patient of any age. It is also the only treatment that has proven curative ability [3,4]. Thus, the concept of resistant endometriosis is fueled primarily by the predictable results of ineffective therapies, which, together with Sampson’s theory of origin of endometriosis by reflux menstruation, have enjoyed a symbiotic relationship for many decades. Clinicians using ineffective treatments such as medical therapy or thermal ablation techniques could point to the notion of recurrence related to Sampson’s theory rather than to the inadequacy of their treatments. Sampson’s theory of origin is flying under an increasing burden of proof, which seems to make it unlikely to be the origin of any form of endometriosis [5]. As support for Sampson’s theory diminishes, realization of the waste associated with ineffective therapies will increase. REMOVAL OF THE UTERUS, TUBES, AND OVARIES FOR ‘‘ ‘‘CURE’’ ’’ OF ENDOMETRIOSIS Endometriosis is a disease that occurs primarily on peritoneal surfaces away from the uterus, tubes, and ovaries [6,7]. Removal of only the uterus, tubes,

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and ovaries with no further treatment to peritoneal endometriosis has been taught to generations of gynecologists as ‘‘definitive’’ therapy for the disease. Such surgery, however, will allow peritoneal disease to be left behind in almost 100% of patients, which is hardly a cure (Figs. 1–4). Many patients with endometriosis may have some associated pathology such as ovulation pain, adhesions, adenomyosis, fibroids, or primary dysmenorrhea that may be relieved by removal of the pelvic organs even if all endometriosis is allowed to remain in the body. If all such nonendometriotic sources of pain coming from the pelvic organs are erroneously ascribed to endometriosis, then surgeons removing the pelvic organs will certainly be impressed by the apparent efficacy of this surgery in relieving pain thought to be caused by endometriosis. Endometriosis appears to be the only disease that is treated by surgical ‘‘cure’’ with the removal of something else. Many reasons have been postulated to explain why removal of the pelvic organs may help symptoms of endometriosis. Apparently many physicians still believe that the hypoestrogenic state will cause endometriosis to disappear by some as yet unexplained cytocidal effect. Others believe that removal of the uterus is important in order to stop reflux menstruation to prevent new endometriosis from forming, although formation of new lesions does not appear to be the natural history of the disease in most patients [7].

FIGURE 1 A small vaginal lesion of endometriosis is seen at the vaginal apex in a woman with previous hysterectomy and bilateral salpingo-oophorectomy. Vaginal endometriosis is almost always an extension of a nodular lesion of a uterosacral ligament or of a nodular lesion associated with obliteration of the cul de sac. This lesion was an extension of a nodule of the right uterosacral ligament.

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FIGURE 2 At laparoscopy, the right uterosacral ligament area looks thickened and nodular but is not particularly hemorrhagic.

FIGURE 3 Retroperitoneal dissection shows that the nodule is in the immediate vicinity of the stumps of the right uterine vessels as well as the ureter.

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FIGURE 4 The fibrosis resulting from the nodule also has incorporated posterior branches of the hypogastric artery. A small hole has been created in one of these branches.

Still others believe that endometriosis is symptomatic because of the monthly cycling of estrogen levels, so removal of the pelvic organs results in a steady state of menopausal levels of estrogen, or a steady state of estrogen due to estrogen replacement therapy in those women who are symptomatic without it. Whatever the reason for treatment of endometriosis by removal of the pelvic organs with retention of the disease, there is no question that some patients undergoing this therapy can continue to have symptoms. Where did this idea come from? How effective is this type of treatment?

THE ORIGIN OF DEFINITIVE SURGERY FOR ENDOMETRIOSIS The origin of the notion that menopause or low levels of estrogen can eradicate endometriosis is an interesting, albeit unfortunate, example of Berkson’s fallacy [8,9]. Berkson described the fallacy but did not commit it. Berkson observed that the nature of a disease process observed in hospitalized patients might not be an accurate reflection of that disease in unhospitalized patients. Such selection bias could lead to gross errors of understanding, which could lead to confusion and have dangerous effects on proposed treatments. Because endometriosis is a disease that has long required hospital-

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ization and surgery to diagnose, it is a disease that could be subject to Berkson’s fallacy. Sampson’s early work was clearly affected by the unseen workings of Berkson’s fallacy. In 1921, writing about only 23 patients with chocolate cysts (and only 10 of those women had biopsy-proved endometriomas), he observed that he had never seen endometriosis in a menopausal patient [10]. This introduced the concept of menopause as treatment. Sampson fervently wanted to believe this and in 1922 he wrote ‘‘.. the implantations will usually, possibly always, atrophy after all ovarian tissue is removed. . . All of them probably cease to grow and actually atrophy after the menopause [11].’’ These multiple and hopeful adverbs notwithstanding, within 2 decades the oldest patient with endometriosis had been reported—age 78 [12]. The thoughts begun by Sampson were echoed in the literature over the years. According to Siegler, ‘‘After the menopause, endometriosis becomes only an asymptomatic relic [13].’’ Kistner wrote ‘‘. . . bilateral oophorectomy will almost always bring about permanent arrest of the disease’’ [14] and that ‘‘. . . functioning ovarian tissue is necessary for the continued activity of the disease [15].’’ Although many cases of endometriosis occurring after natural menopause have been reported in women taking or not taking estrogen [16– 24], even today it is commonly taught that menopause will eradicate endometriosis. If it is believed that natural menopause will eradicate endometriosis, then surely it is a natural extension to suppose that surgical menopause, ‘‘definitive’’ surgery, will do the same. Despite the widespread belief that pregnancy and menopause might eradicate endometriosis, unfortunately no one has gone to the trouble to do the simple studies that would validate this belief. HOW EFFECTIVE IS DEFINITIVE SURGERY FOR ENDOMETRIOSIS? Surgical efficacy can be measured in two ways: (1) eradication of disease (2) symptom reduction. Eradication of endometriosis requires reoperation to detect whether the disease is still present. There has never been a systematic study in reoperated patients validating the efficacy of definitive surgery for eradication of endometriosis. The efficacy of definitive surgery has been measured only by symptom response. Study of the response of symptoms requires a comparison of symptom levels pre- and postoperatively, although it must be borne in mind that not all pelvic pain is caused by endometriosis. Publications describing symptom reduction offer the only evidence of efficacy of definitive surgery. As symptoms may result from causes other than endometriosis, findings of such studies must be interpreted cautiously as they may not address directly the question of treatment of endometriosis symp-

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toms. It should also be remembered that in most studies of patients undergoing hysterectomy and castration as definitive therapy, the endometriosis was always left in place (other than disease that might rarely involve the ovaries, tubes, or uterus, or occasional confirmatory biopsies.) In 1951, Huffman [25] noted that among 77% of castrated women given estrogen replacement therapy, less than 5% had persistent symptoms. Schram [26] reported a single case of endometriosis after removal of the pelvic organs in a patient who had no endometriosis apparent at her previous surgeries. Venter et al. [27] described a woman who had undergone removal of the pelvic organs 15 years previously for whom estrogen was not prescribed postoperatively. Because of severe vasomotor symptoms, she was given oral estrogen and began vaginal bleeding 1 week later. Examination showed a polypoid lesion measuring 3 x 2 cm located at the vaginal apex. This was treated by cessation of estrogen therapy and vaginal removal and cautery by a surgical oncologist, but the lesion and bleeding recurred within 2 years despite a serum estradiol level of 66 pmol/L. The lesion did not respond to massive injections of 400 mg Depo-Provera weekly for 1 year but finally responded partially to external beam irradiation. Metzger et al. [28] reported a case of a 34-year-old black woman who had undergone previous removal of the pelvic organs for presumed pelvic inflammatory disease. A small focus of endometriosis on the uterine serosa was the only evidence of endometriosis at that surgery. Six years later she developed abdominal pain, constipation, urinary frequency, and nocturia. Bilateral hydronephrosis was noted on intravenous pyelography (IVP) as well as a 6-cm mass in the left lower abdominal area. At laparotomy, the mass was incompletely resected. The patient was given intramuscular injections of Depo-Provera 250 mg twice monthly. The mass increased to 15 cm in greatest dimension. Ultrasound-guided transvaginal drainage was done, but the patient ultimately required a repeat laparotomy with posterior exenteration, exploration of the left obturator fossa, and colostomy associated with 15 L of blood loss. The colostomy was later reversed. Immunohistochemical analysis showed that the endometriosis tissue had elevated levels of progesterone receptors, but not of estrogen receptors. Spence et al. [29] reported a single case of endometriosis after removal of the pelvic organs in a woman with no previous diagnosis of endometriosis. The patient had an excellent response to aggressive resection at laparotomy and was placed on oral estrogen immediately after surgery. The authors emphasized, ‘‘In most patients removal of the pelvic organs eradicates endometriosis.’’ Namnoun et al. [30] found that if the ovaries were left in at the time of hysterectomy, the rate of persistent or recurrent symptoms was 62% and the

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rate of reoperation was 31%. In women with removal of the ovaries at the time of hysterectomy, the rate of recurrent/persistent symptoms was 10% and the rate of reoperation was 3.7%. The prevalence of invasive disease or ovarian disease in this population was not discussed. In a retrospective study of 95 patients who had undergone total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) for endometriosis, Hickman et al. [31] found that symptom recurrence was 7% in women beginning estrogen therapy immediately postoperatively, compared with 20% when estrogen was begun 6 weeks or more postoperatively. The overall rate of symptom recurrence in women taking estrogen replacement therapy was 12%. Progesterone therapy did not appear to protect against symptom recurrence, and no case of cancer was observed. Matorras et al. [32] performed a prospective randomized trial in women undergoing castration for treatment of endometriosis. They compared postoperative combined continuous estrogen patch plus cyclic oral micronized progesterone with no therapy. In 57 women not receiving estrogen, there was no case of symptom recurrence, although the rate of vasomotor symptoms was not discussed. In 115 treated patients, there were five with symptomatic recurrence and two of these were confirmed histologically. All five recurrences were in women with impressive evidence of probable invasive endometriosis, including a woman with rectovaginal disease, another with a partially obstructing sigmoid nodule, two others with probable obliteration of the cul de sac who had required supracervical hysterectomy, and another woman with right ureteral obstruction resulting from dense retroperitoneal fibrosis leading to nephrectomy with retention of the pelvic fibrosis. Recurrence of symptoms among patients with supracervcal hysterectomy performed because of probable obliteration of the cul de sac was 22%. In an immunocytochemical study of postmenopausal ovarian endometriosis in 21 women who had never taken estrogen therapy [33], the ovarian disease showed robust biological activity even though the eutopic endometrium was atrophic. The continued activity of endometriosis may be the result of expression of aromatase enzyme by the lesions themselves, which can allow conversion of adrenal precursors into estrogen [34]. Several things seem clear from the evidence cited above. There is no scientific evidence that removal of the pelvic organs and low levels of estrogen eradicate endometriosis, and histologically active symptomatic endometriosis can certainly persist despite low levels of estrogen. However, symptomatic endometriosis occurs in less than 10% of patients after removal of all pelvic organs, especially if estrogen therapy is withheld. Furthermore, reoperation for recurrent symptoms was encountered in less than 5% of cases, although the rates of continuation of symptoms and reoperation seem higher if invasive disease is present at the time of hysterectomy and castration. It is also clear

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that an enormous number of women suffer from symptomatic endometriosis despite hysterectomy and castration. In the United States alone, several hundred thousand hysterectomies are performed annually for definitive treatment of endometriosis. For every 100,000 women undergoing surgery, 10,000 will remain symptomatic and a disproportionate number of these will have invasive disease. Fortunately for those who remain symptomatic because of their endometriosis, excision of persistent disease will result in pain relief [35–37]. MALIGNANT CHANGE OF RETAINED ENDOMETRIOSIS AFTER HYSTERECTOMY AND CASTRATION The possibility of malignant change of endometriosis during estrogen replacement therapy is of some concern. The adenomatous portion of endometriosis could respond to estrogen by developing hyperplastic changes, which could become atypical and then cancerous, similar to what occurs in eutopic endometrium. Maligant change of endometriosis has been reported to occur in the face of estrogen replacement therapy but seems very rare. Anderson et al. [38] reported the case of a 46-year-old woman who underwent hysterectomy and castration for endometriosis associated with ‘‘dense pelvic adhesions.’’ She was placed on postoperative estrogen replacement therapy and 6 months later underwent sigmoid colectomy for bowel obstruction due to endometriosis. By a year after her hysterectomy, a polypoid vaginal tumor was present and biopsies showed benign endometriosis. In response to oral medroxyprogesterone acetate, leuprolide acetate, and repeated biopsies, this tumor grew until it filled the vagina from its origin on a stalk on the right vaginal cuff. The mass was eventually removed by laparotomy almost 4 years after her hysterectomy, and adenosarcoma was diagnosed. The patient later had a recurrence in the right parametrium that was treated by radiation with good response. A similar case of adenosarcoma arising in endometriosis was reported in a 42-year-old woman by Judson et al. [39]. Modesitt et al. [40] reported that 13 of 15 cases of postmenopausal extraovarian cancers arose from endometriosis in the face of unopposed estrogen replacement therapy. Jones et al. [41] reported a case of a 52-year-old woman who had undergone hysterectomy and castration for treatment of deeply infiltrating rectovaginal endometriosis associated with complete obliteration of the cul de sac 12 years previously. Estrogen was administered by pellets for 12 years until she began to have bright red bleeding rectally. Barium studies and colonoscopy were normal except for a polyp of the distal sigmoid that showed atypical hyperplasia. At laparotomy, the lower rectosigmoid was involved with a hard fixed mass, and segmental bowel resection was performed. His-

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tology showed adenocarcinoma arising in a field of endometriosis. The authors mention a literature review showing intestinal adenocarcinoma occurring in eight patients in the face of estrogen replacement therapy (ERT) and in another eight patients without ERT. Vara et al. [42] presented a case of bladder cancer arising from bladder endometriosis in a 62-year-old woman who had undergone TAH/BSO 10 years previously, although they did not mention whether she was receiving ERT. Endometriosis was not found elsewhere in the pelvis. In a review of medical records at M.D. Anderson Cancer Center [43], it was found that malignant change of nonovarian endometriosis was more common in postmenopausal women taking estrogen, whereas malignant change of ovarian endometriosis was not associated with estrogen therapy. It seems clear that there is a low rate of malignant transformation of endometriosis that was left in place at the time of hysterectomy and castration. Malignant transformation can occur without estrogen replacement therapy, although most cases have been associated with unopposed estrogen therapy. Importantly, most cases of malignant transformation of endometriosis after removal of the pelvic organs seem to arise in cases where there is severe invasive rectovaginal or intestinal disease. Some authors have called for consideration of combined ERT plus progesterone therapy. However, malignant change of residual endometriosis with unopposed ERT is rare and can occur even in the absence of ERT. Also, there is no evidence that progestins prevent malignant transformation of endometriosis, and there is some evidence that progesterone is associated with malignant change. Given that endometriosis is so different from native endometrium, it is simplistic and misleading to clinicians and patients to suggest that endometriosis would respond to progestins the way eutopic endometrium would and that progestins might prevent malignant change of endometriosis. For all these reasons, progesterone is currently not indicated in ERT for endometriosis patients after removal of the pelvic organs. An exception might be if a biopsy reveals atypical hyperplasia of the endometriosis in a patient in whom all disease was not removed. The best treatment is aggressive excision of all endometriosis in all patients undergoing surgery so that the issues of malignant transformation and continuing symptoms resulting from endometriosis are rendered moot. INDICATIONS FOR ERT IN PATIENTS WITH ENDOMETRIOSIS AFTER HYSTERECTOMY AND CASTRATION The indications for ERT in endometriosis patients are identical to the indications in any other woman: relief of bothersome symptoms. The primary symptoms of hot flashes or night sweats or symptoms of vaginal dryness are

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classic and easy to identify; however, other lesser symptoms also may occur, even in the absence of the primary symptoms. These include sleeping difficulty, fatigue or lack of energy, depression, mood swings, anxiety, or forgetfulness. These secondary symptoms may sound like a normal response to life in modern times, but the clinician should encourage women to report them. Because progestins are unnecessary, this simplifies things for the clinician and patient. When giving ERT to any patient, consideration should be given to bioavailability of the prescribed estrogen. The same dose of estrogen given to 10 different women might give 10 different levels of serum estradiol depending on intestinal absorption and estrogen metabolism. Additionally, the estrogen ‘‘thermostat’’ may be set higher in some women than in others, so these patients may not feel the full benefit of estrogen if their serum estradiol level is below their set point, even if it is within the normal range. Estrogen replacement therapy in any patient is simplified if the clinician focuses on two things: (1) symptoms and (2) serum estradiol levels. Clinicians should not focus on giving the lowest available dose of estrogen manufactured to all patients, as this ignores the simple truism that people are different for the reasons stated above. Giving the lowest possible dose to all patients will guarantee that many will be symptomatic and unhappy. It is important to be highly flexible and individualize treatment. There is no reason to withhold estrogen for any length of time after removal of the pelvic organs even if all endometriosis is left in place, because there is no evidence that the absence of estrogen is cytocidal to endometriosis and because there is evidence that withholding estrogen for several weeks or months is associated with a higher rate of recurrent painful symptoms in women with retained endometriosis. Estrogen replacement therapy can be started as early as the recovery room with patches, pellets, or injections because patients may be unable to tolerate oral intake for a day or two. When the patient is on a regular diet, pills can be started if that is the plan agreed to by the patient. Regardless of the form of estrogen given, a serum estradiol level should be obtained at the final 6- or 8-week postoperative checkup. By this time, the serum estradiol level will be stable on the patient’s daily dose. The serum estradiol level in young women with normally functioning ovaries ranges between 100 and 300 pg/ml. Estrogen replacement therapy should achieve a blood level in this range, although some patients may continue to have mild symptoms toward the low end of this range. It is popular in some practices for the clinician to be satisfied with a serum estradiol level of around 65, but many patients will feel better at a higher dose. Some might argue that giving estrogen until serum estradiol levels are in the normal range for women in their 20s is unphysiologic because older women have lower estrogen levels. This, of course, is not a valid argument because the end

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result of such flawed logic would be the withholding or withdrawing of estrogen from all women because the inevitable physiologic level will be menopausal as women get older. Even if a patient is doing well on the initial dose of estrogen, some will have a change in absorption or metabolism that may result in a lower serum estradiol level and the appearance of symptoms. For this reason, the serum estradiol level should be checked as needed to help give the proper dose. Some women will have menopausal symptoms forever unless they take estrogen; others may have symptoms for a few years, which may eventually cease. A rare patient may never have symptoms. It may be necessary to intermittently discontinue ERT for 2 or 3 weeks to see if a patient still will benefit from it. Recurrent symptoms should reassure the clinician and the patient that ERT is indicated. Estrogen replacement therapy can be associated with activation of endometriosis in some patients, with worsening symptoms while on therapy. Patients with invasive disease involving parenchymal structures, such as the uterosacral ligaments or rectal wall, may remain symptomatic because of production of aromatase enzyme by the endometriosis with local conversion of adrenal precursors to estrogen. Regardless of whether a patient is on ERT or not, recurrent or continuing symptoms of endometriosis after removal of the pelvic organs are best treated by excision by an experienced endometriosis surgeon rather than by attempts at hormonal manipulation. The Women’s Health Initiative (WHI) [44] study from the United States gives reassuring information about the safety of estrogen replacement therapy in women, as only 19 women per 10,000 taking ERT had excess adverse events such as heart attacks, strokes, or breast cancer. The WHI study of 0.625 mg daily of conjugated estrogens combined with 2.5 mg daily of medroxyprogesterone indicated that this form of ERT will not prevent cardiovascular disease but can reduce colon cancer and hip fractures. Because women who have had removal of their pelvic organs do not need progesterone to prevent eutopic endometrial hyperplasia and as there is no evidence that progesterone has any role in medical treatment of endometriosis, the results of the WHI study may not be transferable to women taking only ERT in some other form. SUMMARY 1. Removal of the uterus, tubes, and ovaries does not make endometriosis go away, as the most common sites of involvement are peritoneal surfaces away from these organs. 2. Removal of the uterus, tubes, and ovaries can relieve most pain in most patients, even when endometriosis is left in.

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3. Some of the pain relieved by removal of the uterus, tubes, and ovaries may have originated in those organs and is mistakenly attributed to the endometriosis. 4. Invasive endometriosis is more likely to remain symptomatic even in the absence of estrogen. 5. Superficial endometriosis is less likely to remain symptomatic in the presence or absence of estrogen. 

Most women with endometriosis have superficial disease, which may explain why the majority do well with removal of the pelvic organs and retention of their disease.

6. When performing a hysterectomy and bilateral salpingo-oophorectomy, remove invasive endometriosis completely when possible to decrease the likelihood of persistent symptoms. 7. Estrogen therapy may be started immediately after removal of the pelvic organs.     



If all endometriosis is removed, there will be no problem. If only superficial endometriosis remains, it is unlikely that there will be a problem. If invasive endometriosis remains, it may be problematic with or without estrogen therapy. There is no evidence that withholding estrogen eradicates the disease. Withholding estrogen is associated with a higher rate of persistent or recurrent pain than if estrogen is begun immediately postoperatively. The serum estradiol level during therapy should be between 100 and 300 pg/ml.

8. Progesterone is not indicated for hormone replacement therapy after removal of the pelvic organs and retention of endometriosis, with the possible exception of atypical endometriosis having been left behind. 9. If endometriosis that was not removed at the time of hysterectomy and bilateral salpingo-oophorectomy is symptomatic with or without estrogen therapy, the patient should be referred to a qualified endometriosis surgical treatment program for excision of the disease. 10. Excision of symptomatic endometriosis persisting after castration cures the disease and will relieve pain caused by endometriosis. 11. Not all pelvic pain in women with endometriosis is necessarily caused by the disease, so it is possible to cure the disease yet still have a patient with pain.

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PRACTICAL POINT .

During hysterectomy and bilateral salpingo-oophorectomy for pelvic pain, make sure to remove all endometriosis.

REFERENCES 1.

2. 3. 4.

5. 6. 7. 8. 9. 10. 11.

12. 13. 14. 15. 16. 17. 18.

Redwine DB. Treatment of endometriosis-associated pain. In: Olive DL, ed. Endometriosis: Infertility and Reproductive Medicine Clinics of North America. Philadelphia: WB Saunders, 1992:697–720. Cullen TS. Adenomyomas of the rectovaginal septum. JAMA 1914; 62:835–839. Wheeler JM, Malinak LR. Recurrent endometriosis. Contrib Gynecol Obstet 1987; 16:13–21. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: Life table analysis of reoperation and persistent or recurrent disease. Fertil Steril 1991; 56:628–634. Redwine DB. Was Sampson wrong? Fertil Steril 2002; 78:686–693. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol 1940; 40:549–557. Redwine DB. The distribution of endometriosis in the pelvis by age groups and fertility. Fertil Steril 1987; 47:173–175. Berkson J. Limitations of the application of fourfold table analysis to hospital data. Biometrics 1946; 2:47–53. Berkson J. The statistical study of association between smoking and lung cancer. Proc Mayo Clinic 1955; 30:319–348. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921; 3:245–323. Sampson JA. Ovarian hematomas of endometrial type (perforating hemorrhagic cysts of the ovary) and implantation adenomas of the endometrial type. Bost Med Surg J 1922; 186:445–456. Haydon GB. A Study of 569 cases of endometriosis. Am J Obstet Gynecol 1942; 43:704–709. Siegler SL, Bisaccio JR. Endometriosis, clinical aspects and therapeutic considerations. Am J Obstet Gynecol 1951; 61:99. Kistner RW. Gynecology—Principles and Practice. 2d ed. Chicago: Year Book Publishers, Inc., 1971:432–457. Kistner RW. Management of endometriosis in the infertile patient. Fertil Steril 1975; 26, 1151–1166. Bennett ET. Endometriosis in the older age group. Am J Obstet Gynecol 1953; 65:100–108. Kempers RD, Dockerty MB, Hunt AB, Symmonds RE. Significant postmenopausal endometriosis. Surg Gynecol Obstet 1960; 3:348–356. Ranney B. Endometriosis. III. Complete operations. Am J Obstet Gynecol 1971; 109:1137–1143.

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19. Punonnen R, Klemi PJ, Nikkanen V. Postmenopausal endometriosis. Eur J Obstet Gynecol Reprod Biol 1980; 11:195–200. 20. Djursing H, Petersen K, Weberg E. Symptomatic postmenopausal endometriosis. Acta Obstet Gynecol Scand 1981; 60:529–530. 21. Madgar I, Ziv N, Many M, Jonas P. Ureteral endometriosis in postmenopausal women. Urology 1982; 20:174. 22. Vorstman B, Lynne C, Politano VA. Postmenopausal vesical endometriosis. Urology 1983; 22:540. 23. Goodman HM, Kredentser D, Deligdisch L. Postmenopausal endometriosis associated with hormone replacement therapy. A case report. J Reprod Med 1989; 34:231–233. 24. Habuchi T, Okagaki T, Miyakawa M. Endometriosis of bladder after menopause. J Urol 1991; 145:361–363. 25. Huffman JW. External endometriosis. Am J Obstet Gynecol 1951; 62:1243–1252. 26. Schram JD. Endometriosis after ‘‘pelvic cleanout.’’ South Med J 1978; 71:1419– 1420. 27. Venter PF, Anderson JD, Van Velden DJJ. Postmenopausal endometriosis: A case report. S Afr Med J 1979; 56:1136–1138. 28. Metzger DA, Lessey BA, Soper JT, McCarty KS, Haney AF. Hormone-resistant endometriosis following hysterectomy and bilateral salpingo-oophorectomy: Correlation with histology and steroid receptor content. Obstet Gynecol 1991; 78:946–950. 29. Spence MR, Maiese S, Amenta PS. Endometriosis occurring eight years after total abdominal hysterectomy and bilateral salpingo-oophorectomy. Am J Gynecologic Health 1992; 6:22–25. 30. Namnoun AB, Hickman TN, Goodman SB, Gehlbach DL, Rock JA. Incidence of symptom recurrence after hysterectomy for endometriosis. Fertil Steril 1995; 64:898–902. 31. Hickman TN, Namnoum AB, Hinton EL, Zacur HA, Rock JA. Timing of estrogen replacement therapy following hysterectomy with oophorectomy for endometriosis. Fertil Steril 1998; 91:673–677. 32. Matorras R, Elorriaga MA, Pijoan JI, Ramon O, Rodriguez-Escudero FJ. Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy. Fertil Steril 2002; 77:303–308. 33. Toki T, Horiuchi A, Li S-F, Nakayama K, Silverberg SG, Fujii S. Proliferative activity of postmenopausal endometriosis: A histopathologic and immunocytochemical study. Int J Gynecol Pathol 1996; 15:45–53. 34. Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, Fushiki S, Osawa Y, Honjo H. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod 1997; 57:514–519. 35. Redwine DB. Endometriosis persisting after castration: Clinical characteristics and results of surgical management. Obstet Gynecol 1994; 83:405–413. 36. Clayton RD, Hawe JA, Love JC, Wilkinson N, Garry R. Recurrent pain after

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hysterectomy and bilateral salpingo-oophorectomy for endometriosis: Evaluation of laparoscopic excision of residual endometriosis. Br J Obstet Gynaecol 1999; 196:740–744. Finan MA, Kwark JA, Joseph GF Jr, Kline RC. Surgical resection of endometriosis after prior hysterectomy. J La State Med Soc 1997; 149:32–35. Anderson J, Behbackht K, De Geest K, Bitterman P. Adenosarcoma in a patient with vaginal endometriosis. Obstet Gynecol 2001; 98:964–966. Judson PL, Temple AM, Fowler WC, Novotny DB, Funkhouer WK. Vaginal adenosarcoma arising from endometriosis. Gynecol Oncol 2000; 76:123–125. Modesitt SC, Tortolero-Luna G, Robinson JB, Gershenson DM, Wolf JK. Ovarian and extraovarian endometriosis-associated cancer. Obstet Gynecol 2002; 100:788–795. Jones KD, Owen E, Berresford A, Sutton C. Endometrial adenocarcinoma arising from endometriosis of the rectosigmoid colon. Gynecologic Oncol 2002; 86:220–222. Vara AR, Ruzics EP, Moussabeck O, Martin DC. Endometrioid adenosarcoma of the bladder arising from endometriosis. J Urol 1990; 143:813–815. Modesitt SC, Tortolero-Luna G, Robinson JB, Gershenson DM, Wolf JK. Ovarian and extraovarian endometriosis-associated cancer. Obstet Gynecol 2002; 788–795. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333.

15 Treatment of Ovarian Endometrioma Haya Al-Fozan and Togas Tulandi McGill University Montreal, Quebec, Canada

INTRODUCTION Ovary is a common site of endometriotic cyst or endometrioma. Perhaps the irregular surface of the ovary allows endometrial tissue to burrow into its substance, predisposing the development of ovarian endometrioma. Sampson in 1927 [1] first described the term ‘‘chocolate cyst’’ for ovarian endometrioma. Similar to that of endometriotic implants, the left ovary is more commonly affected than the right [2].

PATHOGENESIS The exact pathophysiology of ovarian endometrioma remains unclear. Brosens [3] postulated that endometrioma develops by invagination of the endometriosis-affected ovarian cortex. Other theories include metaplasia of the coelomic epithelium covering the ovary [4–6] or secondary involvement of functional ovarian cyst [7]. Endometrioma is often associated with pelvic pain and infertility. The diagnosis is suspected on pelvic examination or ultrasound examination. It is 263

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confirmed at the time of surgery and established by histopathological examination.

ENDOMETRIOMA AND IN VITRO FERTILIZATION The impact of endometrioma on the results of in vitro fertilization (IVF) is controversial. Some authors reported that endometrioma adversely affected the pregnancy outcome and suggested that ovarian endometrioma should be removed before IVF treatment [8,9]. Others found no effect of ovarian endometrioma on IVF outcome [10,11]. In a retrospective study, Isaacs et al. [11] evaluated the effects of aspiration of ovarian endometrioma before IVF. They found no difference in peak serum estradiol level, number of mature follicles, number of oocytes, number of embryos transferred, or clinical pregnancies between women with intact endometrioma and those whose endometrioma was aspirated before IVF [11]. Another study found higher rates of oocyte retrieval and clinical pregnancy in women whose endometrioma was aspirated before IVF [12].

ENDOMETRIOMA AND MALIGNANCY Malignancy rarely arises from endometriosis. The frequency of a malignant tumor arising from ovarian endometriosis varies between 0.3% and 0.8%, and most of these tumors are well-differentiated endometriotic carcinomas [13]. Medical Treatment Endometriosis can be treated medically or surgically. Medical treatment consists of estrogen-progestin combination, progestin only, gonadotropinreleasing hormone analog (GnRHa), or danazol. Recently, aromatase inhibitor has also been tried [14]. However, medical treatment for endometrioma is limited. Ovarian endometriomas larger than 1 cm do not respond favorably to medical treatment with hormonal suppression [15]. Also, Muzii et al. [16] reported that the preoperative use of GnRH-a offered no advantage to surgery or to the recurrence rate. Medical treatment is associated with symptomatic improvement in 50% of the patients, but the symptoms tend to recur 6 to 12 months after cessation of therapy [16–18]. It also has no effect on the pregnancy or on the recurrence rates.

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Aspiration of Endometrioma under Ultrasound Guidance Endometrioma can be aspirated under ultrasound or laparoscopic guidance. Drainage under ultrasound guidance is certainly less invasive [12,19–21], and it can be performed in the office setting under local anesthesia. However, the recurrence rate is high (28.5% to 100%) and the procedure carries the risk of infection and adhesions [22]. Garvey et al. [23] reported a case of ultrasound aspiration of bilateral ovarian endometrioma that was followed by severe pelvic adhesions. This could be caused by leakage of the content of the cyst creating inflammatory reaction and adhesions. Nevertheless, ultrasound aspiration of endometrioma might have a place prior to IVF [12]. Ultrasound-Guided Transvaginal Sclerotherapy To overcome the high recurrence rate of aspiration of ovarian endometrioma, Japanese physicians proposed instillation of a high concentration of ethanol (50%) for 5 minutes into the endometriotic cyst wall (ethanol sclerotherapy). Ethanol produces tissue dehydration [24,25]. In other organs such as thyroid, parathyroid, heart, liver and spleen, its efficacy has been demonstrated with a low rate of recurrence of the benign cyst [26]. Leakage of ethanol into the peritoneal cavity, however, can cause chemical irritation and adhesion formation. In theory, ethanol can cause damage to the ovarian cortex and the germ cells [26]. However, in a retrospective study of 45 women treated with transvaginal ethanol sclerotherapy, the rates of pregnancy, term deliveries, abortion, and retrieved oocytes or quality of embryos were similar to those of control women [25]. Systemic acute alcoholism has also been reported [27]. Laparoscopic Aspiration of Endometrioma Aspiration of endometrioma by laparoscopy allows the surgeon to perform a thorough irrigation and removal of its contents. Furthermore, evaluation of the whole abdominal cavity can be done. The diagnosis is more accurate, and the endometriosis can be staged and excised. However, similar to ultrasound drainage of ovarian endometrioma, laparoscopic aspiration is associated with a high recurrence rate. The reported recurrence rate is 21% to 88% at 6 months’ follow-up [28–30]. Donnez et al. [31] studied the effect of gonadotropin-releasing hormone-agonist (GnRH-a) after laparoscopic fenestration and drainage of endometrioma. At second-look laparoscopy 12 weeks later, the size of the

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endometrioma was found to be reduced by 50%. However, all patients subsequently required further surgery for ablation of the cyst wall. Two-Step Eversion Technique Based on the hypothesis that ovarian endometrioma develops as a consequence of invagination of the ovarian cortex and that active endometriosis is often found on the ovarian surface, a two-step laparoscopic technique was proposed [32]. In most cases, the site of the invagination or inversion can be seen as a dimple on the surface of the endometrioma. The first step is biopsy of the endometriotic lesion, adhesiolysis, wide opening of the inversion site, and excision of the endometriotic rings. The second step is performed 2 to 3 months after the first laparoscopy. Laparoscopic adhesiolysis and coagulation of the neovascularization and the endometriotic implants are then performed. In 18 patients, Brosens et al. reported no recurrence [32]. The drawback of this technique is the need for two laparoscopic procedures. Laparoscopic Fenestration and Ablation of the Cyst Wall Several studies have shown that laparoscopic treatment of ovarian endometrioma is as effective or better than that by laparotomy [33,34]. However, the choice of laparoscopic techniques remains controversial [35]. In general, endometrioma is removed by excising the endometriotic cyst. Some authors prefer fenestration followed by ablation of the cyst wall using laser or electrocoagulation. The proponents of this technique believed it is associated with minimal loss of viable ovarian cortex and less adhesion formation. Laparoscopic Stripping or Excision of the Endometriotic Cyst Wall Metter and Semm [36] first performed laparoscopic treatment of endometrioma by removal of endometriotic cyst wall. First the content of the endometrioma is drained. The cyst wall is then stripped from the normal ovarian tissue. The recurrence rate after this procedure is 5% to 12%. All the procedures are done in a single laparoscopic setting. In our practice, we try to enucleate the whole endometrioma intact (Fig. 1). However, it often ruptures. In this case, stripping of the cyst wall is performed (Fig. 2). Results of Laparoscopic Fenestration and Ablation, and Excision There have been several studies on the results of different laparoscopic treatments of endometrioma. Most were observational studies; confounding fac-

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FIGURE 1 Laparoscopic enucleation of endometrioma.

tors of postoperative medical treatment were not taken into consideration and the follow-up period was short [29]. In a retrospective study, the authors concluded that laparoscopic ablation is as effective as excision of the cyst wall [37]. Contrary to their findings, we found that the recurrence rate after excision is significantly lower than that after ablation [38]. This could be attributed to several factors. We studied a large number of patients and one laparoscopic surgeon performed excision. Furthermore, instead of using a crude rate, our results are reported using Life Table Analysis, which takes into account patients who already had reoperation and were lost to follow-up at a given time. Our findings support a randomized prospective study that demonstrates the superiority of excision to fenestration and coagulation. The authors found that the recurrence rates of dysmenorrhea, dyspareunia, and pelvic pain were lower and the pregnancy rate was higher in the excision group than in the fenestration group. The recurrence rate of endometrioma was 6.2% in the excision group and 18.8% in the fenestration group. This is in agreement with our reoperation rate at 18 months’ follow-up. The concern of loss of viable

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FIGURE 2 Laparoscopic stripping or excision of endometrioma (the whitish tissue is the wall of the cyst, the darker folded tissue is the inner side of the ovarian tissue).

ovarian tissue with excision is unfounded. Histopathology of the excised tissue in our series revealed absence of follicles in all specimens. Ovarian Response after Conservative Laparoscopic Surgery Some investigators feel that ovarian surgery might have a deleterious effect on the residual normal ovarian cortex. However, in a retrospective study of 820 cycles [39], the outcome of IVF-ET after ablation of ovarian endometrioma was similar to that of tubal factors. The clinical pregnancy rate was 37.4% in the endometrioma group and 34.6% in the tubal-factor group. The number of follicles and the number of mature oocytes were similar between the two

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groups. More importantly, the previously operated ovary had a similar response to the nonoperated contralateral ovary [39]. In a smaller series, Marconi et al. [40] reported similar findings.

SUMMARY Ovarian endometriomas larger than 1 cm do not respond favorably to medical treatment. Aspiration of endometrioma either by ultrasound or laparoscopy leads to a high recurrence rate in a short time. However, endometrioma aspiration before in vitro fertilization might be beneficial to the IVF outcome. The best surgical treatment of ovarian endometrioma is laparoscopic excision of the cyst wall. The procedure is technically more demanding than laparoscopic fenestration and ablation of the cyst wall, but is associated with prolonged symptomatic improvement, a lower recurrence of pelvic pain, and a lower reoperation rate. The pregnancy rate after excision is also higher. Concerns that excision of the endometrioma will result in more adhesion formation and the loss of ovarian follicles are not supported by the results of a randomized study. Studies to date have shown that laparoscopic excision of ovarian endometrioma results in a lower reoperation rate, a lower recurrence of symptoms, and a better improvement of pain compared with the ablation technique.

PRACTICAL POINTS 

Ovarian endometrioma larger than 1 cm do not respond to medical treatment.  Aspiration of endometrioma either by ultrasound or laparoscopy leads to a high recurrence rate in a short time.  Laparoscopic excision of the cyst wall is associated with prolonged symptomatic improvement, a lower recurrence of pelvic pain, a lower reoperation rate, and a higher pregnancy rate than after fenestration and ablation.

REFERENCES 1.

Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue in to the peritoneal cavity. Am J Obstet Gynecol 1927; 14:422– 469.

270 2. 3. 4.

5.

6. 7.

8.

9.

10.

11.

12.

13. 14.

15. 16.

17. 18. 19.

Al-Fozan and Tulandi Al-Fozan H, Tulandi T. Left lateral predisposition of endometriosis and endometrioma. Obstet Gynecol 2002; 101:164–166. Brosens J, Puttemans P, Deprest J. Appearance of endometriosis. Bailliere’s Clin Obstet Gynecol 1993; 7:741–757. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997; 68:585–596. Meyer R. Uber den stand der frage der adenomyositis und adenomyome im allgemeinen und insbesondere uber adenomyositis seroepithelialis und adenomyometritis sarcomatosa. Zentralbl Gynakol 1919; 36-:754. Meyer R. Zur Frage der Urnieren-Genese von Adenomyomen. Zentralbl Gynakol 1923; 15:577–587. Nezhat F, Nezhat C, Allan CJ, Metzger DA, Sears DL. Clinical and histologic classification of endometriosis implantation for a mechanism of pathogenesis. J Reprod Med 1992; 37:771–776. Dlugi AM, Loy RA, Dieterle S, Bayer S, Seibel M. The effect of endometriomas on in vitro fertilization outcome. J In-Vitro Fertil Embryo Transfer 1989; 6: 338–341. Wardle PG, McLaughlin EA, McDermont A, Mitchell JD, Ray BD, Hull MGR. Endometriosis and ovulatory disorder. Reduced fertilization in vitro compared with tubal and unexplained infertility. Lancet 1985; 2:236–239. Olivennes F, Feldberg D, Liu HC, Cohen J, Moy F, Rosenwaks Z. Endometriosis: A stage by stage analysis—the role of in vitro fertilization. Fertil Steril 1995; 64:392–398. Isaacs JD, Hines RS, Sopelak VM, Cowan BD. Ovarian endometriomas does not adversely affect pregnancy success following treatment with in vitro fertilization. J Assist Reprod Genet 1997; 12:2282–2285. Dicker D, Goldman JA, Feldberg D, Ashkenazi J, Levy T. Transvaginal ultrasonic needle-guided aspiration of endometriotic cysts before ovulation induction for in vitro fertilization. J In-Vitro Fertil Embryo Transfer 1991; 8:286–289. Heaps JM, Nieberg RK, Berek JS. Malignant neoplasm arising in endometriosis. Obstet Gynecol 1990; 75:1023–1028. Vignali M, Infantino M, Martrone R, Vignali M, Infantino M, Matrone R, Chiodo I, Semolina E, Busch M, Viand P. Endometriosis: Novel etiopathogenetic concept and clinical perspectives. Fertil Steril 2002; 78:665–678. Shaw RW. The role of GnRH analogues in the treatment of endometriosis. Br J Obstet Gynecol 1992; 99:9–12. Muzii L, Marana R, Carina P, Mancuso S. The impact of preoperative gonadotropin releasing hormone agonist treatment on laparoscopic excision of ovarian endometriotic cysts. Fertil Steril 1996; 65:1235–1237. Scheme RS. Gonadotropin-releasing hormone analogs in the treatment of endometrioma. Am J Obstet Gynecol 1990; 162:579–581. Shaw RT. Treatment of endometriosis. Lancet 1992; 340:1267–1271. Aboulghar MA, Mansour RT, Serour GI, Rizk B. Ultrasonic transvaginal aspiration of endometriotic cysts: an optional line of treatment in selected cases of endometriosis. Hum Reprod 1991; 6:1408–1410.

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20. Zanetta G, Lissoni A, Valle CD, Trio D, Pittelli M, Rangoni G. Ultrasoundguided aspiration of endometriomas: Possible applications and limitations. Fertil Steril 1995; 64:709–713. 21. Giorlandino C, Taramanni C, Muzii L, Santillo E, Nanni C, Vizzone A. Ultrasound-guided aspiration of ovarian cysts. Int J Gynecol Obstet 1993; 43:41–44. 22. Muzii L, Marana R, Caruana P, Catalano GF, Mancuso S. Laparoscopic findings after transvaginal ultrasound-guided aspiration of ovarian endometriomas. Hum Reprod 1995; 10:2902–2903. 23. Garvey T, Kazer R, Milad M. Severe pelvic adhesions following attempted ultrasound-guided drainage of bilateral ovarian endometriomas: Case report. Hum Reprod 1999; 14:2748–2750. 24. Noma J, Yoshida N. Efficacy of ethanol sclerotherapy for ovarian endometriomas. Int J Gynecol Obstet 2001; 72:35–39. 25. Koike T, Minakami H, Motoyama M, Ogawa S, Fujiwara H, Sato I. Reproductive performance after ultrasound-guided transvaginal ethanol sclerotherapy for ovarian endometriotic cysts. Eur J Obstet Gynecol 2002; 1005:39–43. 26. Okagaki R, Osuga Y, Momoeda M, Tsutsumi O, Taketani Y. Laparoscopic findings after ultrasound-guided transvaginal ethanol sclerotherapy for ovarian endometrial cyst. Hum Reprod 1999; 14:270. Letters to the editor. 27. Tei A, Ueki M, Yokono S, Ogli K. Acute alcoholism after ethanol fixation for ovarian chocolate cyst. Masui-Jap J Anesthesiol 1996; 45:496–499. 28. Marana R, Caruana P, Muzii L, Catalano GF, Mancuso S. Operative laparoscopy for ovarian cyst: Excision versus aspiration. J Reprod Med 1996; 41: 435– 438. 29. Fayez J, Vogel M. Comparison of different treatment methods of endometriosis by laparoscopy. Obstet Gynecol 1991; 78:660–665. 30. Vercellini P, Vendola N, Bocciolone L, Colombo A, Rognoni M, Bolis G. Laparoscopic aspiration of ovarian endometrioma: Effect of postoperative gonadotropin releasing hormone agonist treatment. J Reprod Med 1992; 37:577–580. 31. Donnez J, Nisolle M, Gillerot S, Anaf V, Clerckx-Braun F, Casanas-Roux F. Ovarian endometrial cyst: The role of gonadotropin-releasing hormone agonists and/or drainage. Fertil Steril 1994; 62:63–66. 32. Brosens I. Management of ovarian endometriomas and pregnancy. Fertil Steril 1999; 71:1166–1167. 33. Catalano GF, Marana R, Caruana P, Muzzi L, Mancuso S. Laparoscopy versus microsurgery by laparotomy for excision of ovarian cyst in patients with moderate or severe endometriosis. J Am Assoc Gynecol Laparosc 1996; 3:267– 270. 34. Milingos S, Loutradis D, Kallipolitis G, Liapi A, Drakakis P, Antsaklis A, Michalas S. Comparison of laparoscopy with laparotomy for the treatment of extensive endometriosis with large endometriomata. J Gynecol Surg 1999; 15: 131–136. 35. Jones KD, Sutton CJG. Endometriotic cysts: The case for ablative laparoscopic surgery. Gynaecol Endosc 2002; 10:1–8. 36. Metter L, Semm K. Three steps medical and surgical treatment of endometriosis. Isr J Med Sci 1993; 152:204.

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37. Hemmings R, Bissonnette F, Bouzayen R. Result of laparoscopic treatments of ovarian endometriomas: Laparoscopic ovarian fenestration and coagulation. Fertil Steril 1998; 70:527–529. 38. Saleh A, Tulandi T. Reoperation after laparoscopic treatment of ovarian endometrioma by excision and by fenestration. Fertil Steril 1999; 72:322–324. 39. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril 2001; 76:662–665. 40. Marconi G, Vilela M, Quintana R, Sueldo C. Laparoscopic ovarian cystectomy of endometrioma does not affect the ovarian response to gonadotropin stimulation. Fertil Steril 2002; 78:876–878.

16 Treatment of Endometriosis-Related Pelvic Pain Kevin Jones Great Western Hospital Swindon, Wiltshire, England

Christopher Sutton Royal Surrey County Hospital Guildford, Surrey, England

INTRODUCTION Painful symptoms of gynecological origin are most commonly due to endometriosis. Patients may present with chronic, nonmenstrual pelvic pain, dyspareunia, and dyschezia as well as cyclical menstrual pain, dysmenorrhea. These symptoms can be managed medically or surgically. The surgical management may be non conservative, where a total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed, or conservatively, where the endometriotic deposits are ablated or excised laparoscopically leaving the reproductive organs in place. This may be combined with a denervation procedure to relieve painful symptoms. Three denervation procedures have been described: laparoscopic uterine nerve ablation, arcus taurinus, and presacral neurectomy. The objective of this chapter is to review the treatment 273

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of painful symptoms resulting from endometriosis and to discuss the controversies surrounding the management strategies.

EPIDEMIOLOGY The main limitation in trying to accurately measure the true prevalence of this disease is that the definitive diagnosis may only be made by laparoscopic examination. The variable appearance of endometriotic lesions at laparoscopy and the ability of gynecologists to recognize these lesions affect the reported incidence. Access to health care, to contraception, cultural patterns of childbearing, and the attitude toward menses also affects the estimated prevalence. The incidence of endometriosis also varies depending on the type of hospitalbased population being investigated. For example, the diagnosis of endometriosis in patients with pelvic pain ranges from 15% [1] to 71% [2], and in women with pelvic pain and infertility, it is as high as 84% [2]. Despite these limitations, population-based studies have been carried out in the United States and the UK, which have estimated the incidence and prevalence of chronic pelvic pain (CPP). An opinion poll-style telephone survey of women aged 18 to 50 years was carried out in the United States [3]. Pelvic pain for longer than 6 months was reported in 925 of 5325 (17.4%) women. After excluding participants who were pregnant or postmenopausal, and those with cyclical pain, 773 of 5263 (14.7%) CPP sufferers were identified. In the UK, a postal survey was conducted [4]. Women aged 18 to 49 years were randomly selected from the Oxfordshire Health Authority register, and those with CPP of longer than 6 months’ duration unrelated to menstruation, intercourse, or pregnancy were identified. The reported prevalence of CPP was 483 of 2016 (25%). Chronic pelvic pain represents a substantial public health care issue, which is frequently underreported. Among the 483 Oxfordshire women with CPP, 195 (40%) had not sought a medical consultation, 127 (26%) reported a past consultation and 139 (29%) reported a recent consultation for pain [4]. Even when CPP is reported, it is often left untreated or underinvestigated. Data from a national database recording contacts with family doctors found that 28% of women with CPP were not given a specific diagnosis and 60% were not referred to hospital [5]. The true incidence of dysmenorrhea and dyspareunia is also difficult to asses. In the group of women with CPP, dysmenorrhea was also reported by 81% and dyspareunia in 41%. Among women who did not have CPP in the Oxford study [4], dysmenorrhea was reported by 58% women and dyspareunia by 14%. Perhaps the best epidemiological study comes from a general practice survey carried out in Sweden. All 19-year-old girls from the town of Gothe-

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burg were sent a questionnaire to investigate the prevalence of dysmenorrhea. The response rate was 90%, which is exceptionally high for such a survey [6]. As many as 73% of the young girls suffered from primary dysmenorrhea and 15% had severe dysmenorrhea that affected their working ability and could not be controlled adequately by analgesics or ovarian suppression. No studies have investigated the epidemiology of dyspareunia or dyschezia specifically.

MEASURING PELVIC PAIN Quantitative studies of pelvic pain are problematic because pain is a subjective phenomenon, and it is extremely easy for the investigator to influence the outcome of investigations where it is an endpoint. This is especially true if a subjective assessment of pain rather than an objective measure, such as a visual analogue score, is used. Pelvic pain is also a global term, made up of components such as dysmenorrhea, dyspareunia, dyschezia, and chronic nonmenstrual elements and it may have nongynecological causes, including psychological problems [7]. Whether a woman with CPP proves to have endometriosis or no evident disease, there is a high likelihood of a concomitant mood disorder [8]. Furthermore, studies that do not exclude sexually inactive and amenorrhoeic women when the assessment of dysmenorrhea and dyspareunia are made will tend to overreport positive results. Visual Analogue Scores There are many different methods for the measurement of chronic pain [9,10]. However, the most commonly used and well-validated technique for quantifying pelvic pain is a linear analogue score [11–13]. This involves the use of a 10-cm line on a piece of white paper, which represents the continuum of the patients’ opinion of the degree of pain. It is explained to the patient that the one extremity of the line represents ‘‘as much pain as she can possible imagine,’’ whereas the other represents ‘‘no pain at all’’. The patient rates the degree of pain by making a mark on the line. Scale values are then obtained by measuring the distance from zero to that mark. The individual scores for different pain symptoms can then be compared before and after treatment. The one disadvantage of this scoring system is that an especially painful incident can skew the result. Quality of Life Instruments Using quality of life measures (QOL) in clinical practice ensures that treatment focuses on the patient rather than the disease [14]. These psychometric instruments are increasingly being used in studies designed to assess treatment for pelvic pain caused by endometriosis. Quality of life indicators for patients

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with pelvic pain have been validated in a national audit [15] and for patients with dysmenorrhea [16], and to measure outcome after conservative surgery for stage III to IV endometriosis [17]. The impact of CPP on health-related QOL has been assessed by use of the SF-36 questionnaire in a populationbased study in Oxfordshire, UK [4] and among women referred by family doctors to gynecology clinics [18]. The SF-36 has eight subscales that can be compressed into two summary scales—the mental component and the physical component. It is best used to detect trends in mental and physical QOL. Staging Endometriosis and Painful Symptoms The r-AFS score [19] classification of endometriosis divides the disease into stages from minimal to severe (stages I to IV). It is generally agreed that the rAFS classification of disease severity is only of use as a prognostic index with regard to potential infertility. The disease stage does not correlate with the severity of painful symptoms [20,21]. However, the evidence is conflicting because other groups have suggested that endometriosis stage is directly related to the persistence of pelvic pain despite medical or conservative surgical therapy [22]. It is interesting to note that the r-AFS scores at laparoscopy were found to be significantly related to self-assignment into pain or no-pain groups; however, the extent of physical disease was not correlated with ratings of pain levels using standardized measures of behavioral and psychosocial factors [23]. Therefore, how pain is measured is of critical importance when interpreting clinical studies.

BASIC SCIENCE To understand how the treatment of pelvic pain resulting from endometriosis may be effective, it is necessary to understand the underlying etiology and pathophysiology of the common symptoms. Anatomy Pelvic pain is transmitted by the sympathetic and parasympathetic nerves to the pelvic organs. The sympathetic fibers leave the lumbar segments (L1–4) of the spinal cord, and the majority of these fibers form the hypogastric (presacral) plexus, which crosses the sacral promontory and divides into two major pelvic nerve bundles to form the deep pelvic plexus before innervating different pelvic organs. The parasympathetic fibers enter the pelvis through the sacral nerves (S2–S4) and travel along the pelvic nerves (nerve eregentes) to reach the Lee-Frankenhauser plexus in the anterior two-thirds of utero-

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sacral ligaments and its attachment to the cervix. Selective division of these nerve pathways is carried out to relieve painful symptoms. Pathophysiology In the early stage of endometriosis, the release of mediators such as prostaglandins, bradykinins, interleukins, and inflammatory products of macrophages from the endometriotic implants cause painful symptoms, which alter the receptive properties of the nociceptor in the pelvis [24,25]. In the advanced stages, infiltrating endometriosis results in a direct mechanical compression of the nociceptors, particularly around the uterosacral ligaments [2,26]. In addition, the fibrosis, muscular hyperplasia, and scarring around the endometriotic implant can induce ischemic changes resulting in pain. C-type pain receptors, found in the peritoneum and viscera, are activated by chemical and mechanical stimuli. Endometriotic deposits that invade deeply into the underlying tissues may cause mechanical disruption of these fibers, leading to pain, or the surrounding local inflammatory response could affect receptor sensitivity. Ablation or excision of the endometriotic deposits would eliminate the mechanical activation of the receptors from infiltrating disease. They would also remove the stimulus for production of pain-mediating chemicals. The degree of stimulation of pain receptors would decrease, with relief of painful symptoms. Histopathology Deep retroperitoneal endometriosis causes pelvic pain [26], and the intensity of the pain is related to the depth to which the lesion penetrates [2]. However, there is evidence that even when there is no visible evidence of endometriosis at laparoscopy, microscopic deposits can be observed histological [27–29]. Deeply infiltrating endometriosis often involves the uterosacral ligaments [2,30,31]. Histological examination of 32 uterosacral ligament biopsies taken from patients with negative laparoscopies found that 6% of patients had endometriosis [27]. In another study, 15 patients had bilateral uterosacral ligament resection regardless of whether there was clinical suspicion of uterosacral ligament invasion by endometriotuc tissue [32]. Eight patients (54%) had histological involvement of the uterosacral ligaments, and all these patients had complete relief of their symptoms. It would appear that retroperitoneal muscular hyperplasia is responsible for much of the pain in these women. In a series of 51 women treated by radical excision of the uterosacral ligament complex, pain relief occurred in 46 of 50 (92%) with dysmenorrhea and 47 of 51 (92%) with dyspareunia; only 50% showed endometrial glands and stroma, the remainder showing fibromuscular hyperplasia alone [33].

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NONSURGICAL TREATMENT Symptomatic relief of pelvic pain may be achieved pharmacologically or with ‘‘alternative’’ medical therapies. Patient support groups and multidisciplinary teams also have an important role to play in the management of endometriosis sufferers. A detailed discussion of the medical treatment of endometriosis is given elsewhere in this book, and an overview of complementary therapies and the multidisciplinary approach to CPP is presented in this section.

Medical Treatments The introduction of the oral contraceptive pill in the early 1960s and the widespread use of nonsteroidal anti-inflammatory drugs revolutionized the treatment of dysmenorrhea. The development and introduction of danazol, gestrinone, progestagens, and, later, gnRH analogues, allowed menstruation to be abolished. This provided relief from pelvic pain and dysmenorrhea, particularly in cases associated with endometriosis [34]. Recently, aromatase inhibitors have been used to treat pelvic pain resulting from endometriosis [35,36]. All the drugs used to treat endometriosis are associated with unpleasant side effects, and the endometriosis tends to recur after the cessation of therapy [34]. Furthermore, they are contraceptive, and a significant proportion of the patients with pelvic pain are trying to conceive. Because of this, surgery is now regarded as the preferable first line treatment of endometriosis. However, it is worth noting that a course of 3 to 6 months of postoperative treatment with a GnRH has been shown to prolong the pain-free interval after conservative surgery for endometriosis, but failed at 1 to 2 years postoperatively [37]. A recent consensus statement from the chronic pelvic pain/ endometriosis working group in the United States, an expert panel composed of practicing gynecologists and experts in consensus in guide development, have issued a statement that is at variance with this [38]. They suggest that if endometriosis is the suspected cause of pelvic pain, laparoscopic confirmation of the diagnosis is unnecessary and a trial of medical therapy, including second line therapy such as danazol, GNRH antagonists, and progestins, is justified, providing there are no other indications for surgery such as the presence of a suspicious adnexal mass. This recommendation is in complete opposition to current clinical practice, which suggests that laparoscopy is the ‘‘gold standard’’ for the diagnosis of endometriosis, and laparoscopic surgery should be performed under the same anesthetic to eradicate all visible and palpable endometriotic disease either with a CO2 laser [39], electrosurgery and sharp dissection [40], or the ultrasonic scalpel. The end results of surgery are similar regardless of the energy source used and depend more on the experience and preference of the surgeon and careful patient selection [41].

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In a randomized controlled trial conducted in the United States, women treated postoperatively with GNRH analogues had a better outcome than those treated by surgery alone plus placebo, and the effect lasted for up to 12 months [42]. The abolition of menses in the analogue-treated group would inevitably bias the results. Nevertheless a further study by Winkel and Bray [43] followed up 240 women with endometriosis and chronic pelvic pain over 2 years. They underwent excision alone, laser ablation alone, or laser ablation followed by leuprolide acetate for 3 to 6 months. In this nonrandomized trial, only 23% of the ablation group was pain-free at 24 months, whereas 70% of the ablation plus GNRH analogue-treated group remained pain-free after the same time interval [43]. Alternative Medical Treatments and Support Groups Acupuncture can relieve dysmenorrhea, but responses to treatment are variable. Relaxation can be achieved with massage, reflexology, aromatherapy, meditation, hypnotherapy, yoga, and tai chi, and these therapies may help to relieve muscle tension that increases pain. Naturopaths and nutritional therapists recommend a diet rich in omega-3 fatty acids, found in oily fish. Several herbs are traditionally used to relieve uterine and pelvic pain. These include black cohosh, dong quai (Chinese angelica), ginger, pulsatilla, chamomile, cramp bark, and wild yam. Medical herbalists may also include herbs believed to reduce menorrhagia like goldenseal, witch hazel, and dandelion root or milk thistle. For women who have not responded to ‘‘conventional’’ medical and surgical treatment, further management demands strategies beyond the capacity of a general gynecology clinic. Pain clinics offer a multidisciplinary approach and tend to focus on functional capacity and the provision of continuity of care. Services include direct pain-relieving interventions such as tricyclic antidepressants, anticonvulsants, or nerve blockade, as well as cognitive behavioral psychotherapy, physiotherapy, nursing support, and the use of complementary treatments. This ‘‘holistic’’ approach has been shown to be effective in a randomized trial [44]. There are also a number of patient selfhelp groups that play an important part in supporting endometriosis suffers. The National Endometriosis Society and the Endometriosis Association are two examples.

SURGICAL TREATMENT The surgical management of endometriosis may be nonconservative, in which a total abdominal hysterectomy and bilateral hysterectomy (TAH/BSO) is performed or conservative, in which the endometriotic deposits are ablated or excised laparoscopically, leaving the reproductive organs in place. These may

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be described as debulking operations, which may be combined with a denervation procedure to relieve painful symptoms. Three denervation procedures have been described, laparoscopic uterine nerve ablation (LUNA), arcus taurinus (AT), and presacral neurectomy (PSN). Debulking Operations Endometriotic implants may be removed from the pelvis by surgical excision or they may be ablated. Both excision and ablative surgery can be achieved using lasers or electrosurgical devices. Three areas of the pelvis are typically involved in the disease: the pelvic peritoneum, the rectovaginal septum, and the ovary. Endometriosis frequently coexists at all these sites, and different etiologies have been postulated for each. Peritoneal Endometriosis Endometriotic implants can occur throughout the pelvic peritoneum. They have variable appearances [45] and are typically superficial. When endometriosis is limited to the peritoneal surfaces, the r-AFS score is generally less than 40 (minimal–moderate disease). Both the CO2 laser and bipolar electrosurgery can be used to ablate these superficial deposits, which may also be excised with scissors and monopolar electrosurgery. By the early 1980s, it was widely reported that some 60% to 70% of patients experienced pain relief and amelioration of dysmenorrhea and dyspareunia with the ablation of the peritoneal endometriotic implants [46–51]. However these were uncontrolled studies. To obtain grade Ib evidence (Table 1), the Guildford Laser Laparoscopy Trial [52] was carried out. Seventy-four women were recruited, and at the time of laparoscopy were randomly allocated to laser treatment or expectant management. The laser

TABLE 1

Classification of Evidence Levels

Ia

Evidence obtained from meta-analysis of randomized controlled trials. Evidence obtained from at least one randomized controlled trial. Evidence obtained from at least one well-designed controlled study without randomization. Evidence obtained from at least one other type of well-designed quasi-experimental study. Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies, and case studies. Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities.

Ib IIa IIb III

IV

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treatment included vaporization of all visible endometriotic implants, adhesiolysis, and uterine nerve transection. The patients in the sham arm had exactly the same incisions, but merely had a diagnostic laparoscopy. Patients were not informed of which treatment group they had been allocated to, and were followed up at 3 months and 6 months after surgery by an independent observer. Of 74 women who entered the study, 63 (32 laser, 31 expectant) completed the study to the 6-month follow-up visit. At 3 months after operation, there was very little difference between the two groups, but at 6 months the difference reached statistical significance and 62.5% of the patients who had the laser treatment had sustained pain relief. Only 22.6% of the patients who had no treatment said they were better. Patients who had not received any treatment but had an established diagnosis were followed up for 6 to 12 months, and the findings of second-look laparoscopies were reported, together with a comparison of the changes in their symptoms [53]. At second look laparoscopy, 10 (42%) patients had no change in the AFS score and (29%) patients had an increased score. One third of the patients (seven cases) had a reduced r-AFS score. These patients had improved or resolved symptoms, whereas in the others the symptomatology was the same or had become more severe. This study suggests that the disease does progress in the majority of patients, but in up to a third it can regress, and in a few of them it disappeared altogether. A long-term follow-up study of the cohort of patients who underwent laser laparoscopy has been reported [54]. Of the 56 laser-treated patients, 38 (67.9%) were contacted. At the time of follow-up, satisfactory symptom relief was reported in 21 of 38 (55.3%) patients. Rectovaginal Endometriosis Rectovaginal endometriosis with obliteration of the cul de sac involves the uterosacral ligaments, posterior cervix, frequently the rectovaginal septum, and the anterior bowel wall. Different surgical approaches to the laparoscopic management of rectovaginal endometriosis have been described. Donnez et al [55] have described a surgical technique based on the assumption that endometriotic involvement of the rectal muscularis or mucosa does not occur. Their technique is to stay within the uterosacral ligaments and dissect the cervix free from the rectum. Once the rectum is free, the vaginal adenomyoma is removed transvaginally and the defect sutured. Nezhat et al [56] and Reich et al [57] have reported laparoscopic dissection and partial proctectomy using a stapling technique. Redwine [58] describes radical en bloc dissection using unipolar electrodiathermy delivered through 3-mm scissors at high settings (90 watt cutting, 50 watt coagulation). Only when the rectum is mobilized completely and free along its length is the endometriotic area excised. Other groups have also reported variations of these techniques for excising [2,17,59] or ablating [60] deeply infiltrating endometriotic implants.

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There are currently no randomized controlled trials comparing surgery for severe endometriosis (stage IV) with placebo; therefore, we have to rely on IIa or b, III, and IV evidence (Table 1). In a series of 130 women [61] who had undergone aggressive surgical management by laparotomy of advanced colorectal endometriosis including low anterior resection, sigmoid resection, disc excision of the rectal wall, or right hemicolectomy, 90% of the patients reported good relief of their pelvic symptomatology. Resection of the uterosacral ligament at laparotomy has also been reported [32]. In this study, dysmenorrhea, dyspareunia, and dyschezia were relieved in 12 of 15 (80%), 7of 12 (58%), and 8 of 11 (77%) patients, respectively. Eight patients (54%) had histological involvement of the uterosacral ligaments, and all these patients had complete relief of their symptoms. However, a presacral neurectomy was also carried out in 12 of 15 (80%) of these patients. Therefore, this study was not able to separate the effect of debulking the endometriosis from radical denervation. A number of reports in the literature have documented the relief of painful symptoms following laparoscopic surgery for severe disease (r AFS score >40) [17,57,59,62–65]. Some of the studies concerned with stage III– IV endometriosis use pain questionnaires for analyses of dysmenorrhea, dyspareunia, and chronic nonmenstrual pain [17,64,65], and one group applied quality of life indicators to assess outcome as well [17]. Laparoscopic resection of deep endometriosis located in the uterosacral ligaments has also been described [59,66,67]. These authors are reporting the results of excision of the uterosacral ligaments rather than vaporization with the carbon dioxide laser. Laparoscopic bilateral uterosacral ligament resection with excision of all other endometriotic lesions was carried out in 21 patients [66]. Dysmenorrhea, dyspareunia, and chronic nonmenstrual pain were relieved in 16 of 19 (84%), 16 of 17 (94%), and seven of nine (77.7%) patients, respectively. The same group of authors reported a larger series of 85 patients undergoing the same operation [61]. In this study, dysmenorrhea and dyspareunia, were relieved in 46 of 50 (92%) and 47 of 51 (92%) patients, respectively. Furthermore, the efficacy of treatment did not differ according to whether the histological results were positive or negative. The r-AFS score or disease stage did not correlate consistently with the frequency and severity of painful symptoms either. The latest report of 110 patients from the same group continues to support the previous findings [59]. The efficacy of resecting the uterosacral ligament in uncontrolled studies has, therefore, been established. Only 50% of the excised specimens in these studies showed histological proof of endometriosis, and excellent pain relief can be obtained by removal of the fibromuscular hyperplasia; therefore, we have used the CO2 laser to vaporize the abnormal tissue rather than undertake the more lengthy pro-

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cedure such as en-bloc excision with sharp dissection or needle electrosurgery. The CO2 laser has the ability to precisely vaporize tissue with the debris removed by suction in the laser plume or any residual carbon flushed away by the irrigation fluid. We use heparinized Ringers lactate solution at 40jC and leave one liter of 3% Icodextrin (Adeptk, Shire Pharmaceuticals, UK) at the end of the procedure to prevent adhesion formation. In fact, postoperative adhesions are rare after laser vaporization in the rectovaginal septum and uterosacral ligaments, but are more likely when the ovaries are involved. Vaporization must be very thorough and should continue until all the fibromuscular hyperplasia, endometrial glands, and stroma have been removed and there is no further release of hemosiderin. Sometimes it is necessary to continue vaporization to a considerable depth to achieve complete clearance of diseased tissue, but it is easy to see and palpate the endpoint when normal soft retroperitoneal fat has been reached. If the endometriotic nodule extends through to the vagina, the operation is completed by the CO2 laser transmitted by the colposcope, taking care to avoid injury to the rectum [68]. Our preoperative workup includes an air contrast barium enema and vaginogram looked at in the lateral view by an experienced radiologist. If there is evidence of a full thickness penetration, we prefer to advise that the patient undergoes an anterior bowel resection by laparotomy carried out by a colorectal surgeon. We followed up a cohort of 78 women with deep infiltrating endometriosis treated between September 1999 and August 2000. The mean age was 34 (20–51) years. The women were complaining of dysmenorrhea (82%), dyspareunia (88%), dyschezia (64%), and cyclical rectal bleeding (18%). Twelve (15%) had laser laparoscopy to the rectovaginal septum alone and 12 (15%) had vaporization to the uterosacral complex alone. Forty-eight (61%) had the arcus taurinus (uterosacral ligaments and rectovaginal septum) and six (9%) had anterior resection by laparotomy. At 12 months’ follow-up, 72 (92%) were pain-free, and six (8%) were not better. The length of the operation was 32 to 80 minutes (mean 48 minutes), and there were no serious complications, rectal perforations, or ureteric or bladder damage. Endometriotic Cysts The choice of which laparoscopic technique to use in the surgical management of endometriotic cysts remains controversial [69]. There are two main schools of thought. The cyst capsule may be excised (stripped out) or ablated (vaporized) with a laser, or coagulated with bipolar diathermy. A number of reports in the literature document the relief of painful symptoms after endoscopic surgery specifically on patients with endometrio-

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mas [70–74]. These represent IIa or b, III, and IV evidence (Table 1). There is one randomized, controlled trial comparing excision with ablation of endometriotic cysts, grade Ib evidence [75]. We have only been able to identify two studies of pain relief after laparoscopic surgery for endometriomas that analyze dysmenorrhea, dyspareunia, and chronic nonmenstrual pain individually using visual analogue scores [75,76]. In the randomized, controlled trial of Beretta et al, visual analogue scores were used to assess three types of pelvic pain during the followup period of 24 months [75]. This study reported the 24-month cumulative pain recurrence rates after surgery. These were 15.8% versus 52.9% for dysmenorrhea, 20% versus 75% for dyspareunia, and 10% versus 52.9% for chronic nonmenstrual pain in the excision and ablation groups, respectively. The results of the Guildford study [76] are better than those reported by Beretta et al [75] for their ablation group. There may be a number of reasons for this, including the surgical technique, instrument used for ablation, and cyst recurrence rate. A number of other papers have reported pain relief after laparoscopic surgery for endometriomas [70–74]. Unfortunately all these studies lack an objective measurement of pain, such as a visual analogue score. We would argue that these authors are reporting an expression of ‘‘patient satisfaction’’ with the procedure, rather than quantifiable, objective measurements of change. In the Guildford study [76], we found that 64 (87.7%) of our patients were satisfied or very satisfied with the treatment at 12 months, and this compares favorably with these other studies. Denervation Operations There are three denervation procedures described in the literature. They may be used in isolation to achieve relief of painful symptoms or as part of a debulking procedure. The denervation procedures have been the subject of prospective cohort studies, grade IIa or IIb, III, IV evidence (Table 1), and randomized controlled trials, as well as meta-analysis, grade Ia and Ib evidence (Table 1). Laparoscopic Uterine Nerve Ablation In 1954 Joseph Doyle from Massachusetts described the procedure of paracervical uterine denervation by transection of the uterosacral ligaments about 1 cm from their insertion into the posterior aspect of the cervix. He carried out this procedure in an attempt to interrupt the sensory parasympathetic fibers to the cervix and some of the sensory sympathetic fibers to the corpus contained in the cervical division of the Lee-Frankenhauser plexus. Doyle

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reported an 86% success rate for complete pain relief from dysmenorrhea and a 95% success rate for complete or partial relief of pelvic pain in 73 patients followed up from 4 months to 4 years postoperatively [78,79]. In order to carry out a laparoscopic uterine nerve ablation (LUNA) procedure, the posterior leaves of the broad ligament are first examined to identify the course of the ureters and pelvic blood vessels. The uterosacral ligaments can be vaporized near the point of their attachments to the posterior aspect of the cervix with a CO2 laser. A crater about 2 cm in diameter and 1 cm deep is formed. The ligaments can also be excised using a combination of electrosurgery and sharp dissection [80]. Arcus Taurinus A refinement of the LUNA procedure is to laser the posterior aspect of the cervix between the insertions of the ligaments to interrupt fibers crossing to the contra lateral side [81]. If the crater between the uterosacral ligaments is extended, the rectovaginal septum is opened, and all abnormal tissue vaporized, including the entire uterosacral ligament complex, it becomes an arcus taurinus (AT), or ‘‘bull’s horn’’ procedure [82]. By definition, radical excisional or ablative surgery for endometriosis in the pouch of Douglas or rectovaginal septum includes the AT procedure [83–86]. The efficacy of LUNA in uncontrolled studies has been reviewed [80,81,85]. The Guildford study [85] found that 16 of 26 (73%) patients improved after a LUNA procedure. However, 15 of 18 (83%) of those having a complete procedure improved, compared to only 1 of 4 (25%) of those having an incomplete procedure. Furthermore, if the patients are undergoing laser vaporization of endometriosis at the same time [85], 86% of the patients improve. Similar results ranging from 75% to 87% have been reported by other workers [50,81]. In the same study, 26 of 35 (74%) women received a partial LUNA and reported an improvement in their symptoms [85]. The LUNA procedure has also been evaluated in prospective, randomized, and double-blind controlled studies [86–88], and these data have been the subject of a recent Cochrane Review [89]. The first of the studies found that in women with severe dysmenorrhea and no obvious pathology, 9 of 11 patients (81%) underwent LUNA and reported almost complete relief of pain at 3 months’ follow-up. This had fallen to 45% at 12 months, and none of those in the control group reported any benefit [86]. During the randomized, double-blind study carried out in Guildford, 24 women received laser vaporization alone, and 27 received a LUNA procedure in addition [87]. Comparisons were made between the two treatment groups for changes in pain scores at 3 and 6 months. The LUNA treatment group had less benefit from their operation than the group who had

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not had a LUNA procedure. These trends reached significance for dysmenorrhea at 3 months ( P = 0.003) and at 6 months ( P = 0.0217). These findings are in keeping with another recent study that also concluded that the addition of a LUNA gives no additional benefit to performing laser vaporization of endometriosis alone [88]. Presacral Neurectomy Presacral neurectomy (PSN) is another surgical technique that has been used to treat women experiencing midline pelvic pain and dysmenorrhea for almost 100 years [90–93]. The hypogastric plexus of nerves at the sacral promontory can be divided during a laparotomy or laparoscopically. The technique has been described in three recent review articles [81,93,94]. A transverse incision is made in the peritoneum overlying the sacral promontory, extending from the ureter on the right side to the inferior mesenteric and superior hemorrhoidal arteries and sigmoid colon on the left. Connective and fatty tissue containing the nerve plexus is dissected, avoiding the middle sacral artery, and isolated in small longitudinal bunches. These are cauterized in two places 1 cm to 2 cm apart, and removed. Some authors recommend a divisional neurotomy because it is quicker and because it appears to be as effective, rather than the traditional excisional neurectomy [95]. A meta-analysis of the summarized case reports from the literature calculated an overall success rate of 79% [92], and these findings have been substantiated more recently in a Cochrane Review [89]. Nonconservative Operations Painful symptoms resulting from endometriosis may be treated by performing a total abdominal hysterectomy (TAH) if there is no desire to conserve the reproductive organs. This is usually combined with a bilateral salpingooophorectomy (BSO) and postoperative hormone replacement (HRT) therapy in young women. There is no evidence that compared with women who had an oophorectomy for endometriosis, patients who undergo hysterectomy with ovarian conservation have a 6.1 times greater risk of developing recurrent pain and 8.1 times greater risk of reoperation [96]. In view of this, it is illogical to conserve unaffected ovaries because estrogen is a stimulus to growth of ectopic endometrial tissue, and if any ovarian tissue remains the disease is likely to recur in as many as 40% of women at 5 years [97]. If ovarian tissue is conserved at the time of hysterectomy for endometriosis, 25% of patients will require subsequent laparotomies, often more than once [98]. It has also been noted that residual ovarian fragments become functional and stimulate

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recurrence of endometriosis [99]. Therefore it is important to explain to the patient that conservation of the ovary may result in recurrent disease, and that malignant transformation of residual endometriosis has been reported [100]. Women who undergo TAH/BSO for pelvic pain and endometriosis at less than 30 years of age are more likely than older women to have residual symptoms [101]. Furthermore, young patients undergoing a TAH/BSO for endometriosis frequently use an HRT preparation, where the risk of disease recurrence is in the order of 3.5% or 0.9% per year [102]. If endometriosis does recur with painful pelvic symptoms after a TAH/BSO, laparoscopic excision of residual disease is effective in relieving endometriosis-associated pain [103].

SUMMARY Painful symptoms resulting from endometriosis can be managed medically or surgically. Medical therapy provides symptomatic relief while the drugs are being taken, with no long-term cure. Surgical procedures have been shown to provide long-term relief of painful symptoms.

PRACTICAL POINT 

Treatment of endometriosis-related pelvic pain could be medical or surgical, but surgical treatment provides long-term relief.

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92. Black WT. Use of presacral sympathectomy in the treatment of dysmenorrhea. Am J Obstet Gynecol 1964; 89:16–22. 93. Biggerstaff ED, Foster SN. Laparoscopic surgery for dysmenorrhea: Uterine nerve ablation and presacral neurectomy. In: Sutton C, ed. Gynecological Endoscopic Surgery. London: Chapman & Hall, 1997:63–83. 94. Biggerstaff ED. Laparoscopic surgery for pelvic pain. In: Sutton CJG, Diamond MD, eds. Endoscopic Surgery for Gynaecologists. 2d ed. London: WB Saunders, 1998:261–271. 95. Daniell JF, Kurtz BR, Gurley LD, Lalonde CJ. Laparoscopic presacral neurectomy vs neurotomy: Use of the argon beam coagulator compared to conventional technique. J Gynecol Surg 1993; 9:169–173. 96. Namnoum AB, Hickman TN, Goodman SB, Gehlbach DL, Rock JA. Incidence of symptom recurrence after hysterectomy for endometriosis. Fertil Steril 1995; 64:898–902. 97. Wheeler JH, Malinak LR. Recurrent endometriosis: Incidence, management and prognosis. Am J Obstet Gynaecol 1983; 146:247–253. 98. Henderson AF, Studd JWW, Watson N. The retrospective study of oestrogen replacement therapy following hysterectomy for the treatment of endometriosis. In: Shaw RW, ed. Advances in Reproductive Endocrynology: Endometriosis. Carnforth, UK: Parthenon Publishers, 1989:131–140. 99. Dmowski WP, Radwanska E, Rana N. Recurrent endometriosis following hysterectomy and oopherectomy: The role of residual ovarian fragments. Int J Gynecol Obstet 1988; 26:93–103. 100. Jones KD, Owen E, Berresford A, Sutton CJG. Endometrial adenocarcinoma arising from endometriosis of the rectosigmoid colon. Gynecol Oncol 2002. In press. 101. MacDonald SR, Klock SC, Magdy PM. Long-term outcome of nonconservative surgery (hysterectomy) for endometriosis-associated pain in women 862 pg/ml, and female age V 32 years [35], level of evidence 2b [2]. In another cohort study, risk factors were serum estradiol z 1385 pg/ml, odds ratio 1.9 (95% CI 1.3 to 2.8) and seven or more follicles z 16 mm, odds ratio 2.1 (95% CI 1.2 to 3.9) [33]. Ovarian Hyperstimulation Syndrome In the sole randomized comparison of superovulation and IVF, hospitalization for ovarian hyperstimulation syndrome occurred in 2 of 59 IVF subjects and 0 of 59 superovulation subjects [26], P= 0.25, level of evidence 1b [2]. Risk of ovarian hyperstimulation syndrome is likely proportional to the degree of aggressiveness of ovarian stimulation. Birth Defects Birth defects may be increased as a result of IVF. The prevalence of major birth defects in infants born after IVF was 9% compared to 4.2% for infants

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TABLE 3

Tummon TT Approximate Relative Costs of Treatment [39]

Treatment

Pregnancy rate per cycle (%)

Estimated cost per pregnancy, $

1.3–4.1 8.3 17.1 20.7

10,000 17,000 50,000

No treatment Clomiphene/insemination Gonadotropins/insemination IVF

conceived without assisted reproduction, odds ratio 2.0 (95% CI 1.5 to 2.9) [36], level of evidence 1b [2]. There are no data with respect to risk of birth defects and superovulation. Economic Analyses Economic implications of treatment with superovulation/insemination or IVF require consideration, but economic analyses are ‘‘essentially parochial activities’’ [37] and results do not necessarily correlate with costs. When insurance coverage limits access to IVF, this may modify the way treatment is done. With reduced access to IVF, embryo numbers transferred may increase and tend to influence the rate of multifetal pregnancy [38]. Economic analyses are unavailable for treatment of endometriosisassociated subfertility using assisted conception. For unexplained subfertility, superovulation/insemination was more cost-effective than IVF [39], as shown in Table 3, level of evidence 2a [2], [26] level of evidence 1b [2], and [40], level of evidence 1b [2].

FLAWS Diagnosis of Endometriosis Laparoscopy—Reference Standard Laparoscopy is the reference standard for diagnosis and staging of endometriosis [41]. Neither wholly sensitive nor specific, laparoscopy is an invasive act, involving a 0.04% to 0.5% risk of major complications [42]. Laparoscopy also requires anesthesia. Although laparoscopy is a core diagnostic test for more than 85% of United States board-certified reproductive endocrinologists [43], it is a test (and treatment) applied selectively [44] and interpreted subjectively [45].

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307

Gray Scale Ultrasound—Noninvasive Alternative for Diagnosis, if Ovarian Only if endometriosis is ovarian, which usually it is not, is there an accurate, useful, noninvasive alternative for diagnosis. This alternative is gray scale transvaginal ultrasound. Systematic review of the accuracy of gray scale ultrasound for diagnosis of ovarian endometriosis gives positive likelihood ratios ranging from 8 to 30 [46], indicating a useful test, level of evidence 3b [2]. Endometriosis is Not Found Because It is not Looked For When populations are defined as ‘‘unexplained infertility’’ but have not undergone laparoscopy, the prevalence of endometriosis is unknown [12,16]. Such populations represent a mix of subjects with and without endometriosis. Assessment Fails to Stratify by Stage of Endometriosis Without treatment [3,4], after surgery [8], and with superovulation/insemination or IVF [15]. the prognosis for endometriosis-associated subfertility varies with the stage of endometriosis. If the stage of endometriosis is not accounted for in assessment of treatment efficacy [12,33], the power of the study will be limited. Endometriosis is Considered ‘‘Unexplained Subfertility’’ Studies of unexplained subfertility have inclusion criteria with either minimal [26] or minimal/mild endometriosis [47] or surgically treated minimal/mild endometriosis [39]. Heterogeneity of Superovulation In a comparison of two protocols of superovulation/insemination, pregnancy rates were superior with gonadotropins compared with clomiphene citrate/ gonadotropins, relative risk 2.1 (95% CI 1.1 to 4.2) [48], level of evidence 1b [2]. Sample Size Limitations In systematic reviews, even large differences may be hidden owing to studies limited by small sample size and adverse effects such as multifetal pregnancies and ovarian hyperstimulation syndrome are unreported in most studies [27].

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External Validity Low IVF results limit the external validity of the only randomized comparison of superovulation/insemination versus IVF. In a population of young women likely to have a good prognosis, IVF cycle fecundity resulting in live birth was 12% [26]. This is well below current levels of endometriosis-specific live birth per treatment cycle 28% [24] and 23% [25] in national IVF registries. This study lacks external validity. Extensive Need for Extrapolation Extrapolation is use of data in situations with important differences from the original study situation. Extrapolations are essential in examining the question of efficacy of IVF or superovulation for endometriosis-associated subfertility. Endometriosis is often not diagnosed; if it is diagnosed, it is often not staged. If endometriosis is diagnosed, if it is staged, it is then sometimes categorized as unexplained subfertility. These circumstances limit our understanding of the prognosis and response to treatment for endometriosis-associated subfertility.

ADVICE Stage of Endometriosis Affects Prognosis Intermediate Prognosis for Minimal/Mild Endometriosis Untreated, the prognosis for minimal/mild endometriosis-associated subfertility is lower than untreated unexplained subfertility [3,4]. A clinical difference appears likely, although pregnancy and birth rates were not statistically different. Starkly Poor Prognosis for Moderate Severe Endometriosis Untreated, the prognosis for moderate/severe endometriosis-associated subfertility is starkly poor. Cumulative live birth rates are 5% (95% CI 0 to 15) after 36 months of untreated observation [3], level of evidence 1b [2]. Treatment Strategy by Stage of Endometriosis Minimal/Mild Endometriosis-Associated Subfertility  

Consider superovulation/insemination, if monitoring can be vigilant. Cancel cycle if more than five mature follicles.

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309



Consider cancellation of cycle if more than three mature follicles and patient age less than 32 years.  Persist for four cycles if response appears normal.  If poor response or no success, advance to IVF. Surgical reduction of minimal/mild endometriosis is primary therapy to enhance fecundity [7]. Superovulation/insemination improves fertility for minimal/mild endometriosis-associated subfertility. Relative benefit of superovulation/insemination over no treatment is a three-to fivefold increase in fecundity, level of evidence 1b [2]. Expected fecundity per cycle, untreated, is 3% and approximately 9% with clomiphene/insemination, and 12% to 15% with gonadotropin/insemination. Danger lurks, however, and after treatment with gonadotropin/insemination, prevalence of high order multifetal pregnancy approximates 8% [33]. For primary prevention of high-order multifetal pregnancy in superovulation/insemination, vigilance in monitoring is essential. Treatment cancellation is strongly suggested if there are five or more mature follicles [35]. Risk of multifetal pregnancy is age dependent and proportionate to ovarian response. Estimates for the critical estradiol thresholds for multifetal pregnancy range from 860 to 1300 pg/ml [33,35]. Estimated crude fecundity per IVF cycle for minimal/mild endometriosis is 40% [15], level of evidence 2b [2], and is not diminished after prior treatment with superovulation/insemination. In national registries, live birth rates for endometriosis are not stratified by stage, and crude fecundity per cycle ranges from 23% to 28% [24,25]. Moderate/Severe Endometriosis-Associated Subfertility 

Consider IVF as first line treatment in assisted reproduction. Implantation rates are unimpaired in patients with endometriosis.  Do not adjust the number of embryos to be transferred on account of a diagnosis of endometriosis. 

Superovulation/insemination for subfertility associated with moderate/ severe endometriosis has a poor prognosis. Cumulative fecundity after six treatment cycles of superovulation/insemination was 10% [15], level of evidence 2b [2]. Using IVF for subfertility associated with moderate/severe endometriosis, cumulative fecundity after three cycles of IVF was approximately 50% [15], level of evidence 2b [2]. As indicated previously, in national registries, live birth rates for endometriosis are unstratified by stage. Live birth rates for endometriosis in toto range from 23% to 28% [24,25].

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Takes Two to Tango Fecundity is best if all subfertility factors are optimized simultaneously. The physician detective cannot limit the focus to endometriosis. PRACTICAL POINT 

Superovulation and insemination could be first considered for minimal and mild endometriosis-related infertility, whereas IVF is more effective in moderate and severe endometriosis.  Superovulation and insemination for minimal and mild endometriosis-related infertility.  IVF for moderate and severe endometriosis-related infertility.

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A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990; 54:1083–1088. Hughes E, Collins J, Vandekerckhove P. Cochrane Database of Systematic Reviews 2002; 4. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: A meta-analysis. Hum Reprod 1997; 12:1865–1872. Sahakyan M, Harlow BL, Hornstein MD. Influence of age, diagnosis, and cycle number on pregnancy rates with gonadotropin-induced controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril 1999; 72:500–504. Burwinkel TH, Buster JE, Scoggan JL, Carson SA. Basal follicle stimulating hormone (FSH) predicts response to controlled ovarian hyperstimulation (COH)intrauterine insemination (IUI) therapy. J Assist Reprod Genet 1994; 11:24–27. Dmowski WP, Pry M, Ding J, Rana N. Cycle-specific and cumulative fecundity in patients with endometriosis who are undergoing controlled ovarian hyperstimulation-intrauterine insemination or in vitro fertilization-embryo transfer. Fertil Steril 2002; 78:750–756. Aboulghar M, Mansour R, Serour G, Abdrazek A, Amin Y, Rhodes C. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril 2001; 75:88–91. Soliman S, Daya S, Collins J, Jarrell J. A randomized trial of in vitro fertilization versus conventional treatment for infertility. Fertil Steril 1993; 59:1239– 1244. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77:1148–1155. Al-Azemi M, Bernal AL, Steele J, Gramsbergen I, Barlow D, Kennedy S. Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosis. Hum Reprod 2000; 15:72–75. Diaz I, Navarro J, Blasco L, Simon C, Pellicer A, Remohi J. Impact of stage IIIIV endometriosis on recipients of sibling oocytes: Matched case-control study. Fertil Steril 2000; 74:31–34. Sung L, Mukherjee T, Takeshige T, Bustillo M, Copperman AB. Endometriosis is not detrimental to embryo implantation in oocyte recipients. J Assist Reprod Genet 1997; 14:152–156. Alsalili M, Yuzpe A, Tummon I, Parker J, Martin J, Daniel S, Rebel M, Nisker J. Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization:>5000 cycles at one centre. Hum Reprod 1995; 10:470–474. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998; 339:573–577. Centers for Disease Control and Prevention. Assisted Reproductive Technology Reports 2000. Assisted Reproductive Technology Success Rates. National Summary and Fertility Clinic Reports, 2000:27 http://www.cdc.gov/nccdphp/drh/ ART00/PDF’s/ART2000.pdf.

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31. 32.

33.

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40.

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42. Munro MG. Laparoscopic access: Complications, technologies, and techniques. Curr Opin Obstet Gynecol 2002; 14:365–374. 43. Glatstein IZ, Harlow BL, Hornstein MD. Practice patterns among reproductive endocrinologists: The infertility evaluation. Fertil Steril 1997; 67:443–451. 44. Tanahatoe SJ, Hompes PGA, Lambalk CB. Investigation of the infertile couple: Should diagnostic laparoscopy be performed in the infertility work up programme in patients undergoing intrauterine insemination? Hum Reprod 2003; 18:8–11. 45. Stripling MC, Martin DC, Chatman DL, Zwaag RV, Poston WM. Subtle appearance of pelvic endometriosis. Fertil Steril 1988; 49:427–431. 46. Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol 2002; 20:630–634. 47. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, Hill JA, Mastroianni L, Buster JE, Nakajima ST, Vogel DL, Canfield RE. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340:177–183. 48. Ransom MX, Doughman NC, Garcia AJ. Menotropins alone are superior to a clomiphene citrate and menotropin combination for superovulation induction among clomiphene citrate failures. [comment]. Fertil Steril 1996; 65:1169–1174. 49. Nulsen JC, Walsh S, Dumez S, Metzger DA. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstet Gynecol 1993; 82:780–786. 50. Tummon IS, Asher LJ, Martin JSB, Tulandi T. Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil Steril 1997; 68:8–12.

18 Does Endometriosis Affect the Results of In Vitro Fertilization? Simon M. Kelly, William M. Buckett, and Seang Lin Tan McGill University Montreal, Quebec, Canada

Endometriosis is commonly linked to infertility. As a disease entity it affects around 10% of all women of reproductive age but as many as 20 to 40% of women who seek help with infertility [1,2]. The exact mechanism by which endometriosis impairs fertility remains elusive and it is most likely a multifactorial effect. In moderate or severe endometriosis, patients may have anatomic distortion of the fallopian tubes or significant damage to the ovaries. In these situations, it is clear how fertility may be adversely affected. The mechanism of fertility impairment associated with milder forms of endometriosis is less apparent. Several factors have been implicated in the pathophysiology of endometriosis-related subfertility. These include various local paracrine chemicals, such as interleukins and other cytokines, autoimmune factors, or an altered inflammatory response [3,4]. In some animal and human studies, detrimental influence of endometriosis may be related to oocyte and early embryo quality [5–7]. 315

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Many patients with endometriosis and infertility will require some assistance to conceive. Ultimately a good proportion may require assisted conception in the form of in vitro fertilization (IVF). The aim of this chapter is to review the evidence on whether endometriosis has an impact on the outcome of IVF treatment. This is a controversial issue and is confounded by a number of conflicting studies. INDICATIONS FOR IVF TREATMENT There is little doubt that IVF is a highly successful treatment for a range of fertility problems [8]. In women with endometriosis, the decision to proceed to IVF treatment will depend on a number of factors aside from the endometriosis itself. These will include the age of the female, duration of infertility, presence of any coexisting diagnosis, and a history of any previous fertility treatment. When these factors allow, more conservative therapies are generally instituted initially. These may include medical or surgical treatments aimed specifically at the endometriosis or simpler fertility treatments such as intrauterine insemination. In a study by Tummon et al. involving patients with mild endometriosis, superovulation treatment combined with intrauterine insemination proved superior to expectant management. The pregnancy rates were 11% and 2%, respectively, between the two groups [9]. Kodama et al. compared expectant management to IVF treatment in patients with mild to moderate endometriosis. There was a shorter duration to conception in the IVF group (20.6 months vs 27.1 months). In addition, the cumulative conception rate was significantly higher (62% vs 43%) [10]. In patients with more advanced endometriosis, IVF also appears to be more successful than a repeated surgical treatment [11]. In the series by Pagidas et al, the cumulative pregnancy rates at 3, 7 and 9 months after surgery were 5.9%, 18.1%, and 24.4%, respectively, whereas after one or two cycles of IVF, the respective cumulative pregnancy rates were 33.3% and 69.6%. The results of these studies and others demonstrate that assisted reproduction and, in particular IVF, is an effective treatment for endometriosisrelated infertility and in certain cases, limits will often be the treatment of choice. Surgical treatments will only lead to a modest improvement in fertility [12,13]. IVF OUTCOME IN ENDOMETRIOSIS-RELATED INFERTILITY The effect of endometriosis on the success rates of IVF treatment remains an issue of some debate. One of the main problems has been a variety of conflicting studies either demonstrating a negative impact of endometriosis or no impact at all.

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There have been two primary theories for the proposed poor outcome after IVF in patients with endometriosis. First, the oocyte quality is poor, resulting in lower fertilization rates. Second, implantation is impaired either as a result of endometrial dysfunction or combined with poor oocyte or embryo quality. Animal studies using serum from infertile women with endometriosis have shown a direct negative effect on both fertilization and early embryogenesis when compared to serum from fertile women without endometriosis [3]. The effect increased with the severity of endometriosis. This implies that any adverse effect of endometriosis is related to impaired oocyte or embryo quality. In addition, studies involving donor oocytes demonstrated similar implantation or pregnancy rates in recipients with endometriosis compared to recipients with other causes of infertility [4,5]. The initial studies on women with endometriosis undergoing IVF treatment suggested that fertilization rates were lower when compared with either tubal or unexplained infertility [13,14]. Today, many larger studies have shown similar fertilization rates in women with endometriosis compared with women with no endometriosis [15,16]. It has been suggested that the presence of endometriosis impairs implantation [17]. Arici et al. retrospectively studied 35 patients undergoing 89 cycles of IVF treatment. The implantation rate in women with a diagnosis of endometriosis was 3.9% compared with 7.2% and 8.1% in those with unexplained and tubal factor infertility, respectively [17]. The concept of impaired implantation was further supported by another study by Simon et al. that demonstrated reduced implantation and pregnancy rates [18]. Interestingly this study also showed that recipients of donor oocytes had lower implantation rates when the oocytes originated from women with endometriosis. To further confuse the issue, several subsequent studies have refuted the effect of endometriosis on implantation or pregnancy rates. In one of the largest series, Olivennes et al. compared 214 patients with endometriosis undergoing 360 cycles of IVF treatment to a control group of 111 patients with tubal factor infertility. There were no differences in the pregnancy rates between the two groups. The pregnancy rates among subgroups of patients with pure endometriosis, endometriosis, and tubal factor or endometriosis and other factors were also similar [19]. Geber et al. compared patients with endometriosis to those with male factor, unexplained, and tubal factor infertility. The implantation rates and clinical pregnancy rates were not statistically different between the four groups [15]. Of interest, the stage of endometriosis had no impact on the outcome [15,20,21]. It suggests that implantation and pregnancy rates are similar in women with minimal to mild disease as in those with moderate to severe endometriosis. It is interesting to note that whereas many of the earlier studies suggested negative impact of endometriosis on the IVF outcome, more recent

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studies demonstrated minimal or no impact. This may be partly the result of the now almost universal use of gonaotropin-releasing hormone agonists (GnRH-a) before ovarian stimulation during IVF. Chedid et al. evaluated 145 patients with endometriosis and 174 IVF cycles. Compared with those not using GnRHa, the pregnancy rates in women pretreated with GnRH-a 3 weeks or 3 months before IVF were higher. There was no difference in the pregnancy rates between the two durations of GnRH-a [22]. Dicker et al. also demonstrated that prolonged treatment with GnRH-a before IVF was superior to IVF without GnRH-a therapy in patients with endometriosis [23]. Marcus and Edwards showed that pregnancy rates were higher when patients with endometriosis were pretreated with prolonged GnRH-a as opposed to the short or ultrashort GnRH-a treatment [24]. However, it is also known that regardless of the diagnosis, the IVF pregnancy rates with long protocol GnRH-a are superior to either not using GnRH-a or the short protocols [25,26]. Whether longer treatment with GnRH-a compared to the standard long protocol will improve the results remains unknown. In a small study, Surrey et al. suggested that a 3-month course of GnRH a before ovarian stimulation in patients with endometriosis led to improved pregnancy rates compared with a standard midluteal GnRH a protocol [27]. OVARIAN ENDOMETRIOMA AND IVF Ovarian endometriomas are relatively common in infertile women. They are unresponsive to medical therapy and often require surgical removal. It has been proposed that endometriomas in particular have a detrimental effect on the outcome of IVF. This is either as a result of the presence of the endometrioma itself or the damage to surrounding ovarian tissue after surgical treatment [28,29]. Nargund et al. showed that women who had had an ovarian cystectomy had lower pregnancy rates after IVF compared with a control group of women who had not had ovarian surgery. In addition the number of oocytes collected from the ovary that had been operated on was significantly lower than from the contralateral ovary. There was no difference in oocyte yield from either ovary in women who had not had surgery [30]. More recent evidence would suggest that the surgical method used might have an impact on subsequent response during IVF treatment. Donnez et al. evaluated 85 women undergoing IVF after fenestration and ablation of the endometrioma and a control group of 289 women with tubal factor infertility. The pregnancy rates were similar [31]. The effectiveness of this technique at minimizing any damage to the surrounding ovarian tissue and limiting any effect on subsequent IVF treatment also has been supported by a number of other studies [32–34].

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It should be remembered, however, that the presence of endometrioma increases the risk of infection after oocyte collection. This is especially the case when the endometrioma is punctured during the collection. Several case reports have shown that ovarian abscess formation and prophylactic antibiotics should be used in these situations [35,36]. From a practical point of view, the question of whether endometriosis has a significant effect on the outcome of IVF remains unclear. However a recent meta-analysis has perhaps given us the most comprehensive assessment of this issue [37]. This meta-analysis included 22 studies involving 2377 women with endometriosis and 4383 women without endometriosis undergoing IVF treatment (Table 1). The results suggest that the chance of achieving a pregnancy is lower for patients with endometriosis (odds ratio of 0.56 compared to tubal factor infertility). When compared to other diagnoses, endometriosis results in a 19% reduction in the chance of pregnancy (Fig. 1). Furthermore, multivariate analysis demonstrated reduced rates of fertilization and implantation for patients with endometriosis. The number of oocytes collected from women with endometriosis was significantly lower. Also, the pregnancy rates in women with severe endometriosis were lower than those with mild disease (odds ratio of 0.60). Accordingly, if endometriosis has an effect, it primarily impairs the developing follicle, oocyte, and early embryo rather than a direct effect on the uterine environment. One potentially confounding factor for many of these studies is the possibility that the control groups may have had endometriosis. It is not clear whether the control groups had endometriosis conclusively excluded by laparoscopy before IVF treatment. Whether endometriosis may have an adverse effect on the uterine environment, especially in the context of controlled ovarian hyperstimulation (COH) during IVF, is unclear. In a small study, Check et al. evaluated the outcomes from a shared oocyte program [38]. The pregnancy rates were similar in recipients receiving oocytes from donors with or without endometriosis. However, there was a trend to lower pregnancy rates in the donors with endometriosis [38]. Previous studies [4,5] had demonstrated that recipients with endometriosis had no reduction in pregnancy rates, suggesting that endometriosis may adversely effect the uterine environment when COH is used. An adverse effect on the uterine environment as a result of COH alone has also been implied from previous studies [39,40]. SUMMARY As a disease entity, endometriosis remains somewhat of an enigma. There are still many unanswered questions relating to its etiology, symptomatology, and treatment. Its relation to infertility is clearer, and it is particularly evi-

1984–1988 1988 1988–1990 1990–1993 1991–1993

1991 1992 1992 1994 1995 1995 1995 1995 1996 1996 1996 1997 1997 1998 1998 1998

Gerber et al (35) Olivennes et al (13) Tanbo et al (37) Arici et al (22) Cahill et al (20)a Padigas et al (14) Huang et al (33) Issacs et al (44) Bergendal et al (34) Pal et al (21) Yanushpolsky et al (24) 1990–1994 1993 1993–1997 1994–1997 1994–1997 1994–1995

1988–’91 1988–’92 1986–’94 1988–’94

Patient type

Endo, I-IV by stage Endo, all stages Endo, all stages Endo, all stages Endo, all stages + other infertility factors Endo, all stages Endo, all stages Endo, I Endo, I-II and Endo III-IV Endo, all stages Endo, II-III Endo, I-II and III-IV Endo, all stages and III-IV Endo, all stages Endo, I-II and III-IV Endo, III-IV

Endo, all stages, +/ tubal factor Endo treated, separated by stage I-II and III-IV Endo, all stages Endo, I-IV by stage Endo, II-III Endo, all stages

Excludes medroxyprogesterone acetate study group. Endo = endometriosis; N/A = not available. Barnhart. IVF in endometriosis-associated infertility. Fertil Steril 2002

a

1986 1986

1985 1986 1987 1987

Wardle et al (40) Matson and Yovitch (10) Devroey et al (42) Frydman and Belaisch-Allart (39) Tummon et al (43) Inoue et al (36) Mills et al (38) Simo´n et al (11) Dmowski et al (12)

1981–1984

1985

Chillik et al (23)

1981–1982

Study dates

1983

Publication date

Characteristics of 22 Studies Used in Meta-analysis

Mahadevan et al (41)

Reference

TABLE 1

129 236 265 89 22 37 75 147 65 85 37

240 309 62 96 119

17 154 16 53

39

14

No. of cycles

Tubal Tubal Tubal Tubal Tubal Tubal Tubal None Tubal None N/A

factor

factor factor factor factor factor factor factor

None All other infertility Tubal factor Tubal factor All other infertility

Tubal factor Tubal factor None Tubal factor

None

Tubal factor

Control type

1,139 160 331 147 48 414 60 0 98 0

0 372 122 96 118

47 40 0 933

0

261

No. of cycles

320 Kelly et al.

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FIGURE 1 Unadjusted meta-analysis of odds of pregnancy in endometriosis patients versus tubal factor controls. Barnhart. IVF in endometriosis-associated infertility. From Ref. 37.

dent when its effect on IVF outcome is considered. Many studies have, unfortunately, resulted in conflicting results, making it difficult for clinicians to counsel such patients adequately. The recent meta-analysis by Barnhart [37] is likely to represent the most up-to-date and detailed review of the impact of endometriosis. It implies a significant negative effect of endometriosis on the likelihood of achieving pregnancy after IVF treatment, compared to other infertility diagnoses. This should not detract from the fact that IVF remains a highly suitable and successful treatment for endometriosis related infertility. It offers a significantly better chance of conception than medical or surgical treatment and is superior to other forms of assisted conception. Patients should be offered IVF treatment with a minimum of delay. PRACTICAL POINT 

IVF is the most successful treatment for endometriosis related infertility.

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30. Nargund G, Cheng WC, Parsons J. The impact of ovarian cystectomy on ovarian response to stimulation during in-vitro fertilization cycles. Hum Reprod 1996; 11:81–83. 31. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril 2001; 76:662–665. 32. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparascopic ovarian cystectomy for endometriotic cysts of >3 cm in diameter. Hum Reprod 2001; 16: 2583–2586. 33. Marconi G, Vilela M, Quintana R, Sueldo C. Laparascopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotropin stimulation. Fertil Steril 2002; 78:876–878. 34. Jones KD, Sutton CJ. Pregnancy rates following ablative laparascopic surgery for endometriomas. Hum Reprod 2002; 17:782–785. 35. Padilla SL. Ovarian abscess following puncture of an endometrioma during ultrasound guided oocyte retrieval. Hum Reprod 1993; 8:1282–1283. 36. Yaron Y, Peyser MR, Samuel D, Amit A, Lessing JB. Infected endometriotic cysts secondary to oocyte aspiration for in-vitro fertilization. Hum Reprod 1994; 9:1759–1760. 37. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77:1148–1155. 38. Check JH, Maze C, Davies E, Wilson C. Evaluation of the effect of endometriosis on oocyte quality and endometrial environment by comparison of donor and recipient outcomes following embryo transfer in a shared oocyte program. Fertil Steril 2002; 76:S201. 39. Check JH, Choe JK, Katsoff D, Summers-Chase D, Wilson C. Controlled ovarian hyperstimulation adversely effects implantation following in vitro fertilization-embryo transfer. J Assist Reprod Gen 1999; 16:416–420. 40. Sterzik K, Dallenbach C, Schneider V, Sasse V, Dallenbach-Hellweg G. In vitro fertilization: The degree of endometrial insufficiency varies with the type of ovarian stimulation. Fertil Steril 1988; 50:457–462.

Index

Add-back therapy, 226 Adhesion molecule, 129 Animal model, 81, 92 Antibody: antiendometrial antibody, 137, 138 antiphospholipid, 152 Antiprogesterone, 176 Appearance: black lesions, 21 deep endometriosis, 4, 10 macroscopic, 85 microscopic, 85 subtle endometriosis, 2, 8, 74 typical endometriosis, 3, 8 white lesions, 21 Aromatase: aromatase expression, 139, 192, 194

[Aromatase] aromatase inhibitor, 176, 189, 196 Aspiration of endometrioma, 265 Baboon, 85, 92 Barium enema, 32 CA-125, 124–125, 127, 130 CA19-9, 128 Cancer, 10 Cellular immune response, 101 Classification, 6, 34, 50, 72 Cloning, 61 Coagulation, 76 Cyst, 3, 10, 263, 283, 318 (see Endometrioma) Cytokeratines, 139 325

326 Cytokines: as a screening tool, 135 chemistry, 131 cytokines, 104, 105, 131, 132, 193 individual, 133 peritoneal fluid, 132 Danazol, 171, 224 Definition, 70 Denervation, 284 Detoxifixation mechanism, 60 Embryo toxicity, 156 Endometrioma 263, 318 Endometrium, 195 Epidemiology, 1, 274 Estrogen, 190, 191, 196, 227, 228, 231 Excision, 76 Fallopian tube, 47 Fenestration and ablation, 266 Genetics, 55, 139 Gestrinone, 171 GnRH: agonist, 173, 174, 198, 219, 221, 227, 237 antagonist, 175, 219, 237 Growth factors, 104, 193

Index Immunotherapy, 99 Implantation, 156, 158, 178 Infertility, 90, 109, 151, 178, 209, 315, 295 Inflammatory changes, 109 Interleukin, 104, 133, 135 Intravenous pyelography, 34 In-vitro fertilization 264, 295, 300, 315 Laparoscopic uterine nerve ablation, 284 Lateral predisposition of endometriosis, 50 LUNA, 285 Luteal defect, 157 Luteinized unruptured follicle, 90, 91 Lymphocytes, 102 Macrophages, 101, 152 Magnetic resonance imaging, 34 Malignancy, 254, 264 Markers: genetic, 139 immunologic marker, 131 peritoneal markers, 123 serum markers, 123 Metaplasia theory, 6 Monocyte chemotactic protein, 106 Natural killer cells, 101

Hormones: after surgery, 253, 255 dysregulation, 156 hormonal pathway, 60 hormonal therapy, 168, 219 hormone receptors, 140 hormones, 60, 140, 207 Humoral immune response, 102, 103 Hypothesis of evolution, 22 Hysterectomy, 245, 247 Immune modulators, 111, 176 Immunology, 88, 99, 131, 131, 154 Immunosuppression, 88

Oocytes: oocyte development, 156 oocyte maturation, 155 sperm-oocyte interaction, 152, 155 Oophorectomy, 245, 247 Oral contraceptives, 160 Oxidative stress, 25, 138 Pain, 76, 110, 207, 273 Pathophysiology, 6, 19, 50, 88, 100, 206, 277 Polypeptides, 125, 130, 193

Index Presacral neurectomy, 286 Prevalence, 8 Primate model, 83 Progestins, 169–170, 203, 224, 233 Pseudopregnancy, 169 Pulmonary endometriosis, 50 RANTES, 107, 135, 193 Receptor, 206 Rectovaginal endometriosis, 19, 31, 71 Recurrence, 211 Red lesions, 21 Research aspect, 69, 82 Resistant endometriosis, 246 Retrocervical endometriosis, 31, 73 Retrograde menstruation, 6, 50, 59, 85, 86 Sampson, 6 Sclerotherapy, 265 Screening, 124 Selective progestrerone receptor modulator, 212 Sites of endometriosis: anatomical sites, 45 bladder, 48 bowel, 48 cesarean section scar, 49 cul de sac, 46 episotomy scar, 49 extrapelvic, 49 ovarian endometriosis, 19, 27, 46, 263, 315 perineal endometriosis, 49 peritoneal endometriosis, 19 rectovaginal endometriosis, 19, 31, 71, 281 retrocervical endometriosis, 31, 73

327 [Sites of endometriosis] umbilical endometriosis, 50 vaginal endometriosis, 248 Sperm: sperm-oocyte interaction, 152, 155 motility, 155 Spontaneous evolution, 89 Stages, 6, 34, 50, 72, 276 Stripping of endometrioma, 266, 268 Superovulation, 295 Theories, 6, 22 Therapy, 75 (see Treatment) Treatment: add-back therapy, 226 alternative treatment, 279 aromatase inhibitor, 197 combination therapy, 210, 232 empirical treatment, 234 hormonal therapy, 168, 189, 219 medical therapy, 167, 177, 203, 264, 278 need of treatment, 75 progestagen, 203, 205 surgical 179, 250, 251, 265, 266, 279 Tumor necrosis factor, 108, 133, 152, 153 Transrectal sonography, 32 Ultrasonography, 32 Ureter, 48 Vascular endothelial growth factor, 108, 134, 152 White blood cells, 88