Ginecologia Novak's Gynecology

Novak's Gynecology: Jonathan S. Berek, 2002 by Lippincott Williams & Wilkins

Novak's Gynecology Contents Editors Dedication Foreword to the Twelfth Edition Preface to the Thirteenth Edition Preface to the First Edition Contributors

Section I Principles of Practice

Chapter 1: Initial Assessment and Communication Jonathan S. Berek Paula J. Adams Hillard Chapter 2: Principles of Patient Care Joanna M. Cain Chapter 3: Quality Assessment, Performance Improvement, and Patient Safety Joseph C. Gambone Robert C. Reiter Paul A. Gluck Chapter 4: Epidemiology for the Gynecologist Daniel W. Cramer

Section II Basic Science

Chapter 5: Anatomy and Embryology Jean R. Anderson Rene Genadry Chapter 6: Molecular Biology and Genetics Vicki V. Baker Otoniel Martínez-Maza Jonathan S. Berek Chapter 7: Reproductive Physiology Steven F. Palter David L. Olive

Section III Preventive and Primary Care

Chapter 8: Preventive Health Care and Screening Paula J. Adams Hillard Chapter 9: Primary Care in Gynecology Dayton W. Daberkow II Thomas E. Nolan Chapter 10: Family Planning Phillip G. Stubblefield Chapter 11: Sexuality, Sexual Dysfunction, and Sexual Assault David A. Baram Chapter 12: Common Psychiatric Problems Nada L. Stotland

Section IV General Gynecology

Chapter 13: Benign Diseases of the Female Reproductive Tract: Symptoms and Signs Paula J. Adams Hillard Chapter 14: Pelvic Pain and Dysmenorrhea Julie A. Jolin Andrea Rapkin Chapter 15: Genitourinary Infections and Sexually Transmitted Diseases David E. Soper Chapter 16: Intraepithelial Disease of the Cervix, Vagina, and Vulva Kenneth D. Hatch Jonathan S. Berek Chapter 17: Early Pregnancy Loss and Ectopic Pregnancy Thomas G. Stovall Chapter 18: Benign Breast Disease Baiba J. Grube Armando E. Giuliano Chapter 19: Preoperative Evaluation and Postoperative Management Daniel L. Clarke-Pearson Angeles Alvarez Laura Havrilesky Johnathan Lancaster Chapter 20: Incontinence, Prolapse, and Disorders of the Pelvic Floor Shawn A. Menefee L. Lewis Wall Chapter 21: Gynecologic Endoscopy Malcom G. Munro Andrew I. Brill Chapter 22: Hysterectomy Thomas G. Stovall

Section V Reproductive Endocrinology

Chapter 23: Puberty Robert W. Rebar Chapter 24: Amenorrhea Wendy J. Schillings Howard McClamrock Chapter 25: Endocrine Disorders Avner Hershlag C. Matthew Peterson Chapter 26: Endometriosis Thomas M. D'Hooghe Joseph A. Hill Chapter 27: Infertility Mylene W. M. Yao Daniel J. Schust Chapter 28: Recurrent Pregnancy Loss Daniel J. Schust Joseph A. Hill Chapter 29: Menopause William W. Hurd Lawrence S. Amesse John F. Randolph, Jr.

Section VI Gynecologic Oncology

Chapter 30: Uterine Cancer John R. Lurain Chapter 31: Cervical and Vaginal Cancer Thomas C. Krivak John W. McBroom John C. Elkas Chapter 32: Ovarian Cancer Jonathan S. Berek Chapter 33: Vulvar Cancer Christine H. Holschneider Jonathan S. Berek Chapter 34: Gestational Trophoblastic Disease Ross S. Berkowitz Donald P. Goldstein Chapter 35: Breast Cancer Dean T. Nora Armando E. Giuliano Appendix: Reference Values

Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak's Gynecology

Editor

Jonathan S. Berek, MD, MMSc Professor and Chair, College of Applied Anatomy Executive Vice Chair, Department of Obstetrics and Gynecology Chief, Division of Gynecologic Oncology David Geffen School of Medicine at UCLA Los Angeles, California Editorial Assistant Rebecca D. Rinehart Assistant Editors Paula J. Adams Hillard, MD Professor, Departments of Pediatrics, and Obstetrics and Gynecology Director of Women's Health University of Cincinnati College of Medicine Cincinnati, Ohio Eli Y. Adashi, MD Presidential Professor of Obstetrics and Gynecology John A. Dixon Professor and Chair University of Utah Health Sciences Center Salt Lake City, Utah Illustration and Graphic Design Timothy C. Hengst, CMI, FAMI

Dedication To my wife, Deborah, whose love, patience and understanding makes my work possible.

Foreword to the Twelfth Edition

In 1940, Emil Novak published the first edition of what has been known as “Novak's Textbook.” Dr. Novak was a mentor and exemplar to so many of those of us who studied gynecology and gynecologic pathology. He clearly saw the importance of this study and this field of medicine, and he provided each of us who have followed in his footsteps with a wonderful example. To us, Emil Novak was the ultimate doctor, a man who saw the study of medicine as a way to provide aid to those who suffered illness. We are indebted to him for having begun this work, taught so many who have worked in this specialty, and provided the means by which his textbook could carry on his work. It is a pleasure and a privilege to have been asked to pen this foreword, as it has been my pleasure and privilege to have worked on this textbook and to have as colleagues in this endeavor so many superb physicians. Dr. Novak would endorse and be thankful that the text is being updated for your use. He knew, as we do, that the pursuit of academic medicine is imperative to the development of medicine in general and our field in particular. In order to provide you with the same superb resource that Emil Novak began 55 years ago, Novak's Textbook of Gynecology must be updated, and a new generation of men and women must accept his challenge. Medicine as a profession has changed and will continue to change, but the basic message that Emil Novak presented in the first textbook is the same: doctors must be concerned with the welfare of patients, and in order to accomplish this task, they must have access to the latest and best information and training. Jonathan Berek and his colleagues are well schooled in the legacy of Emil Novak and all of those who have worked on this book. It is with confidence in the quality of their work that I endorse this 12th edition of Novak's Gynecology. J. Donald Woodruff, MD Richard W. TeLinde Professor Emeritus Johns Hopkins University School of Medicine Baltimore, Maryland Dr. J. Donald Woodruff passed away in 1996. He was a particularly gifted teacher and clinician who helped guide the development of our specialty. I feel it is important to retain the thoughtful comments he contributed to our twelfth edition for this edition of Novak's Gynecology.

Jonathan S. Berek

Preface to the Thirteenth Edition

Novak's Gynecology, 13th edition, has been thoroughly updated and revised to be certain that its contents and bibliography are current and accurate. Its essence is the same as the original—a comprehensive general textbook in gynecology. The substance reflects the wealth of information that has emerged and evolved during the 62 years since the inception of Novak's Textbook of Gynecology. It is an honor to have been asked to continue to shepherd this important book and I hope will retain its value to inform and assist our colleagues for many years. The textbook, originated by the faculty of the Johns Hopkins University School of Medicine, continues to reflect the contributions of that great institution. The book was inaugurated by Dr. Emil Novak, a pioneer in gynecology and pathology. After the fifth edition and subsequent death of Dr. Novak in 1957, many physicians on the faculty of Johns Hopkins, and subsequently some members of the Vanderbilt faculty, have helped carry the torch—Dr. Edmund R. Novak through the ninth edition in 1979; Drs. Howard W. Jones, Jr. and Georgeanna Seegar Jones through the tenth edition in 1981; and Drs. Howard W. Jones, III, Lonnie S. Burnett, and Anne Colston Wentz through the 11th edition in 1988. These editors, assisted by many contributors who have been faculty at Johns Hopkins, especially Drs. J. Donald Woodruff and Conrad G. Julian, have helped define the specialty of gynecology over the latter half of the 20th century. These physicians and authors are responsible for the ideas that shaped the specialty of gynecology as we know it today—its surgical and medical therapies, reproductive endocrinology, assisted reproductive technologies, gynecologic oncology, urogynecology, and infectious diseases. As a graduate of Johns Hopkins University School of Medicine, I am proud to contribute to that rich tradition. Starting with the twelfth edition, this textbook utilized a new format. The design of the book was established by Dr. Leon Speroff and his colleagues in the textbook Clinical Gynecologic Endocrinology and Infertility and was adapted for the book Practical Gynecologic Oncology. This presentation style should facilitate the study of gynecology for the student as well as the specialist. Novak's Gynecology, 13th edition, is presented in six sections. The first, “Principles of Practice,” includes the initial assessment of the gynecologic patient, the history and physical examination, and communication skills. This section addresses ethical principles of patient care, quality assessment and improvement, and the epidemiology of gynecologic conditions. The second section, “Basic Sciences,” summarizes the scientific basis for the specialty—anatomy and embryology, molecular biology and genetics, and reproductive physiology. The third section, “Preventive and Primary Care,” reflects the importance of primary health care for women, which has evolved to address preventive care, screening, family planning, sexuality, and common psychiatric problems. The fourth section, “General Gynecology,” reviews benign diseases of the female reproductive tract, the evaluation of pelvic infections, pain, intraepithelial diseases, the management of early pregnancy loss and ectopic pregnancy, the evaluation of benign breast disease, and the operative management of benign gynecologic conditions. The fifth section, “Reproductive Endocrinology,” summarizes the major disorders affecting the growth, development, and function of women from puberty through menopause. The sixth section, “Gynecologic Oncology,” covers malignant diseases of the female reproductive tract and breast cancer. I have purposely abbreviated the discussion of the historical development of the subjects in each chapter. Space limitations have required a shift in emphasis from the achievements of the past to the relevant issues of the present. I am especially grateful to the many individuals who contributed to this book. Rebecca Rinehart provided superb editorial assistance, manuscript review, and revision. Drs. Paula Hillard and Eli Adashi served as excellent Assistant Editors. Tim Hengst, an outstanding medical illustrator, designed and created the original artwork. At the publishers, Lippincott Williams & Wilkins, Ms. Lisa McAllister supported the editorial process with great enthusiasm. Working with her, Ray Reter, Steven Martin and the rest of their team skillfully produced the manuscript. Expert secretarial support was provided by Kevin Wong and Sergio Huidor. I acknowledge the efforts of my mentors and colleagues—Dean Sherman Mellinkoff, Drs. J. Donald Woodruff, Kenneth J. Ryan, Isaac Schiff, J. George Moore, William J. Dignam, Gautum Chaudhuri, and Neville F. Hacker. Each of these physicians and scholars provided me with guidance, wisdom, and encouragement during the years we shared at our respective university medical schools. My thanks to Nicole Kidman, the chair of the advisory board for the UCLA Women's Reproductive Cancer Program—whose support and friendship has helped stimulate this project. I hope that this book will be a useful resource for my colleagues and for students of the specialty of gynecology. I look forward to the continued impact of the specialty on the enhancement of health care for women throughout the world.

Jonathan S. Berek

Preface to the First Edition

Since the plan and scope of this book represent something of a departure from those followed in other textbooks of gynecology, the author feels impelled to state the ideas which furnished the incentive for the preparation of this work, and which dictated its character and scope. First of all, no especial apology seems necessary for the combined title. While gynecology was formerly often spoken of as a branch of surgery, this is certainly not its present status. Only a small proportion of gynecological patients require surgical treatment. On the other hand, the biological aspects of gynecology have assumed vast importance, chiefly because of the amazing developments in the field of reproductive physiology and endocrinology. Many of these advances find daily application in the interpretation and management of functional disorders in women. In other words, female endocrinology is now an integral and important part of gynecology and it is so considered in this book. Second, it has always seemed to me that the great majority of readers of textbooks on gynecology must be not at all interested in the details of operative technique, to the consideration of which most authors have devoted many pages. Certainly this applies to the general practitioner, while medical educators are now generally agreed that the medical student should not be burdened with such details in his undergraduate years. Since this book is designed for these two groups primarily, the indication seemed clear to omit the consideration of operative details. The plan followed is to carry the patient up to the point of operation, and to discuss the indications, scope and purpose of the latter, without going into descriptions of the technique itself. Diagnosis and treatment have been accented throughout the book, as I believe most readers would wish. The traditional chapters on anatomy, history-taking, and methods of examination have been boiled down to the essentials. On the other hand, functional disorders, including especially the large group of gynecological endocrinopathies, have been treated rather elaborately, in keeping with the avowed plan of covering the combined fields of gynecology and female endocrinology. The list of references appended to each chapter makes no pretense of exhaustiveness, and preference has been given to publications most worth while, those most recent, and those written in English. The pathological aspects of gynecological disease, so fundamental to a proper understanding of the whole subject, have received adequate but not disproportionate consideration. In the consideration of various endocrine disorders a disturbing problem presented itself. In the discussion of endocrine preparations which might be indicated in treatment, there is no doubt that the mention of various products by their commercial names would have had some advantages. On the other hand, these have appeared to be definitely outweighed by the disadvantages of such a plan, apart from its questionable delicacy. These proprietary preparations are constantly multiplying, and their commercial names are being changed from day to day. For example, there are now well over forty estrogenic preparations on the market. It would be almost impossible, in any enumeration of such therapeutic products, to avoid omission of some of them, and this might be very unfair to products perhaps just as effective as those which might be included. A complete list published today is quite likely to be very incomplete within a few months. The sensible plan seemed to be to rely on the intelligence and initiative of the reader, who should have no difficulty in ascertaining good commercial preparations of estrogen, progesterone, chorionic hormone or any other hormone principle to which reference is made in the treatment of various disorders. It will be noted that the work is devoted to “straight” gynecology and male endocrinology and that it does not include a consideration of disorders in allied fields which concededly obtrude themselves frequently into the practice of the gynecologist. For example, many gynecologists include female urology in their practices, while anorectal and abdominal surgical problems are often encountered, as may be problems in almost any field of medicine. For textbook purposes, however, the line must be drawn fairly sharply, and the reader will naturally expect to go to the proper sources for information in any of these allied fields. In short, the purpose of this book is to present to the reader as much information as is possible in as practical a fashion as possible on the subjects of gynecology and female endocrinology. Whether right or wrong, the ideas behind the book represent the crystallization of many years of teaching and practice in gynecology. The author's goal has been to produce a book which would not only be suited to the needs of the medical student, but which could be carried with him into the practice of his profession. It is a pleasant obligation to express my indebtedness to those who have been helpful to me in the preparation of this book. To a number of my friends, especially Dr. R.B. Greenblatt, of Augusta, Georgia, I am grateful for the loan of illustrations; to Dr. E.L. Krieg, for the excellent colored illustrations as well as for other photographic work; to Mr. Chester Reather, for most of the photomicrographs; to Miss Eva Hildebrandt, technician in the Laboratory of Gynecological Pathology at The Johns Hopkins Hospital and to Sister Mary Lucy, technician at Bon Secours Hospital for help in the preparation of sections for microscopic illustration; to my artist, Miss Frances Shultz, for many of the illustrations; and to my faithful secretary, Miss Helen L. Clayton, for much help throughout the project. For permission to use illustrations which have appeared in previously published articles of my own I am indebted to the publishers of the Journal of the American Medical Association; the American Journal of Obstetrics and Gynecology; Surgery, Gynecology and Obstetrics; and the Bulletin of The Johns Hopkins Hospital. Certain illustrations which appeared in one of my previous books, Gynecological and Obstetrical Pathology, do not have a credit line in the caption. For permission to use these I wish to thank WB Saunders Company, the publishers. Finally, it is a genuine pleasure to acknowledge the efficient and wholehearted cooperation of the publishers, Little, Brown and Co., throughout the preparation of this work.

Emil Novak Baltimore

ContributorsEli Y. Adashi, MD

Presidential Professor of Obstetrics and Gynecology John A. Dixon Professor and Chair Departments of Obstetrics and Gynecology University of Utah Health Sciences Center Salt Lake City, Utah Angeles A. Alvarez, MD Associate Professor Department of Obstetrics and Gynecology Duke University Medical Center Durham, North Carolina Lawrence S. Amesse, MD, PhD Assistant Professor Department of Obstetrics and Gynecology Wright State University Associate Program Director Department of Obstetrics and Gynecology Miami Valley Hospital Dayton, Ohio Jean R. Anderson, MD Associate Professor Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore, Maryland Vicki V. Baker, MD Professor Wayne State University Division of Gynecologic Oncology Harper Hospital Detroit, Michigan David A. Baram, MD Clinical Assistant Professor Department of Obstetrics and Gynecology University of Minnesota School of Medicine Minneapolis, Minnesota Attending Physician Regions Hospital St. Paul, Minnesota Jonathan S. Berek, MD, MMSc Professor and Chair, College of Applied Anatomy Executive Vice Chair, Department of Obstetrics and Gynecology Chief, Division of Gynecologic Oncology David Geffen School of Medicine at UCLA Los Angeles, California Ross S. Berkowitz, MD William H. Baker Professor of Gynecology Harvard Medical School Director of Gynecologic and Gynecologic Oncology Brigham and Women's Hospital Dana Farber Cancer Institute Boston, Massachusetts Andrew I. Brill, MD Professor Obstetrics and Gyncology University of Illionios at Chicago Chief of General Obstetrics and Gynecology Department of Obstetrics and Gynecology University of Illinois Chicago, Illinois Joanna M. Cain, MD University Professor and Chair Department of Obstetrics and Gynecology Oregon Health and Science University Portland, Oregon Daniel L. Clarke-Pearson, MD James M. Ingram Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Duke University Medical Center Durham, North Carolina Daniel W. Cramer, MD, ScD Professor of Obstetrics, Gynecology and Reproductive Biology Department of Obstetrics and Gynecology Harvard Medical School Gynecologist, Department of Obstetrics and Gynecology Brigham and Women's Hospital Boston, Massachusetts Dayton W. Daberkow II Associate Professor of Medicine Internal Medicine Residency Program Director, Louisiana State University Health Science Center New Orleans, Louisiana

Dayton W. Daberkow II Associate Professor of Medicine Internal Medicine Residency Program Director, Louisiana State University Health Science Center New Orleans, Louisiana Thomas M. D'Hooghe, MD, PhD Assistant Professor Department of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Brigham and Women's Hospital Boston, Massachusetts John Christopher Elkas, MD Assistant Professor, Department of Obstetrics and Gynecology Uniformed Services University of the Health Services Bethesda, Maryland Attending Physician, Department of Obstetrics and Gynecology Walter Reed Army Medical Center Washington, DC Joseph C. Gambone, DO, MPH Associate Professor Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California Rene Genadry, MD Associate Professor Department of Gynecology and Obstetrics The Johns Hopkins Medical Institutions Baltimore, Maryland Armando E. Giuliano, MD Chief of Surgical Oncology John Wayne Cancer Institute Santa Monica, California Clinical Professor of Surgery David Geffen School of Medicine at UCLA Director, Joyce Eisenberg Keefer Breast Center Saint John's Hospital and Health Center Santa Monica, California Paul A. Gluck, MD Associate Clinical Professor Department of Obstetrics and Gynecology University of Miami School of Medicine Attending Physician, Department of Obstetrics and Gynecology Baptist Hospital of Miami Miami, Florida Donald P. Goldstein, MD Associate Professor Department of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Department of Obstetrics and Gynecology Brigham and Women's Hospital Boston, Massachusetts Baiba J. Grube, MD Assistant Director Joyce Eisenberg Keefer Breast Cancer John Wayne Cancer Institute Saint John's Health Center Santa Monica, California Kenneth D. Hatch, MD Professor and Head Department of Obstetrics and Gynecology University Medical Center Tucson, Arizona Laura J. Havrilesky, MD Fellow, Department of Obstetrics, Gynecology, and Gynecologic Oncology Duke University Medical Center Durham, North Carolina Avner Hershlag, MD Associate Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology New York University School of Medicine New York, New York Medical Director, Department of Obstetrics and Gynecology North Shore University Hospital Manhasset, New York Joseph A. Hill, MD Reproductive Endocrinologist Fertility Center of New England Reading, Massachusetts Paula J. Adams Hillard, MD Professor, Departments of Pediatrics, and Obstetrics and Gynecology Director of Women's Health University of Cincinnati College of Medicine Cincinnati, Ohio

Paula J. Adams Hillard, MD Professor, Departments of Pediatrics, and Obstetrics and Gynecology Director of Women's Health University of Cincinnati College of Medicine Cincinnati, Ohio Christine H. Holschneider, MD Assistant Professor Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California William W. Hurd, MD Nicolas J. Thompson Professor and Chairman Department of Obstetrics and Gynecology Wright State University School of Medicine Dayton, Ohio Julie A. Jolin, MD Resident, Johns Hopkins Hospital Department of Obstetrics and Gynecology Baltimore, Maryland Thomas C. Krivak, MD Fellow, Gynecologic Oncology Walter Reed Army Medical Center Washington, DC Johnathan Lancaster, MD Associate, Department of Obstetrics and Gynecology Division of Gynecologic Oncology Duke University Medical Center John R. Lurain, MD John and Ruth Brewer Professor of Gynecology and Cancer Research Head, Section of Gynecologic Oncology Northwestern University Medical School Chief, Gynecologic Oncology Department of Obstetrics and Gynecology Northwestern Memorial Hospital/Prentice Women's Hospital Chicago, Illinois Otoniel Martínez-Maza, PhD Associate Professor Departments of Obstetrics and Gynecology, and Microbiology, Immunology, and Molecular Genetics David Geffen School of Medicine at UCLA Los Angeles, California John W. McBroom, MD Fellow, Gynecologic Oncology Walter Reed Army Medical Center Washington, DC Howard D. McClamrock, MD Associate Professor and Director Department of Obstetrics, Gynecology, and Reproductive Sciences Division of Reproductive Endocrinology and Infertility University of Maryland School of Medicine Baltimore, Maryland Shawn A. Menefee, MD Assistant Clinical Professor Department of Reproductive Medicine University of California, San Diego Co-director, Section of Female Pelvic Floor Medicine and Reconstructive Surgery Department of Obstetrics and Gynecology Kaiser Permanente San Diego, California Malcolm Gordon Munro, MD Professor of Clinical Obstetrics and Gynecology Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California Thomas E. Nolan, MD, MBA Professor Departments of Obstetrics, Gynecology, and Medicine Louisiana State University Hospital Center Director Department of Women's and Newborn Services Medical Center of Louisiana New Orleans, Louisiana Dean T. Nora, MD Senior Surgical Oncology Fellow John Wayne Cancer Institute Santa Monica, California David L. Olive, MD Professor, Department of Obstetrics and Gynecology Director, Department of Reproductive Endocrinology and Infertility University of Wisconsin—Madison School of Medicine Madison, Wisconsin Steven F. Palter, MD Medical and Scientific Director

Director, Department of Reproductive Endocrinology and Infertility University of Wisconsin—Madison School of Medicine Madison, Wisconsin Steven F. Palter, MD Medical and Scientific Director Reproductive Medicine and Surgery Center Plainview, New York Clinical Assistant Professor Division of Reproductive Endocrinology and Infertility Yale University School of Medicine New Haven, Connecticut C. Matthew Peterson, MD Associate Professor Division of Reproductive Endocrinology Department of Obstetrics and Gynecology University of Utah Medical Center Director of Reproductive Endocrinology LDS Hospital Salt Lake City, Utah John F. Randolph, Jr., MD Associate Professor Department of Obstetrics and Gynecology University of Michigan Ann Arbor, Michigan Andrea Rapkin, MD Professor Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California Robert W. Rebar, MD Associate Executive Director American Society for Reproductive Medicine Birmingham, Alabama Robert C. Reiter, MD Vice President for Quality Management ProMedica Health Systems Toledo Hospital Toledo, Ohio Wendy J. Schillings, MD Clinical Associate Professor of Obstetrics and Gynecology Pennsylvania State College of Medicine Lehigh Valley Hospital Allentown, Pennsylvania Daniel J. Schust, MD Clinical Fellow Department of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Brigham and Women's Hospital Boston, Massachusetts Anne P. Shapter, MD Gynecologic Oncologist Department of Gynecologic Oncology St. Francis Hospital Hartford, Connecticut David E. Soper, MD Professor and Vice Chairman Departments of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina Nada L. Stotland, MD, MPH Professor Department of Psychiatry and Obstetrics and Gynecology Rush Medical College Chicago, Illinois Thomas G. Stovall, MD Professor Department of Obstetrics and Gynecology University of Tennessee, Memphis Memphis, Tennessee Phillip G. Stubblefield, MD Professor Department of Obstetrics and Gynecology Boston University School of Medicine Boston Medical Center Boston, Massachusetts L. Lewis Wall, MD, DPhil Associate Professor Section of Female Pelvic Medicine and Reconstructive Surgery Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis, Missouri Mylene W. M. Yao, MD

Department of Obstetrics and Gynecology Washington University School of Medicine St. Louis, Missouri Mylene W. M. Yao, MD Assistant Professor Department of Obstetrics and Gynecology Columbia University College of Physicians and Surgeons New York, New York

Chapter 1. Initial Assessment and Communication Novak’s Gynecology

Chapter 1

Initial Assessment and Communication Jonathan S. Berek Paula J. Adams Hillard

Communication Variables that Affect Patient Status Communication Skills History and Physical Examination History Physical Examination Follow-up Summary References

The practice of gynecology requires many skills. In addition to medical knowledge, the gynecologist should develop interpersonal and communication skills that promote patient–physician interaction and trust. The assessment must be of the “whole patient,” not only of her general medical status. It should include any apparent medical condition as well as the psychological, social, and family aspects of her situation. Environmental and cultural issues that affect the patient must be taken into account to view her in the appropriate context. This approach is of value in routine assessments, providing opportunities for preventive care and counseling on a continuing basis, as well as in the assessment of medical conditions.

Communication Good communication is essential to patient assessment and treatment. The patient–physician relationship is based on communication conducted in an open, honest, and careful manner so that the patient's situation and problems can be accurately understood and effective solutions determined. Good communication requires patience, dedication, and practice. The foundation of communication is based on key skills: empathy, attentive listening, expert knowledge, and rapport. These skills can be learned and refined (1). After establishing the initial relationship with the patient, the physician must vigilantly pursue interviewing techniques that create opportunities to foster an understanding of the patient's concerns ( 2). Trust is the fundamental element that encourages the patient to communicate her feelings, concerns, and thoughts openly, without withholding information. Although there are many styles of interacting with patients and each physician must determine the best way that he or she can relate to patients, physicians must convey that they are able and willing to listen and that they receive the information with utmost confidentiality ( 3). The Hippocratic oath demands that physicians be circumspect with all patient-related information.

Variables that Affect Patient Status Many external variables exert an influence on the patient and on the care she receives. Some of these factors include the patient's “significant others”—her family, friends, and personal relationships ( Table 1.1). These external variables also include psychological, genetic, biologic, social, and economic issues. Factors that affect a patient's perception of disease and pain and the means by which she has been taught to cope with illness include her education, attitudes, understanding of human reproduction and sexuality, family history of disease, and, in some cases, need for attention ( 3,4 and 5). Cultural factors, socioeconomic status, religion, ethnicity, and sexual preference are important considerations in understanding the patient's response to her care in both illness and health.

Table 1.1. Variables that Influence the Status of the Patient

We are all products of our environment, our background, and our culture. The importance of ascertaining the patient's general, social, and familial situation cannot be overemphasized (1). The context of the family can and should be ascertained directly. The family history, including a careful analysis of those who have had significant illnesses, such as cancer, must be obtained. The psychological and sexual practices of the patient should be understood, and her functional level of satisfaction in these areas should be determined. The physician must avoid being judgmental, particularly with respect to questions about sexual practices and preferences (see Chapter 11 and Chapter 12).

Communication Skills

It is essential for the physician to communicate with a patient in a manner that allows her to continue to seek appropriate medical attention. Not only the words used, but also the patterns of speech, the manner in which the words are delivered, even body language and eye contact, are important aspects of the patient–physician interaction. The traditional role of the physician has been rather paternalistic, with the physician being expected to deliver direct commands and specific guidance on all matters (1). Patients are now demanding more balanced communication with their physicians, and although they do not in most cases command an understanding of medicine, they do expect to be treated with appropriate deference, respect for their intellect, and a manner more equal in stature with the physician ( 6). There is some evidence that giving the patient more control in the relationship with her doctor can lead to better health outcomes ( 3, 7, 8). Physician–Patient Interaction The pattern of the physician's speech can influence interactions with the patient. Some important components of effective communication between patients and physicians are presented in Table 1.2. For this communication to be effective, the patient must feel that she is able to discuss her problems fully. In addition, if the patient perceives that she participates in the decision and that she is given as much information as possible, she will react to the proposed treatment with lower levels of anxiety and depression. There is ample evidence that patient communication and understanding and treatment outcome are improved when discussions with physicians are more dialogue than lecture. In addition, when patients feel they have some room for negotiation, they tend to retain more information regarding health care plans (9).

Table 1.2 Important Components of Communication between the Patient and Physician: The Physician's Role

The notion of collaborative planning between patients and physicians has developed ( 9). This means that the patient becomes more vested in the process of determining health care choices. For example, if the patient is informed about the risks and benefits of hormone replacement therapy and clearly understands them, she may be more likely to comply with the plan once it has been set jointly by she and her physician. There is some evidence that when patients are heard, understood, more vocal, and more inquisitive, their health improves (2). Good communication is essential for the maintenance of a relationship between the patient and physician that fosters ongoing care. Health maintenance, therefore, can be linked directly to the influence of positive, genial interactions. Patients who are comfortable with their physician may be more likely to raise issues or concerns or convey information about potential health risks and may be more receptive to the physician's recommendations. This degree of rapport may promote the effectiveness of early interactions, including behavior modification. It also helps ensure that patients return for regular care because they feel the physician is genuinely interested in their welfare. When patients are ill, they feel vulnerable, physically and psychologically exposed, and powerless. Because the physician has power by virtue of knowledge and status, this relationship can be intimidating. Therefore, it is essential that the physician be aware of this disparity so that the “balance of power” does not shift too far away from the patient. Shifting it back from the physician to the patient may help improve outcomes ( 3, 7, 8). In assessing the effects of the patient–physician interaction on the outcome of chronic illness, three characteristics that are associated with better health care outcomes have been identified (8): 1. Empathetic physician and more patient control of the interview 2. Expression of emotion by both patient and physician 3. Provision of information by the physician in response to the patient's inquiries These findings related to the control of diastolic blood pressure and the reduction of hemoglobin A 1c in patients with diabetes, who experienced improved function and subjective evaluation of health in the presence of these characteristics. The best responses were achieved when an empathetic physician provided as much information and clarification as possible, responded to the patients' questions openly and honestly, and expressed a full range of emotions, including humor, and when the relationship was not entirely dominated by the physician ( 8). In studies of gender and language, men tend to talk more than women, successfully interrupt women, and control the topics of the conversation ( 10). As a result, male physicians may tend to take control and be more assertive than female physicians. Men's speech tends to be characterized by interruptions, command, and lectures, and women's speech is characterized by silence, questions, and proposals ( 11, 12). Some patients may simply feel more reticent in the presence of a male physician, whereas others may be more forthcoming with a male than a female physician (13). Although these generalizations clearly do not apply to all physicians, they can raise awareness about the various styles of communication. These patterns indicate the need for all physicians, regardless of their gender, to be attentive to their style of speech because it may affect their ability to elicit open and free responses from their patients ( 14, 15). Women tend to speak openly in order to express their feelings and to have them validated and shared in an attempt to gain understanding of their concerns ( 9,10 and 11). With regard to communication relating to gynecologic issues, it is important to understand that different styles of communication may affect the physician's ability to perceive the patient's status and to achieve the ultimate goal of optimal assessment and compliance with medical and surgical therapies. The intimate and highly personal nature of many gynecologic conditions requires particular sensitivity to evoke an honest response. Style In general, the art of communication and persuasion is based on mutual respect and development of the patient's understanding of the circumstances of her health (2). Insight is best achieved when the patient is encouraged to query her physician and when she is not pressured to make decisions ( 3, 9). Patients who feel “backed into a corner” have the lowest compliance with recommended treatments (7). Following are techniques to help achieve rapport with patients: 1. 2. 3. 4.

Use positive language (e.g., agreement, approval, and humor). Build a partnership (e.g., acknowledgment of understanding, asking for opinions, paraphrasing, and interpreting the patient's words). Ask rephrased questions. Give complete responses to the patient's questions.

The manner in which a physician guides a discussion with a patient will determine the patient's level of understanding and her compliance. For example, in providing a prescription, if a command is given to take the medication without a discussion of the rationale for it, patients may not comply, particularly if they become confused about the instructions (9). It is obviously inappropriate to prescribe hormone replacement therapy with a statement of simply, “Just take one of these pills every night

before you go to bed,” without a discussion of the risks and benefits of taking estrogen and progesterone. The style of the presentation of information is key to its effectiveness. The physician should avoid “speaking down” to patients, both figuratively and literally. The latter occurs when discussions take place with the patient in the supine or the lithotomy position. Such a position creates a vulnerable situation in which the patient does not feel she is an equal partner in the relationship. Serious discussions about diagnosis and management strategies should be conducted when the patient is fully clothed and face-to-face with a doctor in a private room, with or without an intervening desk. Body language is also important in interactions with patients. The physician should avoid an overly casual stance, which can communicate a lack of caring or lack of compassion. The patient should be viewed directly and spoken to with eye contact so that the physician is not perceived as “looking off into the distance” ( 2). Laughter and Humor Humor is an essential component that promotes open communication. It can be either appropriate or inappropriate. Appropriate humor allows the patient to diffuse anxiety and understand that (even in difficult situations) laughter can be healthy ( 16). Inappropriate humor would horrify, disgust, or offend a patient or generally make her uncomfortable or seem disrespectful of her. Laughter can be used as an appropriate means of relaxing the patient and making her feel better. Laughter is a “metaphor for the full range of the positive emotions” ( 16). It is the response of human beings to incongruities and one of the highest manifestations of the cerebral process. It helps to facilitate the full range of positive emotions—love, hope, faith, the will to live, festivity, purpose, and determination ( 16). Laughter is a physiologic response, a release that helps us all feel better and allows us to accommodate the collision of logic and absurdity. Illness, or the prospect of illness, heightens our awareness of the incongruity between our existence and our ability to control the events that shape our lives and our outcomes. We use laughter to combat stress, and stress reduction is an essential mechanism used to cope with illness. Strategies for Improving Communication All physicians should understand the art of communication during the medical interview. It is essential that interactions with patients are professional, honorable, and honest. Issues that are important to physicians regarding patient–physician interactions are presented in Table 1.3. Following are some general guidelines that can help to improve communication:

Table 1.3 Importance Attached to the Patient–Physician Relationship

1. 2. 3. 4. 5. 6.

Listen more and talk less. Encourage the pursuit of topics introduced by and important to patients. Minimize controlling speech habits such as interrupting, issuing commands, and lecturing. Seek out questions and provide full and understandable answers. Become aware of discomfort in an interview, recognize when it originates in an attempt by the physician to take control, and redirect that attempt. Assure patients that they have the opportunity to discuss their problem fully.

Recognize when patients may be seeking empathy and validation of their feelings rather than a solution. Sometimes all that is necessary is to be there as a compassionate human being. In conducting interviews, it is important for the physician to understand the patient's concerns. In studies of interviewing techniques, it has been shown that although clinicians employ many divergent styles, the successful ones tend to look for “windows of opportunity” (i.e., careful, attentive listening with replies or questions at opportune times) (2). This skill of communication is particularly effective in exploring psychological and social issues during brief interviews. The chief skill essential to allowing the physician to perceive problems is the ability to listen attentively. An interview that permits maximum transmission of information to the physician is best achieved by the following approach ( 2): 1. 2. 3. 4.

Begin with an open-ended question. As the patient begins to speak, pay attention not only to her answers but also to her emotions and general body language. Extend a second question or comment, encouraging the patient to talk. Allow the patient to respond without interrupting, perhaps by employing silence, nods, or small facilitative comments, encouraging the patient to talk while the physician is listening. 5. Summarize and express empathy and understanding at the completion of the interview. Attentiveness, rapport, and collaboration characterize good medical interviewing techniques. Open-ended questions are generally desirable, particularly coupled with good listening skills (“How are you doing? ” “How does that make you feel?”). Premature closure of an interview and inability to get the complete information to the patient may occur for several reasons ( 2). It may arise from a lack of recognition of the patient's particular concern, from not providing appropriate opportunity for discussion, from the physician's becoming uncomfortable in sharing the patient's emotion, or perhaps from the physician's lack of confidence that he or she can deal with the patient's concern. One of the principal factors undermining the success of the interview is lack of time. However, skilled physicians can facilitate considerable interaction even in a short time by encouraging open communication ( 17). Many patients lack accurate information about their illness. Lack of full understanding of an illness can produce dissatisfaction with medical care, increased anxiety, distress, coping difficulties, noncompliance with treatment, and poor treatment response ( 18,19 and 20). As patients increasingly request more information about their illnesses and more involvement in decisions about their treatment, and as physicians attempt to provide more open negotiation, communication problems become more significant. Poor patient understanding stems from poor communication techniques, lack of consultation time, patient anxiety, patient denial, and in some cases, the withholding of information considered detrimental to patient welfare ( 18). If clinical findings or confirmatory testing strongly suggest a serious condition (e.g., malignancy), the gravity and urgency of this situation must be conveyed in a manner that does not unduly alarm or frighten the individual. Honest answers should be provided to any specific questions the patient may want to discuss (19, 20). Allowing time for questions is important, and scheduling a follow-up visit to discuss treatment options after the patient has had an opportunity to consider the options and recommendations may be valuable (19, 20). The patient should be encouraged to bring a partner or family member with her to provide moral support and to assist with questions. The patient should also be encouraged to write down any concerns she may have and bring them with her because important

issues may not come to mind easily during an office visit. If the patient desires a second opinion or if a second opinion is mandated by her insurance coverage, it should be facilitated. Valuable information can be provided by interviews with ancillary support staff and by providing pamphlets and other materials produced for patient education. Some studies have demonstrated that the use of pamphlets is highly effective in promoting an understanding of the condition and treatment options. Others have shown that the use of audiotapes and videotapes has a positive impact on knowledge and can decrease anxiety ( 18). There are numerous medicine websites on the Internet that can be accessed, although the accuracy of the information is variable and must be carefully reviewed by physicians before recommending to patients. The relationship between the patient and her physician is subject to constant change, as is true of all features of social interchange. The state of our health is dynamic. Many of us are fortunate to be in a good state of health for much of our lives, but some are not so fortunate. The goal of open communication between patient and physician is to achieve maximum effectiveness in diagnosis, treatment, and compliance for all patients. Talk to the heart, speak to the soul. Look to the being and embrace the figure's form. Reach deeply, with hands outstretched. Talk intently, to the seat of wisdom, as life resembles grace. Achieve peace within a fragile countenance. Seek the comfort of the placid hour. Through joyous and free reflection know the other side of the flesh's frame. JSB

History and Physical Examination After a dialogue has been established, the patient assessment proceeds with obtaining a complete history and performing a physical examination. Both of these aspects of the assessment rely on good patient–physician interchange and attention to details. During the history and physical examination, the identification of risk factors that may require special attention should be sought. These factors should be reviewed with the patient in developing a plan for her future care (see Chapter 8).

History After the ascertainment of the chief complaint and characteristics of the present illness, the history of the patient should be obtained. It should include her complete medical and surgical history, her reproductive history (including menstrual history), and a thorough family and social history. A technique for obtaining information about the present illness is presented in Table 1.4. The physician should determine what other consultations may be needed to complete the evaluation. In some cases, referral to a social worker, psychologist, psychiatrist, or sexual counselor would be helpful. These issues are covered in Section III, Primary and Preventative Care (see Chapter 8, Chapter 9, Chapter 10, Chapter 11 and Chapter 12). Laboratory testing for routine care and high-risk factors are presented in Chapter 8.

Table 1.4 Technique of Taking the History of the Present Illness

Physical Examination A thorough general physical examination should be performed during each patient assessment ( Table 1.5). In addition to evaluation of the vital signs, examination of the breast, abdomen, and pelvis is an essential part of the gynecologic examination.

Table 1.5 Method of the Female Pelvic Examination

Abdominal Examination With the patient in the supine position, an attempt should be made to have the patient relax as much as possible. Her head should be leaned back and supported gently by a pillow so that she does not tense her abdominal muscles. The abdomen should be inspected for signs of an intraabdominal mass, organomegaly, or distention that would, for example, suggest ascites or intestinal obstruction. Initial palpation of the abdomen is performed to evaluate the size and configuration of the liver, spleen, and other abdominal contents. Evidence of fullness or mass effect should be noted. This is particularly important in evaluating patients who may have a pelvic mass and in determining the extent of omental involvement, for example, with metastatic ovarian cancer. A fullness in the upper abdomen could be consistent with an “omental cake.” All four quadrants should be carefully palpated

for any evidence of mass, firmness, irregularity, or distention. A systematic approach should be used (e.g., clockwise, starting in the right upper quadrant). Percussion should be used to measure the dimensions of the liver. The patient should be asked to inhale and exhale during palpation of the edge of the liver. Auscultation should be performed to ascertain the nature of the bowel sounds. The frequency of intestinal sounds and their quality should be noted. In a patient with intestinal obstruction, “rushes,” as well as the occasional high-pitched sound, can be heard. Bowel sounds associated with an ileus may be less frequent but at the same pitch as normal bowel sounds. Pelvic Examination The pelvic examination is typically performed with the patient in the dorsal lithotomy position ( Fig. 1.1). The patient's feet should rest comfortably in stirrups with the edge of the buttocks at the lower end of the table so that the vulva can be readily inspected and the speculum can be inserted in the vagina without obstruction from the table.

Figure 1.1 The lithotomy position for the pelvic examination.

The vulva and perineal area should be carefully inspected. Evidence of any lesions, erythema, pigmentation, masses, or irregularity should be noted. The skin quality should be noted as well as any signs of trauma, such as excoriations or ecchymosis. The presence of any visible lesions should be quantitated and carefully described with regard to their full appearance and characteristics on palpation (i.e., mobility, tenderness, consistency). Ulcerative or purulent lesions of the vulva should be cultured as outlined in subsequent chapters, and biopsy should be performed on any lesions. After thorough visualization and palpation of the external genitalia, including the mons pubis and the perianal area, a speculum is inserted in the vagina. In a normal adult who is sexually active, a Pederson or Graves speculum is used. The types of specula that are used in gynecology are presented in Fig. 1.2. In general, the smallest speculum necessary to produce adequate visualization should be used. The speculum should be warmed before it is inserted into the vagina, and warm water generally provides sufficient lubrication for this procedure. The patient should be alerted to the fact that the speculum will be inserted so that she is not surprised by its placement. After insertion, the cervix and all aspects of the vagina should be carefully inspected. Particular attention should also be paid to the vaginal fornices because lesions (e.g., warts) may be present in those areas and are not readily visualized unless care is taken to do so.

Figure 1.2 Vaginal specula: 1, Graves extra long; 2, Graves regular; 3, Pederson extra long; 4, Pederson regular; 5, Huffman “virginal”; 6, pediatric regular; and 7, pediatric narrow.

The appropriate technique for a Papanicolaou's (Pap) test is presented in Chapter 16. Any obvious lesions on the cervix or in the vagina should undergo biopsy. An endometrial biopsy is usually performed with a flexible cannula or a Novak curette (see Chapter 13). Any purulence in the vagina or cervix should be cultured (see Chapter 15). After the speculum is removed and the pelvis palpated, the first and second fingers are inserted gently into the vagina after adequate lubrication has been applied to the examination glove. In general, in right-handed physicians, the right hand is inserted into the vagina and the left hand is used on the abdomen to provide counter pressure as the pelvic viscera are moved ( Fig. 1.3). The vagina, its fornices, and the cervix are palpated carefully for any masses or irregularities. The fingers are placed gently into the posterior fornix so that the uterus can be moved. With the abdominal hand in place, the uterus can usually be palpated just above the surface pubis. In this manner, the size, shape, mobility, contour, consistency, and position of the uterus are determined.

Figure 1.3 The bimanual examination.

The adnexa are then palpated gently on both sides, paying particular attention to any enlargements. Again, the size, shape, mobility, and consistency of any adnexal structures should be carefully noted.

A rectal examination is suggested periodically in women 40 years of age and older (see American College of Obstetricians and Gynecologists guidelines , Chapter 8) and in all premenopausal women in whom there is any difficulty ascertaining the adnexal structures ( Fig 1.4). Rectovaginal examination should also be performed in these women to exclude the possibility of concurrent rectal disease ( 21). In postmenopausal women who undergo rectal examination, a stool guaiac test can be performed. During rectal examination, the quality of the sphincter muscles, support of the pelvis, and evidence of masses such as hemorrhoids or lesions intrinsic to the rectum should be noted.

Figure 1.4 The rectovaginal examination.

At the completion of the physical examination, the patient should be informed about the findings. When the results of the examination are normal, the patient can be reassured accordingly. When there is a possible abnormality, the patient should be informed immediately. A plan to evaluate the findings should be outlined briefly and in clear, understandable language. The implications of any proposed procedure (e.g., biopsy) should be discussed, and the patient should be informed when the results of any tests will be available. Pediatric Patients A careful examination is indicated when a child presents with genital complaints. The examiner should be familiar with the normal appearance of the prepubital genitalia. The normal unestrogenized hymenal ring and vestibule can appear mildly erythematous. The technique of examination is different from that used for examining an adult and may need to be tailored to the individual child based on her age, size, and comfort with the examiner. A young child can usually be examined best in a “frog-leg” position on the examining table. Some very young girls (toddlers or infants) do best when held in their mother's arms. Sometimes, the mother can be positioned, clothed, on the examination table (feet in stirrups, head of table elevated) with the child on her lap, the child's legs straddling her mother's. The knee-chest position may also be helpful for the examination ( 22). The child who is relaxed and warned about touching will usually tolerate the examination satisfactorily. Some children who have been abused, who have had particularly traumatic previous examinations, or who are unable to allow an examination may need to be examined with the use of anesthesia, although a gentle office examination should almost always be attempted first. If no obvious case of bleeding is visible externally or within the distal vagina, an examination under anesthesia may be indicated to visualize the vagina and cervix completely. A hysteroscope, cytoscope, or other endoscopic instrument can be used to provide magnification and light source. Adolescent Patients A pelvic examination may be less revealing in an adolescent than in an older woman, particularly if it is the patient's first examination or if it takes place on an emergency basis. Although other diagnostic techniques (such as pelvic ultrasound) can supplement an inadequate or poorly revealing examination, an examination should usually be attempted. The keys to a successful examination lie in earning the patient's trust, explaining the components of her examination, performing only the essential components, and using a very careful and gentle technique. It is important to ascertain whether the patient has had a previous pelvic examination. An adolescent should have a pelvic examination if she has had intercourse, if the results of a pregnancy test are positive, if she has abdominal pain, if she is markedly anemic, or if she is bleeding heavily enough to compromise hemodynamic stability. The pelvic examination occasionally may be deferred in young teenagers who have a classic history of irregular cycles soon after menarche, who have normal hematocrit levels, who deny sexual activity, and who will reliably return for follow-up. Before a first pelvic examination is performed, a brief explanation of the planned examination (which may or may not need to include a speculum), instruction in relaxation techniques, and the use of lidocaine jelly as a lubricant can be helpful. The patient should be encouraged to participate in the examination through voluntary relaxation of the introital muscles or by using a mirror if she wishes. If significant trauma is suspected or the patient finds the examination too painful and is truly unable to cooperate, an examination under anesthesia may occasionally be necessary. The risks of general anesthesia must be weighed against the value of information that would be obtained by the examination. Confidentiality is an important issue in adolescent health care. A number of medical organizations, including the American Medical Association, the American Academy of Pediatrics, and the American College of Obstetrics and Gynecologists, have endorsed adolescents' rights to confidential medical care. Particularly with regard to issues as sensitive as sexual activity, it is critical that the adolescent be interviewed alone, without a parent in the room. The patient should be asked if she has engaged in sexual intercourse, if she used any method of contraception, and if she feels there is any possibility of pregnancy.

Follow-up Arrangements should be made for the ongoing care of patients, regardless of their health status. Patients with no evidence of disease should be counseled regarding health behaviors and the need for routine care. For those with signs and symptoms of a medical disorder, further assessments and a treatment plan should be discussed. The physician must determine whether he or she is equipped to treat a particular problem or whether the patient should be directed to another health professional, either in obstetrics and gynecology or another specialty. If the physician believes it is necessary to refer the patient elsewhere for care, the patient should be reassured that this measure is being undertaken in her best interests and that continuity of care will be ensured.

Summary The management of patients' gynecologic symptoms, as well as abnormal findings and signs detected during examination, requires the full use of a physician's skills and knowledge and poses challenges to practice the art of medicine in a manner that leads to effective alliances between physicians and their patients. Physicians must listen carefully to what patients are saying about the nature and severity of their symptoms. The art of medical history taking must not be minimized. Physicians also must listen carefully for what patients may not be saying: their fears, anxieties, and personal experiences that lead them to react in a certain manner when faced with what is often, to them, a crisis (the diagnosis of an abnormality on examination, laboratory testing, or pelvic imaging). Physicians must use their knowledge of gynecology gained through formal education, personal experience, teachers and mentors, and textbooks, always striving to have the latest information about a given problem. Patients often present a unique set of circumstances, medical issues, or combination of diseases. Today, the use of a textbook chapter is only a beginning. Computers have made the world of information management accessible. Physicians must learn to practice evidence-based medicine—based on the very latest of what is known, not just impressions, recollections, or advice of colleagues. Physicians need to search the medical literature to help discover what they do not know. Patients are searching the medical literature, using computer online services to gain access to medical subject talk-groups, research reports, and the same literature read by physicians. Knowledge derived from an evidence base must be applied, using the art of medicine, to interact with patients to maintain health, alleviate suffering, and manage and cure disease.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

22.

Lipkin M Jr. The medical interview and related skills. In: Branch WT, ed. Office practice of medicine. Philadelphia: WB Saunders, 1987:1287–1306. Branch WT, Malik TK. Using windows of opportunities in brief interviews to understand patients' concerns. JAMA 1993;269:1667–1668. Simpson M, Buckman R, Stewart M, et al. Doctor-patient communication: the Toronto consensus statement. BMJ 1991;303:1385–1387. Ley P. Communicating with patients. London: Croom Helm, 1988. Butt HR. A method for better physician-patient communication. Ann Intern Med 1977;86:478–480. Mishler EG, Clark JA, Ingelfinger J, et al. The language of attentive patient care: a comparison of two medical interviews. J Gen Intern Med 1989;4:325–335. The Headache Study Group of the University of Western Ontario. Predictors of outcome on headache patients presenting to family physicians: a one year perspective study. Headache 1986;26:285–284. Kaplan SH, Greenfield S, Ware JE Jr. Assessing the effects of physician-patient interactions on the outcomes of chronic disease. Med Care 1989;27:S110–S127. Fallowfield L J, Hall A, Macguire GP, Baum M. Psychological outcomes of different treatment policies in women with early breast cancer outside a clinical trial. BMJ 1990;301:575–580. Spender D. Man made language. 2nd ed. New York: Routledge & Kegan Paul, 1985. Tannen D. You just don't understand: women and men in conversation. New York: Ballentine, 1990. West C. Reconceptualizing gender in physician-patient relationships. Soc Sci Med 1993;36:57–66. Todd AD, Fisher S. The social organization of doctor-patient communication. 2nd ed. Norwood, NJ: Ablex Publishing, 1993:243–265. Roter D, Lipkin M Jr, Korsgaard A. Sex differences in patients' and physicians' communication during primary medical care visits. Med Care 1991;29:1083–1093. Lurie N, Slater J, McGovern P, et al. Preventive care for women: does the sex of the physician matter? N Engl J Med 1993;329:478–482. Cousins N. The laughter connection. In: Cousins N, ed. Head first: the biology of hope and the healing power of the human spirit. New York: Penguin Books, 1989:125–153. Levinson W, Chaumetor N. Communication between surgeons and patients in routine office visits. Surgery 1999;125:127–134. Dunn SM, Butow PN, Tattersall MHN, et al. General information tapes inhibit recall of the cancer consultation. J Clin Oncol 1993;11:2279–2285. Baile WB, Kudelks AP, Beale EA, et al. Communication skills training in oncology: description and preliminary outcomes of workshops on breaking bad news and managing patient reactions for illness. Cancer 1999;86:887–897. Maguire P, Faulkner A. Improve the counselling skills of doctors and nurses in cancer case. BMJ 1999;297:847–849. Hochstein E, Rubin AL. Physical diagnosis. New York: McGraw-Hill, 1964. Emans SJ, Goldstein P. The gynecologic examination of the prepubital child with vulvovaginitis: use of the knee-chest position. Pediatrics 1980;65:758–760. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 2. Principles of Patient Care Novak’s Gynecology

Chapter 2

Principles of Patient Care Joanna M. Cain

Patient and Physician Confidentiality Informed Consent Beneficence and Nonmaleficence Professional Relations Conflict of Interest Harassment Stress Management Society and Medicine Justice Health Care Reform References

The practice of gynecology, as with all branches of medicine, is based on ethical principles that guide patient care. These principles and concepts create a framework for ethical decision making that applies to all aspects of practice: Autonomy: a person's right to self-rule, to establish personal norms of conduct, and to choose a course of action based on a set of personal values and principles derived from them Beneficence: the obligation to promote the well-being of others Confidentiality: a person's right to decide how and to whom personal medical information will be communicated Covenant: a binding agreement between two or more parties for the performance of some action Fiduciary relationship: a relationship founded on faith and trust Informed consent: the patient's acceptance of a medical intervention after adequate disclosure of the nature of the procedure, its risks and benefits, and alternatives Justice: the right of individuals to claim what is due them based on certain personal properties or characteristics Maleficence: the act of committing harm (nonmaleficence obliges one to avoid doing harm)

Patient and Physician Health care providers fulfill a basic need—to preserve and advance the health of human beings. Despite the challenges imposed by the commercial aspects of the current medical environment, for most physicians, the practice of medicine remains very much a “calling,” a giving of oneself to the greater good. Although much of medicine is contractual in nature, it cannot be understood in only those terms: “The kind of minimalism that a contractualist understanding of the professional relationship encourages produces a professional too grudging, too calculating, too lacking in spontaneity, too quickly exhausted to go the second mile with his patients along the road of their distress” ( 1). There is a relationship between physician and patient that extends beyond a contract and assumes the elements of a fiduciary relationship—a covenant between parties. The physician, having knowledge about the elements of health care, assumes a trust relationship with the patient whereby her interests are held paramount. Both the patient and the physician have rights and responsibilities in this relationship, and both are rewarded when those rights and responsibilities are upheld. Confidentiality and informed consent are two expressions of that trust or covenantal relationship.

Confidentiality The patient seeking assistance from a health professional has the right to be assured that the information exchanged during that interaction is private. Privacy is essential to the trust relationship between doctor and patient. Discussions are privileged information. The right to privacy prohibits a physician from revealing information regarding the patient unless the patient waives that privilege. Privileged information belongs to the patient except when it impinges on the legal and ethical rights of institutions and society at large, regardless of the setting. In a court situation, for example, physicians cannot reveal information about their patients unless that privilege is waived by the patient. If privilege is waived, the physician may not withhold such testimony. The privilege of privacy must be maintained even when it does not seem intrinsically obvious. A patient's family, friend, or spiritual guide, for example, has no right to medical information regarding the patient unless the patient specifically releases it. This may seem obvious but often can be overlooked, such as when a health care giver receives a call from a concerned parent, spouse, or relative inquiring about the status of a patient. The response may be a natural attempt to reassure and inform a caring individual about the patient's status. However, for her own reasons, the patient may not want certain individuals informed of her medical condition. Thus, confidentiality has been breached. It is wise to ask patients about who may be involved in decision making and who may be informed about their status. If a health care giver is unclear of the patient's wishes regarding the person requesting information, the reply should indicate that the patient's permission is necessary before discussing her status. Finally, when trying to contact individual patients for follow-up of medical findings, it is never appropriate to reveal the reason to an individual other than the patient. Record Keeping Health care professionals are part of a record-keeping organization. Those records are used for multiple purposes in medicine and are a valuable tool in patient care. Unfortunately, there is an increasing tendency for ancillary organizations to collect, maintain, and disclose information about individuals to whom they have no direct connection (2). Given the present lack of universal and nondiscriminatory access to health insurance in the United States, physicians must be aware of this practice and its ramifications. Patients sign a document, often without understanding its meaning, upon registering with a health care institution or insurance plan. That document waives the patient's privilege to suppress access and gives access to the medical record to insurers and often other health care providers who request it. The consequences of such disclosure for patients can be significant in terms of insurance coverage and potential job discrimination ( 3). This concern must be weighed against the need for all health care providers involved with an individual to be informed about past or present diseases or activities that may interfere with or complicate management. The use of illegal drugs, a positive human immunodeficiency virus (HIV) test result, and even a history of cancer or psychiatric illness are all exceptionally important to health care providers in evaluating individual patients. When revealed to outside institutions, however, these factors may affect the patient's ability to obtain and keep medical coverage, insurance, or even credit. It is axiomatic that everything that is written in a patient's record should be important to the medical care of that patient and that extrinsic information should be avoided. Furthermore, it is appropriate for physicians to discuss with patients the nature of medical records and their release to other parties so that patients can make an informed choice about such release. Additional guidelines from the Department of Health and Human Services (DHHS) to protect the security of patient records, known as the Healthcare Information Privacy and Protection Act (HIPPA), will translate into additional requirements for access to these records for clinical research as well as guidelines for electronic medical records protections. The security of medical

records, then, is a concern not just for individual patients and physicians but also for health systems and researchers. Legal Issues The privilege of patients to keep their records or medical information private can be superseded by the needs of society, but only in rare circumstances. The classic legal decision quoted for the needs of others superseding individual patient rights is that of Tarasoff v. Regents of the University of California ( 4). That decision establishes that the special relationship between a patient and doctor may support affirmative duties for the benefit of third persons. It requires disclosure if “necessary to avert danger to others” but still in a fashion “that would preserve the privacy of the patient to the fullest extent compatible with the prevention of the threatened danger.” This principle also is compatible with the various codes of ethics that allow physicians to reveal information in order to protect the welfare of the individual or the community. In other words, “the protective privilege ends where the public peril begins” ( 4). Legislation can also override individual privilege. The most frequent example is the recording of births and deaths, which is the responsibility of physicians. Various diseases are required to be reported depending on state law [e.g., HIV status may or may not be reportable in individual states, whereas acquired immunodeficiency syndrome (AIDS) is reportable in all states]. Reporting injuries caused by lethal weapons, rapes, and battering (e.g., elder and child abuse) is mandatory in some states and not others. The regulations for the reporting of these conditions are codified by law and can be obtained from the state health department. These laws are designed to protect the individual's privacy as much as possible while still serving the public interest. Particularly in the realm of abuse, physicians have a complex ethical role regardless of the law. Victims of abuse, for example, must feel supported and assured that the violent act they have survived will not make a difference in how they are treated as people. Their sense of vulnerability and their actual vulnerability may be so great that reporting an incident may increase their risk for medical harm. Despite the laws, physicians also have an ethical responsibility to see to the patient's best interest, and weighing that ethical responsibility can be difficult.

Informed Consent Informed consent is a process that involves an exchange of information directed toward reaching mutual understanding and informed decision making. Ideally, informed consent should be the practical manifestation of respect for patient preferences (autonomy) ( 5,6). Unfortunately, an act of informed consent is often misunderstood as procurement of a signature on a document. Furthermore, the intent of the individual involved in the consent process often is the protection of the physicians from liability. Nothing could be further from either the legal or ethical meaning of this concept. Informed consent is a conversation between physician and patient that teaches the patient about the medical condition, explores her values, and informs her about the reasonable medical alternatives. Informed consent is an interactive discussion in which one participant has greater knowledge about medical information and the other participant has greater knowledge about that individual's value system and circumstances affected by the information. This process does not require an arduous lecture on the medical condition or extensive examination of the patient's psyche. It does require adjustment of the information to the educational level of the patient and respectful elicitation of concerns and questions. It also requires acknowledgement of the various fears and concerns of both parties. Fear that the information may frighten patients, fear of hearing the information by the patient, lack of ability to decode technical information, and inability to express lack of comprehension are among the many barriers facing physicians and patients engaging in this conversation. Communication skills are part of the art of medicine, and observation of good role models, practice, and good intent can help to instill this ability in physicians ( 7). Autonomy Informed consent arises from the concept of autonomy. Pellegrino (8) defines an autonomous person as “one who, in his thoughts, work, and actions, is able to follow those norms he chooses as his own without external constraints or coercion by others.” This definition contains the essence of what health care providers must consider as informed consent. The choice to receive or refuse medical care must be in concert with the patient's values and freely chosen, and the options must be considered in light of the patient's values. Autonomy is not respect for a patient's wishes against good medical judgment. Consider the example of a patient with inoperable, advanced-stage cervical cancer who demands surgery and refuses radiation therapy. The physician's ethical obligation is to seek the best for the patient's survival (beneficence) and avoid the harm (maleficence) of surgery, even though that is what the patient wishes. Although physicians are not obligated to offer treatment that is of no benefit, the patient does have the right to refuse treatment if it does not fit into her values. Thus, this patient could refuse treatment for her cervical cancer, but she does not have the right to be given any treatment she wishes. Surrogate Decision Makers If the ability to make choices is diminished by extreme youth, mental processing difficulties, extreme medical illness, or loss of awareness, surrogate decision making may be required. In all circumstances, the surrogate must make every attempt to act as the patient would have acted ( 9). The hierarchy of surrogate decision makers is specified by statutory law in each state and differs slightly from state to state. For adults, the first surrogate decision maker is a court-appointed guardian if one exists and second is a durable power of attorney, followed by relatives by degree of presumed familiarity (e.g., spouse, adult children, parents). For children, parents are the surrogate decision makers, except in circumstances in which the decision is life-threatening and might not be the choice a child would make later, when adult beliefs and values are formed. The classic example of this is the Jehovah's Witness parents who refuse life-saving transfusions for their child (10). Although this case is the extreme, it illustrates that the basic principle outlined for surrogate decision making should also apply to parents. Bias that influences decision making (in protection of parental social status, income, or systems of beliefs) needs to be considered by physicians because the potential conflict may lead parents to decisions that are not in the best interest of the child. If there is a conflicting bias that does not allow decisions to be made in the best interest of the child or that involves a medical threat to a child, legal action to establish guardianship (normally through a child protective agency) may be necessary. This action can destroy not only the patient (child)–physician relationship but also the parent–physician relationship and may affect the long-term health and well-being of the child, who must return to the care of the parents. Such decisions should be made only after all attempts to educate, clarify, and find alternatives have been tried. The legal age at which adolescents may make their own decisions regarding their health care varies by state ( 11). However, there is a growing trend to increase the participation of adolescents who are capable of decision making in decisions about their health care. Because minors often have developed a value system and the capacity to make informed choices, their ability to be involved in decisions should be assessed individually rather than relying solely on the age criteria of the law and their parents' views. A unique area for consideration of informed consent is in the international context, either conducting care or clinical research in foreign settings or caring for individuals from other countries with widely differing viewpoints regarding individual informed consent. For example, if the prevailing standard for decision making by a woman is that her closest male relative makes it for her, how is that standard accommodated within our present autonomy-based system? In international research, these issues have presented major concerns when women were assigned to placebo or treatment groups and consent was accepted from male relatives ( 12). Furthermore, the coercive effect of access to health care through clinical trials when no other access to health care is available creates real questions about the validity and freedom of choice for participants in these studies ( 13). Guidelines for limiting coercion and ensuring the ability to choose participation in research are being developed for international research. However, it is important to recognize that these same issues exist in a microcosm when caring for patients from certain cultures and foreign countries in daily practice. Ensuring that the patient can make the choice herself or freely chooses to have a relative make it for her remains an important element of informed consent between individual physicians and individual patients.

Beneficence and Nonmaleficence The principles of beneficence and nonmaleficence are the basis of medical care—the “to do good and no harm” of Hippocrates. However, these issues are often clouded by other decision makers, consultants, family pressures, and sometimes financial constraints or conflicts of interests. Of all the principles of good medical care, benefit is the one that continually must be reassessed. Simple questions often have no answers. What is the medical indication? How does the proposed therapy address this issue? How much will this treatment benefit the patient? How much will it extend the patient's life? Furthermore, when confronted with multiple medical problems and consultants, physicians should ask how much treatment will be of benefit given all the patient's problems (e.g., failing kidneys, progressive cardiomyopathy, HIV-positive status, and respiratory failure) rather than necessarily attempting intubation and respiratory support to treat the immediate problem.

The benefit or futility of the treatment, along with quality-of-life considerations, should be considered in all aspects of patient care. It is best to weigh all of the relevant issues in a systematic fashion. Some systematic approaches depend on a sequential gathering of all the pertinent information in four domains: medical indications (benefit and harm), patient preferences (autonomy), quality of life, and contextual issues (justice) ( 5). Other approaches identify decision makers, followed by facts, and then ethical principles. It is important for physicians to select an ethical model of analysis with which to practice so that, when faced with troubling and complex decisions, a system is available to help clarify the issues. Medical Futility The essence of good medical care is to attempt to be as clear as possible about the outcomes of the proposed interventions. If the proposed intervention (e.g., continued respiratory support or initiating support) has a very low or highly unlikely chance of success, intervention might be considered futile. Physicians have no obligation to continue or initiate therapies of no benefit ( 14). The decision to withdraw or withhold care, however, is one that must be accompanied by an effort to ensure that the patient or her surrogate decision maker is educated about the decision and agrees with it. Other issues, such as family concerns, can and should modify decisions if the overall well-being of the patient and of the family is best served. For example, waiting (within reason) to withdraw life support may be appropriate to allow a family to reach consensus or a distant family member to see the patient for a last time. Quality of Life Quality of life is a much used, often unclear term. In the care of patients, quality of life is the effect of therapy on the patient's experience of living based on her perspective. It is perilous and wholly speculative to assume that physicians know what quality of life represents for a particular patient judging from a personal reaction. It is instructive, however, to attempt to guess what it means and then seek the patient's perspective. The results may be surprising. For example, when offered a new drug for ovarian cancer, a patient might prefer to decline the treatment because the side effects may not be acceptable even when there may be a reasonable chance that her life may be slightly prolonged. In some instances, the physician may not believe that further treatment is justified but the patient finds joy and fulfillment in preserving her existence as long as possible. Controversy exists regarding whether currently available quality-of-life measurement systems will provide information to help patients make decisions ( 15). Information from quality-of-life studies might be judged by criteria that include whether the measured aspects of the patient's life were based on the patient's views or the physician's clinical experience ( 16). Informing patients of others' experiences with alternative treatments may help in their decision making, but it is never a substitute for the individual patient's decisions.

Professional Relations Conflict of Interest All professionals have multiple interests that affect their decisions. Contractual and covenantal relationships between physician and patient are intertwined and complicated by health care payers and colleagues, which creates considerable pressure. The conflict with financial considerations directly influences how patients' lives are affected, often without their consent. Rennie ( 17) described that pressure eloquently: “Instead of receiving more respect (for more responsibility), physicians feel they are being increasingly questioned, challenged, and sued. Looking after a patient seems less and less a compact between two people and more a match in which increasing numbers of spectators claim the right to interfere and referee.” An honest response to this environment is for the physician to attempt to protect his or her efforts by assuming that the physician–patient relationship is contractual, and only contractual, in nature. This allocation of responsibility and authority for the contract precludes the need for the covenant between the physician and patient. For example, a contract, insurance, or managed care plan may discourage referral to a more knowledgeable specialist, removing the physician's responsibility. Thus, the contract establishes the extent of the physician–patient relationship. All health care providers must decide whether they will practice within a covenantal or contractual relationship and whether the relationship they develop remains true to this decision. In either setting, a reasonable perception of that relationship is “one that allows clients as much freedom as possible to determine how their lives are affected as is reasonably warranted on the basis of their ability to make decisions” ( 18). Health Care Payers An insurance coverage plan may demand that physicians assume the role of gatekeeper and administrator. Patients can be penalized for a lack of knowledge about their future desires or needs and the lack of alternatives to address the changes in those needs. Patients are equally penalized when they develop costly medical conditions that would not be covered if they moved from plan to plan. These situations often place the physician in the position of being the arbiter of patients' coverage rather than acting as an advocate and adviser. It is an untenable position for physicians because they often cannot change the conditions or structure of the plan but are made to be the administrators of t. In an effort to improve physician compliance with and interest in decreasing costs, intense financial conflicts of interest can be brought to bear on physicians by health care plans. If a physician's profile on costs or referral is too high, he or she might be excluded from the plan, thus decreasing his or her ability to earn a living or to provide care to certain patients with whom a relationship has developed. Conversely, a physician may receive a greater salary or bonus if the plan makes more money. The ability to earn a living and to see patients in the future is dependent on maintaining relationships with various plans and other physicians. These are compelling loyalties and conflicts that cannot be ignored ( 19,20 and 21). These conflicts are substantially different from those of older fee-for-service plans, although the ultimate effect on the patient can be the same. In fee-for-service plans, financial gain may result in failure to refer a patient, or referral is restricted to those cases in which the financial gain is derived by return referral of other patients (22). Patients may be unaware of these underlying conflicts, a situation that elevates conflict of interest to an ethical problem. A patient has a right to know what her plan covers, to whom she is being referred and why, and the credentials of those to whom she is referred. The reality is that health care providers make many decisions under the pressure of multiple conflicts of interest. Physicians are potentially caught between self-interest and professional integrity. Whether it is the more blatant lying about indications for a procedure in order to receive reimbursement or a more subtle persuasion to sign up for a certain protocol because of points earned for a study group, the outcome for individual and society's relationship with health care providers is damaged by failure to recognize and specifically address conflicts of interest that impede decision making ( 23). Focusing clearly on the priority of the patient's best interest and responsibly rejecting choices that compromise the patient's needs are ethical requirements. Institutions, third-party payers, and legislatures have avoided accountability for revealing conflicts of interest to those to whom they offer services. The restrictions of health care plans are never placed in as equally prominent a position as the coverage. The coverage choices can be quite arbitrary, and there is rarely an easily accessible and usable system for challenging them. The social and financial conflicts of interest of these payers can directly affect the setting and nature of the relationship between physician and patient. To deal with ambiguous and sometimes capricious decision making, revelation of the conflicts of interest and accountability for choices should be demanded by physician and patient ( 24). Legal Problems Abuses of the system (e.g., referral for financial gain) have led to proposals and legislation, often referred to as Stark I and II, affecting physicians' ability to send patients to local laboratories and facilities in which they have a potential for financial gain. Although there have been clearly documented abuses, the same legislation would affect rural clinics and laboratories in which the only capital available is obtained through the rural physicians. States vary on the statutory legislation regarding this issue. Regardless of the laws, however, it is ethically required that financial conflicts of interest be revealed to patients ( 25,26,27 and 28). Another abuse of the physician–patient relationship caused by financial conflicts of interest is fraudulent Medicare and Medicaid billings. This activity resulted in the Fraud and Abuse Act of 1987 (42. U.S.C. at 1320a–7b), which prohibits any individual or entity making false claims or soliciting or receiving any remuneration in cash or any kind, directly or indirectly, overtly or covertly, to induce a referral. Indictments under these laws are felonies, with steep fines, jail sentences, and loss of the license to practice medicine. Physicians should be aware of the legal ramifications of their referral and billing practices ( 23,29).

Harassment

The goal of medicine is excellence in the care of patients and, often, research and education that will advance the practice of medicine. Thus, everyone involved in the process should be able to pursue the common goal on equal footing and without harassment that interferes with employees' or colleagues' ability to work or be equally promoted in that environment. Every office and institution must have written policies on discrimination and sexual harassment that detail inappropriate behavior and state specific steps to be taken to correct an inappropriate situation. The legal sanction for this right is encoded in both statutory law through the Civil Rights Act of 1964 [42 U.S.C.A. at 2000e–2000e–17 (West 1981 and Supp. 1988)] and reinforced with judicial action (case or precedential law) by state and U.S. Supreme Court decisions. In particular, charges of sexual harassment can be raised as a result of unwelcome sexual conduct or a hostile workplace (such as areas of medicine that have been known for antifeminist attitudes in the past). As stated in one legal case, “a female does not assume the risk of harassment by voluntarily entering an abusive, antifemale environment” (Barbetta v. Chemlawn Service Co., 669 F, Supp. 569, WDNY, 1989). The environment must change; it is not acceptable to expect the men or women to adapt because “they knew what it would be like.” The tension in the legal debate regarding harassment (sexual, racial, disability) always hinges on the weight of protection of free speech and the right of the individual to equality and a nonhostile work environment.

Stress Management There is little doubt that the day-to-day stress of practicing medicine is significant. Besides the acknowledged stress of the time pressures and responsibility of medicine, the current health care environment has had a detrimental effect on physicians' job security, with concurrent health risks ( 30). Stress takes a toll not only on cardiac function (31) but also on the practice of medicine and life outside of medicine ( 32). Responding to stress through drug or alcohol abuse increases overall health and marital problems and decreases effectiveness in practice. In a long-term prospective study of medical students, individuals with high-risk (e.g., volatile, argumentative, aggressive) temperaments have been shown to have a high rate of premature death (particularly before 55 years of age) ( 33). Adequate sleep, reasonable working hours, exercise, and nutritional balance have been shown to be directly related to decreases in psychological distress ( 34). Simple relaxation training has been shown to decrease gastroesophageal reflux in response to stress ( 35). The pace that physicians maintain has a seductive quality that can easily mask the need for stress reduction by means of good health practices, exercise, and relaxation training. The answer to increased stress is not to work harder and extract the time to work harder from the relaxing and enjoyable pursuits that exist outside medicine. The outcome (in terms of psychological and physical optimal functioning) of that strategy is in neither the physician's nor the patient's best interest. Both the welfare of the patient and the welfare of the physician are enhanced by a planned strategy of good health practices and relaxation. Furthermore, such a strategy is important to all members of the health care team. By providing such leadership, physicians can contribute to a better work and health care environment for everyone.

Society and Medicine Justice Some of the ethical and legal problems in the practice of gynecology relate to the fair and equitable distribution of burdens and benefits. How benefits are distributed is a matter of great debate. There are various methods of proposed distribution: Equal shares (everyone has the same number of health care dollars per year) Need (only those people who need health care get the dollars) Queuing (the first in line for a transplant gets it) Merit (those with more serious illnesses receive special benefits) Contribution (those who have paid more into their health care fund get more health care) Each of these principles could be appropriate as a measure of just allocation of health care dollars, but each will affect individual patients in different ways. Only recently has just distribution become a major issue in health care. The principles of justice apply only when the resource is desired or beneficial and to some extent scarce (36). The traditional approach to medicine has been for practitioners to accept the intense focus on the individual patient. However, the current changes in medicine will alter the focus from the patient to a population ( 37)—“in the emerging medicine, the presenting patient, more than ever before, will be a representative of a class, and the science that makes possible the care of the patient will refer prominently to the population from which that patient comes.” Physicians are increasingly bound by accumulating outcomes data (population statistics) to modify the treatment of an individual in view of the larger population statistics. If, for example, the outcome of liver transplantation is only 20% successful in a patient with a certain set of medical problems, that transplant may instead be offered to someone who has an 85% chance of success. Theoretically, the former individual might have a successful transplant and the procedure might fail in the latter, but population statistics have been used to allocate this scarce resource. The benefit has been measured by statistics that predict success, not by other forms of justice allocation by need, queuing, merit, or contribution. This approach represents a major change in the traditional dedication of health care to the benefits of individual patients. With scarce resources, the overall benefits for all patients are considered in conjunction with the individual benefits for one patient. There has always been an inequity in the distribution of health care access and resources. This inequity has not been seen by many health care providers who do not care for those patients who are unable to gain access, such as those who lack transportation or live in rural areas or where limits are imposed by lack of health care providers, time, and financial resources. Social discrimination sometimes leads to inequity of distribution of health care. Minorities are less likely to see private physicians or specialists, regardless of their income or source of health care funding ( 38,39 and 40). Thus, health care is rationed by default. Health care providers must shift the paradigm from the absolute “do everything possible for this patient” to the proportionate “do everything reasonable for all patients” (5). To reform the health care system requires not just judicial, legislative, or business mandates but also attention to the other social components that can pose obstacles to efforts to expand health care beyond a focus on individual patients.

Health Care Reform The tension between understanding health as an inherently individual matter (in which the receipt of health care is critical to individual well-being) and as a communal resource (in which distribution of well-being throughout society is the goal) underpins much of the political and social debate surrounding health care reform ( 41). The questions of health care reform are: What is the proper balance between individual and collective good? and Who will pay for basic health care? Because much of health care reform requires a balancing of competing goals, legislation should specifically address how this balance can be achieved. The role of government would be the following: Regulating access of individuals to health care Regulating potential harms to the public health (e.g., smoking, pollution, drug use) Promoting health practices of benefit to large populations (e.g., immunization, fluoridation of water) Decisions regarding both the amount and distribution of resources are often made by health care payers, not individual providers. The health insurance industry determines what are “reasonable and customary” charges and what will be covered. The government decides (often with intense special-interest pressure) what will be covered by Medicare and Medicaid (42,43). These decisions directly affect patient care. For that reason, health care providers cannot ethically remain silent when the health and well-being of their individual patients and their communities are adversely affected by health care reform decisions. Health care providers should assess proposed reforms in light of their value to the community and to individual patients and then formulate their own criteria for judging proposals for health care reform (44,45,46 and 47). Furthermore, initiation and support of research focused on the outcomes of care delivered by gynecologists (financial aspects, quality-of-life measures, survival, morbidity, and mortality) will allow the discipline to have a real voice in determining what choices are made for health care for women.

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Chapter 3. Quality Assessment, Performance Improvement, and Patient Safety Novak’s Gynecology

Chapter 3 Quality Assessment, Performance Improvement, and Patient Safety Joseph C. Gambone Robert C. Reiter Paul A. Gluck

Quality Assurance Principles of Quality Assessment Performance Improvement Knowledge of a System Knowledge of Variation The Theory of Knowledge Newer Methods for Improving Performance Summary References

For more than 20 years, the need to maintain or increase the quality of health care while controlling its cost has stimulated a great deal of interest and activity in quality assessment and performance improvement. A report from the Institute of Medicine (IOM) on patient safety has generated intense public interest and concern about the high estimated number of preventable deaths caused by medical errors ( 1). Although the conclusions of this report are controversial, it raises fundamental and disturbing questions about health care quality and performance. The annual United States per capita expenditure for health care (in constant dollars) had risen steadily from about $950 in 1970 to about $3,400 in 1992 (about 12% increase per year). Although efforts in the 1990s to “manage” care and its costs were reasonably successful in slowing annual health care cost increases, they have recently been returning to double digits. Currently, annual United States per capita expenditure is estimated to exceed $4,500 (about 3.2% increase per year since 1992). The “political” failure and public distrust of 1990s-style managed care has resulted in predictions of its demise despite well-documented economic success ( 2). Before the mid-1990s, much of the increase in health care costs had been shifted from individuals to state and federal governments and to employers ( Fig. 3.1). More recently, employers have been setting limits on their contributions to health care benefits and shifting more of the increased costs to their employees. Currently, the United States spends more on health care (about 14% of gross domestic product) than on education and defense combined. Despite this enormous outlay of resources, there is concern about the overall quality of health care ( 3,4). The health status of U.S. residents (in terms of life expectancy, neonatal mortality, and rates of illness and disability) is poorer than that of people living in most European and Scandinavian countries, the United Kingdom, Japan, and Canada, although these countries spend far less per capita on health care. Quality improvement programs in other industries have shown that management methods can both increase quality and reduce costs. Because of concerns about quality, cost, and safety, patients, as well as private and public third-party payers, are demanding ongoing quality assessment and performance improvement programs in health care delivery systems.

Figure 3.1 Sources of spending in U.S. health care, 1960–1990. Note that third-party payment steadily replaced direct payment during this interval. After a long decline, out of pocket spending is expected to rise. (Data from U.S. Congressional Budget Office, 1992).

Quality Assurance The medical profession traditionally has focused its efforts on assessing and improving the quality of health services through internal, self-imposed, retrospective peer review. Examples of such mechanisms are morbidity and mortality (M&M) conferences, medical society–sponsored and state-legislated peer-review programs, surgical case reviews (tissue committees), and the specialty board certification processes. These programs review adverse occurrences retrospectively (e.g., assessment of medical and surgical complications and review of misdiagnoses). Although useful as part of the peer-review process, these quality assurance (QA) programs are not aimed at prevention of errors and are not designed to assess and improve the effectiveness of health care services and procedures (5). The differences between traditional QA programs and newer performance improvement and quality management programs, such as continuous quality improvement (CQI) or total quality management (TQM), are presented in Fig. 3.2. QA programs are designed to identify and eliminate the small percentage of substandard care represented on the left side of the normal curve (the “bad apple” approach). Most “standard” care occurs in the middle of the curve, however, and is the focus of newer programs like CQI. Such programs are designed to study prospectively the processes of care based on need and to improve outcomes by the reduction of unintended variation ( 6). The right side of the curve represents state-of-the-art practice usually performed under protocols at universities and other large centers of excellence that are monitored by institutional review boards and national research groups such as the National Cancer Institute and the Gynecologic Oncology Group. As more emphasis is placed on quality management programs in health care, innovations should come from both traditional research and performance improvement efforts.

Figure 3.2 The hypothetical relationship between quality assurance (QA) and quality or performance improvement.

Quality management programs such as CQI, TQM, and performance improvement each have three essential elements ( 7): 1. To understand customers (patients, payers, and other clients) and to link that knowledge to the activities of the organization 2. To mold the culture (beliefs and performance characteristics) of the organization through the deeds of leaders; to foster pride, enjoyment, collaboration, and scientific thinking 3. To increase knowledge (of how to improve performance) continuously and to control variation (unintended and wasteful differences in performance) by scientific methods Health care professionals often do not like to refer to health care services as products and patients as customers or consumers. The older, paternalistic attitude (i.e., patients passively agreeing to health care procedures that were determined largely by health care providers) is being replaced by a more egalitarian view of patients as intelligent and informed consumers who should participate in their care ( 8). The consumerism movement in health care is predicated on the belief that health care services should conform to acceptable standards of quality, efficiency, and safety ( 9). This newer attitude may lead to improved communication and shared decision making (between patient and provider) and should alter the wasteful practice of “defensive medicine,” which has been shown to increase health care costs significantly (10,11).

Principles of Quality Assessment Quality means different things in different situations. The concept of quality in products (e.g., consumer goods and state-of-the-art machinery) is different than that of complex services (e.g., health care delivery to people). However, many of the principles of quality assessment and improvement that have been shown to improve the quality of consumer goods and services can also be applied to the evaluation and improvement of health services. There are certain principles of quality assessment that should be considered when attempting to measure and improve health care quality. Efficacy, Effectiveness, and Efficiency Efficacy and effectiveness are similar terms that are often used interchangeably to describe evaluations of outcomes of health care services and procedures. As defined by the Institute of Medicine, efficacy refers to what an intervention or procedure can accomplish under ideal conditions and when applied to appropriate patients ( 12). Effectiveness refers to the actual performance in customary practice of an intervention or procedure. An example of this difference is the theoretical success rate ( efficacy) of oral contraception used for one year (99% successful at preventing pregnancy) versus the actual or use-rate, effectiveness, usually reported to be 93% to 97%. Most health care decisions have been based on efficacy rates obtained from controlled clinical trials rather than the actual effectiveness of such decisions. One of the major challenges for quality assessment and management programs is to develop and use measurements that reflect the actual, or real-life, success rates of treatment options so that evidence-based decision making can replace authority-based decision making. Also, strategies need to be developed to improve patient compliance rates in order to increase the likelihood that the actual effectiveness is as close as possible to theoretical efficacy ( 13). Efficiency describes the relative “waste” or resource use (complications and costs) of alternative effective interventions. To realize meaningful improvements in health services, health professionals and organizations must develop more efficient interventions (e.g., medical therapy or expectant management versus surgical treatment for abnormal bleeding) when appropriate. The goal of health care quality improvement is optimal value. Value is defined as quality divided by the cost, or as the quotient of outcomes (benefits) divided by resources used: Value=outcomes/resource use Optimal versus Maximal Care The assessment of the quality of health care depends on whether the goal of the system is to provide maximally effective or optimally effective care ( 14). Figure 3.3 shows a theoretical representation of the difference between maximally effective health care (Point B), in which every conceivable intervention is offered regardless of cost to those who can afford it, and optimally effective health care (Point A), in which resources are used in a manner that will provide the most good for as many people as possible. Maximized health care emphasizes individual intervention, whereas optimized care emphasizes public health care and prevention. When optimal health care becomes the goal of a health care system, conflicting individual and societal needs must be resolved.

Figure 3.3 The “optimal” versus the “maximal” benefits and costs of medical treatments. On the top panel, the benefits to health and the costs of care are plotted. On the bottom panel, the cost is subtracted from the benefits, illustrating that after a certain point, additions of care may detract from the benefits. (From Donabedian A. The quality of care: How can it be assessed. JAMA 1988;260:1743–1748, with permission.)

Assessing Outcomes A widely accepted system for assessing the quality of health care is based on the measurement of indicators of structure, process, and outcome ( 15). Structure includes the resources, equipment, and people who provide health care. Process is the method by which a procedure or course of action is executed. Outcome includes the complications, adverse events, and short-term results of interventions, as well as the patient's health status and

health-related quality of life after treatment, which reflects the effectiveness of the intervention. Evaluation of health care structure involves the assessment of the stable and tangible resources needed to provide care, such as safe and adequately sized operating rooms and properly functioning equipment. Other examples of structural elements include the aspects of the medical staff's qualifications, such as school accreditation, licensure, continuing medical education credits, and specialty board certification. Although these elements form the foundation of a health care organization or system, there is a weak correlation between structural assessment and other measures of the quality of care, such as clinical outcomes ( 16). Therefore, many health services researchers believe that organizations need to measure clinical outcomes directly (including not only death and short-term morbidity but also disability and health-related quality-of-life issues) if they hope to improve both the effectiveness and efficiency of health care delivery. Their research also emphasizes measurement of clinical or health outcomes that are defined as those that patients can experience and value without the interpretation of a health care provider. Examples of clinical or health outcomes and their corresponding intermediate or surrogate end points are presented in Table 3.1. Ultimately, longevity and quality-of-life factors may be the only relevant outcomes of health care.

Table 3.1. Clinical and Health Outcomes and Their Corresponding Intermediate or Surrogate Endpoints: Some Examples

Quality-of-Life Measurement In the past, traditional quality assessment programs have tended to focus on the assessment of short-term risks and the confirmation of pathologic diagnoses. This effort has usually been limited to quantification of mortality and major morbidity—such as infection, blood transfusion, and reoperation—occurring while the patient was hospitalized and verified by tissue diagnosis. Most standardized lists of clinical QA indicators are from the medical model of outcomes assessment. Although the importance of these kinds of indicators seems obvious, these indicators may have little or no relevance to the more fundamental question of actual effectiveness of a procedure in terms of preserving or enhancing quality of life. For example, if a patient with pelvic pain undergoes a hysterectomy for leiomyomas, experiences no short-term complications, and has a diagnosis that is confirmed histologically, the procedure may be considered successful from the standpoint of surgical risk management, short-term outcome, and histologic verification. However, if the patient continues to experience pain and has no improvement in the quality of her life, the surgery has been, in reality, unsuccessful. Short-term risk indicators often have little or no bearing on whether the procedure actually works. Behavioral Model of Health Outcomes Efforts to measure the success or the effectiveness of health care procedures in the United States are based on the traditional medical model in which a patient is evaluated for a symptom, diagnosed as having a condition, and treated for that diagnosis. A procedure is usually considered successful if the diagnosis is confirmed. Medicine has traditionally relied on short-term risk indicators and histologic confirmation because these measurements seem more objective and quantifiable. Death and infection rates, blood loss, and rates of histologic verification can all be measured and expressed numerically. Crucial to the application of a more predictive behavioral model in clinical outcomes research are several statistically valid and reliable methods to measure health-related quality of life. Many measures have been developed and validated, but few are used in clinical practice ( 17). Using the behavioral model of effectiveness, the concept of quality-adjusted life-years (QALY) has been proposed to measure the benefit, in both quantity and quality of life, of a health care procedure ( 18). The number of QALYs is determined by combining the extra years of life that a procedure offers with a validated measure of eight categories of disability and four measures of distress. The use of this methodology allows standardized comparison of the cost of entirely different health care procedures. Despite its inadequacies, the medical model has been the standard, but the behavioral model of outcomes is now becoming incorporated into health care evaluation and research ( 19). Scales of health-related quality-of-life issues, called the SF-36 and the SF-12 (short form 36 and short form 12, the health-status tool derived from the RAND Medical Outcomes Survey), have been developed ( 20).

Performance Improvement Most methods for the assessment of the quality of health care and the delivery of health services have been based on the premise that quality is the sole responsibility of the health care practitioner. Because the practitioner's technical skills, knowledge, and interpersonal interactions are the basis for quality of patient care and its delivery, many regulatory agencies [e.g., the Joint Commission on the Accreditation of Health Care Organizations (JCAHO)] and hospitals have created traditional QA models that focus mostly on the practitioner. However, quality of care is determined by many interacting forces, and the practitioner clearly does not deliver care in isolation. The delivery of health care requires the integration and management of many processes. The practitioner's ability to deliver care is influenced by the environment, the ability and skill of support staff, policies and procedures, facilities, governing processes, methods of work, and equipment and materials available, as well as innumerable patient variables such as severity of illness, concurrent illness (comorbidity), and social support. Historically, QA efforts attempted to monitor these processes to document bad outcomes. However, this approach has not proved to be adequate in improving the quality of care ( 21). Regulatory agencies and hospitals are now focusing on the overall performance of health care organizations in terms of clinical or health outcomes. Performance improvements in health care have been based on knowledge that physicians and other health care professionals acquired in medical and other professional schools. Improvements have been brought about by clinicians applying knowledge developed by discipline-specific experts ( 22). The recent national emphasis on health care reform is an indication that the past rate of improvements is not sufficient to meet the financial needs and expectations of society. Performance improvements in efficiency must be made at a faster pace because consumers are seeking greater value for and access to health care services. A theoretical basis for organizational change that promotes continuous improvement includes knowledge of a system, knowledge of variation, and the theory of knowledge (23,24).

Knowledge of a System The first component of continuous performance improvement is knowledge of a system. A system is defined as a network of interdependent components that work together to accomplish its aim. A system does not exist without an aim and is only capable of improving if there is a connection between the aim, the means of production, and the means of improving. An open system is one that permits continued access from outside the system. Because health care organizations are accountable to patients and to the community as a whole, they are considered open systems. The aim of an organization involves the integration of the knowledge of the social needs and the needs of patients. Knowledge of a system includes the following aspects: Customer knowledge. This is the basis of an organization's aim. The aim is derived by identifying the organization's customers and by understanding the measures used to judge quality. Meeting patient expectations is one of the most accurate ways to define quality. How the organization provides its services. This is the means of producing a service, which involves knowledge of what is delivered, the processes or steps taken

to deliver the services, the information and materials used to provide services, and the suppliers. How the organization improves what it delivers. This involves knowledge of the aim and identification of areas for improvement that are likely to have the greatest impact. Understanding the interrelationships between the aim, the customers, the primary areas for improvement, and the specific processes that can be improved is known as systems thinking. When a health care organization is focused on providing as many services as possible without consideration for the needs of the community and their customers, it will eventually fail to deliver quality services. Proper perspective for customer needs and preferences gained through a process called strategic planning may even lead to a competitive advantage for a health care organization ( 25).

Knowledge of Variation Another element of continuous improvement is knowledge of variation. Variation is present in every aspect of our lives. Variation is inherent to everyone's behavior, learning styles, and ways of performing a task. Although the presence of variation, or uniqueness, can be considered a kind of quality, most services are judged on the basis of predictability and a low level of variation. When a service is thought to be of high quality, we expect it to be exactly the same each time, and if there is to be any variation, it must be better. To improve health products and services continually, it is necessary to know the customers, their needs, and how they judge the quality of health services. The processes by which health services are delivered must be understood and unintended variations reduced. If an organization is to improve and be innovative, it must plan changes that are based on knowledge of what can be better. Two types of variation found in production processes are those that occur by chance (common cause) and those due to assignable causes (special causes) ( 26). The ability to differentiate between these two types of variation is essential to making improvements in health care. Clinicians regularly make decisions in their practices based on variation. For example, a physician making frequent rounds may note a change in a patient's temperature and may decide to treat or to observe the patient based on the temperature change and on experience (i.e., judgment). If the temperature variation is seen as special cause (i.e., infection), a decision may be made to add an antibiotic. However, if the change or variation is interpreted as common cause variation in temperature due to short-term, normal changes or chance, it may be ignored. If this happens often, the physician may alter the frequency of observation, thereby making an improvement to the monitoring process. Frequently, however, common cause variation is not recognized in health care, and the variation is acted on prematurely, resulting in the overuse of resources and a lower quality of care ( 7). If the approach is to measure and change, too many costly changes might be made. Learning how to respond appropriately to variation in health care processes is a major challenge. Understanding and controlling variation in health care services should be the main emphasis of quality management. The notion of controlling variation, however, causes concern and skepticism in many health care professionals. Physicians who fear any effort to control variation are worried about the loss of options and about restrictions on their judgment. As Berwick points out ( 7), however, “The (problem) is not considered, intentional variation, but rather unintended or misinterpreted variation in the work of health care. Unintended variation is stealing health care blind today. In controlling it, the health care system could potentially recover a bounty in wasted resources that would dwarf the puny rewards of cost-containment to date.” Variation in Utilization One of the earliest and most compelling influences on modern health care quality assessment in the United States was a series of investigations that demonstrated a wide variation in the use of health care procedures ( 27). Although previous investigations had documented a twofold to fourfold difference in the rates of selected procedures both within the United States and between the United States and other industrialized countries, these variations usually were disregarded as secondary to population differences. However, a small-area analysis documented similar or even greater magnitudes of variation within small (25 to 50 miles) geographic regions that could not be explained by differences in patient characteristics or appropriate differences in standards of care ( 28). Variations in utilization have now been analyzed for virtually all major surgical procedures, including hysterectomy and cesarean delivery ( 29,30). Also, variation in the performance of medical procedures, such as those used in the management of acute myocardial infarction and sepsis, have been identified ( 31). On the basis of these analyses, significant variation has been documented in utilization and in important outcomes such as complications, cost, and derived benefit ( 32). This type of analysis does not usually allow accurate assessment of which rate of utilization or outcome is appropriate. However, it can help to focus attention on the quality of health services and the complexities of using statistically valid methods to measure health care quality. Variation in utilization of health care services can be categorized as follows: 1. Necessary and intended variation because of well-recognized patient differences such as severity of illness, comorbidity, and legitimate patient preferences 2. Acceptable but reducible variation because of uncertainty and lack of accurate information about outcomes 3. Unacceptable variation because of nonclinical factors, such as habitual differences in practice style, which are not grounded in knowledge or reason Most of the differences in utilization rates of many health care procedures result from the last two categories. Variation in Women's Health Care Overall, the rate of inpatient surgery for females aged 15 to 44 years is more than 3 times that of males, excluding vaginal deliveries. The most commonly performed major surgical procedure in the United States is cesarean delivery, with about 950,000 procedures performed annually in the United States. Rates of cesarean delivery vary by region, state, and small geographic areas. Overall, the rate of cesarean deliveries is 12% to 40%, and the national mean is about 23%. Comparative rates for the United Kingdom are 6% to 12%. Hysterectomy is the second most frequent inpatient surgical procedure in the United States. The total annual occurrence of hysterectomy for all ages, all indications, and all institutions (federal and nonfederal) in the United States is about 550,000. Hysterectomy rates in the southern and western United States are 50% to 75% higher than those in the Midwest and New England. A twofold to fivefold variation in utilization rates has been documented within states and small geographic areas within the United States (29). National rates in the United States are twice those in the United Kingdom and more than 3 times the rates in Sweden and Norway ( 33). Hysterectomy utilization in the United States varies by both provider and patient characteristics. Studies of utilization patterns have demonstrated that older physicians are more likely to recommend hysterectomy than are younger physicians and that (when controlled for age) gender does not appear to influence hysterectomy decision making (34). With respect to patient variables, although hysterectomy utilization is similar among African American women and white women (35,36), low income and low educational level are risk factors for hysterectomy ( 37). By 65 years of age, the prevalence of hysterectomy is 40% for women with a high school education and 20% for women with a college education. Short-term outcomes of hysterectomy vary significantly by race. African American women have a substantially higher relative risk (RR) for morbidity and in-hospital mortality (RR = 3.1) compared with age- and condition-matched white women (38). The reasons for this variation are not known. Quality management techniques are being applied to research in an attempt to reduce these wasteful variations.

The Theory of Knowledge The final component of knowledge for improvement is the theory of knowledge. The theory of knowledge refers to the need for the application of a scientific method for improving performance. One model for testing small-scale change is called the Plan, Do, Study, Act (PDSA) method (24). Unlike the ideal scientific method recommended for clinical trials, the PDSA method does not include a control group. Although randomized controlled trials have been considered to be the best way to determine the value of health care interventions, they have two distinct disadvantages: they are expensive, and they tend to define the efficacy of an intervention such as a drug or a surgical procedure. Because efficacy is the way an intervention works under ideal conditions, compared with effectiveness, which is the way an intervention works in everyday practice, health services researchers now recognize that it may not be possible to generalize about an intervention's effectiveness

based on its efficacy as measured in a randomized trial. Also, it is too expensive to perform randomized trials in all situations in which the effectiveness of health care services need to be improved. The PDSA cycle has been modified as the Find a process, Organize a team, Clarify the process, Understand the variation, and Select an improvement (FOCUS). The PDCA cycle has tested FOCUS for application to health care improvements ( 24). In this model, the P represents the need to plan an improvement by first identifying a change that might lead to improvement and then testing the change on a small scale. During this phase, who will do what, when the change will occur, and how the change will be communicated to those who will be affected are detailed. The D stands for doing or implementing the plan (change to the process) and collecting the data. The C stands for checking the data to determine whether the change to the process represents an improvement, and the A stands for acting or incorporating the change into the process if it is found to be an improvement. A new cycle with another change is started if an improvement was not recognized. Health care organizations are seeking efficient ways to optimize their delivery of and to improve health care services. The notion that high-quality health care automatically means high cost is no longer accepted without question. At a time when many businesses have transformed themselves by using newer methods of quality management, enabling them to deliver high-quality goods and services at reasonable costs, health care professionals and organizations are beginning to test these improvement methods in medical and surgical practice.

Newer Methods for Improving Performance Health services researchers and clinicians are beginning to develop and validate newer methods for the measurement and improvement of health care quality. For example, there is a need to make valid comparisons of quality between divergent populations and to correlate clinical performance with measurable processes of care. The goal of a new branch of investigation called clinical outcomes sciences is to obtain valid measures of relevant outcomes that are correlated with measurable processes of care so that changes in process can be identified and initiated, thereby improving outcomes. This discipline incorporates methodologies from divergent areas, such as epidemiology, clinical research, management, engineering, economics, and behavioral sciences. Statistical adjustments are used to allow clinically dissimilar populations, such as high-risk and low-risk patients and those with complicated and uncomplicated conditions, to be compared. This procedure is called case-mix adjustment and controls for severity of illness and comorbidity ( 39,40). Outcomes that are assessed include traditional (medical model) measures, such as complications and adverse occurrences, as well as newer, well-validated measures of satisfaction, health, and functional status. Concurrently, the processes of care are assessed. This would include measurement of resources used during an episode of care (e.g., supplies, medications, specialized personnel) and practice parameters (e.g., physician orders and nursing practices). Measurement of the processes and outcomes of health care can be prohibitively expensive if this measurement is not integrated into the daily clinical care. For this reason, another goal of clinical quality outcomes research is to develop and incorporate methods of quality assessment into routine practice. This mechanism could be accomplished, for example, by using the SF-36 as a standard nursing intake form at the time of admission. Analytic methods in clinical outcomes science rely heavily on multivariate statistics and iterative outcomes databases to provide valid correlations between measurable (and changeable) processes and outcomes. However, the mere identification of process changes that would improve outcomes does not ensure that they will, in fact, be used. For this reason, process and outcomes data must be linked to methods that will allow this information to be incorporated into clinical and operational decision making if they are to change behavior and improve outcomes. These analyses must be readily available both geographically and temporally at the point of care (the place and time that the decision is made) if they are to improve outcomes. One approach to QA, performance improvement, and medical decision making that has been recommended (the PREPARED system) uses a checklist to analyze the value of a health care procedure before it is performed ( 9,41). The purpose is to review sequentially the critical data categories of information, each represented by a letter in the word PREPARED, that should be used to determine the most appropriate course of action or choice ( 42): Procedure: & the course of action being considered Reason: & the indication or rationale Expectation: & the chances of benefit and failure Preferences: & patient-centered priorities (utilities) affecting choice Alternatives: & other reasonable options Risks: & the potential for harm from procedures Expenses: & all direct and indirect costs Decision: & fully informed collaborative choice Standardized procedural analysis using this sequenced checklist has been shown to improve health care decision making by increasing patient satisfaction and self-efficacy, thereby facilitating patient choice. It has the potential to improve the assessment of the quality and appropriateness of both provider and patient decision making. Outcomes Research and Outcome-derived Clinical Guidelines In the past, clinical practice guidelines or parameters have been largely derived by expert opinion and consensus. A major goal of clinical outcomes science is to allow for the development of guidelines based on actual measured outcomes that could self-adjust based on performance and newer methods of diagnosis and treatment. One such process for incorporating outcomes data into clinical practice is the critical pathway–case management method (43). In this method, consensus practice parameters for a given condition (e.g., management of preterm labor) are initially developed by a multidisciplinary team consisting of all professional, allied, and support services involved in the care of the target population. This list of parameters is called a critical path or clinical map. The critical path details all laboratory, dietary, consultative, medical, teaching, and nursing activities that are thought to be necessary to obtain specific clinical outcomes. Outcomes of care, as well as variations from the “path,” are monitored and collected continuously. Positive and negative outcomes are then analyzed and correlated with variances from the critical pathway. These data are then returned to the multidisciplinary team, which recommends changes in the entire path based on the outcomes and variance analyses. In one pilot study of a critical pathway method for cesarean delivery, length of stay and cost were reduced by 13% and 14%, respectively. Additionally, five of seven measurements of satisfaction, including quality of care, were improved, and health status was unchanged ( 43). A relatively new federal government agency, the Agency for Healthcare Research and Quality (AHRQ), formerly known as the Agency for Health Care Policy and Research (AHCPR), is responsible for funding developmental efforts, collecting information about clinical care guidelines, and disseminating information. Managed Care Measuring and improving health care quality and performance have received progressively greater support and validation. Health care reform activity and rapidly changing reimbursement patterns are moving away from traditional fee-for-service plans toward negotiated fee-for-service plans, prospective payment, and capitation-based contracting. This trend has led to a rapid application of modern quality management techniques and performance improvement activity aimed at reducing costs. Managed care contracts are being awarded on the basis of both clinical outcomes and cost. Many states and federal agencies have enacted legislation that requires health care providers to collect and disseminate comparative outcomes data in their practices. The National Committee on Quality Assurance (NCQA), which is sponsored by managed care organizations, has mandated the collection of quality performance indicators, referred to as HEDIS, which stands for Healthplan and Employer Data Information Set. If data are collected and analyzed appropriately, these initiatives could improve health care quality and reduce costs by facilitating rational decision making by consumers, providers, and third-party payers. If done hastily or inappropriately, efforts to use outcomes data, although well intended, could undermine these goals. For these reasons, standardized and validated methods for measuring the processes and outcomes of health care must be developed and integrated into daily clinical and operational practice ( 44).

Patient Safety Patient safety has been identified by the IOM as one of the most important dimensions of health care QA and performance improvement. According to a recent report from the IOM, it is estimated that between 44,000 and 98,000 preventable deaths may be due to medical error ( 1). Although there continues to be controversy about the validity of methods used in these analyses, critics admit that even if the actual number of preventable deaths from error is much smaller than estimated, efforts should be made to eliminate as many as possible. Patient safety has its roots in traditional risk management (RM) but there are important conceptual differences between the two ( Fig. 3.4). RM is retrospective and is focused on individual outliers. It is also outcomes oriented and addresses significant adverse (sentinel) events. The goals of RM include sanctions for substandard providers with far less attention to finding systems-oriented improvements that could prevent recurrent medical errors. Patient safety initiatives are prospective, interdisciplinary, and focused on health care process in addition to outcomes. They are designed to be nonpunitive and to recognize that most adverse outcomes are because of systems deficiencies and not individual error. Therefore, system changes in the overall process of delivery of care are necessary to prevent future problems. For example, when the wrong extremity is removed during a therapeutic amputation, RM efforts usually focus on legal liability issues, holding surgeons and operating room personnel accountable. A patient safety initiative would ideally study the entire process of care using a root-cause analysis approach ( Fig. 3.5). All of the members of the health care team, from admission to discharge, would be involved in order to identify and implement preventive measures. This “going beyond blame” approach was a significant recommendation in the IOM report, and it is the approach that is commonly used in other industries, such as aviation safety ( 1). Process changes and improvements, such as having the patient and surgeon sign the correct extremity using indelible ink at the time of admission and sharing the responsibility during the process so that several individuals (operating room personnel, anesthesia personnel, and members of the surgical team) would verify that the correct extremity is prepared and eventually removed. This team accountability approach is now being applied in all specialties, including obstetrics and gynecology.

Figure 3.4 A conceptual evolution of the characteristics of risk management (RM), quality assurance (QA), continuous quality improvement (CQI), and patient safety.

Figure 3.5 Root-cause(s) analysis: getting to the single or multiple causes of adverse outcomes.

The JCAHO has been very active and influential in the evolution of patient safety activities. Starting with an initial requirement that all significant (sentinel) events be reported, it now requires that root-cause(s) analysis be used to investigate the incident, identify contributing factors, and improve the process of care ( 45). Starting with all JCAHO surveys performed after June 2001, the Joint Commission requires documented evidence that a health care organization being reviewed has invested in a “top-down” commitment to patient safety improvement. Business and government are also interested in promoting patient safety activities. A business committee called the Leapfrog Group representing the National Business Roundtable and corporations such as General Electric, General Motors, and Verizon have announced that they will give purchasing preference to health care organizations that have at least the following three patient safety programs that have been shown to improve performance: (a) 24-hour, 7 days per week in-house coverage by intensive care specialists; (b) computerized physician-order systems; and (c) high volume, optimal outcomes, and low complication rates for high-risk procedures such as cardiovascular and transplant surgeries. There are currently several legislative bills before the United States congress addressing patient safety issues, such as practice reform and confidentiality. In addition, government programs such as Medicare and Medicaid are putting into place financial and other incentives for patient safety initiatives. Leaders in health care assessment and performance improvement have recommended five principles to help make health systems safer: 1. Leadership should commit to patient safety in the organization to provide the necessary personnel and financial resources. 2. System design should recognize human limitations. The noted health care improvement researcher, David Eddy, has stated that “the complexity of modern medicine exceeds the limitations of the unaided human mind.” The one-person (“captain-of-the-ship”) accountability of the past may actually lead to more errors in the current health care system. 3. Working and training in teams can help deliver safer care and more dependable accountability. 4. Training should anticipate the unexpected. 5. The organization should foster a learning environment for continual improvement of patient safety. There is a growing consensus that there will need to be a nonpunitive reporting system to identify not only errors but also “near misses” and other hazards so that they may be corrected before the patient is harmed. The aviation industry is a prime example of how measures can be taken to improve safety. Operations are simplified and standardized. Crew resource management empowers the most appropriate individual to correct a problem, even if that person is not the pilot. Simulators and team training are widely employed. The industry has a system, the airline safety reporting system (ASRS), for reporting actual incidents and near misses. Furthermore, this system is confidential and separated from the Federal Aviation Agency (their main regulatory body) by the National Aviation and Space Agency (NASA).

Summary Quality assessment and performance improvement activities are becoming increasingly important components of health care delivery. Although retrospective peer review and other QA efforts are still necessary, newer, prospectively focused methods to improve performance are being introduced. In the past, managing the cost of health care has been a major rationale for quality assessment and performance improvement programs. Recently, however, concerns about patient safety and deficiencies in quality have been prompted by several IOM reports ( 1,3). The complexity of modern health care delivery now requires a multidisciplinary team

approach to quality management and error reduction. Health care professionals need to move away from an atmosphere of blame and individual accountability to a more effective systems approach to improve health care quality and safety significantly.

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In: Spilker B, ed. Quality of life assessment in clinical trials. New York: Raven Press, 1990:131–149. Deyo RA, Patrick DL. Barriers to the use of health status measures in clinical investigation, patient care, and policy research. Med Care 1989;27:S254–268. Maynard A. Developing the health care market. Economic Journal 1991;101:1277–1287. Kaplan RM. An outcomes-based model for directing decisions in women's health care. Clin Obstet Gynecol 1994;37(1):192–206. Ware JE Jr, Kosinski M, Bayliss MS, et al. Comparison of methods for the scoring and statistics of SF-36 health profile and summary measure: summary of outcomes study. Med Care 1995;33[Suppl 4]:AS264–79. Batalden PB, Buchanan DB. Patient care process improvement. In: Batalden PB, Buchanan DB, eds. A course, hospital wide quality: focus on continuous improvement. Nashville: Hospital Corp. of America (QRG), 1990:12. Batalden PB, Nolen TW. Knowledge for the leadership of continual improvement in healthcare. In: Taylor RJ, ed. Manual of health services management. Gaithersburg: Aspen, 1993:1–21. Deming WE. The new economics for industry, government and education. Cambridge, MA: Massachusetts Institute of Technology, 1993. Bataldin PB, Stoltz PK. A framework for the continual improvement of health care: building and applying professional and improvement knowledge to test changes in daily work. Joint Comm J Qual Impr 1993;19(10):424–452. Gambone JC, Chez RA. Strategic planning: a modern tool for obstetricians and gynecologists in a competitive practice environment. Prim Care Update Obstet Gynecol 2000;7:177–180. Shewhart WA. Statistical method from the viewpoint of quality control. Washington, DC: Department of Agriculture, 1993. Wennberg JE, Gittelsohn A. Variations in medical care among small areas. Sci Am 1982;246:120–134. Wennberg JE, Freeman JL, Culp WJ. Are hospital services rationed in New Haven or over-utilized in Boston? Lancet 1987;1:1185–1189. Roos NP. Hysterectomy: variations in rates across small areas and across physicians' practices. Am J Public Health 1984;74(4):327–335. Centers for Disease Control and Prevention. Rates of cesarean delivery—United States. MMWR Morb Mortal Wkly Rep 1993;42:285–289. The Cardiology Working Group. Cardiology and the quality of medical practice. JAMA 1991;265:482–485. Bickell NA, Earp JA, Garrett JM, et al. Gynecologists' sex, clinical beliefs, and hysterectomy rates. Am J Public Health 1994;84:1649–1652. Graves EJ. Summary: national hospital discharge survey. Advance Data From Vital and Health Statistics: No. 199. Hyattsville: National Center for Health Statistics, 1989. Haas S, Acker D, Donahue C, Katz ME. Variation in hysterectomy rates across small geographic areas of Massachusetts. Am J Obstet Gynecol 1993;169:150–154. Carlson KJ, Nichols DH, Schiff I. Indications for hysterectomy. N Engl J Med 1993;328:856–860. Kjerulff K, Langenberg P, Guzinski G. The socioeconomic correlates of hysterectomies in the United States. Am J Public Health 1993;83(5):106–108. Kjerulff KH, Guzinski GM, Langenberg PW, et al. Hysterectomy and race. Obstet Gynecol 1993;82:757–764. Wilcox LS, Koonin LM, Pokras R, et al. Hysterectomy in the United States, 1988–1990. Obstet Gynecol 1994;83(4):549–555. Boyle T. Developing severity-adjusted critical paths using Medisgroups reporting. Am J Med Qual 1991;4:1–12. Zander K. Nursing care management: strategic management of cost and quality outcomes. J Nurs Adm 1988;18:23–30. Gambone JC, Reiter RC. Quality improvement in health care. Curr Probl Obstet Gynecol Fertil 1991;15(5):170–175. Gambone JC, Reiter RC. Promising innovation or needless intervention? J Gynecol Techniques 1995;1:59. Blegen MA, Reiter RC, Goode C, et al. Outcomes of hospital based managed care: a multivariate analysis of cost and quality. Obstet Gynecol 1995;86:809–814. Loegering L, Reiter RC, Gambone JC. Measuring the quality of health care. Clin Obstet Gynecol 1994;37(1):122–136. Gluck PA. Patient safety: a new imperative. ACOG Clin Rev 2001, July/August. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 4. Epidemiology for the Gynecologist Novak’s Gynecology

Chapter 4

Epidemiology for the Gynecologist Daniel W. Cramer

Study Designs Descriptive Studies Analytic Studies Gynecologic Considerations Reproductive Events Illnesses References

Epidemiology is the study of the occurrence of health events in human populations. Epidemiologic studies may encompass broad topics, such as how birth or death rates vary among people of different nationalities, or more narrow topics, such as how risk for a specific disease changes after a specific exposure. A common theme of most epidemiologic studies is the relationship between disease and exposure, but the design, strengths, weaknesses, and validity of epidemiologic studies vary considerably (1,2,3,4,5 and 6). Some definitions that are commonly used in epidemiology are as follows: Age-specific incidence: the number of new events occurring in 5- or 10-year age groups per year Attributable risk: the difference between the occurrence measure in the exposed and the unexposed cohort Bias: a systematic error in the design, conduct, or analysis of a study Clinical trial: a prospective cohort study to evaluate treatments for disease in humans Cohort: a group of people who have some factor in common Confidence interval (CI): a component of statistical inference in which an interval is provided to give the reader some idea of the range in which the “true” statistical measure calculated (e.g., mean, proportion, and relative risk) is expected to occur Confounder: an extraneous variable that accounts for the apparent effect of the study variable or masks the true association Incidence: the rate of occurrence of new cases of a disease or condition over a specific time interval Predictive value of a negative test: the number of true negative results out of all those screened with negative results Predictive value of a positive test: the number of true positive results out of all those screened with positive results Prevalence: the existing number of cases at a specific point in time Recall bias: a type of information bias that may occur if cases are more likely than controls to remember or to reveal past exposures Relative risk: the occurrence in the exposed cohort divided by occurrence in the nonexposed cohort Sensitivity: the proportion of persons with a true positive screening result out of all those who have the disease Specificity: the proportion of persons with a true negative screening result out of all those who do not have the disease Statistical significance: the application of a statistical method to test the null hypothesis (i.e., the hypothesis that two or more factors are not associated) Yield: the exposure odds ratio (or simply odds ratio) in a case-control study (i.e., the ratio of exposed cases to unexposed cases divided by the ratio of exposed to unexposed controls)

Study Designs Epidemiologic studies are primarily descriptive or analytic (i.e., designed to test a hypothesis about an association). This distinction is important in evaluating a medical study.

Descriptive Studies Studies in which the characteristics of a disease are described are among the most common type of study. The two principal types of descriptive studies are case series and cross-sectional studies. Case Reports or Series A simple type of study is the case report or case series in which the characteristics of individuals who have a particular disease are described. Hypotheses about the cause of the disease or its treatment are frequently developed from case series and then explored in analytic studies. For example, a link between oral contraceptives and thromboembolism was first suggested by case reports (7) and later confirmed in a case-control study ( 8). Occasionally, when case series describe the co-occurrence of rare exposures and rare diseases, they are compelling enough on their own to suggest a cause-and-effect relationship. Links between thalidomide and fetal limb reduction ( 9), the Dalkon shield intrauterine device and septic abortion ( 10), and sequential oral contraceptives and premenopausal endometrial cancer (11) emerged through case series that were persuasive enough to initiate public health action without the performance of formal epidemiologic studies. In general, however, just because a high number of members of a case series share a particular characteristic, one cannot assume that there is a cause-and-effect relationship. A number of selection factors could have contributed to the observation. Because of their potential importance, attention should be paid to details of the case selection in case reports or series (e.g., incident or prevalent cases, record-based or personal contact with patients). Investigators should strive to be sure that clear criteria exist for the definition of disease or study variables and that identification of cases was complete. Case series that extend over a long period may suffer from changes in the diagnosis or treatment of the condition that may confuse objectives. Interobserver or reviewer reliability may need to be assessed. Careful assembly of a case series is the first step in performing a case-control study as the logical extension of a case series. A case series does not usually yield any formal epidemiologic measures other than estimates of the frequency of a particular characteristic among members of the case series. This is often referred to as the incidence of a particular characteristic among cases, but prevalence is usually the more appropriate term. Cross-sectional Studies

Design Cross-sectional studies are larger in scope than case series and generally do not focus on a particular disease. Individuals are surveyed to provide a “snapshot” of health events in the population at a particular time. The U.S. Census Bureau counts the population by categories of age, sex, and ethnicity. The U.S. National Center for Health Statistics compiles a wide variety of data on the health of the population, such as occurrence of hospitalization for various conditions. State health departments are required to count the number of births and deaths annually in their population, and some maintain registries to count the number of individuals who have cancer. Yield Incidence is the rate of occurrence of new cases of diseases or conditions over a specific time. Cross-sectional studies often yield incidence rates in which births, new disease cases, or deaths are counted annually for a specified census region and divided by the population size to yield events per population per year. The rate is usually multiplied by a base (1,000, 10,000, or 100,000) to give numbers that can more easily be tabulated. Incidence is an important concept in epidemiology and is often used to calculate other measures of disease frequency, such as prevalence and lifetime risk. Age-specific incidence refers to the number of new events occurring in 5- or 10-year age groups per year. Because of marked differences by age for most illnesses, age-specific incidence rates are the best way to describe event occurrence in a population. If the incidence rate is not specified with regard to age, it is described as “crude.” Prevalence is the existing number of cases at a specific point in time. Prevalence is another measure frequently developed from cross-sectional studies. For example, in 1988, the Family Growth Survey Branch of the National Center for Health Statistics interviewed a sample of married couples and found the prevalence of infertility among married women younger than 45 years of age in the United States to be about 8.0% ( 12). Because prevalence measures disease status in a population rather than events occurring over time, prevalence is a proportion. Although cross-sectional studies are primarily descriptive, they may contribute information on the cause of a disease by showing how that disease varies by age, sex, race, or geography. In ecologic studies, disease rates in various populations are correlated with other population characteristics (e.g., endometrial cancer rates worldwide are positively correlated with per capita fat consumption and negatively correlated with cereal and grain consumption) ( 13). Such observations are valuable in suggesting topics for analytic studies or supporting the consistency of an association.

Analytic Studies The purpose of an analytic epidemiologic study is to test a hypothesis about and to measure an association between exposure (or treatment) and disease occurrence (or prevention) (Fig. 4.1). Analytic studies may be subdivided into nonexperimental and experimental studies.

Figure 4.1 The essential design of an epidemiologic study showing the relationship between exposure (or treatment) and disease.

Nonexperimental analytic studies include cohort and case-control studies and take advantage of “natural experiments” in which individuals do or do not have a particular disease and have or have not had an exposure of potential interest. Experimental studies, such as clinical trials, should meet more rigid criteria than nonexperimental studies. Features they should include are randomization (in which participants are randomly assigned to exposures) and measures to ensure unbiased assessment of outcome. Nonexperimental Studies Cohort Studies Design A cohort is a group of people who have some factor in common. In the context of a survival analysis, the cohort begins with a population that is 100% well at a particular time and is followed over time to calculate the percentage of the cohort still well at later times. Survival analysis describes mortality after disease (i.e., cancer patients who died within 5 years) but can be adapted to other events (e.g., the percentage of women who continue to menstruate after 50 years of age or the percentage of infertile women who conceive after therapy). A cohort is defined by subsets of a population who are, have been, or may in the future be exposed to factors hypothesized to influence the occurrence of a given disease (Fig. 4.2). The exposed and nonexposed subjects are observed long enough to generate person-years as the denominator for incidence or mortality rates in exposed and nonexposed subsets.

Figure 4.2 The format and calculations for a cohort study design.

Cohort studies are also called follow-up, longitudinal, or prospective studies. Although these terms suggest that the exposure is identified before outcome, a retrospective cohort study may also be performed in which the exposure and outcome have already occurred when the study is begun. For example, studies of radiation and subsequent cancer are often based on records of patients who received radiation therapy many years previously. Medical records and death certificates

are used to determine whether a second cancer occurred after the radiation therapy. Yield Cohort studies may yield two measures of an association between exposure and illness. These measures are an attributable risk and a relative risk. Attributable risk is the difference between the occurrence measure in the exposed and the unexposed cohort. The null value is zero—a positive number indicates how many cases of disease may be caused by the exposure, and a negative number indicates how many cases of disease may be prevented by the exposure. Relative risk divides occurrence in the exposed cohort by occurrence in the nonexposed cohort. The null value for the relative risk is 1. A value greater than 1 indicates that exposure may increase risk for the disease (i.e., a relative risk of 1.5 indicates that exposed individuals had 1.5 times, or 50% greater, the risk for disease as unexposed individuals). A value less than 1 indicates that exposure may decrease risk for disease (i.e., a relative risk of 0.5 indicates that the rate in exposed individuals was half that of the rate in the nonexposed individuals). Strengths and Weaknesses The ability to obtain both attributable and relative risks is a strength of cohort studies. In addition, cohort studies are less susceptible to selection and recall bias. Misclassification of exposure and confounding variables can occur, however. Disadvantages of a cohort study generally include higher cost and longer time for completion. Cohort studies are most useful for examining the occurrence of common diseases after a rare exposure. For rare exposures, an investigator may use the general population as the unexposed group. In this type of study, the observed number of cases in the exposed cohort is divided by the number of cases expected if general population rates had prevailed in the exposed cohort. This comparison is called the standardized morbidity or mortality ratio (SMR) and is equivalent to relative risk. Case-control Studies Design A case-control study starts with the identification of individuals with a disease or outcome of interest and a suitable control population without the disease or outcome of interest. The relationship of a particular attribute or exposure to the disease is studied by comparing how the cases and controls differed in that exposure. An alternate term frequently used to describe a case-control study is retrospective because the exposures are assessed after the disease has occurred. Yield The yield of a case-control study is the exposure odds ratio. It is the ratio of exposed cases to unexposed cases divided by the ratio of exposed to unexposed controls. If an entire population could be characterized by its exposure and disease status, the exposure odds ratio would be identical to the relative risk obtainable from a cohort study of the same population. Although it is not feasible to survey the entire population, so long as the sampling of cases or controls from the population was not influenced by their exposure status, the exposure odds ratio will approximate the relative risk. Attributable risk is not directly obtainable in a case-control study (Fig. 4.3).

Figure 4.3 The case-control study design.

Strengths and Weaknesses The advantages of case-control studies are that they are generally lower in cost and easier to conduct than other analytic studies. Case-control studies are most feasible for examining the association between a relatively common exposure and a relatively rare disease. Disadvantages include greater potential for selection bias, information bias, and confounding variables. Because an investigator must assign exposures according to a strict protocol, human experimental studies are limited to the study of measures that will prevent disease or the consequences of disease. Examples of experimental studies are clinical trials and field and community intervention trials. Experimental Studies Clinical Trials The clinical trial is a prospective cohort study to evaluate treatments for disease in humans. Randomization of the treatment assignment is the cornerstone of a good clinical trial because it minimizes bias, which can result from confounding variables or preferential assignment of treatment based on patient characteristics. Evidence must be provided that factors that might influence outcome, such as stage of disease, were similar in patients assigned to the study protocol compared with patients assigned to placebo or traditional treatment. Criteria for successful treatment must be clearly defined. Blinding the subject and clinician to the treatment modality may help ensure unbiased assessment of the outcome. A properly designed clinical trial will have a sufficient number of subjects enrolled to ensure that a “negative” study is powerful enough to rule out a treatment effect. Field and Community Intervention Trials Field and community intervention trials evaluate measures that may prevent disease, such as vaccines, dietary interventions, or screening procedures. In a field trial, the intervention is applied to individuals. In a community intervention trial, the intervention (e.g., water fluoridation) is applied on a community-wide basis rather than to individuals. Both types of studies include subjects who do not yet have disease and may require large numbers of participants, especially for studies of screening procedures to prevent cancer. In the latter context, issues related to the validity of screening tests (i.e., sensitivity, specificity, and predictive value) are quite important (Table 4.1).

Table 4.1. Measures of Validity for a Screening Procedure

Features Features of an analytic study that are considered in judging its scientific validity include statistical significance, biases, dose response, consistency, and biologic credibility. Statistical significance is determined by application of a statistical method to test the null hypothesis (i.e., the hypothesis that two or more factors are not associated). The degree of conflict between the test result and the result predicted by the null hypothesis is indicated by the p value. Typically, p60 mm Hg and PCO2 95%) with hypertension have primary or essential hypertension (cause unknown), whereas less than 5% have secondary hypertension resulting from another disorder. Key factors should be determined in the history and physical examination. The presence of prior elevated readings, previous use of antihypertensive agents, a family history of death from cardiovascular disease prior to age 55, and excessive alcohol and sodium use constitute important historical information. Lifestyle modification is increasingly important in the therapy of hypertension; thus, a detailed history of diet and physical activity should be obtained ( 19). Baseline laboratory evaluations to rule out reversible causes of hypertension (secondary hypertension) are listed in Table 9.4. Diagnosis and management are based on the classification of blood pressure readings in Table 9.5. In addition, patients are stratified into three different risk groups for therapeutic decision making ( Table 9.6).

Table 9.4. Laboratory Tests and Procedures Recommended in the Evaluation of Uncomplicated Hypertension a

Table 9.5. Blood Pressure Classification (Adults 18 years and Older)

Table 9.6. JNC Blood Pressure Risk Group Stratification

Following are general guidelines in assessing individuals for therapy: 1. Patients with high normal readings (systolic blood pressure 130 to 139 mm Hg or diastolic blood pressures 85 to 89 mm Hg) are at high risk for developing hypertension. They should be monitored yearly, and consideration should be given to nonpharmacologic interventions ( 20). A scheme for the treatment of uncomplicated hypertension is found in Fig. 9.2.

Figure 9.2 Algorithm for the treatment of uncomplicated hypertension. See Table 9.6 for definitions of Risk Group A, B, and C. (Modified from The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 1997; NIH publication 99-4080.)

2. A single elevated diastolic blood pressure reading of less than 100 mm Hg should be rechecked within 2 months before initiating therapy. In 33% of patients, elevated readings will spontaneously resolve during the observation period because of so-called white-coat hypertension. 3. If blood pressure control is not easily achieved, systolic blood pressure is higher than 180 mm Hg, or the diastolic reading is higher than 110 mm Hg, referral to an internist is recommended. Referral also is indicated if secondary hypertension is suspected or evidence of end-organ damage (renal insufficiency or congestive heart failure) is detected. Measurement of Blood Pressure An often overlooked but essential variable in the evaluation of hypertension is the method used to obtain measurements and the need to standardize measurements (22). Ambulatory or home monitoring devices, which are becoming less expensive and more reliable, may be appropriate for use by patients who have repeated normal measures outside of the office. In most patients, readings done in the office are all that is necessary to adequately diagnose and monitor hypertension and eliminate problems arising from unreliable commercial devices and patient interpretation skills. Protocols for measurement of blood pressure should be standardized. The patient should be allowed to rest for 5 minutes in a seated position and the right arm used for measurements (for unknown reasons, the right arm has higher readings). The cuff should be applied 20 mm above the bend of the elbow and the arm positioned parallel to the floor. The cuff should be inflated to 30 mm Hg above the disappearance of the brachial pulse, or 220 mm Hg. The cuff should be deflated slowly at a rate no more than 2 mm Hg per second. The cuff size is important. Most cuffs are marked with “normal limits” for the relative size they can accommodate. The most common clinical problem encountered is small cuffs used for obese patients, resulting in so-called cuff hypertension. Phase IV Korotkoff's sounds are described as the point when pulsations are muffled, while phase V is complete disappearance. Most experts in hypertension advocate the use of phase V Korotkoff sounds, but phase IV sounds may be used in special circumstances, with the reason documented. The use of automated devices may help eliminate discrepancies in measurements. Regardless of the method or device used, two measurements should be obtained with less than a 10 mm Hg disparity to be judged adequate. When repeated measures are performed, there should be a 2-minute rest period between readings. Blood pressure has a diurnal pattern, so determinations preferably should be done at the same time of day. Ambulatory monitoring is not cost effective in all patients but should be used in some situations, mainly to evaluate resistance to therapy, to detect white-coat hypertension, and to assess whether syncopal episodes are related to hypotension or episodic hypertension ( 23). Therapy The definition of what constitutes systolic hypertension requiring treatment has been contested for years. Patients with systolic blood pressure higher than 160 mm Hg benefit from antihypertensive therapy regardless of their diastolic pressures (21). Middle-aged to elderly patients treated for systolic hypertension have a significant decrease in cerebral vascular accidents and coronary artery disease. Lifestyle modification should be initiated for patients with systolic blood pressures greater than 130 mm Hg but less than 160 mm Hg or diastolic blood pressures greater than 85 mm Hg but less than 100 mm Hg and belonging to risk groups A or B (Fig. 9.2). Nonpharmacologic interventions or lifestyle modification should be attempted prior to initiation of medication unless the systolic blood pressure exceeds 159 mm Hg, the diastolic blood pressure exceeds 99 mm Hg, or the systolic blood pressure exceeds 139 mm Hg or diastolic blood pressure exceeds 89 mm Hg and the patient has any target-organ damage or diabetes mellitus with or without any other risk factors. Drug therapy should also be initiated for systolic blood pressure higher than 130 mm Hg or diastolic blood pressure higher than 85 mm Hg in those with heart failure, diabetes mellitus, or renal failure ( Fig. 9.2). An important element in lifestyle modifications is to modify all contributors to cardiovascular disease. Weight loss in obese patients, especially in individuals with truncal and abdominal obesity, can prevent the development of atherosclerosis ( 24). A loss of just 10 pounds has been reported to lower blood pressure ( 25). Patients should be advised to eliminate excess salt in their diets, specifically certain food groups that are high in sodium such as canned goods, snack food, pork products, and soy sauce. Reducing salt intake to 3 grams per day would decrease annual mortality by 70,000 deaths ( 26). Intake of cholesterol and fat should be limited. Following an exercise program, losing weight, and limiting alcohol intake to no more than 2 drinks per day contributes to overall cardiovascular health. Aerobic exercise alone may prevent hypertension in 20% to 50% of normotensive individuals ( 27). The goal of therapy is to lower blood pressure into the normal range, a systolic reading less than 130 mm Hg and a diastolic reading less than 85 mm Hg. If lifestyle modifications are not sufficient to control blood pressure, pharmacologic intervention is indicated. The number of antihypertensive medications has exploded over the past decade. Currently, only diuretics and b-blocking agents have been proved to reduce mortality and morbidity ( 28). Diuretics The most commonly used medication for initial blood pressure reduction is hydrochlorthiazide. The mechanism of action is to reduce plasma and extracellular fluid volume. This lowering of volume is thought to decrease peripheral resistance. Cardiac output initially decreases and then normalizes. The important long-term effect is a slight decrease in extracellular fluid volume. The maximal therapeutic dose of thiazide should be 25 mg rather than the commonly used 50 mg. The benefit of higher doses is eliminated by the corresponding increase in side effects. Potassium-sparing diuretics (spironolactone, triamterene, or amiloride) are usually available in fixed doses and should be prescribed to prevent hypokalemia. Potassium supplementation is less effective than the use of potassium-sparing agents. Thiazide diuretics are best used in patients with creatinine levels less than 2.5 g/L. Loop diuretics (furosemide) work better than thiazide diuretics at lower glomerular filtration

rates and higher serum creatinine levels. Control of hypertension with concurrent renal insufficiency is difficult and is probably best handled by an internist or nephrologist. Thiazides and loop diuretics should not be used concurrently because they cause profound diuresis, which may lead to renal impairment. Concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) limits the effectiveness of thiazides. Other side effects, which further limit the usefulness of thiazide diuretics, include hyperuricemia, which may contribute to acute gout attacks, glucose intolerance, and hyperlipidemias ( 29). The metabolic side effects of these drugs have limited their popularity recently. Adrenergic Inhibitors b-Blockers have been used extensively for years as antihypertensive agents. The mechanism of action is decreasing cardiac output and plasma renin activity with some increase in total peripheral resistance. As a class, they are an excellent source of first-line therapy, especially for migraine sufferers. The original formulation, propranolol, was highly lipid soluble, which contributed to bothersome side effects such as depression, sleep disturbances (nightmares in the elderly), and constipation in higher doses. Formulations such as atenolol are water soluble, are b1 selective, and have fewer side effects. At higher doses, however, b 2 effects emerge. Despite speculation that b 1-selective agents may be safe in asthmatics, they should never be used in these patients. Additional advantages of water-soluble agents are longer half-lives and reduced dosing schedules, which improve compliance. Metabolic changes, similar to those of thiazide diuretics, have reduced the popularity of these drugs. These side effects include an increase in triglyceride levels, a decrease in high-density lipoprotein (HDL) cholesterol levels, and blunting of adrenergic release in response to hypoglycemia. These metabolic problems far outweigh the benefits in patients with diabetes mellitus ( 30). NSAIDs may also decrease the effectiveness of b-blockers. Additional contraindications are COPD, sick sinus syndrome, or any bradyarrhythmia. A popular use of b-blockers is for treatment of angina and myocardial infarctions. If these drugs are acutely withdrawn, however, a rebound phenomenon of ischemia may occur, leading to acute myocardial infarction. b-Blockers continue to be useful, despite these potential problems, especially to counteract reflex tachycardia common with smooth muscle–relaxing drugs. a1-Adrenergic drugs became popular in males because they have minimal effects on potency and a unique relationship to lipids. Interestingly, they may contribute to stress urinary incontinence in women as a result of altered urethral tone ( 31). As single agents, they decrease total cholesterol and low-density lipoprotein (LDL) cholesterol while increasing HDL cholesterol levels, in contrast to the metabolic effects of b-blockers. Mode of action is to promote vascular relaxation by blocking postganglionic norepinephrine vasoconstriction in the peripheral vascular smooth muscle. Prazosin and doxazosin are currently the most popular preparations available in this class. A serious side effect of these drugs, most commonly described in the elderly, is called the first-dose effect. In susceptible individuals, severe orthostasis was reported when therapy was initiated, but it subsided after several days. In combination with diuretics, hypotension may be further exacerbated. Therapy should begin with small bedtime doses followed by incremental increases. Other side effects, which may limit usefulness in some patients, include tachycardia, weakness, dizziness, and mild fluid retention. Angiotensin-converting Enzyme Inhibitors Angiotensin-converting enzyme inhibitors (ACE inhibitors) have rapidly become a first-line drug in the treatment of hypertension. Their rapid rise in popularity is due to the introduction of new formulations that allow for once- or twice-daily dosing with a good therapeutic response. There are relatively few side effects; chronic cough is the most worrisome and is the most common cause of discontinuing therapy for this group of drugs. Other side effects are occasional first-dose hypotension and blood dyscrasias. Occasionally patients will suffer from rashes, loss of taste, fatigue, or headaches. Because use is strictly contraindicated during pregnancy, other agents should be considered for women who could become pregnant. ACE inhibitors can be used in combination with other agents, including diuretics, calcium-channel antagonists, and b-blockers. In contrast to b-blockers, these medications can be used in patients with asthma, COPD, depression, and diabetes or peripheral vascular disease. For unknown reasons, they are less effective in African Americans unless a diuretic is used concomitantly. Combined with diuretics, the effectiveness of both drugs increases, but hypovolemia may result. If renal failure is present, hyperkalemia may result from potassium supplementation and altered tubular metabolism. Any NSAID, including aspirin, may decrease the antihypertensive effectiveness. Angiotensin Receptor Antagonists Angiotensin receptor antagonists such as losartan and valsartan are drugs that interfere with the binding of angiotensin-II to AT-I receptors. They are as effective as ACE inhibitors in lowering blood pressure without causing the side effect of coughing. Their efficacy in protecting the heart and kidney, similar to ACE inhibitors, remains to be established. Calcium-channel Blockers Calcium-channel blockers have been a major therapeutic breakthrough for patients with coronary artery disease and have been found to be effective in patients with hypertension and peripheral vascular disease. The mechanism of action is to block calcium movement across smooth muscle, therefore promoting vessel wall relaxation. Calcium-channel blockers are especially useful in treating concurrent hypertension and coronary artery disease. Additionally, these drugs have been shown to be particularly effective in the elderly and African Americans. Side effects noted include headache, dizziness, constipation, and peripheral edema. The introduction of long-acting calcium-channel blockers has made these preparations more amenable for use in hypertension. Heart failure or conduction disturbances are relative contraindications for use of these drugs. Direct Vasodilators Hydralazine is a potent vasodilator used for years in obstetrics for severe hypertension associated with preeclampsia and eclampsia. The mechanism of action is direct relaxation of vascular smooth muscle, primarily arterial. Major side effects include headaches, tachycardia, and fluid (sodium) retention that may result in paradoxical hypertension. Several combinations have been used to counter the side effects and enhance antihypertensive effects. Diuretics may be added to reverse fluid retention caused by sodium retention. When used in combination with b-blockers, tachycardia and headaches may be controlled without compromising the objective of lowering blood pressure. Drug-induced lupus erythematosus has been widely stated as a potential side effect but is rare in normal therapeutic doses of 25 to 50 mg three times per day. Minoxidil is another extremely potent drug in this class, but it is of limited use to the gynecologist due to its side effects in women (beard growth). Because of minoxidil's potency, only experienced practitioners should use it. Central-acting Agents Central-acting agents (methyldopa and clonidine) have long been used in obstetrics. The mechanism of action is to inhibit the sympathetic nervous system, resulting in peripheral vascular relaxation. The popularity of this group of drugs has been limited by side effects such as taste disorders and dry mouth, as well as the need for frequent dosing (except for the transdermal form of clonidine). Sudden withdrawal of clonidine may precipitate a hypertensive crisis and induce angina. The clonidine withdrawal syndrome is more likely with concomitant use of b-blockers. Compliance is always a major issue in patient care, and side effects can have a major impact. With the introduction of new classes of drugs with improved efficacy and reduced side effects, the use of medications in this class is expected to decline.

Monitoring Therapy For patients with slightly elevated blood pressure who are being managed with lifestyle modification, blood pressure readings should be monitored frequently by a professional nurse, the patient, or medical office staff at 1- to 2-week intervals. If the patient has other diseases (i.e., cardiovascular or renal), therapy should be initiated earlier and should be directed to the target organ. If lifestyle modification alone is successful, close monitoring is necessary at 3- to 6-month intervals. When lifestyle modification is unsuccessful, blood pressure medication should be administered to decrease target organ disease. When beginning therapy, concurrent medical conditions that can be treated with a common agent should be considered. Gender, as a consideration in choosing an antihypertensive agent, has been found unimportant. Concurrent diseases that are important include (a) migraine headaches, for which b-blockers or calcium-channel blockers may be the best choice, (b) diabetes mellitus, for which ACE inhibitors should be used, and (c) patients who have had myocardial infarctions who should receive b-blockers because they reduce the risk for sudden death and recurrent myocardial infarctions. In addition, African Americans are noted to respond better to a combination of diuretics and calcium-channel blockers.

Once antihypertensive medications are initiated, monitoring should be frequent. Selected agents and dosages for therapy are found in Table 9.7 and are not meant to be all-inclusive. Patients capable of home blood pressure monitoring should be encouraged to measure blood pressure at the same time twice weekly ( 32) and maintain a log for physician review of effectiveness of therapy. Once medications are begun, a return appointment should be scheduled in 2 to 4 weeks to monitor effectiveness and side effects. Where possible, single agents (monotherapy) should be used to improve compliance. Monotherapy should control 50% to 60% of patients with mild-to-moderate hypertension. If initial doses are ineffective, then a higher dose should be used prior to changing agents. If resistance to therapy continues, then a different class may be started or a second drug should be added.

Table 9.7. Selected Medications and Dosage for Control of Essential Hypertension

If intolerable side effects develop, a different class of medications should be started and monitored. In the past, step therapy was used, starting with thiazides, followed by the addition of b-blockers, and finally followed by vasodilator drugs. The newer drugs (ACE inhibitors, postadrenergic ganglionic blockers, and calcium-channel blockers) are more potent, have longer half-lives, and may be used as single agents. Patients whose blood pressure is difficult to control with monotherapy should be considered for referral. Causes of resistance to therapy include diseases and secondary causes of hypertension missed during the initial evaluation, unrecognized early end-stage disease, and poor compliance. Patients with evidence of target-organ disease should also be considered for transfer or referral to the appropriate specialist for more intensive diagnostic workup and therapy.

Cholesterol It has been stated that cholesterol is the most highly decorated small molecule in biology ( 33). The dietary influence of cholesterol on atherosclerosis and its relationship to hypertension and cardiovascular events (myocardial infarction and stroke) has been widely debated in both the scientific and lay communities ( 34). The controversy centers on the influence of dietary cholesterol in risk assessment and prevention of cardiovascular disease ( 35). Many assume that all cholesterol and fat in the diet have negative health consequences. Furthermore, cholesterol metabolism is complex and our understanding in some cases is extrapolated from animal models. The role of cholesterol testing (who, when, and at what age) is hotly debated among health care professionals. Cholesterol testing is fraught with multiple variables that affect results. The purpose of the following discussion is to identify patients at risk for complications of hypercholesterolemia and better understand overall metabolism and therapy. Terms and Definitions Exclusively LDL and HDL cholesterol do not determine cholesterol metabolism, despite popular discussion. Cholesterol is usually found in an esterized form with various proteins and glycerides that characterize the stage of metabolism. The following components are important lipid particles in cholesterol metabolism. Chylomicrons These are large lipoprotein particles that consist of dietary triglycerides and cholesterol. Chylomicrons are secreted in the intestinal lumen, absorbed in the lymph, and then passed into general circulation. In adipose tissue and skeletal muscle, they adhere to binding sites on the capillary wall and are metabolized for energy production. Lipoprotein Particle A lipoprotein particle is made from three major components. The core consists of nonpolar lipids (triglycerides and cholesterol esters) that are present in varying amounts, depending on which stage of the metabolic pathway they are found. Surrounding the nonpolar core is a surface coat of phospholipids that is made of apoproteins and structural proteins. Apoprotein Attached to all lipoprotein particles is an apoprotein. This is a specific recognition protein exposed at the surface of a lipoprotein particle. Apoproteins have specific receptors and demarcate the stage of cholesterol metabolism. Certain apoproteins are associated with specific types of cholesterol. For example, apoprotein A-I and apoprotein A-II are associated with HDL cholesterol, the so-called scavenger cholesterol. Apoprotein C-II has additional activity as a cofactor for lipoprotein lipase. Lipoprotein Class Lipoprotein particles are separated into five classes that are dependent on physical characteristics. Lipoprotein classes are determined by the separation of lipids in an electrophoretic field; however, in vivo they are in a continuum. The various cholesterol metabolites are separated by density. As lipoprotein particles are metabolized and lipids are removed for energy production, they become denser. Additionally, attached apoproteins are modified as cholesterol moves from the so-called exogenous pathway (dietary) to the endogenous pathway (postabsorption and metabolized by the liver). Subdivisions of the lipoprotein classes are described below and summarized in Fig. 9.3.

Figure 9.3 Metabolic pathways for lipid metabolism.

Prehepatic Metabolites Chylomicrons and Remnants These metabolites are composed of major lipids and apoproteins of the A, B-48, C, and E classes. Their density is 1.006 g/ml. As expected, these are large particles made up of dietary cholesterol molecules that are absorbed with triglycerides.

Posthepatic Metabolites Very-low-density Lipoprotein These metabolites are transient remnants found after initial liver metabolism and comprise only 10% to 15% of cholesterol particles. Very-low-density lipoproteins (VLDLs) consist of endogenously synthesized triglycerides with a density of 1.006 g/ml. The diameter is considerably smaller than that of the chylomicrons, ranging from 300 to 800 nm. Intermediate-density Lipoprotein (IDL) The major lipids in this group consist of cholesterol esters that are posthepatic remnants but are derived from dietary sources. Associated apoproteins are B-100, C-III, and E. Apoprotein B-48 is lost after the initial hepatic metabolism and B-100 is substituted. Apoprotein E, which is a liver recognition apoprotein, is found only in VLDLs and intermediate-density lipoproteins (IDL). IDL metabolites are transient lipoproteins and are measured only in certain pathologic conditions. The density is 1.019 g/ml with a diameter of 250 nm—a very significant drop in diameter from 800 nm found in the VLDL. LDL Cholesterol The major lipid in this group is the cholesterol ester and is associated with B-100 apoprotein. LDL cholesterol accounts for approximately 60% to 70% of total cholesterol. Elevated levels of LDL cholesterol have been associated with increased rates of myocardial infarction in women over 65 years of age. There is a structural class called LDL(a') that is associated with myocardial infarction. Several families have been described with structurally abnormal B-100 apoprotein and are at high risk for myocardial infarction due to lipid buildup and premature atherosclerosis ( 36). Density ranges from 1.019 to 1.063, with a diameter of 180 to 280 nm. HDL Cholesterol This is composed of cholesterol esters with apoproteins A-I and A-II. These particles account for 20% to 30% of total cholesterol and are the densest, with a weight of 1.063 to 1.120 g/ml. The diameter of this group of proteins is 50 to 120 nm. Metabolism Cholesterol metabolism is divided into two pathways. The first pathway is the exogenous pathway derived from dietary sources. The second pathway is called the endogenous pathway or the lipid transport pathway. Individual variations exist in the ability to metabolize cholesterol, with patients classified as normals, hyporesponders, and hyperresponders ( 37). Hyporesponders may be given cholesterol-loaded diets with no effect on serum cholesterol measurements. The hyperresponder, in contrast, has high serum cholesterol levels, regardless of dietary intake. Explanations of differences are well described in animal models but not in humans. Once a meal is eaten, cholesterol is transported as dietary fat. The average American diet contains approximately 100 grams of triglyceride and approximately 1 gram of cholesterol daily. Dietary fats are saponified in the intestinal lumen by pancreatic lipases and synthesized into chylomicrons that are first absorbed by active transport into intestinal lymph and then into the general circulation. Capillaries in the adipose tissue and skeletal muscle are able to incorporate triglycerides and fats by the action of lipoprotein lipase. As schematically depicted in Fig. 9.3, metabolic utilization may occur during either phase of metabolism (e.g., dietary or endogenous). During absorption and synthesis of chylomicrons, apoproteins are incorporated. Apoprotein C-II is important as a cofactor to activate lipoprotein lipase, which enzymatically liberates fatty acids (for energy) and monoglycerides. These fatty acids may enter endothelial, adipose, or muscle cells, where they are either oxidized into active metabolic products or reesterified to triglycerides. Triglycerides are found in the core lipoprotein particles and are removed through the capillary endothelium and the chylomicron. Predominant apoproteins are B-48 or B-100 and E apoproteins. When chylomicron synthesis occurs in the intestine, the primary B apoprotein is B-48; upon leaving adipose cells, muscle cells, or the liver the second B apoprotein, or B-100, is substituted. Abnormal forms of B-100 are associated with premature cardiovascular disease and are currently used as genetic markers in research laboratories ( 38). Another apoprotein added during cellular metabolism is apoprotein E. Apoprotein E plays an important role in liver recognition of chylomicron remnants. Theories suggest that hypo- and hyperresponders to dietary cholesterol may be secondary to the liver's ability to recognize and metabolize apoprotein E (39). In the animal model, populations with large numbers of liver receptors for apoprotein E easily metabolize cholesterol and are labeled hyporesponders. Individuals with a reduced number of apoprotein E receptors are unable to metabolize cholesterol as readily, which increases the number of lipid particles in their blood. These individuals are labeled hyperresponders. Despite dietary cholesterol modification, these individuals continue to have high serum cholesterol levels. After metabolic degradation of dietary chylomicrons, apoprotein substitution occurs and liver metabolism of cholesterol esters begins. Lipid transport is now in the endogenous pathway. Carbohydrates are synthesized to fatty acids and esterified with glycerol to form triglycerides. These newly formed triglycerides are not of dietary origin and are placed in the core of VLDLs. VLDL particles are relatively large and carry 5 to 10 times more triglyceride than cholesterol esters with apoprotein B-100. Hypertriglyceridemia is an independent risk factor for cardiovascular disease ( 40). The relationship between hypertriglyceridemia and cardiovascular disease is well known but poorly defined. VLDL particles are transported to tissue capillaries, where they are broken down to usable fuels, monoglycerides, and fatty acids. Apoproteins C and E are still present within this lipoprotein particle. After metabolic enzymatic degradation in the peripheral tissues, the IDLs remain. IDLs are either catabolized in the liver by binding to LDL receptors or are modified in the peripheral tissues. As noted above, they are associated with apoprotein E receptors, the liver recognition receptors. During the transformation from IDL to LDL cholesterol, all apoproteins are removed, except apoprotein B-100. The LDL cholesterol, or the so-called high-risk cholesterol, is found in high circulating levels. Despite the negative connotation of LDL cholesterol in cardiovascular research, it is a very important cellular metabolite that is a precursor for adrenocortical cells, lymphocytes, and renal cells. LDL receptors on cell surfaces allow for LDL cholesterol incorporation into cellular metabolism. In target cells, these lipid particles are hydrolyzed to form cholesterol for use in membrane synthesis and as precursors for steroid hormones (such as estrogen and progesterone). Once the cell has incorporated the necessary cholesterol, the cell surface receptor reforms limiting further absorption. The liver uses the LDL cholesterol for bile acids synthesis and free cholesterol, which is secreted into the bile. In the normal human, 70% to 80% of LDL is removed from the plasma each day and secreted in the bile by utilization of the LDL receptor pathway. The final metabolic pathway is the transformation of HDL cholesterol in extrahepatic tissue. HDL cholesterol carries the plasma enzyme lecithin cholesterol acyltransferase (LCAT). LCAT allows HDL cholesterol to resynthesize lipids to VLDL cholesterol and recycle the lipid cascade. The fate of newly synthesized VLDL cholesterol is the same as absorbed VLDL and it eventually becomes LDL cholesterol. HDL cholesterol acts as a “scavenger” and therefore reverses the deposit of cholesterol into tissues. There is good evidence that HDL cholesterol is responsible for the reversal of atherosclerotic changes in vessels, hence the term the good cholesterol. (41,42). Hyperlipoproteinemia When cholesterol is measured, various fractions are reported. Plasma cholesterol or total cholesterol consists of cholesterol and unesterified cholesterol fractions. If triglycerides are analyzed in conjunction with cholesterol, then assumptions can be made concerning which metabolic pathway may be abnormal. The elevation of both total cholesterol and triglyceride levels signifies a problem with chylomicrons and VLDL synthesis. If the triglyceride-to-cholesterol ratio is greater than 5:1, then the predominant fractions are chylomicrons and VLDL. When the triglycerides-to-cholesterol ratio is less than 5:1, then the problems exist in the VLDL and LDL fractions. Establishing a “normal population” and then setting various limits at the 10th and 90th percentiles define hyperlipoproteinemias. A recent standard for women sets the 80th percentile for cholesterol at 240 mg/dl and the 50th percentile at 200 mg/dl ( Table 9.8). Researchers continue to argue that populations vary and may have different cutoff limits depending on the amount of fat versus vegetable and fiber consumption within the diet ( 43).

Table 9.8. Initial Classification Based on the Total Cholesterol and HDL Cholesterol Levels

Laboratory Testing The consensus of most researchers is that office laboratory analyses of total cholesterol are virtually worthless as an accurate measure of cholesterol. The easurement techniques are extremely variable. In well-controlled studies, it has been shown that the variation in readings is large ( 44). Therefore, despite their popularity, they are totally inadequate for either screening or monitoring treatment of patients with hypercholesterolemia. There are multiple environmental causes of variation in cholesterol measurements ( 45). Major sources of variation within individuals include diet, obesity, smoking, ethanol intake, and the effects of exercise. Other clinical conditions that affect cholesterol measurements include hypothyroidism, diabetes mellitus, acute or recent myocardial infarction, and recent weight changes. Other variables include the fasting state, position while the sample is drawn, and the use and duration of venous occlusion. Anticoagulants and storage and shipping conditions also can alter lipoprotein measurements ( 46). Intraperson variation has been well described. If a single individual has total cholesterol measured 4 times during the day, the variation is 2.5%. If retested within 1 month, on a twice-weekly basis, the coefficient of variation increases to 4.8%. Monthly measurements over 1 year may result in a variation as high as 6.1%. Therefore, for accurate standardization, at least two and preferably four specimens taken 1 month apart should be collected in the same dietary state in order for a lipid value to be considered accurate. Age and sex contribute to variations in total cholesterol measurements. Before age 50, women have lower lipid values than men; after age 50, lipid values increase. Exogenous oral conjugated estrogens are thought to contribute to this effect. The genetic basis for interperson variability is thought to be mediated by apolipoprotein receptors. Seasonal variation also occurs. In December or January, lipid samples taken were found to be approximately 2.5% higher than those measured in June or July. LDL cholesterol and total cholesterol were higher, with no significant variation found for HDL cholesterol. The index population was found to weigh approximately 6% more in December and January than in June or July, which may account for the differences. The effect of diet and obesity has been well studied. Some researchers felt this effect may be related to hypo- and hyperresponder status. However, weight reduction in an obese individual generally affects the triglyceride level, which may decrease as much as 40%. Total cholesterol and LDL cholesterol levels decrease less than 10% with diet changes; however, HDL cholesterol levels increase approximately 10%. Weight gain negates any benefit from prior weight loss. Therefore, accuracy of lipid measurements depends on the stability of the patient's weight. Alcohol and cigarette smoking are well-known modifiers of cholesterol levels. Moderate sustained alcohol intake is noted to increase HDL cholesterol and decrease LDL cholesterol levels; however, there is a complementary increase in triglyceride levels. Alcohol has a protective effect when taken in moderation (defined as approximately 2 ounces of absolute alcohol per day), but this effect is negated with higher quantities. The increase in HDL cholesterol levels is in the HDL 3 fraction, important in the scavenger mechanism of removing LDL cholesterol. Smoking has the opposite effect, by increasing LDL cholesterol and triglyceride levels and decreasing HDL cholesterol levels. The HDL 3 fraction decreases with cigarette smoking. The critical number of cigarettes smoked is 15 to 20 per day, regardless of sex. Caffeine has a mixed effect on lipoprotein measurements but should be avoided in the 12 hours prior to blood collection. Exercise is an important variable in overall risk management for heart disease. Federal agencies have recognized that moderate levels of exercise are as important in overall cardiovascular health as control of hypertension and cessation of cigarette smoking. Strenuous exercise lowers the concentrations of triglycerides and LDL and increases HDL in the serum. To obtain accurate measurements, vigorous exercise should not be performed within 12 hours of obtaining blood samples. Because of the diurnal variation of blood triglyceride levels, blood samples should be collected in the morning after a 12-hour fast. Excessive quantities of water should not be consumed before the blood is drawn. The patient should be sitting quietly for approximately 15 minutes prior to the blood draw. Patients who were placed in the supine position for 30 minutes and then required to stand for 30 minutes had a 9% increase in total cholesterol, LDL cholesterol, and VLDL cholesterol fractions, while the HDL cholesterol increased by 10% and triglyceride levels increased by 12%. Additionally, if the tourniquet time is more than 5 minutes, causing vascular stasis, all measurements increase by 10% to 15%. After even 2 minutes of venous occlusion, serum cholesterol increases can be 2% to 5%. Therefore, collection of the cholesterol sample should be done first if multiple blood samples are required. Finger-stick samples are approximately 8.5% lower for all component measurements than venous blood due to contamination from interstitial and lymph fluids. Collection tube anticoagulants may have a profound effect on lipoproteins. The total cholesterol level has been observed to change depending on the anticoagulant used: ethylenediaminetetraacetic acid (EDTA) increases measurements by 3%, oxalate increases by 9%, citrate increases by 14%, and fluoride by 18%. EDTA is considered the standard anticoagulant for cholesterol measurement. If cholesterol measurements cannot be run in a reasonable time, the samples may be stored at 0°C for up to 4 days, at –20°C for 6 months, or at –50° to –80°C indefinitely. Specimens transported by mail should be placed on dry ice. One of the most important aspects of overall standardization of lipoprotein measurements is the laboratory used. Currently, laboratory levels should be within ±5% of CDC standards for lipoprotein measurements. Approximately 80% of laboratories in one study met this criteria ( 47). Therefore, to accurately assess cholesterol values, the clinician should be knowledgeable about the laboratory used. It may be useful to consult with the clinical pathologist of a hospital to determine if the laboratory complies with CDC standards for cholesterol and lipoprotein measurements. Disease States and Medication Effects Certain disease states and medications have an impact on cholesterol measurements. As noted previously, diuretics and propranolol increase triglyceride and decrease HDL cholesterol levels. Diuretics may also increase total cholesterol levels. Patients with diabetes mellitus, especially those with poor control, may have very high levels of triglycerides, LDL cholesterol, and decreased HDL cholesterol. This may explain why they are prone to cardiovascular diseases. Diabetics under “tight” control generally have improved lipoprotein levels. Pregnancy is associated with decreased total serum cholesterol in the first trimester with continuous increases of all fractions over the second and third trimesters (48). The LDL and triglyceride concentrations are the lipoproteins most affected by pregnancy. Limited studies have been done on standardization of lipid levels in pregnancy. Because of the short span, interventions would be of little clinical significance. Lastly, patients with hypothyroidism are also noted to have increased levels of total cholesterol and LDL cholesterol. Management Once hyperlipidemia is confirmed on at least two separate occasions, secondary causes should be diagnosed or excluded by taking a detailed medical and drug history, measuring serum creatinine and fasting glucose levels, and performing thyroid and liver function tests. For obese patients, diet and weight loss is the first

level of therapy. Figure 9.4 shows a suggested algorithm for cholesterol control based on the LDL level. Cholesterol- and fat-lowering diets abound in most bookstores and allow the patient to choose a diet she will best follow. The role of exercise and cigarette cessation should be stressed to all patients. Patients with family history of cardiovascular disease (history of premature coronary artery problems and strokes) should be tested and started on conservative programs when they are in their twenties. After 3 to 6 months, if the LDL cholesterol level remains above 160 mg/dl, or above 130 mg/dl with risk factors, medical therapy should be initiated. Since the second report of the Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP II) was published in 1993, evidence from recent clinical trials has suggested a lower treatment threshold for patients with established coronary artery disease.

Figure 9.4 Treatment decisions based on the LDL cholesterol level. (Adapted from the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:3015–3023.)

The bile acid–binding resins cholestyramine and colestipol were the mainstay of therapy for years but are associated with constipation, bloating, nausea, and heartburn. These agents also may interfere with the absorption of many drugs, which has limited their usefulness. Nicotinic acid (500 mg 3 times a day) decreases triglyceride, LDL, and lipoprotein(a) levels and increases HDL levels more than any other drug. However, flushing, pruritus, and gastrointestinal distress are a few of the adverse effects of nicotinic acid. Starting at a low dose and pretreating with aspirin (325 mg) or ibuprofen (200 mg) can minimize the facial flushing. Fibric acid derivatives like clofibrate and gemfibrozil are used mainly to lower triglycerides and increase HDL but may increase LDL levels in some patients. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (“statins”) include atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. These medicines inhibit HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in cholesterol synthesis. Several clinical trials have shown that pravastatin, simvastatin, and lovastatin have a beneficial effect in cardiovascular disease. Statins are generally better tolerated than other lipid-lowering drugs, but severe myalgias, muscle weakness with increases in creatine phosphokinase levels, and rarely rhabdomyolysis leading to renal failure have been reported. Symptomatic hepatitis is rare, but serum glutamic oxaloacetic transaminases should be measured 6 and 12 weeks after initiation of therapy, and semiannually once therapeutic levels are reached. The usual daily starting doses for the statin drugs are the following: atorvastatin (10 mg), fluvastatin (20 mg), lovastatin (20 mg), pravastatin (20 mg), and simvastatin (20 mg) (49).

Diabetes Mellitus Diabetes mellitus (DM) is a chronic disorder of altered carbohydrate, protein, and fat metabolism from a deficiency in the secretion or function of insulin. The disease is defined by either fasting hyperglycemia or elevated plasma glucose levels after an oral glucose tolerance test (OGTT). The major complications of DM are primarily vascular and metabolic complications. Only 50% of an estimated 13 million Americans with DM have been diagnosed. The prevalence of DM is higher in women and certain ethnic groups, although a background rate in the general population is 2.5% ( 50). Risk factors for DM are (a) age greater than 45 years, (b) adiposity or obesity, (c) a family history of diabetes, (d) race and ethnicity, (e) hypertension (140/90 or greater), (f) HDL cholesterol less than or equal to 35 mg/dl with or without a triglyceride level greater than or equal to 250 mg/dl, and (g) history of gestational diabetes or delivery of baby over 9 pounds. Lifestyle may be the most important variable for type 2 diabetes, as discussed below. Major complications of DM include blindness, renal disease, gangrene of an extremity, heart disease, and stroke. Diabetes is one of the four major risk factors for cardiovascular disease ( 51).

Classification In January of 1999, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus published a report revising the system that had been in use since 1979 (52). The goal of the revision is to provide guidelines for nomenclature and testing that may reduce diagnostic confusion and improve patient well-being ( Table 9.9). The terms insulin-dependent diabetes mellitus (IDDM) and non–insulin-dependent diabetes mellitus (NIDDM) should be eliminated to reduce confusion regarding the meaning of each of these categories. These terms should be replaced by the designations of type 1 and type 2 diabetes mellitus.

Table 9.9. Classification of Diabetes Mellitus

Type 1 Diabetes Mellitus The major metabolic disturbance of type 1 diabetes is the absence of insulin from destruction of b cells in the pancreas. Insulin is necessary for glucose metabolism and cellular respiration. When insulin is absent, ketosis results. The cause of type 1 diabetes is unknown; however, data suggest an autoimmune factor from either a viral infection or toxic components in the environment. Studies in the past decade have shown a correlation between many autoimmune diseases and the human leukocyte antigens (HLA). Insulin-sensitive tissues (muscle, liver, and fat) fail to metabolize glucose efficiently in the absence of insulin. In uncontrolled type 1 diabetes, additional excess of counterregulatory hormones (cortisol, catecholamines, and glucagon) contributes to further metabolic dysfunction. In the absence of adequate amounts of insulin, increasing breakdown products of muscle (amino acid proteolysis), fat (fatty acid lipolysis), and glycogen (glucose glycogenolysis) are recognized. Additionally, there is an increase in glucose production from noncarbohydrate precursors from gluconeogenesis and ketogenesis in the liver. If not promptly treated, severe metabolic decompensation (i.e., diabetic ketoacidosis [DKA]) will occur and may lead to death. Type 2 Diabetes Mellitus Type 2 diabetes mellitus is a heterogeneous form of diabetes that commonly occurs in older age groups (>40 years), and is more frequently noted to have familial tendency than type 1 diabetes. In contrast to an absence of insulin that occurs with type 1 diabetes, altered metabolism of insulin occurs in type 2

diabetes, resulting in insulin resistance. This condition is characterized by impaired glucose uptake in target tissues. A compensatory increase in insulin secretion results, with higher-than-normal circulating insulin levels ( 53). Obesity is present in 85% of affected patients. The cause of type 2 diabetes is unknown, but defects in both the secretion and action of insulin are suspected. Many patients diagnosed with type 2 diabetes at an early age eventually exhaust endogenous pancreatic insulin and require injected insulin. When under severe stress, such as infection or surgery, they may develop DKA, or a hyperglycemic hyperosmolar nonketotic state (HHNS). Risk factors for type 2 diabetes include ethnicity, obesity, strong family history of DM, sedentary lifestyle, impaired glucose tolerance, upper body adiposity, history of gestational diabetes, and hyperinsulinemia. The presence of risk factors strongly influences the development of type 2 diabetes in susceptible populations. Diagnosis Three methods are available to diagnose diabetes mellitus in nonpregnant adults: 1. A single fasting blood glucose greater than or equal to 126 mg/dl on two separate occasions; 2. A random blood glucose equal to or above 200 mg/dl in an individual with classic signs and symptoms of diabetes (polydipsia, polyuria, polyphagia, and weight loss); and 3. A 2-hour OGTT (fasting sample, 60- and 120-minute samples) after a 75-gram load of glucose. A 2-hour OGTT should not be performed if the first two criteria are present. Diagnostic criteria for impaired glucose intolerance (IGT) testing are a fasting glucose ³110 mg/dl but Figure 10.17 Technique for bipolar electrocoagulation tubal sterilization.

Figure 10.18 Placement of the Falope ring for tubal sterilization.

Figure 10.19 Filshie clip for tubal sterilization.

The electric and band or clip techniques each have advantages and disadvantages. Bipolar coagulation can be used with any fallopian tube. The Falope ring and Hulka and Filshie clips cannot be applied if the tube is thickened from previous salpingitis. There is more pain during the first several hours after Falope ring application. This can be prevented by bathing the tubes with a few milliliters of 2% lidocaine just before ring placement. Failures of the Falope ring or the clips generally result from misapplication, and pregnancy, if it occurs, is usually intrauterine. After bipolar sterilization, pregnancy may result from tuboperitoneal fistula and is ectopic in more than 50% of cases. If inadequate electrical energy is used, a thin band of fallopian tube remains that contains the intact lumen and allows intrauterine pregnancy to occur. Thermocoagulation, the use of heat probes rather than electrical current, is employed extensively in Germany for laparoscopic tubal sterilization but has had little use in the United States. Risks of Tubal Sterilization Tubal sterilization is remarkably safe. In 1983, the total complication rate in a large series from several institutions was 1.7 per 100 ( 210). Complications were increased by use of general anesthesia, previous pelvic or abdominal surgery, history of PID, obesity, and diabetes mellitus. The most common significant complication was unintended laparotomy for sterilization after intraabdominal adhesions were found. In another series, 2,827 laparoscopic sterilizations were performed with the Silastic band using local anesthesia and intravenous sedation. Only four cases could not be completed (a technical failure rate of 0.14%), and laparotomy was not needed (211). Rarely, salpingitis can occur as a complication of the surgery. This occurs more often with electric coagulation than nonelectric techniques. From 1977 until 1981, there were four deaths per 100,000 procedures in the United States, less than the risk of one pregnancy; almost half of the deaths were from complications of general anesthesia, usually related to the use of mask ventilation ( 212). The last U.S. national study was of sterilizations performed in 1979 to 1980. There were a total of 9 to 10 deaths per 100,000 sterilizations, but only 1 to 2 per 100,000 were attributed to the sterilization procedure alone ( 213). When general anesthesia is used for laparoscopy, endotracheal intubation is mandatory because the pneumoperitoneum increases the risk for aspiration. International data from the Association for Voluntary Surgical Contraception show a similar record of safety from Third World programs: 4.7 deaths per 100,000 female sterilizations and 0.5 per 100,000 vasectomies ( 214). Family Health International has reported large randomized multicenter trials of the different means for tubal sterilization. The Filshie and Hulka clips were compared in two trials. A total of 2,126 women were studied, of which 878 had either clip placed by minilaparotomy and 1,248 had either clip placed by laparoscopy, and were then evaluated at up to 24 months (215). Pregnancy rates were 1.1 per 1,000 women with the Filshie clip and 6.9 per 1,000 with the Hulka clip at 12 months, a difference in rates that was close to statistically significant ( p = 0.06). This same group compared the Filshie clip to the Silastic tubal ring in a similar study with a total of 2,746 women, of which 915 had the devices placed at minilaparotomy and 1,831 had laparoscopy ( 216). Pregnancy rates at 12 months were the same for the Filshie clip and the tubal ring: 1.7 per 1,000 women. The ring was judged more difficult to apply, but three women spontaneously expelled the Filshie clip during the 12 months of

follow-up. Benefits of Tubal Sterilization In addition to providing excellent contraception, tubal ligation is associated with reduced risk for ovarian cancer that persists for as long as 20 years after surgery (217). Sterilization Failure Many “failures” occur during the first month after laparoscopy and are the result of a pregnancy already begun when the sterilization was performed. Contraception should be continued until the day of surgery, and a sensitive pregnancy test should be routinely performed on the day of surgery.Because implantation does not occur until 6 days after conception, however, a woman could conceive just before her surgery and there would be no way to detect it. Scheduling sterilization early in the menstrual cycle obviates the problem but adds to the logistic difficulty. Another cause of failure is the presence of anatomic abnormalities, usually adhesions surrounding and obscuring one or both tubes. An experienced laparoscopic surgeon with proper instruments can usually lyse the adhesions, restore normal anatomic relations, and positively identify the tube. In some circumstances, however, successful sterilization will not be possible by laparoscopy, and the surgeon must know before surgery whether the patient is prepared to undergo laparotomy, if necessary, to accomplish sterilization. Most studies of sterilization failure are short term. The Centers for Disease Control and Prevention's Collaborative Review of Sterilization (CREST) reported on a cohort of 10,685 women sterilized between 1978 and 1986 at any of 16 participating centers in the United States who were followed from 8 to 14 years ( 218). The true failure rates for 10 years obtained by the life-table method are given in Table 10.10. Pregnancies resulting from sterilization during the luteal phase of the cycle in which the surgery was performed were excluded. Thirty-three percent of all remaining pregnancies were ectopic. The most effective methods at 10 years were unipolar coagulation at laparoscopy and postpartum partial salpingectomy, generally a modified Pomeroy procedure. Bipolar tubal coagulation and the Hulka-Clemens clip were least effective. Younger women had higher risk for failure, as would be expected because of their greater fecundity.

Table 10.10. Ten-year Life-table Cumulative Probability of Pregnancy per 1,000 Procedures with Different Methods of Tubal Sterilization, United States, 1978–1986.

Over the years since the CREST study began, sterilization by unipolar electrosurgery was abandoned because of risk for bowel burns and was replaced with bipolar electrosurgery or the nonelectric methods (tubal ring, Hulka-Clemens clip, and more recently, the Filshie clip). An important later analysis of the CREST data found that bipolar sterilization could have a very low long-term failure rate if an adequate portion of the tube is coagulated. CREST study subjects who were sterilized with bipolar electrosurgery in 1985 to 1987 had lower failure rates than those sterilized earlier (1978 to 1985). The important difference was in the technique of application of the electric energy to the tubes. Women whose bipolar procedure involved coagulation at three sites or more had low 5-year failure rates (3.2 per 1,000 procedures), whereas women who had fewer than three sites of tubal coagulation had a 5-year failure rate of 12.9 per 1,000 ( p = 0.01) (219). Reversal of Sterilization Reversal of sterilization is more successful after mechanical occlusion than after electrocoagulation because the latter method destroys much more of the tube. With modern microsurgical techniques and an isthmus-to-isthmus anastomosis, pregnancy follows in about 75% of cases ( 220). A substantial risk for ectopic pregnancy exists after reversal. Late Sequelae of Tubal Sterilization Increased menstrual irregularity and pain have been attributed to previous tubal sterilization. In patients who underwent the older laparoscopy technique with unipolar electrical destruction of a major portion of the tube, these concerns may be warranted ( 221). Study of the problem is complicated by the facts that many women develop these symptoms even though they have not had tubal surgery, and OCs reduce pain and create an artificially normal menstrual cycle. Therefore, women who discontinued OC use concurrent with tubal sterilization will experience more dysmenorrhea, which is entirely unrelated to the sterilization. The best answer presently available also comes from the CREST study (222). A total of 9,514 women who had undergone tubal sterilization were compared with 573 women whose partners had undergone vasectomy. Both groups were followed up to 5 years with annual standardized telephone interviews. Women who had undergone tubal sterilization were no more likely to report persistent changes in intermenstrual bleeding or length of the menstrual cycle than women whose partners had vasectomy. The sterilized women, in fact, reported decreases in days of bleeding, amount of bleeding, and menstrual pain but were slightly more likely to report cycle irregularity (OR, 1.6; 95% CI, 1.1 to 2.3). Hence, this study found no evidence to support the existence of a posttubal ligation syndrome.

Vasectomy Vasectomy, excision of a portion of the vas deferens, is readily accomplished with local anesthesia in an office setting. It does not decrease sexual performance ( 223). The basic technique is to palpate the vas through the scrotum, grasp it with fingers or atraumatic forceps, make a small incision over the vas, and pull a loop of the vas into the incision. A small segment is removed, and then a needle electrode is used to coagulate the lumen of both ends. Improved techniques include the no-scalpel vasectomy, in which the pointed end of the forceps is used to puncture the skin over the vas. This small variation reduces the chance of bleeding and avoids the need to suture the incision. Another variation is the open-ended vasectomy, in which only the abdominal end of the severed vas is coagulated while the testicular end is left open. This is believed to prevent congestive epididymitis ( 224). Reversibility Vasectomy must be regarded as a permanent means of sterilization; however, with microsurgical techniques, vasovasostomy will result in pregnancy about half the time. The longer the interval since vasectomy, the poorer the chance of reversal. Safety Operative complications include scrotal hematomas, wound infection, and epididymitis, but serious sequelae are rare. There have been no reports of deaths from vasectomy in the United States in many years, and the death rate in a large Third World series was only 0.5 per 100,000. Studies of vasectomized monkeys showed accelerated atherosclerosis, but several large-scale human studies have found no connection between vasectomy and vascular disease ( 225,226). Concerns about long-term safety recurred with the report of a possible association between prostate cancer and vasectomy ( 227). Prostate cancer is largely a disease of the Western world and is strongly linked to dietary animal fat, family history, and race ( 228). In the West, it is more common in men of African American ancestry and rare in men of Asian descent. Recent studies are reassuring. A large multiethnic case-control study from the United States and Canada compared 1,642 men with prostate cancer

to 1,636 controls and found no overall association (OR, 1.1; 95% CI, 0.83 to 1.3) ( 229). Older reports may reflect bias, perhaps that higher-status men, with diets higher in animal fat, were more likely than lower-status men to choose vasectomy.

Abortion Given the desire in developed countries to limit families to one or two children and the efficacy of contraception in general use, it is extremely likely that any normal couple will experience at least one unwanted pregnancy at some time during their reproductive years. In Third World countries, desired family size is larger, but access to effective contraception is limited. As a result, abortion is common. Worldwide, about 26 to 31 million legal abortions and an estimated 10 to 22 million clandestine abortions are performed every year ( 230). Where abortion is legal, it is generally reasonably safe; where it is illegal, complications are common, and about 150,000 women die every year from these complications ( 231). Societies cannot prevent abortion, but they can determine whether it will be illegal and dangerous or legal and safe. Many countries in which abortion is completely illegal have very high rates of clandestine abortion. Abortion rates in representative countries are given in Table 10.11 (232).

Table 10.11. Rates of Induced Abortion in Representative Countries, 1985–1991 per 1,000 Women Aged 15–44 Years

Death from illegal abortion was once common in the United States. In the 1940s, more than 1,000 women died each year of complications from abortion ( 233). In 1992, the last year for which complete data are available, there were 17 deaths from spontaneous abortion, 10 deaths from legally induced abortion, and no deaths from illegal abortion (abortion induced by a nonprofessional) in the entire United States. ( 234). The American Medical Association's Council on Scientific Affairs has reviewed the impact of legal abortion and attributes the decline in deaths during this century to the introduction of antibiotics to treat sepsis; the widespread use of effective contraception beginning in the 1960s, which reduced the number of unwanted pregnancies; and, more recently, the shift from illegal to legal abortion ( 235). Much of the continued decline in non–abortion-related maternal mortality of recent years can be attributed to choice of legal abortion by women at high risk for pregnancy mortality. The United States has a serious problem with teenage pregnancy. Without legal abortion, there would be almost twice as many teenage births each year. The number of abortions reported each year in the United States—1,186,039 in 1997 according to the Centers for Disease Control and Prevention—has been decreasing since 1990. In 1997, the national abortion ratio was 306 abortions for every 1,000 live births, and the national abortion rate was 20 per 1,000 women aged 15 to 44 years (236). Most women who obtain abortions are unmarried (79% in 1997), and the ratio of abortions to live births is 9 times higher for unmarried women than for married women. Use of abortion varies markedly with age. In 1997, 20% of women obtaining abortions were 19 years of age or younger, and 51.8% were 24 years of age or younger. In 1997, the last year for which detailed information is available, the abortion ratio for women younger than 15 years of age was 729 per 1,000 live births, almost as many abortions as births ( Fig. 10.2). The lowest abortion ratio, 161 per 1,000 live births, is for women aged 30 to 34 years. Legal abortion rates and ratios reached their highest in the early 1980s as they replaced illegal abortions, and both have declined since, especially for the youngest women ( Fig. 10.20) (16).

Figure 10.20 Abortion ratios, by age group and by year, United States, 1974–1997. Ratio equals induced abortions per 1,000 live births. [From Koonin LM, Strauss LT, Chrisman CE, et al. Abortion surveillance, 1997. MMWR Morb Mortal Wkly Rep 2000,49(SS-11):14, with permission.]

Regardless of personal feelings about the ethics of interrupting pregnancy, health professionals have a duty to know the medical facts about abortion and to share them with their patients (237). Providers are not required to perform abortions against their ethical principles, but they have a duty to help patients assess pregnancy risks and to make appropriate referrals.

Safety Issues The risk for death from legal abortion was 0.7 per 100,000 induced abortions in 1996 ( 234). In contrast, total maternal mortality is about 7 or 8 per 100,000 live births. The risk for death from legal abortion before 16 weeks is 10-fold less than that from continuing the pregnancy to delivery. As shown in Table 10.12, the risk for death increases with gestational age ( 238). For individual women with high-risk conditions (e.g., cyanotic heart disease), even late abortion is a safer alternative to birth. Because of the availability of low-cost, out-of-hospital first-trimester abortion, 88% of legal abortions are performed during the first trimester (before 13 weeks of amenorrhea), when abortion is the safest ( 238). The type of procedure is another determinant of risk. First-trimester abortions are virtually all performed by vacuum curettage; however, in the midtrimester, a variety of techniques can be used. Risk for death from abortion by the various techniques at different gestational ages is given in Table 10.13. The data clearly show the greater safety of instrumental evacuation of the uterus [dilation and evacuation (D & E)] performed in the early midtrimester. Another determinant of risk is anesthesia. Use of general anesthesia increases the risk for perforation of the uterus, visceral injury, hemorrhage, hysterectomy, and death (239). The preferred alternative is paracervical block with local anesthetic, augmented with conscious sedation when needed.

Table 10.12. Death to Case Rates for Legal Abortion Mortality by Weeks of Gestation, United States, 1972–1987

Table 10.13. Death to Case Rates for Legal Abortions by Type of Procedure and Weeks of Gestation, United States, 1974–1987 2

Techniques for Abortion Most abortions are performed by vacuum curettage. Early procedures (5 to 7 weeks from beginning of last normal menses) can be readily performed in an office setting using simple instruments: a 5- to 6-mm flexible plastic cannula and a modified 50-mL plastic syringe as vacuum source ( 240). After 7 weeks, somewhat larger rigid plastic cannulas (8 to 12 mm in diameter) are generally used, depending on gestational age, with an electric pump as the vacuum source. Most abortions in the United States are performed outside of hospitals, usually in freestanding specialty clinics, at a cost far below that of hospital services. General anesthesia is unnecessary. Adequate pain relief is provided by infiltrating the cervix with local anesthetic, augmented with intravenous sedatives and analgesics for conscious sedation (241). Medical Means for Abortion Mifepristone (RU486), an analogue of the progestin norethindrone, has strong affinity for the progesterone receptor but acts as an antagonist, blocking the effect of natural progesterone. Given alone, the drug was moderately effective in causing abortion of early pregnancy; however, the combination of mifepristone with a low dose of prostaglandin proved very effective. In a series of almost 17,000 cases, 600 mg of mifepristone orally followed in 36 to 48 hours by either sulprostone or gemeprost produced complete abortion in 95% of cases ( 242). The only significant complications of this method to date have been three myocardial infarctions, with one death. All three myocardial infarctions occurred in women older than 35 years of age who were heavy smokers and occurred at the time of administration of sulprostone, a prostaglandin E 2 analogue (243). No myocardial infarctions have occurred with the prostaglandin E 1 analogue gemeprost. Misoprostol, another prostaglandin E 1 analogue, seems to have fewer side effects and a greater margin of safety than sulprostone. It is very effective when combined with mifepristone and is the prostaglandin used with mifepristone in the United States (244). The 600-mg dose of mifepristone used initially is actually far more than needed. Several investigators have shown that a 200-mg dose is equally effective (245,246,247 and 248). Initially, misoprostol was given orally, but the vaginal route of administration is more effective, probably because it provides sustained blood levels of the drug over several hours ( 249). The combination of 200 mg mifepristone orally followed by 800 mg of vaginal misoprostol produced complete abortion in 98% of women treated, after up to 63 days of amenorrhea, and appears to be the regimen of choice ( 246). Misoprostol can be given 1 to 3 days after the mifepristone with no loss of efficacy (248). Initially, patients returned to the clinics to receive misoprostol and remained on site for several hours. Half or more expel the pregnancy within 4 to 5 hours after misoprostol is given. However, it has been shown that patients may safely be given the misoprostol for self-administration at home (250). Methotrexate and Misoprostol The antifolate methotrexate provides another medical approach to pregnancy termination. Widely used to treat ectopic pregnancies without surgery ( 251), it can also be used with intrauterine gestations. Methotrexate, 50 mg/M2 given intramuscularly, followed by misoprostol, 800 mg inserted vaginally, produced abortion in six pregnancies up to 56 days from the last menstrual period ( 252). Methotrexate used alone without the misoprostol is also successful, although bleeding does not begin until an average of 24 days after treatment ( 253). In a large multicenter trial, 53% of patients aborted after the first dose of misoprostol and an additional 15% after the second dose. A total of 92% had successful abortion by 35 days after the initial methotrexate injection (254). The methotrexate-misoprostol regimen takes longer than mifepristone-methotrexate and is not as effective, but it is much less expensive. Methotrexate is usually given as an intramuscular injection, but a 50-mg oral dose is equally effective (255).

Second-trimester Abortion Most legal abortions are performed before 13 menstrual weeks. Abortions performed after 13 weeks include those done because of fetal defects, medical or psychiatric illness that had not manifested earlier in pregnancy, and changed social circumstances, such as abandonment by the spouse. Young age is the single greatest factor determining the need for late abortion. In 1997, 24.9% of abortions for women younger than 15 years of age were midtrimester, whereas 16.8% of abortions for women 15 to 19 years of age and only 9.3% of abortions for women 30 to 34 years of age were performed after 12 weeks of gestation ( 236). These proportions have changed little in a decade. Dilation and Evacuation D & E is the most commonly used method of midtrimester abortion in the United States (236). Typically, the cervix is prepared by insertion of hygroscopic dilators, stems of the seaweed Laminaria japonicum (laminaria). Placed in the cervical canal as small sticks, these devices take up water from the cervix and swell, triggering dilation. When these are removed the following day, sufficient cervical dilation is accomplished to allow insertion of strong forceps and a large-bore vacuum cannula to extract the fetus and placenta (256,257). Ultrasound guidance during the procedure is helpful ( 258). For more advanced procedures, sequential insertion of laminaria over 2 or more days is practiced, in order to achieve a greater degree of cervical dilation ( 259). At the end of the midtrimester, procedures that combine serial multiple laminaria dilation of the cervix with intrafetal injection of digoxin, induction of labor, and assisted expulsion of the fetus are used ( 260). Labor-induction Methods Hypertonic Solutions Amnioinfusion of hypertonic saline is historically important as one of the oldest labor-induction methods for abortion. Saline has serious

hazards: cardiovascular collapse, pulmonary and cerebral edema, and renal failure occur if the solution is injected intravenously. All patients are at risk for serious disseminated intravascular coagulopathy ( 261). However, attention to proper technique for amnioinfusion, with the saline instilled by gravity flow through connecting tubing from a single-dose bottle under ultrasound guidance, reduces the frequency of such mishaps. Hypertonic urea is safer than saline. It is combined with low doses of prostaglandin to increase efficacy and shorten the interval from injection to abortion. Prostaglandins Prostaglandins, oxygenated metabolites of C 20 carboxylic acid, are found naturally in most biologic tissues, where they act as modulators of cell function. They act through specific receptors of the G-protein family that are coupled to a variety of intracellular signal mechanisms, which may stimulate or inhibit adenyl cyclase, or phosphatidylinositol ( 262). Prostaglandins of the E and F series can cause uterine contraction at any stage of gestation. These agents can be given by intraamniotic infusion, by intramuscular injection, or by vaginal suppository. The 15 methyl analogues of prostaglandin F 2a (carboprost) and prostaglandin E 2 (dinoprostone) are highly effective but frequently produce side effects of vomiting and diarrhea. Vaginal misoprostol (200 mg every 2 hours) has been shown to be as effective as dinoprost suppositories (20 mg every 3 hours) in patients with fetal death or intact pregnancy at 12 to 22 weeks of gestation ( 263). In this study, patients with a living fetus were treated with ultrasound-guided intracardiac injection of potassium chloride to ensure fetal death before administration of misoprostol. Misoprostol-treated patients experienced fewer side effects of fever, uterine pain, vomiting, and diarrhea. Misoprostol was much less expensive and easier to administer. A comparison of 200-, 400-, and 600-mg doses of misoprostol at 12-hour intervals produced rates of abortion of 70.6%, 82%, and 96%, respectively, within 48 hours; however, the side effects of vomiting, diarrhea, and fever increased with increasing dose ( 264). Doses as high as 400 mg vaginally every 3 hours have been used (265), but caution is needed because there is risk for uterine rupture with higher doses used in the later midtrimester. More investigation is needed to determine the ideal dosage; one regimen is 400 mg of misoprostol at 6-hour intervals. There is also interest in midtrimester abortion induced with combinations of mifepristone and misoprostol. Pretreatment with mifepristone would undoubtedly increase the effect of misoprostol, reducing the necessary dose of the second drug. A French protocol used 600 mg of mifepristone, followed at 26 hours with placement of laminaria into the cervix, after which misoprostol was administered. The method was highly effective, with very short time intervals from the onset of misoprostol administration to abortion; however, one case of uterine rupture occurred in a patient with a uterine scar ( 266). About one third of patients treated with 20-mg doses of dinoprostone have a temperature elevation of 1°C or more. This phenomenon is not seen with carboprost tromethamine, which slightly reduced body temperature. The effect of misoprostol on body temperature is dose related; generally, there is no effect at 200 mg given every 12 hours, but the effect increases as the dose increases and intervals are shortened. Transient fetal survival can be a problem with all prostaglandin methods used in the midtrimester. To prevent this problem, and to shorten the interval to abortion and avoid failed abortion, many centers use a fetal intracardiac injection of potassium chloride (3 mL of a 2-mmol solution) or 1.5 mg of digoxin. Others perform amniocentesis and inject a small volume of intraamniotic hypertonic saline (60 mL of a 23% solution). Retained placenta is common with all prostaglandin abortions. Instrumental extraction is necessary in about half of cases. Oxytocin in very high doses is as effective as dinoprostone at 17 to 24 weeks of pregnancy ( 267). Patients initially receive an infusion of 50 units of oxytocin in 500 mL of 5% dextrose and normal saline over 3 hours, 1 hour of no oxytocin, followed by a 100-unit, 500-mL solution over 3 hours, another hour of rest, and then a 150-unit, 500-mL solution over 3 hours, alternating 3 hours of oxytocin with 1 hour of rest. The oxytocin is increased by 50 units in each successive period until a final concentration of 300 units per 500 mL has been reached. Complications The labor-induction methods share common hazards: failure of the primary procedure to produce abortion within a reasonable time, incomplete abortion, retained placenta, hemorrhage, infection, and embolic phenomena. Failed abortion can lead to serious infection and continued blood loss. If fetal expulsion has not occurred after 24 to 36 hours, consideration should be given to a D & E procedure.

Selective Reduction Multifetal pregnancies are at risk for extremely premature birth, with major neonatal complications resulting. To prevent this, selective reduction of higher-order multiple gestation to twins is often practiced. In a series of 463 pregnancies treated with ultrasound-guided fetal intracardiac injection of potassium chloride (0.2 to 0.4 mL of a 2-mmol solution in the first trimester, 0.5 to 3.0 mL in the second trimester), 83% of the surviving fetuses delivered at 33 weeks or later ( 268). Another indication for selective reduction is one anomalous fetus of a multifetal gestation. A 1999 series reported 402 patients treated as described for this indication ( 269). Rates of pregnancy loss after the procedure by gestational age at the time of procedure were 5.4% at 9 to 12 weeks, 8.7% at 13 to 18 weeks, 6.8% at 19 to 24 weeks, and 9.1% at 25 weeks or more. No maternal coagulopathy occurred, and no ischemic damages or coagulopathies were seen in the surviving neonates. Selective induction should not be attempted with monoamniotic twins or with twin–twin transfusion syndrome because of the possibility of embolic phenomena and infarction in the surviving twin. Maternal serum a-fetoprotein remains elevated into the second trimester after first-trimester procedures.

Induced Abortion and Subsequent Reproduction Legal abortion, as currently practiced in the United States, has no measurable adverse effect on later reproduction ( 270). Even two or more induced abortions have no detectable adverse effect (271). Abortion as practiced in the United States is not associated with low birth weight, premature birth, or increased perinatal loss (272). Concerns about infertility as a result of induced abortion are unfounded, except for the rare severe complication managed by hysterectomy ( 273). The lack of adverse effects on later pregnancy probably reflects the safety of current abortion technology in the United States.

The Future Contraceptive development is extremely slow in the United States because of the legal climate, the great cost of meeting regulatory requirements, and the low priority given this area by the medical community. On the international scene, a number of new approaches to contraception are in development. The two-rod version of Norplant (Norplant II) should soon be available. Levonorgestrel in a biodegradable rod of caprolactone that does not require removal is currently being tested, as is the single-rod implant releasing 3-keto-desogestrel. The GyneFix, a frameless copper IUD now available in Europe, consists of a surgical suture with small copper cylinders crimped to it. The knot on the proximal end of the suture is pushed 1 cm into the uterine wall with a special inserter. Comparative trials have found it more effective than the copper T380A and to have fewer expulsions and fewer removals for pain and bleeding ( 274). It is of considerable interest for these reasons and also because of excellent retention after postaortal insertion. Silastic vaginal rings releasing either progestin or progestin-estrogen combinations have been studied for years and are now undergoing field trials in a number of countries. A patch for transdermal release of estrogen and progestin for contraception is being tested in the United States. Both of these methods for steroid delivery have the advantage of greater ease of compliance for the user. There is great interest in developing compounds that could be used as a vaginal contraceptive and that would be protective against HIV. One such compound is a phenyl phosphate derivative of zidovudine. It has both spermicidal and antiretroviral activity and has proved nontoxic in short-term trials in mice ( 275). Current methods of tubal sterilization require abdominal surgery. To meet the coming demand for vast numbers of sterilizations worldwide, easier means must be devised. Considerable effort has gone into developing transuterine methods of female sterilization that would avoid the need to open the abdominal cavity to gain access to the fallopian tubes. Hysteroscopy with tubal cannulation and electrofulguration or the injection of Silastic that forms in place into tubal plugs have been explored and largely abandoned ( 276). A simpler option is placement of quinine pellets in the uterus through an IUD inserter. It has been known for years that intrauterine quinine can produce sclerosis of the proximal fallopian tube. This method has recently been rediscovered and is being seriously explored. A pellet containing 252 mg of quinacrine is inserted into the uterus during the proliferative phase of the cycle and again 1 month later. In a large trial, the 1-year pregnancy rate for 9,461 women who received two doses was 2.63 per 100 woman-years. The rate of ectopic pregnancy was 0.89 per 1,000 woman-years ( 277). Immunologic contraception-sterilization has been pursued for many years. Talwar and colleagues in India have worked for many years toward vaccination against human chorionic gonadotropin (hCG) and have performed trials in humans ( 278). Another area of interest is in vaccinating men or women against specific sperm

antigens and the zona pellucida ( 279). Chinese researchers have developed a method of percutaneous occlusion of the vas that has been used in more than 100,000 men, is effective, and appears to be reversible. Polyurethane elastomer is injected into the vas, where it solidifies and forms a plug, providing an effective block to sperm. The plugs are removed using local anesthesia, and fertility returns in most cases after as long as 4 years with the plugs in situ (280). Gossypol, an extract of cottonseed, was evaluated in China as a male contraceptive but abandoned because of problems with hypokalemia in users. When gossypol was reevaluated in a multinational study, hypokalemia was not a problem. Of 134 men treated, 65% had sperm counts less than 1 million/mL. About half of men followed more than 1 year after treatment recovered to a normal sperm count. Gossypol may be an alternative to vasectomy (281).

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Chapter 11. Sexuality, Sexual Dysfunction, and Sexual Assault Novak’s Gynecology

Chapter 11

Sexuality, Sexual Dysfunction, and Sexual Assault David A. Baram

Sexuality Sexual Practices The Sexual Response Cycle Factors Affecting Sexual Response Sexual Dysfunction Sexual Assault Childhood Sexual Abuse Rape References

Sexuality is an important and integral part of every woman's life. Questions and concerns about sexuality span a woman's entire lifetime, from questions about puberty to concerns about change in sexual function with menopause and aging. The obstetrician-gynecologist, as a primary health care provider for women, should include a sexual history as a routine part of a woman's periodic health assessment. Concerns about sexuality and sexual dysfunction are common in the general population. Surveys have found that almost two thirds of the women questioned had concerns about their sexuality (1,2,3,4 and 5). One third of women lacked interest in sex, 20% said sex was not always pleasurable, 15% experienced pain with intercourse, up to 50% experienced difficulty becoming aroused, 50% noted difficulty reaching orgasm, and up to 25% were unable to experience orgasm. In addition, obstetrician-gynecologists should routinely inquire about a history of childhood sexual abuse or adult sexual assault because these experiences are common and often have a lasting and profound effect on a woman's mental and sexual function as well as her general health and well-being. One of eight American women will be forcibly raped during her lifetime ( 6), and nearly half of women in the United States report some type of contact sexual victimization ( 7). Fifty percent of American women report uninvited sexual attention in the workplace ( 7). Despite the importance of these issues to their health care, many women find it difficult to talk to their physicians about sexual concerns, and many physicians are uncomfortable discussing sexual issues with their patients (8). In a recent survey, 71% of adults said they thought their doctor would dismiss any concerns about sexual problems they might bring up, and 68% said they were afraid that discussing sexuality would embarrass their physician ( 9). Surveys of primary care physicians reveal that fewer than half ask their new patients about sexual practices and concerns and that many physicians make incorrect assumptions about their patients' sexual activity based on marital status, profession, age, race, or socioeconomic status (10,11).

Sexuality Physicians may be concerned that patients will be offended by questions about their sexual practices or may believe that little useful information will be gained by asking patients about sexual concerns or a history of sexual assault. In addition, some physicians may have anxiety about their perceived inability to treat sexual concerns, may believe that they have too little time to obtain a sexual history, may be distressed by their patient's history of sexually related violence, or may experience personal discomfort when discussing sexual matters with their patients ( 12). However, surveys of patients reveal that they expect their physician to be able to address sex-related concerns and believe it is appropriate for questions about sexuality to be included as a routine part of the gynecologic history ( 8). Not asking about sexuality suggests to the patient that sexuality is not important and is not to be discussed. Furthermore, not discussing sexual abuse implies that sexual assault has no long-term consequences. Physicians will feel more comfortable talking to their patients about sex if they have an understanding of the normal sexual response and know how to approach the evaluation and treatment of common sexual dysfunctions. Asking about sexual concerns gives physicians an opportunity to educate patients about the risk for sexually transmitted infections (STIs), counsel patients about safe sex practices, evaluate patients' needs for contraception, and dispel sexual myths and misconceptions. Furthermore, patients are given permission to address sexual issues in a professional, confidential, and nonjudgmental setting (13). Even if patients are initially uncomfortable discussing these sensitive and private issues, they know that their physician will be receptive if they want to discuss sexual concerns in the future. When taking a sexual history, it is important to allow patients to feel comfortable and safe ( 14). The physician's personal values and potential biases should be left out of the discussion. Physicians should use a private location for the interview and let the patient know that the conversation will be confidential. Good listening skills and attention to nonverbal cues are helpful. It is important to use straightforward language that the patient can understand and acknowledge that many people find it difficult to discuss sensitive and intimate issues. Most sexual concerns can be resolved by providing factual information, reassurance, and appropriate medical intervention. Only a few open-ended questions are required to elicit a basic sexual history from patients. These questions should be a part of the medical history taken during a routine examination and can be obtained in either a face-to-face interview or in a written history the patient completes before seeing the physician ( 12,15): “Are you currently sexually active?” “With men, women, or both?” “Are you or your partner having any sexual difficulties?” “Has there been any change in your sexual activity?” “Have you ever experienced any unwanted or harmful touching or sexual activity?” If a positive response is elicited by any of these questions, further evaluation of the patient may be warranted. Follow-up questions might include: “Are you having difficulty initiating a sexual encounter or becoming aroused when you want to be sexual?” “Do you experience as much arousal as you would like?” “Do you experience vaginal dryness during intercourse?” “Do you have orgasms when you want to?” “Are you satisfied with your sexual relationship?” “Do you have pain with intercourse?” “Has this difficulty always been present, or is it new to you?” “Have you had this difficulty with all of your partners or just with the current one?” “Is the difficulty always there or just some of the time?” “Does anything make it better or worse?”

“How much of a concern is this for you and your partner?” “Do you have any idea what may have caused your sexual difficulty?” “Have you received any treatment for this difficulty?” “What are your expectations and goals for treatment? ” Further inquiries about specific sexual dysfunction or the sequelae of sexual abuse can be addressed when appropriate, and the patient can be referred for psychological counseling or sex therapy when necessary ( 16).

Sexual Practices Two recent comprehensive surveys provide an interesting and useful description of the sexual behavior of Americans ( 2,3,17). Sexual activity among adolescents in the United States has increased significantly during the past 20 years. The average age for first intercourse in both men and women is 16 years. By 19 years of age, 66% to 75% of women and 79% to 86% of men will have had intercourse. Most young men and women have multiple, serial sexual partners. They use condoms infrequently and inconsistently, thus exposing themselves to STIs and unintended pregnancy. A survey of American men and women between the ages of 18 and 59 years revealed the following findings ( 2): Most men and women are satisfied with their sex lives, even those who rarely have sex. Among married men and women, 87% reported that they were satisfied with their sexual relationship. Sexual dysfunction was reported in 43% of women and was more likely in women with poor physical and emotional health, unmarried women, younger women, uneducated women, women who had experienced sexual victimization, women who were sexually inexperienced, and women with negative experiences in prior sexual relationships ( 3). Women have sex with a partner from a few times per month (47%), to 2 to 3 times per week (32%), to 4 or more times per week (7%). Twelve percent of women have sex a few times per year, and 3% have never been sexually active. The most appealing sexual activity for both men and women is vaginal intercourse. Watching their partner undress and receiving and giving oral sex were also considered very pleasurable. Most Americans are monogamous. Of married men and women, 75% and 85%, respectively, said they had never been unfaithful. There may be fewer homosexuals than previously believed—2.7% of men and 1.3% of women had a homosexual partner in the past year. Since puberty, 7.1% of men and 3.8% of women had same-gender sexual partners. Twenty-two percent of women said they had been forced to do something sexual, usually by someone they loved, but only 3% of men admitted to forcing themselves on a woman. Perhaps men and women have different ideas about what constitutes sexual coercion.

The Sexual Response Cycle The sexual response cycle in women is mediated by the complex interplay of psychological, environmental, and physiologic (hormonal, vascular, muscular, and neurologic) factors. The initial phase of the sexual response cycle is interest and desire, followed by the four successive phases originally described by Masters and Johnson (18): arousal, plateau, orgasm, and resolution. There is wide variability in the way women respond sexually, and each phase can be affected by aging, illness, medication, alcohol, illicit drugs, and relationship factors. An attempt has been made to redefine the linear progression of sexual response described by Masters and Johnson. The Basson model postulates that the sexual cycle in women is cyclical rather than linear and that arousal and desire are interchangeable ( 19,20). In this model, the starting point for sexuality is the desire for intimacy and closeness rather then a need for physical sexual release. Many women are satisfied with an intimate encounter that does not necessarily include intercourse or orgasm. For most women, the clitoris is the most sexually sensitive part of their anatomy, and stimulation of the clitoris produces the greatest sexual arousal and the most intense orgasms. Other sexually sensitive areas are the nipples, breasts, labia, and, to a lesser extent, the vagina. Although the lower third of the vagina is responsive to touch, the upper two thirds of the vagina is sensitive primarily to pressure. There has been speculation about the existence of a G spot (named after Ernest Graefenberg, who first described it in 1944), an area of the vagina located anteriorly midway between the symphysis pubis and the cervix that is believed to be exquisitely sensitive to deep pressure. This area, believed to be similar to the male prostate, has been described as glandular tissue capable of secreting prostatic acid phosphatase into the urethra, sometimes in such copious amounts that women seem to ejaculate during orgasm. However, analysis of the fluid “ejaculate” has proved that it is probably urine, not prostatic fluid. It is not uncommon for women who are normally continent to leak urine during orgasm. These women should be reassured that this is a common phenomenon and does not require medical intervention. Desire Phase Sexual desire is the motivation and the inclination to be sexual. It is a “subjective feeling state” that may be triggered by both internal (fantasy) and external (an interested partner) sexual cues and is dependent on adequate neuroendocrine functioning ( 20). The sensation of desire is under the influence of dopamine-sensitive excitatory centers located in the limbic system. Testosterone is responsible for desire and arousal in both men and women. Drive is the biologic component of desire and is characterized by sexual thoughts, erotic interest in others, genital tingling, and seeking out of sexual activity ( 20). Desire is influenced by sexual orientation, preferences, psychological mindset, beliefs and values, expectations, willingness to behave sexually, and environmental setting. Arousal (Excitement) Phase The arousal (excitement) phase is mediated by the parasympathetic nervous ystem and is characterized by erotic feelings and the appearance of vaginal lubrication. Sexual arousal increases blood flow to the vagina, and the resulting vasocongestion and changes in capillary permeability create a condition that increases the capillary filtration fraction. The filtered capillary fluid transudates between the intercellular spaces of the vaginal epithelium, causing droplets of fluid to form on the walls of the vagina. In addition to feelings of sexual tension, sexually excited women experience tachycardia, rapid breathing, an elevation in blood pressure, a generalized feeling of warmth, breast engorgement, generalized muscle tension (myotonia), nipple erection, mottling of the skin, and a maculopapular erythematous rash (“sex flush”) over the chest and breasts. During this phase, the clitoris and labia become swollen; the vagina lengthens, distends, and dilates; and the uterus elevates out of the pelvis ( 18,20). During the latter stages of arousal, sexual tension and erotic feelings intensify, and vasocongestion reaches maximum intensity (plateau). The skin becomes more mottled, the breasts become more engorged, and the nipples become more erect. The labia become more swollen and turn dark red, and the lower third of the vagina swells and thickens to form the “orgasmic platform” (18,20). The clitoris becomes more swollen and elevates to lie nearer the symphysis pubis. The uterus elevates fully out of the pelvis. With adequate sexual stimulation, women reach the point of orgasmic inevitability (threshold point). Orgasm Phase Orgasm is a myotonic response mediated by the sympathetic nervous system. It is experienced as a sudden release of the tension that has built up during the arousal. Orgasm is the most intensely pleasurable of the sexual sensations. It consists of multiple (3 to 15) 0.8-second reflex rhythmic contractions of the muscles (pubococcygeal) surrounding the vagina, perineum, anus, and orgasmic platform. Uterine contractions are also experienced by many women during orgasm (18). Thus, some women describe the sensation of an orgasm as different after hysterectomy. Many women who are orgasmic prefer to have orgasms before intercourse, during the time when clitoral stimulation is most intense. Unlike men, who are relatively unresponsive to sexual stimulation after orgasm (refractory period), women are potentially multiorgasmic and capable of experiencing more than one orgasm during a single sexual cycle. Thus, they can experience orgasms both before and during intercourse if adequate clitoral stimulation is provided. Resolution Phase Following the sudden release of sexual tension brought about by orgasm, women experience a feeling of relaxation and well-being. The physiologic

changes that took place during arousal are reversed, and the body returns to a resting state. Complete uterine descent, detumescence of the clitoris and orgasmic platform, and decongestion of the vagina and labia takes about 5 to 10 minutes.

Factors Affecting Sexual Response Aging Aging and the cessation of ovarian function accompanying menopause have a significant effect on the sexual response cycle of women. Sexual desire and the frequency of intercourse decrease gradually as women age, although women retain interest in sex and continue to have the potential for sexual pleasure for their entire lives. The need for closeness, love, and intimacy does not change with age. The way women function sexually as they grow older is largely dependent on health status, partner availability, and how frequently they had sex and how much they enjoyed sex when they were younger ( 21). Results of a study of healthy men and women aged 80 to 101 years living in retirement communities indicated that these elderly people were still very sexually active ( 22). Sexual touching and caressing, followed by masturbation and then intercourse, were the most common sexual activities in this population. Anatomic changes that accompany aging are noted in Table 11.1. These changes predispose women to more frequent episodes of vulvovaginitis and urinary tract infections that, along with decreased vaginal lubrication, may cause dyspareunia. The effects of aging on sexual physiology are noted in Table 11.2. Women who remain coitally active after menopause have less vulvar and vaginal atrophy than abstinent women ( 23). Illnesses that accompany aging may also have an impact on sexual function. Arteriosclerosis may decrease vaginal blood flow and cause decreased arousal, lubrication, and orgasmic intensity. Chronic obstructive pulmonary disease may cause lowered testosterone levels, impairing sexual desire. Pain from an arthritic hip may make it difficult for a woman to find a comfortable position for intercourse.

Table 11.1. Anatomic Changes of Aging

Table 11.2. Sexual Physiology—Effects of Aging

Several psychosocial factors may influence an older woman's sexual activity. Older women may lack a sexual partner, or their partner may develop erectile dysfunction. The couple may have had an unsatisfactory sexual relationship earlier in life and may not be able to negotiate the changes and possible sexual dysfunctions that can come with aging. Couples may find that they can no longer function sexually as they did in the past and are unable to make the transition or adapt to a new (noncoital) way of lovemaking. Other factors include privacy issues (such as living in a nursing home), reluctance to masturbate, and the negative attitudes of society toward sexuality in older women ( 23). Aging men and women may experience performance anxiety as they enter into new relationships ( 24,25 and 26). As women age, many tend to be less fit. Improved physical fitness is positively related to the frequency of sexual intimacy, which in turn is related to longevity (26). Suggestions for aging patients might include taking a warm bath before lovemaking to loosen stiff joints, making love in the morning when the couple is less fatigued, and experimenting with oral or manual sexual stimulation to orgasm without having intercourse. Management of sexual difficulties in older women should include estrogen or testosterone supplementation ( 27,28 and 29). Local or systemic estrogen supplementation can alleviate vaginal dryness, urinary tract symptoms, and dyspareunia. Estrogen replacement restores vaginal cells, decreases pH, and increases vaginal blood flow, thus alleviating vaginal dryness, urinary tract symptoms, and dyspareunia. Estrogen replacement also seems to benefit sexual desire, sexual fantasy, arousal, sexual enjoyment, and orgasmic frequency in postmenopausal women ( 27). In addition, estrogen supplementation improves insomnia, hot flushes, and other menopausal symptoms (e.g., sense of well-being) that may interfere with sexual function. The addition of progesterone to the hormone replacement therapy regimen partially opposes the beneficial effects of estrogen by decreasing vaginal blood flow ( 27). Estrogen supplementation also decreases free testosterone levels by nearly 50% by increasing levels of sex hormone–binding globulin, thus decreasing free testosterone levels ( 29,31). Testosterone levels gradually decrease in women as they age ( 29). Testosterone supplementation, either alone or in combination with estrogen, has been demonstrated to improve libido, arousal, sexual responsiveness, frequency of sexual fantasies and dreams, clitoral sensitivity, and frequency of orgasm in women who are testosterone deficient (12 cm) and is relatively contraindicated in patients with peritonitis, severe ileus, or bowel obstruction. In these settings, laparotomy is preferable.

Cyclic Pain: Primary and Secondary Dysmenorrhea Dysmenorrhea is a common gynecologic disorder affecting up to 50% of menstruating women (11). Primary dysmenorrhea refers to menstrual pain without pelvic pathology, whereas secondary dysmenorrhea is defined as painful menses associated with underlying pathology. Primary dysmenorrhea usually appears within 1 to 2 years of menarche, when ovulatory cycles are established. The disorder affects younger women but may persist into the 40s. Secondary dysmenorrhea usually develops years after menarche and can occur with anovulatory cycles. The differential diagnosis of secondary dysmenorrhea is outlined in

Table 14.3 (2).

Table 14.3. Peripheral Causes of Chronic Pelvic Pain

Primary Dysmenorrhea The cause of primary dysmenorrhea is increased endometrial prostaglandin production ( 12,13,14 and 15). These compounds are found in higher concentration in secretory endometrium than in proliferative endometrium. The decline of progesterone levels in the late luteal phase triggers lytic enzymatic action, resulting in a release of phospholipids with the generation of arachidonic acid and activation of the cyclooxygenase pathway. The biosynthesis and metabolism of prostaglandins and thromboxane derived from arachidonic acid are depicted in Fig. 14.2 (14). Women with primary dysmenorrhea have higher uterine tone with high-amplitude contractions resulting in decreased uterine blood flow ( 16). Vasopressin concentrations are also higher in women with dysmenorrhea ( 17).

Figure 14.2 The biosynthesis and metabolism of prostaglandins and thromboxane derived from arachidonic acid. (From Chaudhuri G. Physiologic aspects of prostaglandins and leukotrienes. Semin Reprod Endocrinol 1985;3:219, with permission.)

Symptoms The pain of primary dysmenorrhea usually begins a few hours before or just after the onset of a menstrual period and may last up to 48 to 72 hours. The pain is similar to labor, with suprapubic cramping, and may be accompanied by lumbosacral backache, pain radiating down the anterior thigh, nausea, vomiting, diarrhea, and rarely syncopal episodes. The pain of dysmenorrhea is colicky in nature and is improved with abdominal massage, counterpressure, or movement of the body, unlike abdominal pain due to chemical or infectious peritonitis. Signs On examination, the vital signs are normal. The suprapubic region may be tender to palpation. Bowel sounds are normal, and there is no upper abdominal tenderness and no abdominal rebound tenderness. Bimanual examination at the time of the dysmenorrheic episode often reveals uterine tenderness; however, severe pain with movement of the cervix or palpation of the adnexal structures is absent. The pelvic organs are normal in primary dysmenorrhea. Diagnosis To diagnose primary dysmenorrhea, it is necessary to rule out underlying pelvic pathology and confirm the cyclic nature of the pain. The differential diagnosis of secondary dysmenorrhea includes primary dysmenorrhea and noncyclic pelvic pain. Whereas the diagnosis of primary dysmenorrhea is based on history and presence of a normal pelvic examination, the diagnosis of secondary dysmenorrhea may require review of a pain diary and an ultrasound examination or laparoscopy. During the pelvic examination, the size, shape, and mobility of the uterus, the size and tenderness of adnexal structures, and nodularity or fibrosis of uterosacral ligaments or rectovaginal septum should be assessed. Cervical studies for gonorrhea and chlamydia and, if relevant, a complete blood count with an ESR are helpful to rule out subacute salpingo-oophoritis. If no abnormalities are found, a tentative diagnosis of primary dysmenorrhea can be established. Treatment Prostaglandin synthase inhibitors are effective for the treatment of primary dysmenorrhea in about 80% of women (18,19). The inhibitors should be taken just before or at the onset of pain and then continuously every 6 to 8 hours to prevent reformation of prostaglandin by-products. The medication should be taken for the first few days of menstrual flow. A 4- to 6-month course of therapy is warranted before confirming treatment failure. Changes in dosages and types of inhibitors should be attempted if initial treatment is not successful. The medication may be contraindicated in patients with gastrointestinal ulcers or bronchospastic hypersensitivity to aspirin. Side effects are usually mild and include nausea, dyspepsia, diarrhea, and occasionally fatigue. For the patient with primary dysmenorrhea who has no contraindications to oral contraceptive agents or who desires contraception, the oral contraceptives are the agent of choice. Oral contraceptives decrease endometrial proliferation and create an endocrine milieu similar to the early proliferative phase, when prostaglandin levels are lowest. More than 90% of women with primary dysmenorrhea experience relief with oral contraception (20). If the patient does not respond to this regimen, hydrocodone or codeine may be added for 2 to 3 days per month; however, before addition of the narcotic medication, psychological factors and other organic pathology should be ruled out with diagnostic laparoscopy. Pain management, in particular acupuncture or transcutaneous electrical nerve stimulation (TENS), may also be useful ( 21,22 and 23). In one study of women with primary dysmenorrhea undergoing TENS, 30% reported marked pain relief, 60% moderate pain relief, and 10% no relief ( 24). To evaluate more fully the evidence for treating primary dysmenorrhea with TENS and acupuncture, a forthcoming study by the Cochrane Library aims to analyze all prospective randomized controlled trials comparing these modalities with medical treatment or placebo (25). Methods used only rarely to treat primary dysmenorrhea include surgical laparoscopic uterine nerve ablation and presacral neurectomy.

Secondary Dysmenorrhea Secondary dysmenorrhea usually occurs years after the onset of menarche. The definition does not reflect age of onset but rather is cyclic menstrual pain that occurs in association with underlying pelvic pathology. The pain of secondary dysmenorrhea often begins 1 to 2 weeks before menstrual flow and persists until a few days after the cessation of bleeding. The mechanisms underlying secondary dysmenorrhea are diverse and not fully elucidated, although most involve either excess prostaglandin production or hypertonic uterine contractions secondary to cervical obstruction, intrauterine mass, or the presence of a foreign body. However,

nonsteroidal antiinflammatory agents and oral contraceptive pills are less likely to provide pain relief in women with secondary dysmenorrhea than in those with primary dysmenorrhea. The most common cause of secondary dysmenorrhea is endometriosis, followed by adenomyosis and intrauterine device (for a discussion of endometriosis, see diagnosis of acute and chronic pain, this chapter and Chapter 26). The differential diagnosis of secondary dysmenorrhea is outlined in Table 14.3. The management of secondary dysmenorrhea is treatment of the underlying disorder. Adenomyosis Dysmenorrhea associated with adenomyosis often begins up to a week before menses and may not resolve until after the cessation of menses. Associated dyspareunia, dyschezia, and metrorrhagia increase the probability of the diagnosis. Whereas endometriosis is characterized by ectopic endometrium appearing within the peritoneal cavity, adenomyosis is defined as presence of endometrial tissue within the myometrium, at least one high-power field from the basis of the endometrium. Adenomyosis, endometriosis, and uterine leiomyomas frequently coexist. Although occasionally noted in women in the younger reproductive years, the average age of symptomatic women is usually older than 40 years. Symptoms Adenomyosis often is asymptomatic. Symptoms typically associated with adenomyosis include excessively heavy or prolonged menstrual bleeding and dysmenorrhea, often beginning up to a week before the onset of a menstrual flow. Signs The uterus is diffusely enlarged, although usually less than 14 cm in size, and is often soft and tender, particularly at the time of menses. Mobility of the uterus is not restricted, and there is no associated adnexal pathology. Diagnosis Adenomyosis is a clinical diagnosis, and imaging studies, although helpful, are not definitive. Because of their cost and negligible improvement in diagnostic accuracy, these studies are not recommended routinely. In women with diffuse uterine enlargement and a negative pregnancy test, secondary dysmenorrhea may be attributed to adenomyosis; however, the pathologic confirmation of suspected adenomyosis can be made only at the time of hysterectomy. In one study to confirm preoperative diagnosis of adenomyosis before hysterectomy, the clinical diagnosis of adenomyosis was confirmed in only 48% of the cases ( 26). Management The management of adenomyosis clearly depends on the patient's age and desire for future fertility. Relief of secondary dysmenorrhea due to adenomyosis can be ensured after hysterectomy, but less invasive approaches can be tried initially. Nonsteroidal antiinflammatory agents, oral contraceptives, and menstrual suppression using progestins have all been found to be useful.

Chronic Pelvic Pain Chronic pelvic pain remains an inclusive, general diagnosis that encompasses many more specific causes from endometriosis to nerve entrapment syndrome. Various forms of chronic pelvic pain affect 12% to 15% of women in the United States (27). The differential diagnosis of chronic pelvic pain is outlined in Table 14.3. Patients with chronic pelvic pain are frequently anxious and depressed. Their marital, social, and occupational lives have usually been disrupted. These patients have often had poor treatment outcomes after traditionally effective gynecologic and medical therapy and may have undergone multiple unsuccessful surgical procedures for pain. About 12% of hysterectomies are performed for pelvic pain, and 30% of patients who present to pain clinics have already had a hysterectomy (28,29). Anywhere from 20% to 80% of patients undergoing laparoscopy for chronic pelvic pain have no intraperitoneal pathology or have tissue distortion that does not correlate with the pain (2). Additionally, the relationship can be inconsistent between the pain response and certain types of prevalent intraperitoneal pathology, such as endometriosis, adhesions, or venous congestion (2). Nongynecologic causes of pain, such as irritable bowel syndrome, interstitial cystitis, abdominal wall or pelvic floor myofascial syndrome, or nerve entrapment, are frequently overlooked but common causes of chronic pelvic pain. Recent investigations have suggested that “plasticity” of the nervous system or alterations in signal processing may be involved in the maintenance of painful states (2,4,30). Various neurohumoral modulators, such as prostaglandins, vasoactive intestinal peptide, substance P, and endorphins, can modulate peripheral neurotransmission and also affect neurotransmission at the level of the spinal cord ( 31). The spinal cord is not a simple conduit between the periphery and the brain. It is an important site of “gating” mechanisms, such as excitation, inhibition, convergence, and summation of neural stimuli ( 32). The pain sensation is also modified by neurotransmitters within the brain, such as norepinephrine, serotonin, and g-aminobutyric acid (GABA), as well as by endogenous endorphin and nonendorphin algesic systems. Different regions of the brain are also important in altering the sensory and affective components of the pain response. Evidence from animal studies indicates that supraspinal factors can interact at the level of the dorsal horn to modulate the sensory perception of pain from the pelvic viscera (33). The sensory and affective component of pain is affected by early experience, conditioning, fear, arousal, depression, and anxiety ( 30,34).

Evaluation of Chronic Pelvic Pain Figure 14.3 outlines an approach to the patient with chronic pelvic pain. On the first visit, a thorough pain history should be performed, addressing the nature of each pain complaint: location, radiation, severity, aggravating and alleviating factors; effect of menstrual cycle, stress, work, exercise, intercourse, and orgasm; the context in which pain arose; and the social and occupational toll of the pain.

Figure 14.3 Evaluation of chronic pelvic pain.

The patient should be questioned about symptoms specific to the types of pathology (see Table 14.3): 1. 2. 3. 4.

Genital (abnormal vaginal bleeding, discharge, dysmenorrhea, dyspareunia, infertility) Enterocoelic (constipation, diarrhea, flatulence, hematochezia, and relationship of pain to bowel movements) Musculoskeletal (trauma, exacerbation with exercise, or postural changes) Urologic (urgency, frequency, nocturia, dysuria, incontinence, hematuria)

The history should include gynecologic, medical, and surgical factors; medication intake; prior evaluations for pain; and operative and pathology reports ( 2).Symptoms

of an acute process (fever, anorexia, nausea, emesis, significant diarrhea, obstipation, abdominal distention, undiagnosed uterine bleeding, pregnancy, or recent abortion) should alert the physician to the possibility of an acute condition requiring immediate medical or surgical intervention. This occurrence is especially important if symptoms are accompanied by elevated temperature, orthostasis, peritoneal signs, pelvic or abdominal mass, abnormal complete blood count, positive genital or urinary tract cultures, or a positive pregnancy test. A complete physical examination should be performed, with particular attention directed to the abdominal, lumbosacral, external genital, vaginal, bimanual, and rectovaginal examination. The examination should include evaluation of the abdomen with muscles tensed (head raised off the table or with straight leg raising) to differentiate abdominal wall and visceral sources of pain. Abdominal wall pain is augmented and visceral pain is diminished with these maneuvers ( 35,36). The patient should be examined while standing for hernias, both abdominal (inguinal and femoral) and pelvic (cystocele and enterocele). An attempt should be made to locate by palpation the tissues that reproduce the patient's pain. If abdominal wall sources of pain are noted, it is useful to block these areas with local anesthetics and then perform the pelvic examination (35,36).

The Psychological Component A pain history includes the current and past psychological history addressing psychosocial factors; history of past (or current) physical, sexual, or emotional abuse; history of psychiatric hospitalization; suicide attempts; and chemical dependency ( 2). The attitude of the patient and her family toward the pain, resultant behavior of the patient and her family, and current upheavals in the patient's life should be discussed. The part of the history addressing sensitive issues may have to be reobtained after establishing rapport with the patient. It is vital to appreciate the various influences that can distort pain perception and expression. A distinction can be drawn between factors leading to a painful condition and those now maintaining it. Whatever the original cause of the pain, when pain has persisted for any length of time, it is likely that other facts are now maintaining or at least contributing to it. The full physical evaluation, outlined previously, should be accompanied by a review of psychosocial factors. Pain is commonly accompanied by anxiety and depression, and these conditions need to be carefully assessed and treated ( 2). In a typical gynecologic setting, referral to a psychologist for parallel evaluation can evoke resistance. The inference is drawn that the referring physician is ascribing the pain to psychological causes. The patient needs to understand the reason for this referral and to be reassured that it is a routine and necessary part of the evaluation.

Gynecologic Causes The most common gynecologic pathologies noted at the time of laparoscopy performed for chronic pelvic pain are endometriosis and adhesions. For a thorough discussion of endometriosis and treatment, see Chapter 26. Other Gynecologic Pathology: Leiomyomas, Ovarian Tumors, Pelvic Relaxation Patients with obvious gynecologic pathology, such as benign or malignant ovarian cysts, uterine leiomyomas of sufficient size to encroach on supporting ligaments or other somatic structures, or significant pelvic relaxation should be evaluated and managed as is appropriate for the underlying condition (see Chapter 13 and Chapter 20). Pain associated with these conditions is generally not severe, and appropriate surgical management is therapeutic. Endometriosis Endometriosis can be demonstrated in 15% to 40% of patients undergoing laparoscopy for chronic pelvic pain (37). Endometriosis produces a low-grade inflammatory reaction (38). However, the cause of the pain is not well established. There is no correlation between the location of disease and pain symptoms ( 39,40). There also appears to be no relationship between the incidence or severity of pain and the stage of the endometriotic lesions, and as many as 30% to 50% of patients have no pain regardless of stage. Similarly, 40% to 60% of patients have no tenderness on examination regardless of stage ( 40). However, deeply infiltrating rectovaginal septum lesions are strongly associated with pain ( 41,42), and vaginal and uterosacral endometrioses are associated with complaints of deep dyspareunia (43). Prostaglandin E and F 2a production from explants of petechial lesions present in mild, low-stage disease was found to be significantly greater than from the explants of powder-burn or black lesions, which are more common in patients with higher-stage endometriosis ( 44). Therefore, prostaglandin production may account for severe pain in some patients with mild disease. Clinically, it is possible to determine whether there is a relationship between pain and endometriosis because of the hormonal sensitivity of the disease. It has been debated whether a laparoscopic diagnosis of chronic pelvic pain secondary to endometriosis is necessary to initiate treatment. Recent reports have suggested otherwise, including one study that showed significant efficacy of gonadotropin-releasing hormone (GnRH) agonist treatment based on empirical diagnosis (45). After induction of a hypoestrogenic state with GnRH analogues, those patients with pelvic pain and dysmenorrhea related to endometriosis should experience relief. The pain relief usually occurs within 2 months of treatment, but pain often returns to the pretreatment level by 18 months after treatment ( 46). During long-term (12 or more months) treatment with GnRH analogues, hormonal add-back therapy (i.e., norethindrone acetate, 5 mg daily, with or without estrogen) prevents the long-term hypoestrogenic side effects, such as bone loss, with continued pain relief (47). Intermenstrual pain that is not as consistently associated with endometriosis as is dysmenorrhea is somewhat less responsive to hormonal manipulation. Endometriosis may benefit from surgical intervention, such as electrodissection, laser vaporization, or excision. In fact, in one recent prospective, randomized, double-blinded study with 63 women, laparoscopic laser treatment benefited 90% of women who initially responded at 1-year follow-up (48). Adhesions Adhesions noted at the time of laparoscopy are often in the same general region of the abdomen as the pelvic pain complaint ( 49); however, neither the specific location (i.e., adnexa structures, parietal, visceral peritoneum, or bowel) nor density of the adhesions correlates consistently with the presence of pain symptoms (50). Uncontrolled prospective studies of adenolysis have not consistently demonstrated a significant reduction in pain scores ( 51). In one study of lysis of adhesions, a subgroup of women with anxiety, depression, multiple somatic symptoms, and social and occupational disruption responded poorly to adhesiolysis. The group without these symptoms did have significant improvement in pain ( 51). A prospective study, however, noted a significant improvement in pain on two of three methods of assessment only if the adhesions were dense and involved the bowel ( 52). Symptoms Noncyclic abdominal pain, sometimes increased with intercourse or activity, is a common pain complaint in women with adhesions, but there is no symptom pattern specific for adhesions. Chronic pelvic pain developing from adhesions likely results from restriction of bowel mobility and distention (53). Furthermore, dense adhesions involving bowel can result in a partial or complete bowel obstruction. Signs The abdominal wall must be carefully elevated for myofascial or neurologic sources of pain. Most women with adhesions with have had a prior surgical procedure with possible injury to abdominal wall structures that may be the cause of pain. Decreased mobility of pelvic organs or adnexal enlargement can often be noted in patients with adhesions. Diagnosis Diagnostic laparoscopy is recommended if other somatic causes are ruled out and the results of the psychological evaluation are negative. Recent advances in microlaparoscopy have enabled the development of a new technique known as “conscious pain mapping,” whereby physicians may better locate the specific adhesions associated with pelvic pain using local anesthesia and conscious sedation (54). In an observational study of 50 women using local anesthesia, manipulation of appendiceal and pelvic adhesions contributed to observed pelvic pain (55). Further studies are needed to correlate the lysis of such painful adhesions with pain relief.

Management At this time, the causal role of adhesions in the genesis of pelvic pain is uncertain, and lysis is recommended only after thorough multidisciplinary evaluation and in the context of an integrated treatment approach that addresses stress, mood, and associated behavioral responses. Repeated surgical procedures for lysis are not recommended. Pelvic Congestion In 1954, Taylor suggested that emotional stress could lead to autonomic nervous system dysfunction manifested as smooth muscle spasm and congestion of the veins draining the ovaries and uterus ( 56). Transuterine venography in women with chronic pelvic pain often reveals delayed disappearance of contrast medium from the uterine and ovarian veins ( 57). Considering that pregnant and postpartum women have asymptomatic pelvic congestion, the role of congested veins in the causation of pelvic pain is uncertain. The specific neurotransmitters involved in mediating sympathetic efferent maintained pain syndrome are unknown. Signs and Symptoms Typical symptoms include lower abdominal and back pain, secondary dysmenorrhea, dyspareunia, abnormal uterine bleeding, chronic fatigue, and irritable bowel symptoms. Pain usually begins with ovulation and lasts until the end of menses. The uterus is often bulky, and the ovaries are enlarged with multiple functional cysts. The uterus, parametria, and uterosacral ligaments are tender. Diagnosis Transuterine venography has been the primary method for diagnosis, although other modalities, such as pelvic ultrasound, magnetic resonance imaging, and laparoscopy, may demonstrate varicosities (58). Because of the cost and possible side effects of treatment, further management should be based on related symptoms and not simply on the presence of varicosities. Management Treatment of suspected pelvic congestion ranges from the less invasive hormonal suppression and cognitive behavioral pain management to the more invasive ovarian vein embolization or hysterectomy. Low-estrogen, progestin-dominant continuous oral contraceptives, high-dose progestins, and GnRH analogues often provide pain relief. Hormonal suppression should be the initial mode of treatment for women with suspected pelvic congestion. Medroxyprogesterone acetate, 30 mg daily, has been found to be useful ( 59). Concurrently, a multidisciplinary approach incorporating psychotherapy, behavioral pain management, or both is important. A positive interaction between medroxyprogesterone acetate and pain management has been noted ( 59). Technically more invasive, transcatheter embolotherapy selectively catheterizes the ovarian and internal iliac veins, followed by contrast venography and embolization (60). Several small, uncontrolled studies with limited follow-up have reported pain reduction with transcatheter embolization of pelvic veins (61,62 and 63). For women who have completed their childbearing, hysterectomy with possible oophorectomy is a reasonable option. Salpingo-oophoritis Patients with salpingo-oophoritis usually present with symptoms and signs of acute infection. Atypical or partially treated infection may not be associated with fever or peritoneal signs. Subacute or atypical salpingo-oophoritis is often a sequela of chlamydia or mycoplasma infection. Alternatively, a patient with multiple partners may develop frequent recurrent infections ( 64). Patients with initial gonococcal PID are more likely to develop recurrent infections ( 65). The mechanism for this increased susceptibility to future infections has not been delineated, although it has been suggested that the fallopian tube and cervix may lose some of their natural protective mechanisms against microorganisms. Abdominal tenderness, cervical motion, and bilateral adnexal tenderness are typical of pelvic infection. A complete blood count and ESR as well as cervical study for gonorrhea and chlamydia should be performed. In all situations, laparoscopy, with peritoneal fluid cultures, is usually diagnostic. Patients with either abnormal ESR or abnormal clinical examination should be treated empirically for salpingo-oophoritis before laparoscopy. Ovarian Remnant Syndrome Chronic pelvic pain in a patient who has had a hysterectomy and bilateral salpingo-oophorectomy for severe endometriosis or PID may be caused by the ovarian remnant syndrome. Ovarian remnant syndrome results from residual ovarian cortical tissue that is left in situ after a difficult dissection in an attempt to perform an oophorectomy. Often, the patient has had multiple pelvic operations with the uterus and adnexa removed sequentially. Symptoms The patient usually complains of lateralizing pelvic pain, often cycling with ovulation or the luteal phase, described as sharp and stabbing or as constant, dull, and nonradiating, possibly with associated genitourinary or gastrointestinal complaints ( 66). Symptoms tend to arise 2 to 5 years after initial oophorectomy. A tender mass in the lateral region of the pelvis is pathognomonic. Diagnosis Ultrasonography usually confirms a mass with the ultrasonographic characteristics of ovarian tissue. In a patient who has had bilateral salpingo-oophorectomy and is not taking hormonal replacement, estradiol and follicle-stimulating hormone (FSH) assays reveal a characteristic premenopausal picture, although on occasion the remaining ovarian tissue may not be active enough to suppress FSH levels ( 67,68). Management Initial medical treatment with either danazol, high-dose progestins, or oral contraceptives usually provides mixed results. Patients usually experience relief of pain with a GnRH agonist, although these medications are impractical for long-term therapy. Those who achieve relief with GnRH agonists also were relieved by subsequent surgery (69). Laparoscopic examination is usually nonproductive because the ovarian mass may be missed or adhesions may prevent accurate diagnosis. Laparotomy is necessary for treatment, and the corrective surgery tends to be arduous, often involving inadvertent cystotomy, enterotomy, postoperative small bowel obstructions, and hematoma formation. Surgical pathology usually reveals the presence of ovarian tissue, sometimes with endometriosis, corpus lutea or follicle cysts, and fibrous adhesions ( 67,68).

Gastroenterologic Causes The uterus, cervix, and adnexa share with the lower ileum, sigmoid colon, and rectum the same visceral innervation, with pain signals traveling through sympathetic nerves to spinal cord segments T10 to L1 ( 70). It is often difficult, therefore, to determine whether lower abdominal pain is of gynecologic or enterocoelic origin. Skillful medical history and examination are necessary to distinguish gynecologic from gastrointestinal etiology of pain. P> Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is one of the more common causes of lower abdominal pain and may account for up to 60% of referrals to the gynecologist for chronic pelvic pain (70). The exact etiology of IBS is unknown; however, patients with IBS have pain with smaller volume of distention of the bowel than those without IBS (71). These patients also have an abnormal pain referral pattern with colonic distention. Visceral hypersensitivity or hyperalgesia has been postulated as the cause of

pain, although the cause of this hyperalgesia is not known ( 72). Symptoms The predominant symptom of IBS is abdominal pain. Other symptoms include abdominal distention, excessive flatulence, alternating diarrhea and constipation, increased pain before a bowel movement, decreased pain after a bowel movement, and pain exacerbated by events that increase gastrointestinal motility, such has high-fat diet, stress, anxiety, depression, and menses. The pain is usually intermittent, occasionally constant, cramplike, and more likely to occur in the left lower quadrant. The criteria for diagnosis include at least 12 weeks (not necessarily consecutive) in the preceding 12 months of abdominal discomfort or pain that has at least two of the following features: relief with defecation, onset associated with change in stool frequency, or onset associated with change in form (appearance) of stool. Signs On physical examination, the finding of a palpable tender sigmoid colon or discomfort during insertion of the finger into the rectum and finding hard feces in the rectum are suggestive of IBS (70). Diagnosis The diagnosis of IBS is usually based on history and physical examination, and although suggestive, especially in young women, the findings are not specific. In one study, 91% of patients with IBS had two or more IBS symptoms (abdominal distention, relief of pain with bowel movement, more frequent bowel movements with the onset of pain, looser bowel movements with the onset of pain), whereas 30% of patients with organic disease had two or more of these symptoms ( 73). Therefore, a complete blood count, stool sample to test for white cells and occult blood, and sigmoidoscopy or colonoscopy or barium enema are usually required, particularly in older individuals and in young individuals who have not responded to initial treatment. The results of these studies are all normal in patients with IBS. Management Current medical therapy for IBS is generally unsatisfactory, and placebo response rates are high ( 74). A multidisciplinary program consisting of medical and psychological approaches is recommended. The treatment consists of reassurance, education, stress reduction, bulk-forming agents, and low-dose tricyclic antidepressants. The multidisciplinary management approach addresses the cognitive, affective, and behavioral components of the pain. Therapy may decrease the intensity of nociceptor stimulation as well as change the interpretation of the meaning of pain. Inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, infectious enterocolitis, intestinal neoplasms, appendicitis, and hernia must be ruled out with appropriate history and physical examination, complete blood count, and stool cultures as well as visualization of colonic mucosa when appropriate.

Urologic Causes Chronic pelvic pain of urologic origin may be related to recurrent cystourethritis, urethral syndrome, sensory urgency of uncertain cause, as well as interstitial cystitis. With an appropriate diagnostic workup, infiltrating bladder tumors, ureteral obstruction, renal lithiasis, and endometriosis can easily be ruled out as possible causes. Urethral Syndrome Urethral syndrome is defined as a symptom complex including dysuria, frequency and urgency of urination, suprapubic discomfort, and often dyspareunia in the absence of abnormality of urethra or bladder. The cause of urethral syndrome is uncertain and has been attributed to a subclinical infection, urethral obstruction, and psychogenic and allergic factors ( 75). Symptoms Urinary urgency, frequency, suprapubic pressure, and other less frequent symptoms such as bladder or vaginal pain, urinary incontinence, postvoid fullness, dyspareunia, and suprapubic pain are commonly observed. Signs Physical and neurologic examinations should be performed. The anal reflex should document that S2 to S4 spinal segments have not been interrupted ( 75). Anatomic abnormalities, including pelvic relaxation, urethral caruncle, and hypoestrogenism, should be evaluated. The patient should also be evaluated for vaginitis. The urethra should be carefully palpated to detect purulent discharge. Diagnosis A clean catch or catheterized urine specimen for routine urinalysis and culture should be obtained to rule out urinary tract infection. As indicated, urethral and cervical cultures for chlamydia should be obtained, and a wet prep for vaginitis should be performed. Urethral syndrome should be considered if the results of urine and urethral cultures are negative, the evaluation does not disclose vulvovaginitis, and no allergic phenomenon causing contact dermatitis of the urethra can be detected. Ureoplasma, chlamydia, candida, trichomonas, gonorrhea, and herpes should be ruled out. Cystoscopic evaluation should be performed to rule out urethral diverticulum, interstitial cystitis, and cancer. Management Various forms of therapy have been suggested for urethral syndrome. Those patients in whom no infectious agent is present but who have sterile pyuria respond to a 2- to 3-week course of doxycycline or erythromycin (75). Long-term, low-dose antimicrobial prophylaxis is often used in women with urgency and frequency symptoms who have had a history of recurrent urinary tract infections. Some of these women may continue to have symptoms when their urine is not infected and then redeveloped bacteria over time (75). It is recommended that all postmenopausal women be given a trial of local estrogen therapy for about 2 months. If there is no improvement after antibiotic or estrogen therapy, urethral dilation can be considered. Positive results also have been noted with biofeedback techniques ( 75). Interstitial Cystitis Interstitial cystitis occurs more often in women than men. Most patients are between 40 and 60 years of age. The cause of interstitial cystitis is unknown, although an autoimmune etiology is generally accepted ( 75). Symptoms Symptoms include severe and disabling urinary frequency and urgency, nocturia, dysuria, and occasional hematuria. Suprapubic, pelvic, urethral, vaginal, or perineal pain is common and can be relieved partially by emptying of the bladder. Signs Pelvic examination usually reveals anterior vaginal wall and suprapubic tenderness. Urinalysis may reveal microhematuria without pyuria, although results may be normal.

Diagnosis The diagnosis is based on symptoms and characteristic cystoscopic findings ( 75,76). Cystoscopy performed in the awake patient may reveal only bladder hypersensitivity; under anesthesia, however, with sufficient distention of the bladder, submucosal hemorrhages and cracking of the mucosa may be noted ( 70). Although the histologic features of the biopsy specimen are nonspecific, there is usually submucosal edema, vasodilation, and infiltration by macrophages, plasma cells, and eosinophils. Management Because the etiology is uncertain, management has been empirical. Various pharmaceutical approaches, including anticholinergic, antispasmodic, and antiinflammatory agents, have been used. Response to treatment also has been noted with the use of tricyclic antidepressants or pentosan polysulfate sodium, which is approved for therapy (77). Hydrostatic bladder distention may produce temporary relief by creating detrussor ischemia and decreased innervation of the bladder wall. Biofeedback and behavioral therapy has also been used with some success ( 75).

Neurologic and Musculoskeletal Causes Nerve Entrapment Abdominal cutaneous nerve injury or entrapment may occur spontaneously or within weeks to years after transverse suprapubic skin or laparoscopy incisions ( 35,78). The ilioinguinal or ileohypogastric nerves may become trapped between the transverse and internal oblique muscles, especially when the muscles contract. Alternatively, the nerve may be ligated or traumatized during the surgery. Symptoms of nerve entrapment include burning, aching pain in the dermatomal distribution of the involved nerve (79,80). Hip flexion and exercise exacerbate pain. The pain is usually judged as coming from the abdomen, not the skin. Signs On examination, the pain usually can be localized with the fingertip. The maximal point of tenderness in an iliohypogastric or ilioinguinal injury is usually at the rectus margin, medial and inferior to the anterior iliac spine. Tentative diagnosis is confirmed with the diagnostic nerve block with 0.25% bupivacaine. Patients usually report immediate relief of symptoms after injection, and at least 50% experience relief lasting longer than a few hours ( 35). Management Many patients may require no further intervention, although some patients require up to five biweekly injections. If injection is successful in producing only limited pain relief and there are no contributory visceral or psychological factors, cryoneurolysis or surgical removal of the involved nerve is recommended. Myofascial Pain Myofascial syndrome has been documented in about 15% of patients with chronic pelvic pain ( 81). These patients are noted to have trigger points if examined carefully (82). Trigger points are initiated by pathogenic autonomic reflex of visceral or muscular origin ( 82,83). The referred pain of the trigger point occurs in a dermatomal distribution, and it is thought to be due to nerves from the muscle or deeper structures sharing a common second-order neuron in the spinal cord. Painful trigger points characteristically can be abolished with the injection of local anesthetic into the painful points ( 82). Trigger points are often present in women with chronic pelvic pain irrespective of presence or type of underlying pathology. In one study, 89% of women with chronic pelvic pain had abdominal, vaginal, or lumbosacral trigger points ( 82). In the absence of the initial or continued organic pathology, various factors are theorized to predispose to the chronicity of the myofascial syndrome, including psychological, hormonal, and biomechanical factors ( 83,84). Symptoms Abdominal wall pain is often exacerbated during the premenstrual period or by stimuli to the dermatome of trigger points (e.g., full bladder, bowel, or any stimulation to organs that share the dermatome of the involved nerve) ( 36). Signs On examination, fingertip pressure on the trigger points evokes local and referred pain. Tensing of the rectus muscles by either straight leg lifting or raising the head off the table increases the pain. A specific jump sign can be elicited by palpation with fingertip or a cotton swab. An electric (tingling) sensation confirms correct needle placement (36,82). Management Injection of the trigger point with 3 mL of 0.25% bupivacaine provides relief that usually outlasts the duration of the anesthetic action. After four to five biweekly injections, the procedure should be abandoned if long-lasting relief is not obtained ( 82). Concomitant with injection of trigger points, multidisciplinary pain management should be undertaken, especially if anxiety, depression, history of physical or sexual abuse, sexual dysfunction, or social or occupational disruption are present. Low Back Pain Syndrome Women complaining of lower back pain without pelvic pain rarely have gynecologic pathology as the cause of their pain. However, low back pain may accompany gynecologic pathology. Back pain may be caused by gynecologic, vascular, neurologic, psychogenic, or respondologenic (related to the axial skeleton and its structure) pathology (2). Symptoms Women with low back pain syndrome often have pain occurring after trauma or physical exertion, in the morning on arising, or with fatigue. Nongynecologic low back pain can intensify with the menstrual cycle. Signs Examination consists of inspection, evaluation with movement, and palpation. Various anatomic structures in the spine should be considered as sources of pain. Muscles, vertebral joints, and disks (including lumbosacral junction, paravertebral sacrospinal muscles, and sacroiliac joints) are common sources of spondylogenic pain that must be examined carefully ( 2,85). Diagnosis Diagnostic imaging studies performed while the patient is standing, lying, and sitting with maximal flexion can be helpful. An elevated ESR suggests pain of inflammatory or neoplastic origin. Management Orthopedic or rheumatologic consultation should be sought before initiating management for back pain unless the source could be referred gynecologic pain.

Psychological Factors From a psychological perspective, various factors may promote the chronicity of pain, including the meaning attached to the pain, anxiety, the ability to redirect attention, personality, mood state, past experience, and reinforcement contingencies that may amplify or attenuate pain ( 2). The Minnesota Multiphasic Personality Inventory (MMPI) studies of women with chronic pelvic pain reveal a high prevalence of a convergence “V” profile (elevated scores on the hypochondriasis, hysteria, and depression scales). Studies of MMPI profiles of women with chronic pain without obvious pathology compared with women with endometriosis-related pain or controls suggest that MMPI profiles are unable to distinguish patients with obvious organic findings. Both pain groups differ from controls ( 2). Furthermore, treatment resulting in subjective improvement in pain severity and increased activity level produces a significant improvement in personality profile (86). There is also a close relationship between depression and pain ( 87). Both give rise to similar behavior, such as behavioral and social withdrawal and decreased activity, and may be mediated by the same neurotransmitters, including as norepinephrine, serotonin, and endorphins ( 2). Antidepressants appear to relieve both depression and pain. Childhood physical and sexual abuse has also been noted to be more prevalent in women with chronic pelvic pain than those with other types of pain and controls (52% versus 12%) (88). In a comparison of women with chronic pelvic pain, women with nonpelvic chronic pain (headache), and pain-free women, a higher lifetime prevalence of major sexual abuse (56%) and physical abuse (50%) was found in the chronic pelvic pain group (89). Individual differences in personality and habitual coping strategies may also influence response to pain and pain recurrence.

Management Approach In patients with no obvious pathology and in those with pathology that has an equivocal role in pain production, multidisciplinary therapy is usually preferable. This approach incorporates the skills of the gynecologist, psychologist, and ideally anesthesiologist. A low dose of a tricyclic antidepressant is combined with behavioral therapy directed toward reducing reliance on pain medication, increasing activity, and relieving the impact the pain has on the women's overall lifestyle ( 2). Women with depression should be treated with an appropriate therapeutic dose of antidepressant medication ( 90). Only one small, randomized, controlled trial has looked at the effect of selective serotonin reuptake inhibitors on pelvic pain. It failed to show a significant difference in pain or functional ability in a short follow-up period (91). The approach to women with chronic pain must be therapeutic, supportive, and sympathetic. Offering regular follow-up appointments instead of asking the patient to return only if pain persists reinforces pain behavior. Specific skills can be taught to the patient using cognitive behavioral approaches. Women are offered ways to enhance opportunities for control of pain. Psychotherapy is indicated for women who have pronounced depression, sexual difficulties, or indications of past trauma. Various strategies, including relaxation techniques, stress management, sexual and marital counseling, hypnosis, and other psychotherapeutic approaches, have been found to be useful. Acupuncture may also be helpful ( 92). Diagnostic uterosacral, hypogastric, or epidural nerve blocks can be used (93). Multidisciplinary Approach Various studies of multidisciplinary pain management have been performed. Retrospective, uncontrolled studies revealed relief of pain in 85% of the subjects ( 92,94). One prospective randomized study revealed a similar response rate, which was significantly better than that of traditional therapy ( 95). Surgical Therapy Laparoscopy Those women with disabling cyclic pain that does not respond to nonsteroidal antiinflammatory medication or oral contraceptives should undergo laparoscopic evaluation. Diagnostic laparoscopy has become a standard procedure in the evaluation of patients with chronic noncyclic pelvic pain; however, laparoscopy should be withheld until other nongynecologic somatic or visceral causes of pain have been eliminated. During diagnostic laparoscopy, endometriotic lesions should be excised for biopsy, and if infection is suspected, cultures should be performed. All visible endometriosis should be surgically excised or electrocoagulated. Patients with dysmenorrhea may benefit from transection of the uterosacral ligaments. The uterosacral ligaments carry the principal afferent nerve supply from the uterus to the hypogastric nerve. The original procedure was performed by a colpotomy and was noted to have a success rate of 70% ( 96). Laparoscopic nerve ablation was found to relieve dysmenorrhea in 85% of patients ( 97). Nonrandomized retrospective and prospective studies have suggested that diagnostic laparoscopy provides a positive psychological effect on the treatment of chronic pelvic pain (98). Lysis of Adhesions The role of pelvic adhesions in pain is unclear ( 2). Adhesiolysis, even by laparoscopy, is frequently complicated by adhesion reformation ( 99). However, other etiologies must be treated first. Psychological consultation and management should precede or accompany the lysis of adhesions. Presacral Neurectomy Presacral neurectomy or sympathectomy was first described for dysmenorrhea (100). The discovery of highly successful medical therapies has largely supplanted presacral neurectomy; however, presacral neurectomy may be indicated for primary or secondary dysmenorrhea unrelieved by traditional therapy and unresponsive to multidisciplinary pain management. The response rate to presacral neurectomy for secondary dysmenorrhea varies between 50% and 75% ( 2,99). The neurectomy only relieves pain deriving from the cervix, uterus, and proximal fallopian tubes (T11 to L2). The nerve supply to the adnexal structures (T9 to T10) bypasses the hypogastric nerve. Therefore, lateralizing visceral pain is unlikely to be relieved by presacral neurectomy. Intraoperative complications, such as hemorrhage or ureteral injury, can occur in a small percentage of cases. The sacral nerve supply is unaffected by division of the presacral nerve; thus, normal micturition, defecation, and parturition are preserved. A local anesthetic hypogastric block performed under fluoroscopic guidance can help to predict the response to this operation. Hysterectomy Hysterectomy has often been performed to cure pelvic pain; however, 30% of patients presenting to pain clinics have already undergone hysterectomy without experiencing pain relief (28). Hysterectomy is particularly useful for women who have completed childbearing and have secondary dysmenorrhea or chronic pain related to endometriosis, to uterine pathology, such as adenomyosis, or to pelvic congestion. Before recommending hysterectomy for pain or unilateral adnexectomy for unilateral pain, it is useful to apply the PREPARE pneumonic in discussions with the patient ( 101): the Procedure that is being done, Reason or indication, Expectation or desired outcome of the procedure, Probability that the outcome will be achieved, Alternatives and nonsurgical options, and Risks as well as Expense (see Chapter 3). Hysterectomy for central pelvic pain in women with dysmenorrhea, dyspareunia, and uterine tenderness provided relief of pain in 77% of women in one retrospective study (102) and in 74% of women in one prospective cohort study ( 103). Nevertheless, 25% of women in the retrospective study noted a persistence or worsening of pain at 1-year follow-up ( 104).

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104. ACOG Criteria Set. Hysterectomy, abdominal or vaginal for chronic pelvic pain. Number 29, November 1997. Committee on Quality Assessment. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1998;60:316–317. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 15. Genitourinary Infections and Sexually Transmitted Diseases Novak’s Gynecology

Chapter 15

Genitourinary Infections and Sexually Transmitted Diseases David E. Soper

The Normal Vagina Vaginal Infections Bacterial Vaginosis Trichomonal Vaginitis Vulvovaginal Candidiasis Inflammatory Vaginitis Atrophic Vaginitis Cervicitis Pelvic Inflammatory Disease Other Major Infections Genital Ulcer Disease Genital Warts Human Immunodeficiency Virus Urinary Tract Infection Acute Cystitis Recurrent Cystitis Urethritis Acute Pyelonephritis References

Genitourinary tract infections are among the most frequent disorders for which patients seek care from gynecologists. By understanding the pathophysiology of these diseases and having an effective approach to their diagnosis, physicians can institute appropriate antimicrobial therapy to treat these conditions and reduce long-term sequelae.

The Normal Vagina Normal vaginal secretions are composed of vulvar secretions from sebaceous, sweat, Bartholin, and Skene glands; transudate from the vaginal wall; exfoliated vaginal and cervical cells; cervical mucous; endometrial and oviductal fluids; and microorganisms and their metabolic products. The type and amount of exfoliated cells, cervical mucus, and upper genital tract fluids are determined by biochemical processes that are influenced by hormone levels ( 1). Vaginal secretions may increase in the middle of the menstrual cycle because of an increase in the amount of cervical mucus. These cyclic variations do not occur when oral contraceptives are used and ovulation does not occur. The vaginal desquamative tissue is made up of vaginal epithelial cells that are responsive to varying amounts of estrogen and progesterone. Superficial cells, the predominant cell type in women of reproductive age, predominate when estrogen stimulation is present. Intermediate cells predominate during the luteal phase because of progestogenic stimulation. Parabasal cells predominate in the absence of either hormone, a condition that may be found in postmenopausal women who are not receiving hormonal replacement therapy. The normal vaginal flora is predominantly aerobic, with an average of six different species of bacteria, the most common of which is hydrogen peroxide–producing lactobacilli. The microbiology of the vagina is determined by factors that affect the ability of bacteria to survive ( 2). These factors include vaginal pH and the availability of glucose for bacterial metabolism. The pH of the normal vagina is lower than 4.5, which is maintained by the production of lactic acid. Estrogen-stimulated vaginal epithelial cells are rich in glycogen. Vaginal epithelial cells break down glycogen to monosaccharides, which can then be converted by the cells themselves and lactobacilli to lactic acid. Normal vaginal secretions are floccular in consistency, white in color, and usually located in the dependent portion of the vagina (posterior fornix). Vaginal secretions can be analyzed by a wet-mount preparation. A sample of vaginal secretions is suspended in 0.5~mL of normal saline in a glass tube, transferred to a slide, covered with a slip, and assessed by microscopy. Some clinicians prefer to prepare slides by suspending secretions in saline placed directly on the slide. Secretions should not be placed on the slide without saline because this method causes drying of the vaginal secretions and does not result in a well-suspended preparation. Microscopy of normal vaginal secretions reveals many superficial epithelial cells, few white blood cells (less than 1 per epithelial cell), and few, if any, clue cells. Clue cells are superficial vaginal epithelial cells with adherent bacteria, usually Gardnerella vaginalis, which obliterates the crisp cell border when visualized microscopically. Potassium hydroxide 10% (KOH) may be added to the slide, or a separate preparation can be made, to examine the secretions for evidence of fungal elements. The results are negative in women with normal vaginal microbiology. Gram stain reveals normal superficial epithelial cells and a predominance of gram-positive rods (lactobacilli).

Vaginal Infections Bacterial Vaginosis Bacterial vaginosis (BV) has previously been referred to as nonspecific vaginitis or Gardnella vaginitis. It is an alteration of normal vaginal bacterial flora that results in the loss of hydrogen peroxide–producing lactobacilli and an overgrowth of predominantly anaerobic bacteria ( 3,4). The most common form of vaginitis in the United States is BV (5). Anaerobic bacteria can be found in less than 1% of the flora of normal women. In women with BV, however, the concentration of anaerobes, as well as G. vaginalis and Mycoplasma hominis, is 100 to 1,000 times higher than in normal women. Lactobacilli are usually absent. It is not known what triggers the disturbance of normal vaginal flora. It has been postulated that repeated alkalinization of the vagina, which occurs with frequent sexual intercourse or use of douches, plays a role. After normal hydrogen peroxide–producing lactobacilli disappear, it is difficult to reestablish normal vaginal flora, and recurrence of BV is common. Numerous studies have shown an association of BV with significant adverse sequelae. Women with BV are at increased risk for pelvic inflammatory disease (PID) ( 6), postabortal PID (7), postoperative cuff infections after hysterectomy ( 8), and abnormal cervical cytology ( 9). Pregnant women with BV are at risk for premature rupture of the membranes (10), preterm labor and delivery (10), chorioamnionitis, and postcesarean endometritis ( 11). It is not known whether screening for, and treatment of, BV will decrease the risk for these adverse sequelae.

Diagnosis Bacterial vaginosis is diagnosed on the basis of the following findings ( 12): 1. 2. 3. 4.

A fishy vaginal odor, which is particularly noticeable following coitus, and vaginal discharge are present. Vaginal secretions are gray and thinly coat the vaginal walls. The pH of these secretions is higher than 4.5 (usually 4.7 to 5.7). Microscopy of the vaginal secretions reveals an increased number of clue cells, and leukocytes are conspicuously absent. In advanced cases of BV, more than 20% of the epithelial cells are clue cells. 5. The addition of KOH to the vaginal secretions (the “whiff” test) releases a fishy, amine-like odor. Culture of G. vaginalis is not recommended as a diagnostic tool because of its lack of specificity. Treatment Ideally, treatment of BV should inhibit anaerobes but not vaginal lactobacilli. The following treatments are effective ( 13): 1. Metronidazole, an antibiotic with excellent activity against anaerobes but poor activity against lactobacilli, is the drug of choice for the treatment of BV. A dose of 500 mg administered orally twice a day for 7 days should be used. Patients should be advised to avoid using alcohol during treatment with oral metronidazole and for 24 hours thereafter. 2. Metronidazole gel, 0.75%, one applicator (5 g) intravaginally once or twice daily for 5 days, may also be prescribed. 3. An alternative regimen uses a single, 2-g oral dose of metronidazole. The overall cure rates range from 75% to 84% for the above regimens ( 13). Clindamycin in the following regimens also is effective: 1. Clindamycin cream, 2%, one applicator full (5 g) intravaginally at bedtime for 7 days 2. Clindamycin, 300 mg, orally twice daily for 7 days 3. Clindamycin ovules, 100 mg, intravaginally once at bedtime for 3 days Many clinicians prefer intravaginal treatment because of a lack of systemic side effects such as mild-to-moderate gastrointestinal upset and unpleasant taste. Treatment of the male sexual partner has not been shown to improve therapeutic response and therefore is not recommended.

Trichomonal Vaginitis Trichomonal vaginitis is caused by the sexually transmitted, flagellated parasite, Trichomonas vaginalis. The transmission rate is high; 70% of males contract the disease after a single exposure to an infected female, which suggests that the rate of male-to-female transmission is even higher. The parasite is an anaerobe that has the ability to generate hydrogen to combine with oxygen to create an anaerobic environment. It exists only in trophozoite form. Trichomonal vaginitis often accompanies BV, which can be diagnosed in up to 60% of patients with trichomonal vaginitis. Diagnosis Local immune factors and inoculum size influence the appearance of symptoms. Symptoms and signs may be much milder in patients with a smaller inoculum of trichomonads, and trichomonal vaginitis often is asymptomatic ( 14,15). 1. 2. 3. 4. 5. 6. 7.

Trichomonal vaginitis is associated with a profuse, purulent, malodorous vaginal discharge that may be accompanied by vulvar pruritus. Vaginal secretions may exude from the vagina. In patients with high concentrations of organisms, a patchy vaginal erythema and colpitis macularis (“strawberry” cervix) may be observed. The pH of the vaginal secretions is usually higher than 5.0. Microscopy of the secretions reveals motile trichomonads and increased numbers of leukocytes. Clue cells may be present because of the common association with BV. The whiff test may also be positive.

Morbidity associated with trichomonal vaginitis may be related to BV. Patients with trichomonal vaginitis are at increased risk for postoperative cuff cellulitis following hysterectomy (8). Pregnant women with trichomonal vaginitis are at increased risk for premature rupture of the membranes and preterm delivery. Because of the sexually transmitted nature of trichomonal vaginitis, women with this infection should be tested for other sexually transmitted diseases (STDs), particularly Neisseria gonorrhoeae and Chlamydia trachomatis. Serologic testing for syphilis and human immunodeficiency virus (HIV) infection should also be considered. Treatment The treatment of trichomonal vaginitis can be summarized as follows: 1. Metronidazole is the drug of choice for treatment of vaginal trichomoniasis. Both a single-dose (2 g orally) and a multidose (500 mg twice daily for 7 days) regimen are highly effective and have cure rates of about 95%. 2. The sexual partner should also be treated. 3. Metronidazole gel, although highly effective for the treatment of BV, should not be used for the treatment of vaginal trichomoniasis. 4. Women who do not respond to initial therapy should be treated again with metronidazole, 500 mg, twice daily for 7 days. If repeated treatment is not effective, the patient should be treated with a single 2-g dose of metronidazole once daily for 3 to 5 days. 5. Patients who do not respond to repeated treatment with metronidazole and for whom the possibility of reinfection has been excluded should be referred for expert consultation. In these uncommon refractory cases, an important part of management is to obtain cultures of the parasite to determine its susceptibility to metronidazole.

Vulvovaginal Candidiasis It is estimated that as many as 75% of women experience at least one episode of vulvovaginal candidiasis (VVC) during their lifetimes ( 16). Almost 45% of women will experience two or more episodes (17). Fortunately, few are plagued with a chronic, recurrent infection. Candida albicans is responsible for 85% to 90% of vaginal yeast infections. Other species of Candida, such as C. glabrata and C. tropicalis, can cause vulvovaginal symptoms and tend to be resistant to therapy. Candida are dimorphic fungi existing as blastospores, which are responsible for transmission and asymptomatic colonization, and as mycelia, which result from blastospore germination and enhance colonization and facilitate tissue invasion. The extensive areas of pruritus and inflammation often associated with minimal invasion of the lower genital tract epithelial cells suggest that an extracellular toxin or enzyme may play a role in the pathogenesis of this disease. A hypersensitivity phenomenon also may be responsible for the irritative symptoms associated with VVC, especially for patients with chronic, recurrent disease. Patients with symptomatic disease usually have an increased concentration of these microorganisms (15% within 12 to 24 hours. A borderline fall may represent interassay variability. A repeat level should be obtained in 24 to 48 hours to confirm the decline. If the uterus is evacuated and the pregnancy is extrauterine, the hCG level plateaus or continues to increase, indicating the presence of extrauterine trophoblastic tissue. Culdocentesis Culdocentesis has been used widely as a diagnostic technique for ectopic pregnancy. With the use of hCG testing and transvaginal ultrasound, however, culdocentesis is rarely indicated. The purpose of the procedure is to determine the presence of nonclotting blood, which increases the likelihood of ruptured ectopic pregnancy. After exposing the posterior vaginal fornix with a bivalve vaginal speculum, the posterior lip of the cervix is grasped with a tenaculum. The cul-de-sac is then entered through the posterior vaginal wall with an 18- to 20-gauge spinal needle with a syringe attached. As the cul-de-sac is entered, suction is applied, and the intraperitoneal contents are aspirated. If nonclotting blood is obtained, the results are positive. In the presence of serous fluid, results are negative. A lack of fluid return or clotted blood is nondiagnostic. Historically, if the culdocentesis results were positive, laparotomy was performed for a presumed diagnosis of ruptured tubal pregnancy. However, the results of culdocentesis do not always correlate with the status of the pregnancy. Although about 70% to 90% of patients with ectopic pregnancy have a hemoperitoneum demonstrated by culdocentesis, only 50% of patients have a ruptured tube ( 131). Furthermore, about 6% of women with positive culdocentesis results do not have an ectopic gestation at the time of laparotomy. Nondiagnostic taps occur in 10% to 20% of patients with ectopic pregnancy and, therefore, are not definitive. Laparoscopy Laparoscopy is the gold standard for the diagnosis of ectopic pregnancy. Generally, the fallopian tubes are easily visualized and evaluated, although the diagnosis of ectopic pregnancy is missed in 3% to 4% of patients who have very small ectopic gestations. The ectopic gestation is usually seen distorting the normal tubal architecture. With earlier diagnosis, there is an increasing possibility that a small ectopic pregnancy may not be visualized. Pelvic adhesions or previous tubal damage may compromise assessment of the tube. False-positive results occur when tubal dilation or discoloration is misinterpreted as an ectopic pregnancy, in which case the tube can be incised unnecessarily and damaged. Diagnostic Algorithm The presenting symptoms and physical findings of patients with an unruptured ectopic pregnancy are similar to those of patients with a normal intrauterine pregnancy (89). History, risk factor assessment, and physical examination are the initial steps in the management of suspected ectopic pregnancy. Patients in a hemodynamically unstable condition should undergo immediate surgical intervention. Patients with a stable, relatively asymptomatic condition may be assessed as outpatients. If the diagnosis of ectopic pregnancy can be confirmed without laparoscopy, several potential benefits result. First, both the anesthetic and surgical risks of laparoscopy are avoided; second, medical therapy becomes a treatment option. Because many ectopic pregnancies occur in histologically normal tubes, resolution without surgery may spare the tube from additional trauma and improve subsequent fertility. An algorithm for the diagnosis of ectopic pregnancy without laparoscopy proved to be 100% accurate in a randomized clinical trial ( 132,133) (Fig. 17.4). This screening algorithm combines the use of history and physical examination, serial hCG levels, serum progesterone levels, vaginal ultrasonography, and dilation and curettage. When hCG levels and transvaginal ultrasonography are available in a timely fashion, serum progesterone screening is not required. Serial hCG levels are used to assess pregnancy viability, correlated with transvaginal ultrasonography findings, and measured serially after a suction curettage.

Figure 17.4 Nonlaparoscopic algorithm for diagnosis of ectopic pregnancy.

In this algorithm, transvaginal ultrasonography is used as follows: 1. The identification of an intrauterine gestational sac or pregnancy effectively excludes the presence of an extrauterine pregnancy. If the patient has a rising hCG level of more than 2,000 mIU/mL, and no intrauterine gestational sac is identified, the patient is considered to have an extrauterine pregnancy and can be treated without further testing. 2. Adnexal cardiac activity, when seen, definitively confirms the diagnosis of ectopic pregnancy. 3. A tubal mass as small as 1 cm can be identified and characterized. Masses greater than 3.5 cm with cardiac activity or larger than 4 cm without cardiac activity should not be treated with medical therapy. Suction curettage is used to differentiate nonviable intrauterine pregnancies from ectopic gestations (less than 50% rise in hCG level over 48 hours, an hCG level of less than 2,000 mIU/mL, and an indeterminate sonogram). Performance of this procedure avoids unnecessary use of methotrexate in patients with abnormal intrauterine pregnancy that can only be diagnosed by evacuating the uterus. An unlikely potential problem with suction curettage is missing either an early nonviable intrauterine pregnancy or combined intrauterine and extrauterine pregnancies.

Treatment Ectopic pregnancy can be treated either medically or surgically. Both methods are effective, and the choice depends on the clinical circumstances, the site of the ectopic pregnancy, and the available resources. Surgical Treatment Operative management is the most widely used treatment for ectopic pregnancy. There has been debate about which surgical procedure is best. Salpingo-oophorectomy was once considered appropriate because it was theorized that this technique would eliminate transperitoneal migration of the ovum or zygote, which was thought to predispose to recurrent ectopic pregnancy ( 134). Ovarian removal results in all ovulations occurring on the side with the remaining normal fallopian tube. Subsequent studies have not confirmed that ipsilateral oophorectomy increases the likelihood of conceiving an intrauterine pregnancy; therefore, this practice is not recommended (135). Salpingectomy Versus Salpingostomy Linear salpingostomy is currently the procedure of choice when the patient has an unruptured ectopic pregnancy and wishes to retain her potential for future fertility. The products of conception are removed through an incision made into the tube on its antimesenteric border. The procedure can be accomplished with either a needle tip cautery, laser, scalpel, or scissors. It can be done by operative laparoscopic techniques or laparotomy. In a study in which patients treated with either salpingectomy or salpingostomy were followed for a period of 3 years to about 12.5 years, there was no difference in pregnancy rates ( 136). A history of infertility is the most significant determinant of future fertility, and such patients are probably served better by salpingectomy to decrease their subsequent chance of a recurrent ectopic pregnancy. Linear salpingostomy is as effective as segmental resection with primary reanastomosis, even for ectopic pregnancies occurring in the isthmic tubal segment, and it is technically less difficult and has a shorter operative time ( 137). Milking the tube to effect a tubal abortion has been advocated; if the pregnancy is fimbrial, this technique may be effective. However, when milking was compared with linear salpingostomy for ampullary ectopic pregnancies, milking was associated with a twofold increase in the recurrent ectopic pregnancy rate ( 138). Laparotomy Versus Laparosocpy Salpingostomy, salpingectomy, or segmental resection can be accomplished by laparoscopy or laparotomy. The approach used depends on the hemodynamic stability of the patient, the size and location of the ectopic mass, and the surgeon's expertise. Laparotomy is indicated when the patient becomes hemodynamically unstable, whereas laparoscopy is reserved for patients who are hemodynamically stable. A ruptured ectopic pregnancy does not necessarily require laparotomy. However, if large blood clots are present or the intraabdominal blood cannot be evacuated in a timely manner, laparotomy should be considered. Cornual or interstitial pregnancies often require laparotomy, although laparoscopic management has been described ( 139). Laparotomy is chosen for the management of most ovarian and abdominal pregnancies. In some cases, the patient may have extensive abdominal or pelvic adhesive disease, making laparoscopy difficult and laparotomy more feasible. Laparoscopy has advantages over laparotomy for management of ectopic pregnancy. In a case-control study of 50 patients comparing the use of laparoscopy and laparotomy for ectopic pregnancy management, hospital stay was significantly shorter (1.3 ± 0.8 versus 3.0 ± 1.1 days), operative time was shorter (78 ± 26 versus 104 ± 27 minutes), and convalescence was shorter (9 ± 8 versus 26 ± 16 days) in the laparoscopy group ( 140). In a randomized study in which 30 patients in each group were compared, patients undergoing laparoscopic management had less estimated blood loss, shorter hospital stay, equivalent tubal pregnancy rates, and similar pregnancy and persistent trophoblast rates ( 141). In another study, patients were assigned during alternate months to undergo laparoscopic management (n = 26) or laparotomy (n = 37) (142). There were no differences in operative time, although patients undergoing laparoscopy had a significant decrease in blood loss, postoperative hospital stay, narcotic requirement, and time to return to normal activity. Laparoscopic management was associated with significant cost savings when compared with laparotomy (more than $5,528 ± $1,586 versus more than $6,793 ± $155). Using a prospective analysis, 105 patients with tubal pregnancy were stratified with regard to age and risk factors and then randomized to undergo either laparoscopic management or laparotomy ( 143). Subsequently, 73 patients underwent second-look laparoscopy to assess the degree of adhesion formation. Patients treated by laparotomy had significantly more adhesions at the surgical site than those treated by laparoscopy, but tubal patency rates were similar. Pregnancy rates were not analyzed. Reproductive Outcome Reproductive outcome after ectopic pregnancy is usually evaluated by determining tubal patency by hysterosalpingography, the subsequent intrauterine pregnancy rate, and the recurrent ectopic pregnancy rate. Pregnancy rates are similar in patients treated by either laparoscopy or laparotomy. Tubal patency on the ipsilateral side after conservative laparoscopic management is about 84%. In a study of 143 patients followed after undergoing laparoscopic procedures for ectopic pregnancy, the overall intrauterine pregnancy rates for laparoscopic salpingostomy (60%) and laparoscopic salpingectomy (54%) were not significantly different ( 144). If the patient had evidence of tubal damage, pregnancy rates (42%) were significantly lower than in those women who did not have tubal damage (79%). In another study, the reproductive outcome of 188 patients followed for a mean of 7.2 years (range, 3 to 15 years) was reported after conservation by laparotomy for ectopic pregnancy ( 145). An intrauterine pregnancy occurred in 83 (70%) patients, with a recurrent ectopic pregnancy rate of 13%, suggesting that reproductive outcome after an ectopic pregnancy treated by laparotomy is similar to that of patients undergoing laparoscopic or medical management. Thus, when compared with medical therapy, surgical management appears to have equal reproductive outcome,

although a prospective randomized trial has not been reported. Medical Treatment The drug most frequently used for medical management of ectopic pregnancy is methotrexate, although other agents have been studied, including potassium chloride (KCl), hyperosmolar glucose, prostaglandins, and RU-486. These agents may be given systemically (intravenously, intramuscularly, or orally) or locally (laparoscopic direct injection, transvaginal ultrasound–directed injection, or retrograde salpingography). Methotrexate Methotrexate is a folic acid analogue that inhibits dehydrofolate reductase and thereby prevents synthesis of DNA. It has been used extensively in the treatment of gestational trophoblastic disease (see Chapter 34). Commonly reported side effects include leukopenia, thrombocytopenia, bone marrow aplasia, ulcerative stomatitis, diarrhea, and hemorrhagic enteritis. Other reported side effects include alopecia, dermatitis, elevated liver enzyme levels, and pneumonitis ( 146). However, no significant side effects have been reported at the low doses used for ectopic pregnancy treatment. Minor side effects have been reported with multiple doses; citrovorum factor reduces the incidence of these side effects and is generally used when prolonged treatment is required. Importantly, long-term follow-up of women treated with methotrexate for gestational trophoblastic disease shows no increase in congenital malformations, spontaneous abortions, or tumors recurring after chemotherapy (147). A smaller total dose of methotrexate is required, and shorter treatment duration is used for treatment of ectopic pregnancy than for gestational trophoplastic disease. Initially, methotrexate was used for the treatment of trophoblastic tissue left in situ after exploration for an abdominal pregnancy (148). In 1982, Tanaka and colleagues treated an unruptured interstitial gestation with a 15-day course of intramuscular methotrexate (149). The use of methotrexate for primary treatment of ectopic pregnancy has been reported in more than 300 patients ( 150,151,152,153,154,155,156,157,158 and 159). A trial of intramuscular methotrexate (1 mg/kg/day) followed by citrovorum factor (0.1 mg/kg/day) on alternate days was given to 100 patients with a success rate of 96% (153,155). This outpatient treatment protocol used methotrexate plus citrovorum factor given only until the hCG level began to decline. Treatment was given until there was at least a 15% decline between two consecutive daily hCG levels. Citrovorum factor is given on the day after the methotrexate is administered, even if no further methotrexate is indicated. Once methotrexate is discontinued, hCG levels are measured weekly until the results are negative. A second course of methotrexate plus citrovorum factor is given only if there is a plateau or rise in the hCG level. Of the 96 patients successfully treated, 17 required only one methotrexate and citrovorum factor dose, and 19 required four doses. Four patients treated with methotrexate failed therapy and required surgical treatment for tubal rupture, and each of these cases differed with respect to ectopic pregnancy size, hCG level, and time of rupture. Of five ectopic pregnancies with cardiac activity, four were successfully treated. No conclusions can be drawn regarding risk factors or predictors of ectopic pregnancy rupture. Single-dose intramuscular methotrexate for ectopic pregnancy treatment was administered to 31 patients with an injection of 50 mg/m 2 without citrovorum factor. Of 30 patients, 29 (96.7%) were successfully treated, and no patients experienced methotrexate-related side effects. Some 200 patients have now been treated using the single-dose protocol outlined in Table 17.3. Compared with the multidose protocol, single-dose methotrexate is less expensive, patient acceptance is greater because less monitoring is required during treatment, the incidence of side effects is decreased, and the treatment results and prospects for future fertility are comparable.

Table 17.3. Single-dose Methotrexate Protocol for Ectopic Pregnancy

Initiating Methotrexate Table 17.4 outlines a checklist that should be followed by the physician before initiating methotrexate. It also lists instructions that are helpful to the patient.

Table 17.4. Initiation of Methotrexate: Physician Checklist and Patient Instructions

Patient Follow-up After intramuscular administration of methotrexate, patients are monitored on an outpatient basis. Patients who report severe pain or pain that is prolonged are evaluated by measuring hematocrit levels and performing transvaginal ultrasonography. The ultrasonography findings during follow-up, although not usually helpful, can be used to provide reassurance that the tube has not ruptured ( 160). Cul-de-sac fluid is very common, and the amount of fluid may increase if a tubal abortion occurs. However, it is usually not necessary to intervene surgically unless the patient has a precipitous drop in hematocrit levels or she becomes hemodynamically unstable. Patients are asked not to become pregnant for at least 2 months after treatment. Hysterosalpingography can be performed, although the procedure is not mandatory. Candidates for Methotrexate In order to maximize the safety of treatment and to eliminate the possibility of treating in the presence of a nonviable or early viable intrauterine pregnancy, patients considered candidates for methotrexate treatment should include those to whom the following factors apply: 1. An hCG level is present after salpingostomy or salpingotomy. 2. A rising or plateaued hCG level is present at least 12 to 24 hours after suction curettage. 3. No intrauterine gestational sac or fluid collection is detected by transvaginal ultrasound, the hCG level is greater than 2,000 mIU/mL, and an ectopic pregnancy mass of at least 3.5 to 4 cm is demonstrated.

Ultrasound findings should be interpreted with caution because most unruptured ectopic pregnancies will be accompanied by fluid in the cul-de-sac. Side Effects Opponents of methotrexate therapy cite potential side effects as the reason not to use it. Most reported side effects have occurred in patients treated with intravenous methotrexate with higher doses and for more prolonged treatment courses than are now required. When using the single-dose intramuscular regimen, the incidence of side effects is less than 1%, and the failure rate is comparable to that of conservative laparoscopic surgery. One problem that remains puzzling is the inability to predict treatment failures with the use of methotrexate. However, the same is true with conservative surgical procedures; thus, the need to monitor hCG levels after either salpingostomy or methotrexate remains. In a review of more than 350 women treated with intramuscular methotrexate, Lipscomb and associates found that a high hCG concentration was the most important factor associated with failure of treatment with a single-dose methotrexate protocol (161). In patients with an hCG level of less than 10,000 mIU/mL, the overall success rate was 93.4%, as compared with 60.7% when the hCG level was greater than 10,000 mIU/mL. Although surgical management of ectopic pregnancy remains the mainstay of treatment worldwide, methotrexate treatment is appropriate in select patient populations. Reproductive Function Although there are few data, reproductive function after methotrexate treatment can be assessed on the basis of tubal patency and pregnancy outcome. Tubal patency is reported to be 50% to 100%, with a mean of 71%, after systemic methotrexate treatment. In two separate reports of 23 and 62 patients, the tubal patency rates on the ipsilateral side were 81.4% and 82.3%, respectively ( 156,162). Pregnancy outcome after methotrexate administration was reported in a group of 14 patients who attempted pregnancy after multiple intramuscular doses. Of these 14 women, 11 (78.6%) became pregnant; 10 of 11 (90.9%) were intrauterine pregnancies, and one (9%) was an extrauterine pregnancy ( 156). The mean time from first attempting to achieving pregnancy was 2.3 months (range, 1 to 4 months). In another study of 49 patients who were attempting pregnancy after completion of single-dose intramuscular methotrexate administration, 39 (80%) became pregnant; 34 (87%) were intrauterine pregnancies, and 5 (13%) were ectopic pregnancies (163). The mean time from attempting to achieving pregnancy was 3.2 ± 1.1 months. In 87 pregnancies after methotrexate therapy, the combined intrauterine pregnancy rate was 86%, and the ectopic pregnancy rate was 14%. In a combined series of 527 patients treated by laparoscopic linear salpingostomy or salpingotomy, the intrauterine pregnancy rate was 54%, and the recurrent ectopic pregnancy rate was 13% (164). Comparison of laparoscopically treated patients with methotrexate-treated patients suggests that the two methods have similar reproductive outcomes. Other Drugs and Techniques Salpingocentesis is a technique in which agents such as KCl, methotrexate, prostaglandins, and hyperosmolar glucose are injected into the ectopic pregnancy transvaginally using ultrasound guidance, by transcervical tubal cannulization, or by laparoscopy. Agents injected under ultrasound guidance have included methotrexate (165,166,167,168 and 169), KCl (170), combined methotrexate and KCl (171), and prostaglandin E2 (172). The potential advantages of salpingocentesis include a one-time injection with the potential avoidance of systemic side effects. Reproductive function after this form of treatment has not been reported. Because of the limited experience, this treatment cannot be recommended until there is further study. Agents injected into the amniotic sac at laparoscopy have included prostaglandin F2a (173), hyperosmolar glucose (174), and methotrexate (175). This method has the obvious disadvantage of requiring laparoscopy, but it can be used if laparoscopy has been performed. Other agents reported for the treatment of ectopic pregnancy include RU-486 (176) and anti-hCG antibody ( 177).

Types of Ectopic Pregnancy Spontaneous Resolution Some ectopic pregnancies resolve by resorption or by tubal abortion, obviating the need for medical or surgical therapy (178,179,180,181 and 182). The proportion of ectopic pregnancies that resolve spontaneously and the reason they do so while others do not are unknown. There are no specific criteria for patient selection that predict successful outcome after spontaneous resolution. A falling hCG level is the most common indicator used, but ectopic pregnancy rupture can occur even with falling hCG levels. Persistent Trophoblastic Tissue Persistent ectopic pregnancy occurs when a patient has undergone conservative surgery (e.g., salpingostomy, fimbrial expression) and viable trophoblastic tissue remains. Histologically, there is no identifiable embryo, the implantation is usually medial to the previous tubal incision, and residual chorionic villi are usually confined to the tubal muscularis. Peritoneal trophoblastic tissue implants may also be responsible for persistence ( 183,184,185,186,187 and 188). The incidence of persistent ectopic pregnancy has increased with the increased use of surgery that conserves the tubes. Persistence is diagnosed when the hCG levels plateau after conservative surgery. Persistent ectopic gestation is best diagnosed by an initial measurement of serum hCG or progesterone 6 days postoperatively and at 3-day intervals thereafter ( 186). Risk factors for persistent ectopic pregnancy are based on the type of surgical procedure, the initial hCG level, the duration of amenorrhea, and the size of the ectopic pregnancy. A slower decline of serum hCG levels has been seen in patients treated by salpingostomy compared with patients treated by salpingectomy. The incidence of persistence after laparoscopic linear salpingostomy ranges from 3% to 20% ( 189,190). It is uncertain whether the incidence of persistent ectopic pregnancy is the same or greater when the procedure is performed by laparoscopy versus laparotomy. In a review of medical records from 157 patients who underwent salpingostomy for intact ampullary ectopic pregnancy, 16 of 103 patients (16%) undergoing laparoscopic salpingostomy were treated for persistent ectopic pregnancy, whereas 1 of 54 women (2%) who had salpingostomy by laparotomy was treated for persistent ectopic pregnancy ( 185). Lundorff and colleagues reported that 23% of women with a preoperative hCG level of less than 3,000 mIU/mL developed persistent ectopic pregnancy, whereas only 1 of 67 with a level of more than 3,000 mIU/mL persisted (187). They also noted that 36% of women with an hCG level of more than 1,000 mIU/mL on the second postoperative day and 64% of patients with an hCG level of more than 1,000 mIU/mL on the seventh postoperative day developed persistence. Amenorrhea of less than 7 weeks' duration and ectopic mass smaller than 2 cm have also been reported to increase the risk for persistent ectopic pregnancy ( 185,187). Treatment of persistent ectopic pregnancy can be either surgical or medical; surgical therapy consists of either repeat salpingostomy or, more commonly, salpingectomy. Methotrexate offers an alternative to patients who are hemodynamically stable at the time of diagnosis. Methotrexate may be the treatment of choice because the persistent trophoblastic tissue may not be confined to the tube and, therefore, not readily identifiable during repeat surgical exploration ( 190,191 and 192). Chronic Ectopic Pregnancy Chronic ectopic pregnancy is a condition in which the pregnancy does not completely resorb during expectant management. The condition arises when there is persistence of the chorionic villi with bleeding into the tubal wall, which is distended slowly and does not rupture. It may also arise from chronic bleeding from the fimbriated end of the fallopian tube with subsequent tamponade. In a series of 50 patients with a chronic ectopic pregnancy, pain was present in 86%, vaginal bleeding was present in 68%, and both symptoms were present in 58% ( 193). Ninety percent of the patients had amenorrhea ranging from 5 to 16 weeks (mean, 9.6 weeks). Most patients develop a pelvic mass that is usually symptomatic. The hCG level is usually low but may be absent; ultrasound may be helpful in the diagnosis; and rarely, bowel involvement or ureteral compression or obstruction exists ( 193,194). This condition is treated surgically with removal of the affected tube. Often, the ovary must be removed because there is inflammation with subsequent adhesion development. A hematoma may be present secondary to chronic bleeding. Nontubal Ectopic Pregnancy

Cervical Pregnancy The incidence of cervical pregnancy in the United States ranges from 1 in 2,400 to 1 in 50,000 pregnancies ( 195). A variety of conditions are thought to predispose to the development of a cervical pregnancy, including previous therapeutic abortion, Asherman's syndrome, previous cesarean delivery, diethylstilbestrol exposure, leiomyomas, and IVF (195,196 and 197). The diagnostic criteria for cervical pregnancy were established based on histologic analysis of a hysterectomy specimen ( 195). Clinical criteria include the following findings (197): 1. 2. 3. 4.

The uterus is smaller than the surrounding distended cervix. The internal os is not dilated. Curettage of the endometrial cavity is nonproductive of placental tissue. The external os opens earlier than in spontaneous abortion.

Ultrasonographic diagnostic criteria have also been described that are helpful in differentiating a true cervical pregnancy from an ongoing spontaneous abortion (Table 17.5). Magnetic resonance imaging of the pelvis has also been used in this situation ( 198). Other potential diagnoses that must be differentiated from cervical pregnancy include cervical carcinoma, cervical or prolapsed submucous leiomyomas, trophoblastic tumor, placenta previa, and low-lying placenta.

Table 17.5. Ultrasound Criteria for Cervical Pregnancy

When a cervical pregnancy is diagnosed before surgery, the preoperative preparation should include blood typing and cross-matching, establishment of intravenous access, and detailed informed consent. This consent should include the possibility of hemorrhage that may require transfusion or hysterectomy. Nonsurgical treatment, including intraamniotic and systemic methotrexate administration, has been used successfully ( 199,200). The diagnosis may not be suspected until the patient is undergoing suction curettage for a presumed incomplete abortion and hemorrhage occurs. In some cases, bleeding is light, whereas in others, there is hemorrhage. Various techniques that can be used to control bleeding include uterine packing, lateral cervical suture placement to ligate the lateral cervical vessels, placement of a cerclage, and insertion of an intracervical 30-mL Foley catheter in an attempt to tamponade the bleeding. Alternatively, angiographic artery embolization can be used; or, if laparotomy is required, an attempt can be made to ligate the uterine or internal iliac arteries (201,202 and 203). When none of these methods is successful, hysterectomy is required. Ovarian Pregnancy A pregnancy confined to the ovary represents 0.5% to 1% of all ectopic pregnancies and is the most common type of nontubal ectopic pregnancy. The incidence ranges from 1 in 40,000 to 1 in 7,000 deliveries ( 204,205). The diagnostic criteria were described in 1878 by Spiegelberg ( Table 17.6). Unlike tubal gestation, ovarian pregnancy is associated with neither PID nor infertility. The only risk factor associated with the development of an ovarian pregnancy is the current use of an intrauterine device.

Table 17.6. Criteria for Ovarian Pregnancy Diagnosis

Patients have symptoms similar to those of ectopic pregnancies in other sites. Misdiagnosis is common because it is confused with a ruptured corpus luteum in up to 75% of cases (204). As with other types of ectopic pregnancy, an ovarian pregnancy has also been reported after hysterectomy ( 206). Ultrasonography has made preoperative diagnosis possible in some cases ( 207). The treatment of ovarian pregnancy has changed. Whereas oophorectomy has been advocated in the past, ovarian cystectomy has become the preferred treatment (208). It is possible to perform cystectomy using laparoscopic techniques ( 209,210). Treatment with methotrexate or prostaglandin injection has also been reported (210). Abdominal Pregnancy Abdominal pregnancies are classified as primary and secondary. Table 17.7 lists criteria for classifying a primary abdominal pregnancy. Secondary abdominal pregnancies are by far the most common and result from tubal abortion or rupture or, less often, from subsequent implantation within the abdomen after uterine rupture. The incidence of abdominal pregnancy varies from 1 in 372 to 1 in 9,714 live births ( 211). Abdominal pregnancy is associated with high morbidity and mortality, with the risk for death 7 to 8 times greater than from tubal ectopic pregnancy and 90 times greater than from intrauterine pregnancy. There are scattered reports of term abdominal pregnancies. When this occurs, perinatal morbidity and mortality are high, usually as a result of growth restriction and congenital anomalies such as fetal pulmonary hypoplasia, pressure deformities, and facial and limb asymmetry. The incidence of congenital anomalies ranges from 20% to 40% (212).

Table 17.7. Studdiford's Criteria for Diagnosis of Primary Abdominal Pregnancy

The presentation of patients with an abdominal pregnancy varies and depends on the gestational age. In the first and early second trimester, the symptoms may be the same as with tubal ectopic gestation; in advanced abdominal pregnancy, the clinical presentation is more variable. The patient may complain of painful fetal movement, fetal movements high in the abdomen, or sudden cessation of movements. Physical examination may disclose persistent abnormal fetal lies, abdominal tenderness, a displaced uterine cervix, easy palpation of fetal parts, and palpation of the uterus separate from the gestation. The diagnosis may be suspected when there are no uterine contractions after oxytocin infusion. Other diagnostic aids include abdominal x-ray, abdominal ultrasound, computed tomography scanning, and magnetic resonance imaging (213,214). Because the pregnancy can continue to term, the potential maternal morbidity and mortality are very high. As a result, surgical intervention is recommended when an abdominal pregnancy is diagnosed. At surgery, the placenta can be removed if its vascular supply can be identified and ligated, but hemorrhage can occur, requiring abdominal packing that is left in place and removed after 24 to 48 hours. Angiographic arterial embolization has been described ( 215). If the vascular supply cannot be identified, the cord is ligated near the placental base, and the placenta is left in place. Placental involution can be monitored using serial ultrasonography and hCG levels. Potential complications of leaving the placenta in place include bowel obstruction, fistula formation, and sepsis as the tissue degenerates. Methotrexate treatment appears to be contraindicated because a high rate of complications has been reported, including sepsis and death, believed to be a result of rapid tissue necrosis (216). Interstitial Pregnancy Interstitial pregnancies represent about 1% of ectopic pregnancies. These patients tend to present later in gestation than those with tubal pregnancies. Interstitial pregnancies often are associated with uterine rupture; therefore, they represent a disproportionately large percentage of fatalities from ectopic pregnancy. Treatment is cornual resection by laparotomy, although laparoscopic management has also been described ( 217). Interligamentous Pregnancy Interligamentous pregnancy is a rare form of ectopic pregnancy that occurs in about 1 in every 300 ectopic pregnancies ( 218). An interligamentous pregnancy usually results from trophoblastic penetration of a tubal pregnancy through the tubal serosa and into the mesosalpinx, with secondary implantation between the leaves of the broad ligament. It can also occur if a uterine fistula develops between the endometrial cavity and the retroperitoneal space. As with an abdominal pregnancy, the placenta may be adherent to the uterus, bladder, and pelvic sidewalls. If possible, the placenta should be removed; when this is not possible, it can be left in situ and allowed to resorb. As in abdominal pregnancy, there are reported cases of live birth with this type ectopic gestation ( 218). Heterotropic Pregnancy Heterotropic pregnancy occurs when there are coexisting intrauterine and ectopic pregnancies. The reported incidence varies widely from 1 in 100 to 1 in 30,000 pregnancies ( 219). Patients who have undergone ovulation induction have a much higher incidence of heterotropic pregnancy than those who have a spontaneous conception. An intrauterine pregnancy is seen during ultrasound examination, and an extrauterine pregnancy may be overlooked easily. Serial hCG levels are often not helpful because the intrauterine pregnancy causes the hCG level to rise appropriately. The treatment of the ectopic pregnancy is operative; once the ectopic pregnancy has been removed, intrauterine pregnancy continues in most patients. It may be possible to use nonchemotherapeutic medical treatment such as KCl by transvaginal or laparoscopically directed injection for treatment of the ectopic pregnancy. Multiple Ectopic Pregnancies Twin or multiple ectopic gestations occur less frequently than heterotropic gestations and may appear in a variety of locations and combinations. About 250 twin ectopic gestations have been reported ( 220). Although most reports are confined to twin tubal gestations, ovarian, interstitial, and abdominal twin pregnancies have been reported. Twin and triplet gestations have been reported following partial salpingectomy ( 221) and IVF (222). Management is similar to that for other types of ectopic pregnancy and is somewhat dependent on the location of the pregnancy. Pregnancy After Hysterectomy The most unusual form of ectopic pregnancy is one that occurs after either vaginal or abdominal hysterectomy ( 223,224). Such a pregnancy may occur after supracervical hysterectomy because the patient has a cervical canal that may provide intraperitoneal access. Pregnancy may occur in the perioperative period with implantation of the fertilized ovum in the fallopian tube. Pregnancy after total hysterectomy probably occurs secondary to a vaginal mucosal defect that allows sperm into the abdominal cavity.

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Fertility after ectopic pregnancy. Fertil Steril 1993;60:231–235. Timonen S, Nieminen U. Tubal pregnancy: choice of operative methods of treatment. Acta Obstet Gynecol Scand 1967;46:327–339. Smith HO, Toledo AA, Thompson JD. Conservative surgical management of isthmic ectopic pregnancies. Am J Obstet Gynecol 1987;157:604–610. Hill GA, Segars JH Jr, Herbert CM III. Laparoscopic management of interstitial pregnancy. J Gynecol Surg 1989;5:209–212. Brumsted J, Kessler C, Gibson C, et al. A comparison of laparoscopy and laparotomy for the treatment of ectopic pregnancy. Obstet Gynecol 1988;71:889–892. Vermesh M, Silva PD, Rosen GF, et al. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73:400–404. Murphy AA, Nager CW, Wujek JJ, et al. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Fertil Steril 1992;57:1180–1185. Lundorff P, Hahlin M, Kallfelt B, et al. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertil Steril 1991;55:911–915. Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993;81:710–715. Langer R, Raziel A, Ron-El R, et al. Reproductive outcome after conservative surgery for unruptured tubal pregnancies—a 15-year experience. Fertil Steril 1990;53:227–231. Berkowitz RS, Goldstein DP, Jones MA, et al. Methotrexate with citrovorum factor rescue: reduced chemotherapy toxicity in the management of gestational trophoblastic neoplasms. Cancer 1980;45:423–426. Rustin GJS, Rustin F, Dent J, et al. No increase in second tumors after cytotoxic chemotherapy for gestational trophoblastic tumors. N Engl J Med 1983;308:473–476. St. Clair JT, Whealer DA, Fish SA. Methotrexate in abdominal pregnancy. JAMA 1969;208:529–531. Tanaka T, Hayashi H, Kutsuzawa T, et al. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982;37:851–852. Ory SJ, Villanueva AL, Sand PK, et al. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986;154:1299–1306. Ichinoe K, Wake N, Shinkai N, et al. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies. Am J Obstet Gynecol 1987;156:484–487. Sauer MV, Gorrill MJ, Rodi IA, et al. Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial. Fertil Steril 1987;48:752–755. Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51:435–438. Stovall TG, Ling FW, Gray LA, et al. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol 1991;77:749–753. Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77:754–757. Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993;170:1840–1841. Hoppe D, Bekkar BE, Nager CW. Single-dose system methotrexate for the treatment of persistent ectopic pregnancy after conservative surgery. Obstet Gynecol 1994;83:51–54. Schafer D, Kryss J, Pfuhl JP, et al. Systemic treatment of ectopic pregnancy with single-dose methotrexate. J Am Assoc Gynecol Laparosc 1994;1:213–218. Henry MA, Gentry WL. Single injection of methotrexate for treatment of ectopic pregnancies. Am J Obstet Gynecol 1994;171:1584–1587. Brown DL, Felker RE, Stovall TG, et al. Serial endovaginal sonography of ectopic pregnancies treated with methotrexate. Obstet Gynecol 1991;77:406–409. Lipscomb GH, McCord ML, Stovall TG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–1978. Kooi S, Kick HCLV. Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients. Fertil Steril 1990;54:580–584. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol 1990;162:1620–1624. Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1990;53:382–387. Menard A, Crequat J, Mandelbrot L, et al. Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil Steril 1990;54:47–50. Shalev E, Peleg D, Bustan M, et al. Limited role for intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1995;63:20–24. Tulandi T, Atri M, Bret P, et al. Transvaginal intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1992;58:98–100. Fernandez H, Benifla JL, Lelaidier C, et al. Methotrexate treatment of ectopic pregnancy: 100 cases treated by primary transvaginal injection under sonographic control. Fertil Steril 1993;59:773–777. Fernandez H, Pauthier S, Daimerc S, et al. Ultrasound-guided injection of methotrexate versus laparoscopic salpingotomy in ectopic pregnancy. Fertil Steril 1995;63:25–29. Oelsner G, Admon D, Shalev E, et al. A new approach for the treatment of interstitial pregnancy. Fertil Steril 1993;59:924–925. Aboulghar MA, Mansour RT, Serour GI. Transvaginal injection of potassium chloride and methotrexate for the treatment of tubal pregnancy with a live fetus. Hum Reprod 1990;5:887–888. Feichtinger W, Kemeter P. Treatment of unruptured ectopic pregnancy by needling of sac and injection of methotrexate or PGE 2 under transvaginal sonography control. Arch Gynecol Obstet 1989;246:85–89. Hagstrom HG, Hahlin M, Sjöblom P, et al. Prediction of persistent trophoblastic activity after local prostaglandin F 2a injection for ectopic pregnancy. Hum Reprod 1994;9:1170–1174. Laatikainen T, Tuomivaara L, Kauppila K. Comparison of a local injection of hyperosmolar glucose solution with salpingostomy for the conservative treatment of tubal pregnancy. Fertil Steril 1993;60:80–84. Kojima E, Abe Y, Morita M, et al. The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control. Obstet Gynecol 1990;75:723–725. Kenigsberg D, Porte J, Hull M, et al. Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 1987;47:702–703. Frydman R, Fernandez H, Troalen F, et al. Phase I clinical trial of monoclonal anti-human chorionic gonadotropin antibody in women with an ectopic pregnancy. Fertil Steril 1989;52:734–738. Garcia AJ, Aubert JM, Sama J, et al. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987;48:395–400. Carson SA, Stovall TG, Ling FW, et al. Low human chorionic somatomammotropin fails to predict spontaneous resolution of unruptured ectopic pregnancies. Fertil Steril 1991;55:629–630. Fernandez H, Rainhorn JD, Papiernik E, et al. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988;71:171–174. Gretz E, Quagliarello J. Declining serum concentrations of the beta-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940–941. Makinen JI, Kivijarvi AK, Irjala KMA. Success of non-surgical management of ectopic pregnancy. Lancet 1990;335:1099. Seifer DB, Gutmann JN, Doyle MB, et al. Persistent ectopic pregnancy following laparoscopic linear salpingostomy. Obstet Gynecol 1990;76:1121–1125. Pouly JL, Mahnes H, Mage G, et al. Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steril 1986;46:1093–1097. Seifer DB, Gutmann JN, Grant WD, et al. Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic pregnancy. Obstet Gynecol 1993;81:378–382. Vermesh M, Silva PD, Sauer MV, et al. Persistent tubal ectopic gestation: patterns of circulating beta-human chorionic gonadotropin and progesterone, and management options. Fertil Steril 1988;50:584–588. Lundorff P, Hahlin M, Sjoblom P, et al. Persistent trophoblast after conservative treatment of tubal pregnancy: prediction and detection. Obstet Gynecol 1991;77:129–133. Cartwright PS. Peritoneal trophoblastic implants after surgical management of tubal pregnancy. J Reprod Med 1991;36:523–524. Foulot H, Chapron C, Morice PH, et al. Failure of laparoscopic treatment for peritoneal trophoblastic implants. Hum Reprod 1994;9:92–93. Higgins KA, Schwartz MB. Treatment of persistent trophoblastic tissue after salpingostomy with methotrexate. Fertil Steril 1986;45:427–428. Rose PG, Cohen SM. Methotrexate therapy for persistent ectopic pregnancy after conservative laparoscopic management. Obstet Gynecol 1990;76:947–949. Bengtsson G, Bryman I, Thorburn J, et al. Low-dose oral methotrexate as second-line therapy for persistent trophoblast after conservative treatment of ectopic pregnancy. Obstet Gynecol 1992;79:589–591. Cole T, Corlett RC Jr. Chronic ectopic pregnancy. Obstet Gynecol 1982;59:63–68. Rogers WF, Shaub M, Wilson R. Chronic ectopic pregnancy: ultrasonic diagnosis. J Clin Ultrasound 1977;5:257–260. Parente JT, Ou CS, Levy J, et al. Cervical pregnancy analysis: a review and report of five cases. Obstet Gynecol 1983;62:79–82. Weyerman PC, Verhoeven ATM, Alberda AT. Cervical pregnancy after in vitro fertilization and embryo transfer. Am J Obstet Gynecol 1989;161:1145–1164. Hofmann HMH, Urdl W, Hofler H, et al. Cervical pregnancy: case reports and current concepts in diagnosis and treatment. Arch Gynecol Obstet 1987;241:63–69. Bader-Armstrong B, Shah Y, Rubens D. Use of ultrasound and magnetic resonance imaging in the diagnosis of cervical pregnancy. J Clin Ultrasound 1989;17:283–286. Stovall TG, Ling FW, Smith WC, et al. Successful nonsurgical treatment of cervical pregnancy with methotrexate. Fertil Steril 1988;50:672–674. Oyer R, Tarakjian D, Lev-Toaff A, et al. Treatment of cervical pregnancy with methotrexate. Obstet Gynecol 1988;71:469–471. Bernstein D, Holzinger M, Ovadia J, et al. Conservative treatment of cervical pregnancy. Obstet Gynecol 1981;58:741–742. Wharton KR, Gore B. Cervical pregnancy managed by placement of a Shirodkar cerclage before evacuation: a case report. J Reprod Med 1988;33:227–229. Nolan TE, Chandler PE, Hess LW, et al. Cervical pregnancy managed without hysterectomy: a case report. J Reprod Med 1989;34:241–243. Hallatt JG. Primary ovarian pregnancy: a report of twenty-five cases. Am J Obstet Gynecol 1982;143:55–60. Grimes HG, Nosal RA, Gallagher JC. Ovarian pregnancy: a series of 24 cases. Obstet Gynecol 1983;61:174–180. Malinger G, Achiron R, Treschan O, et al. Case report: ovarian pregnancy-ultrasonographic diagnosis. Acta Obstet Gynecol Scand 1988;67:561–563. DeVries K, Atad J, Arodi J, et al. Primary ovarian pregnancy: a conservative surgical approach by wedge resection. Int J Fertil 1981;26:293–294. Van Coevering RJ, Fisher JE. Laparoscopic management of ovarian pregnancy: a case report. J Reprod Med 1988;33:774–776. Russell JB, Cutler LR. Transvaginal ultrasonographic detection of primary ovarian pregnancy with laparoscopic removal: a case report. Fertil Steril 1989;51:1055–1056. Koike H, Chuganji Y, Watanabe H, et al. Conservative treatment of ovarian pregnancy by local prostaglandin F 2a injection [Letter]. Am J Obstet Gynecol 1990;163:696. Atrash HK, Friede A, Hogue CJR. Abdominal pregnancy in the United States: frequency and maternal mortality. Obstet Gynecol 1987;69:333–337. Rahman MS, Al-Suleiman SA, Rahman J, et al. Advanced abdominal pregnancy-observations in 10 cases. Obstet Gynecol 1982;59:366–372. Stanley JH, Horger EO III, Fagan CJ, et al. Sonographic findings in abdominal pregnancy. AJR Am J Roentgenol 1986;147:1043–1046. Harris MB, Angtuaco T, Frazer CN, et al. Diagnosis of a viable abdominal pregnancy by magnetic resonance imaging. Am J Obstet Gynecol 1988;159:150–151. Martin JN Jr, Ridgway LE III, Connors JJ, et al. Angiographic arterial embolization and computed tomography-directed drainage for the management of hemorrhage and infection with abdominal pregnancy. Obstet Gynecol 1990;76:941–945. Martin JN Jr, Sessums JK, Martin RW, et al. Abdominal pregnancy: current concepts of management. Obstet Gynecol 1988;71:549–557. Pasic R, Wolfe WM. Laparoscopic diagnosis and treatment of interstitial ectopic pregnancy: a case report. Am J Obstet Gynecol 1990;163:587–588. Vierhout ME, Wallenburg HCS. Intraligamentary pregnancy resulting in a live infant. Am J Obstet Gynecol 1985;152:878–879. Reece EA, Petrie RH, Sirmans MF, et al. Combined intrauterine and extrauterine gestations: a review. Am J Obstet Gynecol 1983;146:323–330. Olsen ME. Bilateral twin ectopic gestations with intraligamentous and interstitial components: a case report. J Reprod Med 1994;39:118–120. Adair CD, Benrubi GI, Sanchez-Ramos L, et al. Bilateral tubal ectopic pregnancies after bilateral partial salpingectomy: a case report. J Reprod Med 1994;39:131–133. Goffner L, Bluth MJ, Fruauff A, et al. Ectopic gestation associated with intrauterine triplet pregnancy after in vitro fertilization. J Ultrasound Med 1993;12:63–64. Jackson P, Barrowclough IW, France JT, et al. A successful pregnancy following total hysterectomy. Br J Obstet Gynaecol 1980;87:353–355. Nehra PC, Loginsky SJ. Pregnancy after vaginal hysterectomy. Obstet Gynecol 1984;64:735–737. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 18. Benign Breast Disease Novak’s Gynecology

Chapter 18

Benign Breast Disease Baiba J. Grube Armando E. Giuliano

Detection History Physical Examination Breast Self-examination Breast Imaging Breast Biopsy Benign Breast Conditions Fibrocystic Change Benign Tumors Breast Conditions Requiring Evaluation Nipple Discharge Erosive Adenomatosis of the Nipple Fat Necrosis Breast Abscess Disorders of Breast Augmentation References

Diagnosis and management of common benign breast conditions, particularly those that mimic malignancy, and an appreciation of treatment options are essential for the practicing gynecologist ( 1). Benign breast disease is a complex entity of its own with a range of physiologic changes and clinical manifestations that have an impact on a woman's health independent of breast cancer risk ( 2).

Detection History Evaluation of a new breast complaint begins with symptom assessment by a thorough clinical history ( 3). The history should include questions regarding current symptoms, duration of the condition, fluctuation of the signs and symptoms, and factors that aggravate or relieve the complaint. Specific questions should address the following points: Nipple discharge Characteristics of discharge (appearance, spontaneous or nonspontaneous, unilateral or bilateral, single or multiple duct involvement) Breast mass (size and change in size, density, or texture) Breast pain (cyclic versus continuous) Association of symptoms with menstrual cycle Change in breast shape, size, or texture Previous breast biopsies. The patient should be questioned about risk factors: Age of menarche Age of first pregnancy Age of menopause Family history of breast cancer Number of first-degree relatives with breast cancer and their ages when diagnosed Other malignancies (ovary, colon, and prostate) Pathology of previous breast biopsy. It is important to obtain a thorough list of medications taken, including hormone therapy and herbal medications such as phytoestrogens. The gestational history should take into consideration the possibility of a current pregnancy. A personal history of exposure to radiation, especially in the treatment of childhood malignancies, is associated with a higher incidence of developing breast cancer ( 4). The goal of breast evaluation is to determine clearly if the complaint represents a benign breast condition or is suggestive of a neoplastic process.

Physical Examination Breast tumors, particularly cancerous ones, usually are asymptomatic and are discovered only by physical examination or screening mammography. Typically, the breast changes slightly during the menstrual cycle. During the premenstrual phase, most women have increased innocuous nodularity and mild engorgement of the breast. Rarely, this can obscure an underlying lesion and make examination difficult. Findings should be carefully documented in the medical record to serve as a baseline for future reference. Inspection Inspection is done initially while the patient is seated comfortably with her arms relaxed at her sides. The breasts are compared for symmetry, contour, and skin appearance. Edema or erythema is identified easily, and skin dimpling or nipple retraction is shown by having the patient raise her arms above her head and then press her hands on her hips, thereby contracting the pectoralis muscles ( Fig. 18.1). Palpable and even nonpalpable tumors that distort Cooper's ligaments may lead to skin dimpling with these maneuvers.

Figure 18.1 Raising the arm reveals retraction of the skin of the lower outer quadrant caused by a small palpable carcinoma. (From Giuliano AE. Breast disease. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology, 3rd ed. Baltimore: Lippincott Williams & Wilkins, 2000:640, with permission.)

Palpation While the patient is seated, each breast should be palpated methodically. Some physicians recommend palpating the breast in long strips, but the exact palpation technique used is probably not as important as the thoroughness of its application over the entire breast. One very effective method is to palpate the breast in enlarging concentric circles until the entire breast has been covered. A pendulous breast can be palpated by placing one hand between the breast and the chest wall and gently palpating the breast between both examining hands. The axillary and supraclavicular areas should be palpated for enlarged lymph nodes. The entire axilla, the upper outer quadrant of the breast, and the axillary tail of Spence are palpated for possible masses. While the patient is supine with one arm over her head, the ipsilateral breast is again methodically palpated from the clavicle to the costal margin. If the breast is large, a pillow or towel should be placed beneath the scapula to elevate the side being examined; otherwise the breast tends to fall to the side, making palpation of the lateral hemisphere more difficult. The major features to be identified on palpation of the breast are temperature, texture and thickness of skin, generalized or focal tenderness, nodularity, density, asymmetry, dominant masses, and nipple discharge. Most premenopausal patients have normally nodular breast parenchyma. The nodularity is diffuse but predominantly in the upper outer quadrants where there is more breast tissue. These benign parenchymal nodules are small, similar in size, and indistinct. By comparison, breast cancer is usually a nontender, firm mass with irregular margins. This mass feels distinctly different from the surrounding nodularity. A malignant mass may be fixed to the skin or to the underlying fascia. A suspicious mass is usually unilateral. Similar findings in both breasts are unlikely to represent malignant disease (5).

Breast Self-examination Breast self-examination (BSE) increases early detection of cancer and may improve the survival of patients with breast carcinoma ( 6,7 and 8). In fact, most breast cancers are detected first by the patient rather than by the physician. Although young women have a low incidence of breast cancer, it is important to teach self-examination early so that it becomes habitual. Organizations such as the American Cancer Society sponsor courses in BSE. Reassurance, support, and patient education may encourage women to overcome psychological barriers to routine BSE ( 9). One study evaluated three different methods of instruction to determine compliance with BSE (10). The first arm evaluated the impact of physician message alone, the second arm assessed physician message in conjunction with a BSE class, and the third arm added follow-up reinforcement by phone or postcard to physician message and BSE class. The third produced the highest percentage of women doing BSE and is the ideal method of engaging patients to perform BSE. The woman should inspect her breasts while standing or sitting before a mirror, looking for any asymmetry, skin dimpling, or nipple retraction. Elevating her arms over her head or pressing her hands against her hips to contract the pectoralis muscles will highlight any skin dimpling. While standing or sitting, she should carefully palpate her breasts with the fingers of the opposite hand. This may be performed while showering, because soap and water may increase the sensitivity of palpation. Finally, she should lie down and again palpate each quadrant of the breast, as well as the axilla. Premenopausal women should examine their breasts monthly during the week after menses. It is helpful for all women to examine their breasts at the same time each month to develop a routine. All women should be instructed to report any abnormalities or changes to their physicians. If the physician cannot confirm the patient's findings, the examination should be repeated in 1 month or after her next menstrual period.

Breast Imaging Mammography and ultrasonography are the most reliable and common imaging techniques for early detection of breast lesions (11,12). Full-field digital mammography is a modification of screen-film mammography, which records mammographic images on a computer (13). The U.S. Food and Drug Administration (FDA) approved a digital mammography system in March 2000 (14). This technology is still considered investigational and is not widely available ( 15). Some proposed advantages include lower radiation exposure, ability to manipulate a computerized image for optimal viewing, and distance consultations through telemammography (16). Magnetic resonance imaging (MRI) may be valuable for assessing breast lesions of an indeterminate nature detected by clinical and mammographic examination or occurring in patients who have implants ( 17). MRI and positron emission tomography (PET) have been used to identify occult lesions ( 18,19). Novel developments in breast imaging can be anticipated that will use functional imaging and molecular biology to create better methods to quantify the extent of disease as well as response to therapeutic interventions ( 20,21). A promising new approach uses technetium-99m ( 99mTc) sestamibi to detect breast cancer, especially in women with dense breast tissue (22). Mammography Slowly growing breast cancers can be identified by mammography at least 2 years before the mass reaches a size detectable by palpation (23). In fact, mammography is the only reproducible method of detecting nonpalpable breast cancer. However, its accurate use requires state-of-the-art equipment and a skilled radiologist. Vigorous compression of the breast is necessary to obtain good images, and patients should be forewarned that breast compression is uncomfortable. With a good technique and well-maintained modern equipment, the average mean glandular dose per mammographic image for all facilities in the United States inspected under the Mammography Quality Standards Act in the first one-half of 1997 was 1.6 mGy (160 mrad) ( 24). Indications for Mammography There are several indications for mammography: 1. To screen, at regular intervals, women who are at high risk for developing breast cancer. About one-third of the abnormalities detected on screening mammography prove malignant when biopsy is performed (25). 2. To evaluate a questionable or ill-defined breast mass or other suspicious change in the breast. 3. To establish a baseline breast mammogram and reevaluate patients at yearly intervals to diagnose a potentially curable breast cancer before it has been diagnosed clinically. 4. To search for occult breast cancer in a patient with metastatic disease in axillary nodes or elsewhere from an unknown primary origin. 5. To screen for unsuspected cancer prior to cosmetic operations or biopsy of a mass. 6. To monitor breast cancer patients who have been treated with a breast-conserving operation and radiation. Screening

Approximately 35% to 50% of early breast cancers can be discovered only by mammography, and about 20% can be detected only by palpation. Mass screening programs to evaluate asymptomatic, healthy women combine physical examination with mammographic screening to identify breast abnormalities. During the past 25 years, there has been an increase in mammography, mammographic screening, and public awareness. The cancer detection rate for screening mammograms is 5 per 1,000 screening examinations (26). It is 11-fold higher for diagnostic mammograms at 55 per 1,000 diagnostic mammographic examinations (26). The mean diameter of breast cancers at diagnosis has decreased from 3 cm from 1979 to 1983 to 2 cm from 1989 to 1993, and this downward trend appears to be continuing ( 27,28). As the mean maximal diameter of breast cancers has decreased, there has been a simultaneous decrease in the number of positive axillary lymph nodes (28). Detecting breast cancer before it has spread to the axillary nodes greatly increases the chance of survival; about 85% of such women will survive at least 5 years (28). Mammography's lack of sensitivity in dense breast tissue has led to questions concerning its screening value in women 40 to 50 years of age. In February 1993, the National Cancer Institute (NCI) held an international workshop on screening for breast cancer ( 23). The purpose of this workshop was to undertake a critical review of recent clinical screening trials. The participants examined only randomized studies and focused on clinical evidence related to the efficacy of breast cancer screening in various age groups. Of the eight randomized trials identified, only the Health Insurance Plan (HIP) project demonstrated a beneficial effect of screening for women between 40 and 49 years of age. This benefit was seen 10 to 18 years after entry into the study and resulted in a 25% decrease in deaths from breast cancer. Several Swedish trials showed a 13% decrease in breast cancer mortality for women in this age group after 12 years of follow-up; however, this decrease was not statistically significant ( 29,30). In a metaanalysis of five randomized trials, the breast cancer rates were independent of screening in women aged 40 to 49 years ( 31). The beneficial effect of screening in women aged 50 to 69 years was confirmed by all clinical trials. The efficacy of screening in women older than 70 years of age was inconclusive because of the small sample size. This topic was once again revisited in 1997. The American Cancer Society (ACS) convened a workshop on breast cancer screening in 1997 to establish guidelines for early detection of breast cancer ( 32). The ACS recommends monthly BSE and clinical breast examination every 3 years between ages 18 and 39. They recommend a baseline mammogram at age 40 and annual mammography for women beginning at age 40 with no upper age limit (32). This recommendation has been adopted by the American Medical Association, American College of Radiology, American Society of Clinical Oncology, and the American College of Obstetricians and Gynecologists (33,34). In contrast, the NCI also met in 1997 to discuss, debate, and reach a consensus statement for breast cancer screening ( 35). They concluded that a beneficial effect was seen in women over 50 years of age, but a 17% reduction in breast cancer deaths in the 40- to 49-year age group with screening was not felt to be significant enough to mandate annual mammography examinations. The NCI recommendations for women with an average risk of breast cancer is screening mammography every 1 to 2 years for women between ages 40 and 49. Women with higher risk should seek the advice of a physician and have their individual risk assessed. In an overview of breast cancer screening, Kopans condemns the arbitrary categorization of women into two age groups (400 mOsm), whereas urine sodium concentration is low (30 mEq/L). Finally, changes in sodium can give insight into the degree of extracellular fluid excess or deficit. In the average person, the serum sodium rises by 3 mmol/L for every liter of water deficit and falls by 3 mmol/L for each liter of water excess. One must be careful in making these estimates, however, because patients with prolonged water and electrolyte loss can have low serum sodium levels and marked water deficits. Specific Electrolyte Disorders Hyponatremia Because sodium is the major extracellular cation, shifts in serum sodium levels are usually inversely correlated with the hydration state of the extracellular fluid compartment. The pathophysiology of hyponatremia, then, is usually expansion of body fluids leading to excess total body water ( 27,28). Symptomatic hyponatremia usually does not occur until the serum sodium is below 120 to 125 mEq/L. The severity of the symptoms (nausea, vomiting, lethargy, seizures) is related more to the rate of change of serum sodium than to the actual serum sodium level. Hyponatremia in the form of extracellular fluid excess can be seen in patients with renal or cardiac failure as well as in conditions such as nephrotic syndrome, in which total body salt and water are increased, with a relatively greater increase in the latter. Administration of hypertonic saline to correct the hyponatremia would be inappropriate in this setting. The treatment should include, in addition to correcting the underlying disease process, water restriction with diuretic therapy. Inappropriate secretion of antidiuretic hormone (ADH) can occur with head trauma, pulmonary or cerebral tumors, and states of stress. The abnormally elevated ADH results in excess water retention. Treatment includes water restriction and, if possible, correction of the underlying cause. Demeclocycline has been shown to be effective in this disorder via its action in the kidney. Inappropriate replacement of body salt losses with water alone will result in hyponatremia. This will typically occur in patients losing large amounts of electrolytes secondary to vomiting, nasogastric suction, diarrhea, or gastrointestinal fistulas, and who received replacement with hypotonic solutions. Simple replacement with isotonic fluids and potassium will usually correct the abnormality. Rarely, rapid correction of the hyponatremia is necessary, in which case hypertonic saline (3%) can be administered. Hypertonic saline should be administered very cautiously in order to avoid a rapid shift in serum sodium, which will induce central nervous system dysfunction. Hypernatremia Hypernatremia is an uncommon condition that can be life-threatening if severe (serum sodium >160 mEq/L). The pathophysiology is extracellular fluid deficit. The resultant hyperosmolar state leads to decreased water volume in cells in the central nervous system, which, if severe, can cause disorientation, seizures, intracranial bleeding, and death. The causes include excessive extrarenal water loss, which can occur in patients who have a high fever, have undergone tracheostomy in a dry environment, or have extensive thermal injuries; who have diabetes insipidus, either central or nephrogenic; and who have iatrogenic salt loading. The treatment involves correction of the underlying cause (correction of fever, humidification of the tracheostomy, administration of pitressin for control of central diabetes insipidus) and replacement with free water either by the oral route or intravenously with D5W. As with severe hyponatremia, marked hypernatremia should be corrected slowly. P>Hypokalemia Hypokalemia may be encountered preoperatively in patients with significant gastrointestinal fluid loss (prolonged emesis, diarrhea, nasogastric suction, intestinal fistulas) and marked urinary potassium loss secondary to renal tubular disorders (renal tubular acidosis, acute tubular necrosis, hyperaldosteronism, prolonged diuretic use). It can also arise from prolonged administration of potassium-free parenteral fluids in patients who are restricted from ingesting anything by mouth. The symptoms associated with hypokalemia include neuromuscular disturbances, ranging from muscle weakness to flaccid paralysis, and cardiovascular abnormalities, including hypotension, bradycardia, arrhythmias, and enhancement of digitalis toxicity. These symptoms rarely occur unless the

serum potassium is 7 mEq/L) can result in bradycardia, ventricular fibrillation, and cardiac arrest. The treatment chosen depends on the severity of the hyperkalemia and whether there are associated cardiac abnormalities detected with electrocardiography. Calcium gluconate (10 ml of a 10% solution), given intravenously, can offset the toxic effects of hyperkalemia on the heart. One ampule each of sodium bicarbonate and D50, with or without insulin, will cause a rapid shift of potassium into cells. Over the longer term, cation exchange resins such as sodium polystyrene sulfate (Kayexalate), taken orally or by enema, will bind and decrease total body potassium. Hemodialysis is reserved for emergent conditions in which other measures are not sufficient or have failed. Postoperative Fluid and Electrolyte Management Several hormonal and physiologic alterations in the postoperative period may complicate fluid and electrolyte management. The stress of surgery induces an inappropriately high level of circulating ADH. Circulating aldosterone levels also are increased, especially if sustained episodes of hypotension have occurred either intraoperatively or postoperatively. The elevated levels of circulating ADH and aldosterone make patients prone to sodium and water retention postoperatively. Total body fluid volume may be altered significantly postoperatively. First, 1 ml of free water is released for each gram of fat or tissue that is catabolized and, in the postoperative period, several hundred milliliters of free water is released daily from tissue breakdown, particularly in the patient who has undergone extensive intraabdominal dissection and who is restricted from ingesting food and fluids by mouth. This free water is often retained in response to the altered levels of ADH and aldosterone. Second, fluid retention is further enhanced by third spacing, or sequestration of fluid in the surgical field. The development of an ileus may result in an additional 1 to 3 liters of fluid per day being sequestered in the bowel lumen, bowel wall, and peritoneal cavity. In contrast to renal sodium homeostasis, the kidney lacks the capacity for retention of potassium. In the postoperative period, the kidneys will continue to excrete a minimum of 30 to 60 mEq/L of potassium daily, irrespective of the serum potassium level and total body potassium stores ( 27). If this potassium loss is not replaced, hypokalemia may develop. Tissue damage and catabolism during the first postoperative day usually result in the release of sufficient intracellular potassium to meet the daily requirements. However, beyond the first postoperative day, potassium supplementation is necessary. Correct maintenance of fluid and electrolyte balance in the postoperative period starts with the preoperative assessment, with emphasis on establishing normal fluid and electrolyte parameters prior to surgery. Postoperatively, close monitoring of daily weight, urine output, serum hematocrit, serum electrolytes, and hemodynamic parameters will yield the necessary information to make correct adjustments in crystalloid replacement. The normal daily fluid and electrolyte requirements must be met, and any unusual fluid and electrolyte losses, such as from the gastrointestinal tract, lungs, or skin, must be replaced. After the first few postoperative days, third-space fluid begins to mobilize back into the intravascular space, and ADH and aldosterone levels revert to normal. The excess fluid retained perioperatively is thus mobilized and excreted through the kidneys, and exogenous fluid requirements decrease. The patient with inadequate cardiovascular or renal reserve is prone to fluid overload during this time of third-space reabsorption, especially if intravenous fluids are not appropriately reduced. The most common fluid and electrolyte disorder in the postoperative period is fluid overload. The fluid excess can occur concomitant with normal or decreased serum sodium. Large amounts of isotonic fluids are usually infused intraoperatively and postoperatively to maintain blood pressure and urine output. Because the infused fluid is often isotonic with plasma, it will remain in the extracellular space. Under such conditions, serum sodium will remain within normal levels. Fluid excess with hypotonicity (decreased serum sodium) can occur if large amounts of isotonic fluid losses (e.g., blood and gastrointestinal tract) are inappropriately replaced with hypotonic fluids. Again, the predisposition toward retention of free water in the immediate postoperative period compounds the problem. An increase in body weight occurs concomitant with the fluid expansion. In the patient who is not allowed anything by mouth, catabolism should induce a daily weight loss as great as 300 g/day. Clearly, the patient who is gaining weight in excess of 150 g/day is in a state of fluid expansion. Simple fluid restriction will correct the abnormality. When necessary, diuretics can be used to increase urinary water excretion. States of fluid dehydration are uncommon but will occur in patients who have large daily fluid losses that are not replaced. Gastrointestinal losses should be replaced with the appropriate fluids. Patients with high fevers should be given appropriate free water replacement, because up to 2 L/day of free water can be lost through perspiration and hyperventilation. Although these increased losses are difficult to monitor, a reliable estimate can be obtained by monitoring body weight. Postoperative Acid-base Disorders A variety of metabolic, respiratory, and electrolyte abnormalities in the postoperative period can result in an imbalance in normal acid-base homeostasis, leading to alkalosis or acidosis. Changes in the respiratory rate will directly affect the amount of carbon dioxide that is exhaled. Respiratory acidosis will result from carbon dioxide retention in patients who have hypoventilation from central nervous system depression. This condition can result from oversedation with narcotics, particularly in the presence of concurrent severe chronic obstructive pulmonary disease. Respiratory alkalosis can result from hyperventilation caused by excitation of the central nervous system by drugs, pain, or excess ventilator support. Numerous metabolic derangements can result in alkalosis or acidosis. Proper fluid and electrolyte replacement as well as maintenance of adequate tissue perfusion will help prevent most acid-base disorders that occur during the postoperative period. Alkalosis The most common acid-base disorder encountered in the postoperative period is alkalosis (27). Alkalosis is usually of no clinical significance and resolves spontaneously. Several etiologic factors may include hyperventilation associated with pain; posttraumatic transient hyperaldosteronism, which results in decreased renal bicarbonate excretion; nasogastric suction, which removes hydrogen ions; infusion of bicarbonate during blood transfusions in the form of citrate, which is converted to bicarbonates; administration of exogenous alkali; and use of diuretics. Alkalosis can usually be corrected easily with removal of the inciting cause, as well as with correction of extracellular fluid and potassium deficits ( Table 19.1). Full correction can usually be safely achieved over 1 to 2 days.

Table 19.1. Causes of Metabolic Alkalosis

Marked alkalosis, with serum pH higher than 7.55, can result in serious cardiac arrhythmias or central nervous system seizures. Myocardial excitability is particularly pronounced with concurrent hypokalemia. Under such conditions, fluid and electrolyte replacement may not be sufficient to correct the alkalosis rapidly. Acetazolamide (250 to 500 mg), orally or intravenously, can be given 2 to 4 times daily to induce renal bicarbonate diuresis. Treatment with an acidifying agent is rarely necessary and should be reserved for acutely symptomatic patients (i.e., those with cardiac or central nervous system dysfunction) or for patients with

advanced renal disease. Under such conditions, HCl (5 to 10 mEq/hr of a 100-mmol solution) can be given via a central intravenous line. Ammonium chloride can also be given orally or intravenously but should not be given to patients with hepatic disease. Acidosis Metabolic acidosis is less common than alkalosis during the postoperative period, but acidosis can potentially be serious because of its effect on the cardiovascular system. Under conditions of acidosis, there are decreased myocardial contractility, a propensity for vasodilation of the peripheral vasculature leading to hypotension, and refractoriness of the fibrillating heart to defibrillation ( 27). These effects promote decompensation of the cardiovascular system and can hinder attempts at resuscitation. Metabolic acidosis results from a decrease in serum bicarbonate levels caused by the consumption and replacement of bicarbonate by circulating acids or the replacement by other anions such as chloride. The proper workup includes a measurement of the anion gap:

The anion gap is also composed of circulating protein, sulfate, phosphate, citrate, and lactate ( 29). With metabolic acidosis, the anion gap can be increased or normal. An increase in circulating acids will consume and replace bicarbonate ion, thus increasing the anion gap. The causes include an increase in circulating lactic acid secondary to anaerobic glycolysis, such as that seen under conditions of poor tissue perfusion; increased ketoacids, as with cases of severe diabetes or starvation; exogenous toxins; and renal dysfunction, which leads to increased circulating sulfates and phosphates (30). The diagnosis can be established via a thorough history and measurement of serum lactate (normal 500 nmol/L (18 to 20 µg/dl) indicates adequate adrenal function ( 155). If the history regarding exogenous steroid use is unclear, then the cosyntropin stimulation test should be performed preoperatively to determine if the patient will need perioperative glucocorticoid coverage. Guidelines for perioperative steroid coverage have been recommended by Salem and co-workers based on clinical and research findings ( 155). The amount of glucocorticoid replacement should be equivalent to the normal physiologic response to surgical stress. In response to major surgical procedures, adults secrete 75 to 150 mg glucocorticoid a day. In contrast, during minor procedures only 50 mg of glucocorticoid is released ( 156). For minor surgical stress, the glucocorticoid target is approximately 25 mg of hydrocortisone equivalent. Therefore, the patient should receive 25 mg of hydrocortisone preoperatively and then resume the normal glucocorticoid dose the next day. For moderate surgical stress (i.e., as with abdominal hysterectomy) the glucocorticoid target is 50 to 75 mg of hydrocortisone equivalent per day for 1 to 2 days. The patient should receive her normal daily dose preoperatively, followed by 50 mg of hydrocortisone intravenously administered during surgery. Salem and co-workers recommended that patients should receive 60 mg hydrocortisone (20 mg every 8 hours) intravenously on postoperative day 1 and then return to their preoperative dose, given either enterally or parenterally on postoperative day 2. For major surgical stress, the glucocorticoid target range is 100 to 150 mg hydrocortisone equivalent per day for 2 to 3 days. The patient should receive her normal daily dose within 2 hours preoperatively, followed by 50 mg of hydrocortisone intravenously every 8 hours after the initial dose for the first 2 to 3 days after surgery ( 155). Whether patients need even this amount of perioperative steroids is unknown. A randomized blinded trial evaluating perioperative steroid use in patients with secondary adrenal insufficiency was performed at the Veterans Affairs Medical Center. Patients who had been taking at least 7.5 mg of prednisone daily and had secondary adrenal insufficiency were randomized to two groups. The subjects underwent major surgical procedures; one group received perioperative saline injections and the other received cortisol. All patients received their usual daily steroid dose. Two patients had hypotension, one from each group, which was reversible with fluid replacement. When given their daily dose of steroids for surgical procedures, patients with secondary adrenal insufficiency do not experience serious hypotension secondary to insufficient glucocorticoid levels ( 157). Therefore, perioperative glucocorticoid coverage should be individualized, based on the patient's preoperative dosage requirements and the type of surgical procedure ( 155). Administration of high-dose steroids should be stopped as soon as possible postoperatively because it can inhibit wound healing and promote infection. Hypertension and glucose intolerance also can develop. It is safe to abruptly discontinue steroid use after a few days of therapy. Addison's disease is uncommon but should be considered in the differential diagnosis if the patient develops perioperative hypotension. In addition to blood and isotonic fluid replacement, a “stress” dose of steroids should be given if adrenal insufficiency is suspected and sepsis and hypovolemia have been excluded. When a prolonged or involved procedure is performed and longer steroid use is necessary, careful tapering will be required. The recommended approach is to halve the dose of hydrocortisone on a daily basis until a dose of 25 mg is reached. Eliminating one dose each day until the drug has been stopped is the safest method of withdrawal.

Cardiovascular Diseases The incidence of perioperative cardiovascular complications has decreased markedly as a result of improvements in preoperative detection of high-risk patients, preoperative preparation, and surgical and anesthetic techniques ( 158). Preoperative Evaluation The goal of a preoperative cardiac evaluation is to determine the presence of heart disease, its severity, and the potential risk to the patient during the perioperative period. Every patient should be questioned about symptoms of cardiac disease including chest pain, dyspnea on exertion, peripheral edema, wheezing, syncope, claudication, or palpitations. Patients with a history of cardiac disease should be evaluated for worsening of symptoms, which indicates progressive or poorly controlled disease. Records of previous treatment should be obtained. Prescriptions for antihypertensive, anticoagulant, antiarrhythmic, antilipid, or antianginal medications may be the only indication of cardiac problems. In patients without known heart disease, the presence of DM, hyperlipidemia, hypertension, tobacco use, or a family history of heart disease identifies a group of patients at higher risk for heart disease who should be more carefully screened. On physical examination, the presence of findings such as hypertension, jugular venous distention, laterally displaced point of maximum impulse, irregular pulse, third heart sound, pulmonary rales, heart murmurs, peripheral edema, or vascular bruits should prompt a more complete evaluation. Laboratory evaluation of patients with known or suspected heart disease should include a blood count and serum chemistry analysis. Patients with heart disease tolerate anemia poorly. Serum sodium and potassium levels are particularly important in patients taking diuretics and digitalis. Blood urea nitrogen and creatinine values provide information on renal function and hydration status. Assessment of blood glucose levels may detect undiagnosed DM. Chest radiograph and electrocardiography are mandatory as part of the preoperative evaluation, and the results may be particularly helpful when compared with those of previous studies. Coronary Artery Disease Coronary artery disease is a major risk factor for patients undergoing abdominal surgery. In an adult population without a prior history of myocardial infarction, the incidence of myocardial infarction following surgery is 0.1% to 0.7% (159). In patients who have had a prior myocardial infarction, however, the reinfarction rate is 2.8% to 7% (160). The risk of reinfarction is inversely proportional to the length of time between infarction and surgery. At 3 months or less, the risk of reinfarction is 5.7%, and from 3 to 6 months, the rate falls to 2.3%. Six months after myocardial infarction, the reinfarction rate is 1.5% ( 159). Fortunately, careful perioperative management can lower the reinfarction rate even in patients who have had recent infarctions. Perioperative myocardial infarction is associated with a mortality rate of 26% to 70% (160). Because of the high mortality and morbidity associated with perioperative myocardial infarction, much effort has been made to predict perioperative cardiac risk. A prospective evaluation of preoperative cardiac risk factors using a multivariate analysis identified independent cardiac risk factors for patients undergoing noncardiac surgery (161). Using these factors, a cardiac risk index was created that placed a patient in one of four risk classes. High-risk clinical factors included age over 70 years, myocardial infarction within 6 months prior to surgery, congestive heart failure, and atrial and ventricular arrhythmias. More recent studies have added to and modified the commonly accepted list of risk factors, which are listed in Table 19.8 (160). Additional risk factors include unstable angina, DM, uncontrolled hypertension, history of stroke, and abnormal electrocardiogram.

Table 19.8. Risk Factors for Perioperative Cardiovascular Risk ( 160)

In addition to clinical predictors, cardiac risk is also determined by the risk level of the proposed operation and the functional capacity of the patient. High-risk procedures include emergent major operations, aortic and vascular procedures, and prolonged surgical procedures associated with large fluid shifts or blood loss. Intermediate-risk procedures include other intraperitoneal operations, whereas low-risk procedures include endoscopic surgery, breast surgery, and superficial procedures. The patient's functional status is assessed by a thorough history; risk classification is ummarized in Table 19.9. Patients with poor functional capacity have higher perioperative cardiac risk and should be considered for preoperative cardiac function testing ( 160).

Table 19.9. Functional Capacity Assessment from Clinical History (160)

In an effort to quantitate preoperative cardiac risk, several tests have been used to assess cardiovascular function. Exercise stress testing prior to surgery can identify patients who have ischemic heart disease not apparent at rest. These patients have been shown to be at increased risk of developing cardiac complications in the perioperative period. In a study of patients undergoing peripheral vascular surgery, a high-risk group of patients was identified who had ischemic electrocardiographic changes when they exercised to less than 75% of their maximal predicted heart rate. In this group, the incidence of perioperative myocardial infarction was 25% and the overall cardiac mortality rate was 18.5%. Conversely, no perioperative infarctions occurred in patients who were able to exercise to more than 75% of their maximal predicted heart rate and who had no electrocardiographic evidence of ischemia ( 162). However, the prognostic value of stress testing was not supported in another prospective study that found that only an abnormal preoperative resting electrocardiogram was an independent risk factor ( 163). The exercise stress test must be selectively applied to a high-risk population because its predictive value is dependent upon the prevalence of the disease. Therefore, it is not prudent to screen all patients preoperatively; it is preferable to rely on a careful history to identify patients with symptoms of cardiac disease for whom the test would be most predictive. Exercise stress testing is limited in some patients who cannot exercise because of musculoskeletal disease, pulmonary disease, or severe cardiac disease. Dipyridamole-thallium scanning may be used to overcome the limitations of exercise stress testing. This study has a high degree of sensitivity and specificity, and it relies on the ability of dipyridamole to dilate normal coronary arteries but not stenotic vessels. Normally perfused myocardium readily takes up thallium when it is given intravenously. Conversely, hypoperfused myocardium does not demonstrate good uptake of thallium when scanned 5 minutes after injection. Reperfusion and uptake of thallium 3 hours after injection identify viable but high-risk myocardium. Old infarctions are identified as areas without uptake. Several studies have shown a risk of perioperative myocardial infarction in patients with areas of reperfusion of thallium uptake ranging from 20% to 33% ( 164,165). The dipyridamole-thallium scan is applicable for patients who are unable to exercise because it uses a medically induced “stress.” Dobutamine stress echocardiography is another test to evaluate cardiac risk in patients who are unable to exercise. This method identifies regional cardiac wall motion abnormalities after dobutamine infusion to identify patients at high risk for cardiac events. Positive and negative predictive values are similar to those of dipyridamole-thallium testing ( 166,167). It is rare for patients who are younger than 50 years and who do not have diabetes, hypertension, hypercholesterolemia, or coronary artery disease to suffer a perioperative myocardial infarction. However, patients with coronary artery disease are at increased risk of myocardial infarction in the postoperative period. Prevention, early recognition, and treatment are important, because myocardial infarctions that occur in the postoperative period have mortality rates of approximately 50% and are more lethal than those that are not associated with surgery. Nearly two-thirds of postoperative myocardial infarctions occur during the first 3 days postoperatively. Although the pathophysiologic factors are complex, the causes of postoperative myocardial ischemia and infarction are related to decreased myocardial oxygen supply coupled with increased myocardial oxygen requirements. In postoperative patients, conditions that decrease oxygen supply to the myocardium include tachycardia, increased preload, hypotension, anemia, and hypoxia ( 168). Conditions that increase myocardial oxygen consumption are tachycardia, increased preload, increased afterload, and increased contractility. Tachycardia and increased preload are the most important causes of ischemia, because both conditions decrease oxygen supply to the myocardium while simultaneously increasing myocardial oxygen demand. Tachycardia decreases the diastolic time which, when the coronary arteries are perfused, decreases the volume of oxygen available to the myocardium. Increased preload increases the pressure exerted by the myocardial wall on the arterioles within it, thus decreasing myocardial blood flow. Other factors associated with perioperative myocardial ischemia include physiologic responses to the stress of intubation, intravenous or intraarterial line placement, emergence from anesthesia, pain, and anxiety. This stress results in catecholamine stimulation of the cardiovascular system, resulting in increased heart rate, blood pressure, and contractility, which may induce or worsen myocardial ischemia. Loss of intravascular volume because of third spacing of fluids or postoperative hemorrhage can also induce ischemia. Postoperative myocardial infarction is often difficult to diagnose. Chest pain, which is present in 90% of nonsurgical patients with myocardial infarction, may be present in only 50% of patients with postoperative infarction, because of the masking of myocardial pain by coexisting surgical pain and the use of analgesia ( 159). Thus, it is important to maintain a high level of suspicion for postoperative infarction in patients with coronary artery disease. The presence of arrhythmia, congestive heart failure, hypotension, dyspnea, or elevations of pulmonary artery pressure may indicate infarction and should prompt a thorough cardiac investigation and electrocardiographic monitoring. Measurement of creatinine phosphokinase myocardial band (CPK-MB) isoenzyme and troponin T levels are the most sensitive and specific indicators of myocardial infarction, and assessments should be obtained for all patients suspected of myocardial infarction. Despite the high incidence of silent myocardial infarction, routine use of postoperative electrocardiography (ECG) for all patients with cardiovascular disease is controversial. Many patients will exhibit P-wave changes that spontaneously resolve and do not represent ischemia or infarction. Conversely, patients with proven myocardial infarctions may show few, if any, ECG abnormalities. If routine screening of asymptomatic patients is desired, ECGs should be obtained 24 hours following surgery, because it has been shown that significant ECG changes that occur immediately postoperatively will persist for 24 hours. It is prudent to continue serial ECG assessments for at least 3 days postoperatively. Postoperative management of patients with coronary artery disease is based on maximizing delivery of oxygen to the myocardium as well as decreasing myocardial oxygen utilization. Most patients benefit from supplemental oxygen in the postoperative period, although special care should be exercised in patients with chronic obstructive pulmonary disease. Oxygenation can be easily monitored by pulse oximetry. Anemia is detrimental because of loss of oxygen-carrying capacity as well as resultant tachycardia and should, therefore, be carefully corrected in high-risk patients. Patents with coronary artery disease may benefit from pharmacologic control of hyperadrenergic states that result from increased postoperative catecholamine production. b-Blockers decrease heart rate, myocardial contractility, and systemic blood pressure, all of which are increased by adrenergic stimulation. Perioperative b-blockade with atenolol has been shown to significantly reduce perioperative ischemia, myocardial infarction, and overall mortality caused by cardiac death and congestive heart failure in the perioperative period ( 169,170). For patients receiving b-blockade therapy prior to surgery, that therapy should be continued in the perioperative period because abrupt withdrawal results in a rebound hyperadrenergic state. Although prophylactic nitrates have been used in the perioperative period for many years, this practice remains controversial. Nitroglycerin enhances blood flow to ischemic areas, increases collateral flow, increases myocardial oxygenation, and reduces angina ( 171,172,173 and 174). The route of administration, dosage, and duration of therapy are controversial; thus, perioperative treatment with nitrates should be initiated in consultation with a cardiologist. Likewise, calcium-channel

blockers have not proved useful in the prophylaxis of perioperative myocardial ischemia ( 175). Congestive Heart Failure Patients with congestive heart failure (CHF) face a substantially increased risk of myocardial infarction during and after surgery (161). The postoperative development of pulmonary edema is a grave prognostic sign and results in death in a high percentage of patients ( 176). Because patients with heart failure at the time of surgery are significantly more likely to develop pulmonary edema perioperatively, every effort should be made to diagnose and treat CHF before surgery ( 177). The signs and symptoms of CHF are listed in Table 19.10 and should be assessed based on preoperative history and physical examination. Patients who are able to perform usual daily activities without developing CHF are at limited risk of perioperative heart failure.

Table 19.10. Signs and Symptoms of Congestive Heart Failure

To prevent severe postoperative complications, congestive heart failure must be corrected preoperatively. Treatment usually relies on aggressive diuretic therapy, although care must be taken to avoid dehydration, which may result in hypotension during the induction of anesthesia. Hypokalemia can result from diuretic therapy and is especially deleterious to patients who are also taking digitalis. In addition to diuretics and digitalis, treatment often includes the use of preload- and afterload-reducing agents. Optimal use of these drugs and correction of CHF may be aided by consultation with a cardiologist. In general, it is preferable to continue the usual regimen of cardioactive drugs throughout the perioperative period. In patients with severe or intractable CHF, the perioperative measurement of left ventricular filling (wedge) pressure with a pulmonary artery catheter (Swan-Ganz) may be extremely helpful to guide perioperative fluid management. Postoperative CHF results most frequently from excessive administration of intravenous fluids and blood products. Other common postoperative causes are myocardial infarction, systemic infection, pulmonary embolism, and cardiac arrhythmias. The cause of postoperative heart failure must be diagnosed because, to be successful, treatment should be directed simultaneously to the underlying cause. Postoperative diagnosis of CHF is often more difficult than preoperative diagnosis because the signs and symptoms of CHF are not specific and may result from other causes (Table 19.10). The most reliable method of detecting CHF is chest radiography, in which the presence of cardiomegaly or evidence of pulmonary edema is a helpful diagnostic feature. Acute postoperative CHF frequently manifests as pulmonary edema. Treatment of pulmonary edema may include the use of intravenous furosemide, supplemental oxygen, including morphine sulfate, and elevation of the head of the bed. Intravenous aminophylline may be useful if cardiogenic asthma is present. Electrocardiography, in addition to laboratory evaluation, including arterial blood gas, serum electrolyte, and renal function chemistry measurements, should be obtained expediently. If the patient's condition does not improve rapidly, she should be transferred to an intensive care unit. Arrhythmias Nearly all arrhythmias found in otherwise healthy patients are asymptomatic and of limited consequence. In patients with underlying cardiac disease, however, even brief episodes of arrhythmias may result in significant cardiac morbidity and mortality. Preoperative evaluation of arrhythmias by a cardiologist and anesthesiologist is important because many anesthetic agents as well as surgical stress contribute to the development or worsening of arrhythmias. In patients undergoing continuous electrocardiographic monitoring during surgery, a 60% incidence of arrhythmias, excluding sinus tachycardia, has been reported ( 178). Patients with heart disease have an increased risk of arrhythmias, most commonly ventricular arrhythmias (178). Conversely, patients without cardiac disease are more likely to develop supraventricular arrhythmias during surgery. Patients taking antiarrhythmic medications prior to surgery should continue taking those drugs during the perioperative period. Initiation of antiarrhythmic medications is rarely indicated preoperatively, but consultation with a cardiologist is recommended for patients in whom arrhythmias are detected prior to surgery. Patients with first-degree atrioventricular (AV) block or asymptomatic Mobitz I (Wenckebach) second-degree AV block require no preoperative therapy. Conversely, a pacemaker is appropriate in patients with symptomatic Mobitz II second- or third-degree AV block before elective surgery ( 179). In emergency situations, a pacing pulmonary artery catheter can be used. Prior to performing surgery on patients with a permanent pacemaker, the type and location of the pacemaker should be determined because electrocautery units may interfere with demand-type pacemakers ( 180). When performing gynecologic surgery on patients with pacemakers, it is preferable to place the electrocautery unit ground plate on the leg to minimize interference. In patients with a demand pacemaker in place, the pacemaker should be converted preoperatively to the fixed-rate mode. Surgery is not contraindicated in patients with bundle branch blocks or hemiblocks. Complete heart block rarely develops during noncardiac surgical procedures in patients with conduction system disease (181,182 and 183). However, the presence of a left bundle branch block may indicate the presence of aortic stenosis, which can increase surgical mortality if it is severe. Valvular Heart Disease Although there are many forms of valvular heart disease, primarily two types—aortic and mitral stenosis—are associated with significantly increased operative risk (184). Patients with significant aortic stenosis appear to be at greatest risk, which is further increased if atrial fibrillation, congestive heart failure, or coronary artery disease is also present. Significant stenosis of aortic or mitral valves should be repaired prior to elective gynecologic surgery ( 160). Severe valvular heart disease is usually evident during physical exertion. Common findings in such patients are listed in Table 19.11. The classic history presented by patients with severe aortic stenosis includes exercise dyspnea, angina, and syncope, whereas symptoms of mitral stenosis are paroxysmal and effort dyspnea, hemoptysis, and orthopnea. Most patients have a remote history of rheumatic fever. Severe stenosis of either valve is considered to be a valvular area of less than 1 cm2, and diagnosis can be confirmed by echocardiography or cardiac catheterization.

Table 19.11. Signs and Symptoms of Valvular Heart Disease

Patients with valvular abnormalities have been subdivided by the American Heart Association into risk groups for the development of subacute bacterial endocarditis following surgery (185). Patients with prosthetic valves are classified as high risk, whereas patients with mitral valve prolapse with regurgitation, history of rheumatic heart disease, or bicuspid aortic valve are considered at moderate risk. Patients in both high- and moderate-risk groups should receive prophylactic antibiotics immediately preoperatively to prevent subacute bacterial endocarditis. Table 19.12 outlines the American Heart Association recommendations for antibiotic prophylaxis (185).

Table 19.12. Recommendations for Prophylaxis of Bacterial Endocarditis for Genitourinary and Gastrointestinal Procedures ( 185)

Patients with aortic and mitral stenosis tolerate sinus tachycardia and other tachyarrhythmias poorly. In patients with aortic stenosis, sufficient digitalization should be provided to correct preoperative tachyarrhythmias, and propranolol may be used to control sinus tachycardia. Patients with mitral valve stenosis often have atrial fibrillation and, if present, digitalis should be used to reduce rapid ventricular response. Patients with mechanical heart valves usually tolerate surgery well ( 186). Management of these patients requires antibiotic prophylaxis ( Table 19.12) and discontinuation of anticoagulant therapy during the perioperative period. Usually, warfarin (Coumadin) is withheld several days prior of surgery and anticoagulation is obtained by intravenous administration of heparin (187). The heparin is discontinued 6 to 8 hours prior to surgery and resumed a few days postoperatively ( 188). The patient is returned to oral warfarin maintenance therapy. Alternatively, warfarin can be stopped 1 to 3 days perioperatively and restarted several days postoperatively. Perioperative heparinization is indicated in patients who have more thrombogenic valves, such as the Starr-Edwards valve, and valves in the tricuspid position ( 179). Both methods of management have essentially no risk of thromboembolic complications and bleeding complication rates of approximately 15%. In the postoperative period, patients with mitral stenosis should be carefully monitored for pulmonary edema because they may not be able to compensate for the amount of intravenous fluid administered during surgery. Patients with mitral stenosis also frequently have pulmonary hypertension and decreased airway compliance. Therefore, they may require more pulmonary support and therapy postoperatively, including prolonged mechanical ventilation. For patients with significant aortic stenosis, it is imperative that a sinus rhythm be maintained during the postoperative period. Even sinus tachycardia can be deleterious because it shortens the diastolic time. Bradycardia less than 45 beats per minute should be treated with atropine. Supraventricular dysrhythmias may be controlled with verapamil or direct-current cardioversion. Particular attention should be provided to the maintenance of proper fluid status, digoxin levels, electrolyte levels, and blood replacement. Hypertension Patients with controlled essential hypertension have no increased risk of perioperative cardiac morbidity or mortality ( 177). However, patients with concomitant heart disease are at elevated risk and should be completely evaluated by a cardiologist preoperatively. Laboratory studies should include an ECG, chest radiograph, blood count, urinalysis, and serum electrolytes and creatinine measurement. Antihypertensive medications should be continued perioperatively. Of note, b-blockers should be continued, parenterally if necessary, to avoid rebound tachycardia, hypercontractility, and hypertension. Patients with diastolic pressures higher than 110 mmHg or systolic pressures higher than 180 mmHg should receive medication to control their hypertension prior to surgery. Chronically hypertensive patients are very susceptible to intraoperative hypotension because of impaired autoregulation of blood flow to the brain and, therefore, require a higher mean arterial pressure to maintain adequate perfusion ( 189). Conversely, during induction of anesthesia episodes of hypertension occur, and such episodes are seen more frequently in patients with baseline hypertension. Postoperative hypertension is usually treated parenterally because gastrointestinal absorption may be diminished, and transdermal absorption can be erratic in patients who are cold and rewarming. Commonly used parenteral antihypertensives are listed in Table 19.13.

Table 19.13. Common Parenteral Antihypertensives

Hemodynamic Monitoring Hemodynamic monitoring has become integral to the perioperative management of patients with cardiovascular and pulmonary disease. The major impetus for this advancement resides in the need for the quantitative estimate of cardiac function, resulting in the development of bedside pulmonary artery catheterization. The impact of monitoring of cardiac function is demonstrated by the significant reduction of myocardial infarctions in high-risk patients who are aggressively monitored for 72 to 96 hours postoperatively (190). Before the development of the pulmonary artery catheter, central venous pressure (CVP) measurement was used to assess intravascular volume status and cardiac function. To measure the CVP, a catheter is placed in the central venous system, most frequently the superior vena cava. A water manometer or a calibrated pressure transducer is connected to the CVP line, thus allowing an estimation of right atrial pressure to be obtained. Right atrial pressure is determined by the balance between cardiac output and venous return. Cardiac output is determined by heart rate, myocardial contractility, preload, and afterload. Thus, if the pulmonary vascularity and left ventricular function are normal, the CVP accurately reflects the left ventricular end-diastolic pressure (LVEDP). The LVEDP reflects cardiac output or systemic perfusion and has been considered the standard estimator of left ventricular pump function. Venous return is determined primarily by the mean systemic pressure, which propels blood toward the heart, balanced against resistance to venous return, which acts in the opposite direction. Thus, if right ventricular function is normal, the CVP accurately reflects intravascular volume. Left and right ventricular function is frequently abnormal or discordant; therefore, the relationship of CVP to cardiac function and to intravascular volume is not maintained. When this occurs, measurement of pulmonary artery occlusion pressure is required to accurately assess volume status and cardiovascular function. The use of a pulmonary artery catheter also allows detection of changes in cardiovascular function with more sensitivity and rapidity than clinical observation. The balloon-tipped pulmonary artery catheter (Swan-Ganz catheter) can provide measurement of pulmonary artery and pulmonary artery occlusion pressures ( 191). The catheter can measure cardiac output, be used to perform intracavitary electrocardiography, and provide temporary cardiac pacing. The standard pulmonary artery occlusion catheter is a 7-French, radiopaque, flexible, polyvinyl chloride, 4-lumen catheter with a 1.5-ml latex balloon at its distal tip. Most often, a right internal jugular cannulation is used for placement of the catheter, because this site provides the most direct access into the right atrium and has fewer complications when compared with a subclavian route of placement. After the catheter is placed into the right atrium, the balloon is inflated and the catheter is pulled by blood flow through the right ventricle into the pulmonary artery. The position of the catheter can be identified and followed by the various pressure waveforms generated by the right atrium, right ventricle, and pulmonary artery. As the catheter passes through increasingly smaller branches of the pulmonary artery, the inflated balloon eventually occludes the pulmonary artery. The distal lumen of the catheter, which is beyond the balloon, measures left atrial pressure (LAP) and, in the absence of mitral valvular disease, LAP approximates LVEDP. Thus, pulmonary–capillary wedge pressure (PCWP) equals the LAP, which equals LVEDP and is normal at 8 to 12 mm Hg. Additionally, because the standard pulmonary artery catheter has an incorporated thermistor, thermodilution studies can be performed to determine cardiac output. This thermodilution method is performed by injecting cold 5% dextrose in water through the proximal port of the catheter, which cools the blood entering the right atrium. The change in temperature measured at the more distal thermistor (4 cm from the catheter tip) generates a curve proportional to cardiac output. Knowledge of the cardiac output is helpful in establishing cardiovascular diagnoses. For example, a patient with hypotension, low-to-normal wedge pressure, and a cardiac output of 3 L/min is most likely hypovolemic. Conversely, the same patient with a cardiac output of 8 L/min is probably septic with resultant low systemic vascular resistance. Pulmonary artery catheters are associated with a small but significant complication rate. The complications can be grouped into those occurring during venous cannulation and those resulting from the catheter or its placement. The most common problems encountered during venous access are cannulation of the carotid or subclavian artery and introduction of a pneumothorax. Problems resulting from the catheter itself include dysrhythmias, sepsis, and disruption of the pulmonary artery. Pulmonary artery catheters should be placed under the supervision of experienced personnel in a setting in which complications can be rapidly diagnosed and treated. The effect of pulmonary artery catheter use on patient outcome has become controversial. In 1996 Dalen and Bone recommended a reevaluation of pulmonary artery catheters and initiation of randomized clinical trials to assess their benefit ( 192). At that time, Connors and others published a large study demonstrating a higher mortality rate in patients who received a pulmonary artery catheter than those that did not have a pulmonary artery catheter ( 193). The design of this study was questionable, however, and it was retrospective and not randomized. A recent metaanalysis evaluating 12 randomized clinical trials demonstrated a statistically significant reduction in morbidity (63% versus 74%, P < 0.01) in the pulmonary artery catheter group, but no significant difference in mortality ( 194). Future large randomized clinical trials comparing pulmonary artery catheters to central venous catheters for the treatment of critical care patients are currently under way, and it is hoped a consensus regarding who will benefit from pulmonary artery catheters will eventually be established.

Hematologic Disorders The presence of hematologic disorders, although uncommon in gynecologic patients, significantly affects operative morbidity and mortality and therefore should be considered routinely in preoperative evaluation. Preoperative assessment should include consideration of anemia, platelet and coagulation disorders, white blood cell function, and immunity. Anemia Moderate anemia is not in itself a contraindication to surgery because it can be corrected by transfusion. If possible, surgery should be postponed until the cause of the anemia can be identified and the anemia corrected without resorting to transfusion. Current anesthetic and surgical practice ideally recommend a hemoglobin level of >10 g/dl or a hematocrit of >30%. Such numbers are only guidelines, and should be applied on an individual basis. Oxygen-carrying capacity and tissue oxygenation is provided by the circulating blood volume. Usually this capacity is reflected by the hemoglobin level and hematocrit. Under certain circumstances, however, this is not the case. After an acute blood loss or before plasma expansion by extracellular fluid has occurred, hematocrit measurements may be normal despite a low circulating blood volume. Conversely, overhydration may result in low hematocrit and hemoglobin levels despite adequate red blood cell mass. Individual tolerance of anemia depends on overall physical fitness and cardiovascular reserve. The effects of anemia depend on its magnitude, the rate at which it occurs, the oxygen requirement of the patient, and the ability of physiologic mechanisms to compensate ( 195). Maintenance of adequate tissue perfusion requires an increase in cardiac output as hemoglobin concentration falls ( 196). A patient with ischemic heart disease will not tolerate anemia as well as a healthy young patient. Therefore, the presence of cardiac, pulmonary, or other serious illness justifies a more conservative approach to the management of anemia. Conversely, patients with longstanding anemia may have normal blood volume levels and tolerate surgical procedures well. There is no evidence that mild to moderate anemia increases perioperative morbidity or mortality ( 197). Patients with normal hematocrit levels may store three or more units of autologous blood preoperatively to reduce the need for allogenic blood transfusion and minimize the risk of infections and immunologic problems ( 198). Recombinant human erythropoietin may increase collection and reduce preoperative anemia in these patients (199). Further, intraoperative blood collection and homologous transfusion can be employed to limit need for allogenic blood transfusion. Platelet and Coagulation Disorders Surgical hemostasis is provided by platelet adhesion to injured vessels, which plugs the opening as the coagulation cascade is activated, resulting in the formation of fibrin clots. Thus, functional platelets and coagulation pathways are necessary to prevent excessive surgical bleeding. Platelet dysfunction is encountered more frequently preoperatively than coagulation disorders. Platelets may be deficient in both number and function. The normal peripheral blood count is 150,000 to 400,000 per mm 3, and the normal lifespan of a platelet is approximately 10 days. Although there is no clear-cut correlation between the degree of thrombocytopenia and the presence or amount of bleeding, several generalizations can be made. If the platelet count is higher than 100,000/mm 3 and the platelets are functioning normally, there is little chance of bleeding during surgical procedures. Patients with a platelet count higher than 75,000/mm 3 almost always have normal bleeding times, and a platelet count higher than 50,000/mm 3 is probably adequate. A platelet count lower than 20,000/mm3 will often be associated with severe and spontaneous bleeding. Platelet counts higher than 1,000,000/mm3 are often, paradoxically, associated with bleeding.

If the patient's platelet count is lower than 100,000/mm 3, an assessment of bleeding time should be obtained. If the bleeding time is abnormal and surgery must be performed, an attempt should be made to raise the platelet count by administering platelet transfusions immediately before surgery. In patients with immune destruction of platelets, human leukocyte antigen (HLA)–matched donor-specific platelets may be required to prevent rapid destruction of transfused platelets. If surgery can be postponed, a hematology consultation should be obtained to identify and treat the cause of the platelet abnormality. Abnormally low platelet counts result from either decreased production or increased consumption of platelets. Although there are numerous causes of thrombocytopenia, most are exceedingly uncommon. Decreased platelet production may be drug induced and has been associated with the use of sulfonamides, cinchona alkaloids, thiazide diuretics, nonsteroidal antiinflammatory drugs (NSAIDs), gold salts, penicillamine, anticonvulsants, and heparins (200). Decreased platelet count is a feature of several diseases, including vitamin B 12 and folate deficiency, aplastic anemia, myeloproliferative disorders, renal failure, and viral infections. Inherited congenital thrombocytopenia is extremely rare. More commonly, thrombocytopenia results from immune destruction of platelets by diseases such as idiopathic thrombocytopenia purpura and collagen vascular disorders. Consumptive thrombocytopenia is a feature of disseminated intravascular coagulation (DIC), which is encountered most frequently in conjunction with sepsis or malignancy in the preoperative population. Platelet dysfunction is most often acquired, but may be inherited. Occasionally, a patient with von Willebrand's disease, the second most common inherited disorder of coagulation, may be encountered in the preoperative setting. More commonly, however, platelet dysfunction results from the use of drugs (e.g., aspirin and amitriptyline), and patients with resulting prolonged bleeding times should have the drug withheld for 7 to 10 days before surgery. Uremia and hepatic diseases can also affect platelet function. Platelet dysfunction is more difficult to diagnose than abnormalities of platelet count. A history of easy bruising, petechiae, bleeding from mucous membranes, or prolonged bleeding from minor wounds may signify an underlying abnormality of platelet function. Such dysfunction can be identified with the help of a bleeding time, but full characterization of the underlying etiology should be carried out with hematologic consultation. If at all possible, surgery should be postponed until therapy has been instituted. Similarly, disorders of the coagulation cascade are often diagnosed through a personal or family history of excessive bleeding during minor surgery, childbirth, or menses. Deficiency of factor VIII (hemophilia) and factor IX (Christmas disease) are the most commonly encountered inherited disorders of coagulation. There are few commonly prescribed drugs that affect coagulation factors, the exceptions being warfarin and heparin. Disease states that may be associated with decreased coagulation factor levels are primarily liver disease, vitamin K deficiency (secondary to obstructive biliary disease, intestinal malabsorption, or antibiotic reduction of bowel flora), and DIC. Preoperative laboratory screening for coagulation deficiencies is controversial. Routine screening in patients without historical evidence of a bleeding problem is not warranted (201). However, patients who are seriously ill or who will be undergoing extensive surgical procedures should undergo testing preoperatively to determine prothrombin time, partial thromboplastin time, fibrinogen level, and platelet count. White Blood Cells and Immune Function Abnormally high or low white blood cell counts are not an absolute contraindication to surgery; however, they should be considered relative to the need for surgery. Evaluation of an elevated or decreased white blood cell count should be undertaken prior to elective surgery. Clearly, patients with absolute granulocyte counts lower than 1,000/mm3 are at increased risk of severe infection and perioperative morbidity and mortality, and should undergo surgery only for life-threatening indications (202). Blood Component Replacement Most hematologic problems observed in the postoperative period are related to perioperative bleeding and blood component replacement. Although the primary cause of the bleeding is usually lack of surgical hemostasis, other factors, including deranged coagulation, may compound the problem. Such coagulopathy can result from massive transfusion (less than one blood volume) and is thought to be due to dilution of platelets and labile coagulation factors by platelet- and factor-poor packed red blood cells (PRBCs), fibrinolysis, and DIC. Reports of massive transfusions in soldiers reveal that for those in whom thrombocytopenia developed following red blood cell replacement, bleeding diatheses that responded to infusion of fresh blood but not fresh-frozen plasma (FFP) also developed ( 203). The investigators concluded that dilutional thrombocytopenia is a major cause of posttransfusion bleeding. However, more recently, in a prospective, randomized, double-blind study, prophylactic platelet administration during massive transfusion was not helpful ( 204). Although it seems that these studies are contradictory, they demonstrate the need for obtaining platelet counts during transfusion of large amounts of blood. If clinical evidence of excessive bleeding exists and the platelet count is lower than 100,000/mm 3, platelets should be transfused, because they are consumed during surgery and higher levels are required to maintain hemostasis following surgery. Packed red blood cells, which may be stored for several weeks, are used for most postoperative transfusions. Most clotting factors are stable for long periods. The exceptions are factors V and VIII, which decrease to 15% and 50% of normal, respectively. Despite this loss, these factors rarely decrease below levels required for hemostasis. In 1985, a National Institutes of Health consensus conference concluded that there was little or no scientific evidence to support the use of FFP for bleeding diatheses following multiple blood transfusions except in the presence of clinical bleeding, platelet count higher than 100,000/mm 3, and a partial thromboplastin time greater than 1.5 times control. A task force of the American Society of Anesthesiologists ( 205) recently recommended critical values for replacement in patients with massive transfusion and microvascular bleeding: 1. Platelet counts 1.5 times normal) prothrombin or activated partial thromboplastin time values 3. Coagulation factor concentrations less than 30% 4. Fibrinogen concentrations less than 80 to 100 mg/dl. Donor blood is stored in the presence of citrate, which chelates calcium to prevent clotting, raising the theoretical risk of hypocalcemia following massive transfusion. However, citrate is metabolized at a rate equivalent to 20 units of blood transfused per hour; thus, routine supplementation of calcium is unnecessary. Close monitoring of calcium levels is required in patients with hypothermia, liver disease, or hyperventilation, because citrate metabolism may be slowed. Hepatic metabolism of citrate to bicarbonate can result in metabolic alkalosis following transfusion, resulting in subsequent hypokalemia, despite the high level of extracellular potassium in stored blood.

Pulmonary Disease In patients undergoing abdominal surgery, several pulmonary physiologic changes occur secondary to immobilization, anesthetic irritation of the airways, and the splinting of breathing that inevitably occurs with incisional pain. Pulmonary physiologic changes include a decrease in the functional residual capacity (FRC) and vital capacity (VC), an increase in ventilation–perfusion mismatching, and impaired mucociliary clearance of secretions from the tracheobronchial tree. These changes result in transient hypoxemia and atelectasis that, untreated, can progress to pneumonia in the postoperative period ( 206,207). Postoperative pulmonary dysfunction is more pronounced in patients with advanced age, preexisting lung disease, obesity, a significant history of smoking, and upper abdominal surgery ( 206). Most postoperative pulmonary complications occur in patients who have preexisting pulmonary disease. In these patients, the incidence of pulmonary complications is higher than 70%, as compared with the low incidence (2% to 5%) that occurs in individuals with healthy lungs ( 206,208). The risk of postoperative pulmonary complications is lower in patients undergoing lower abdominal surgery as compared with upper abdominal surgery and in those undergoing nonthoracic, nonabdominal surgery as compared with abdominal operations. The presence of chronic obstructive pulmonary disease markedly increases the risk ( 206,209). Preoperative spirometry is of unproved value in patients undergoing abdominal surgery in whom the risk of postoperative pulmonary complications is low (210,211,212 and 213). In high-risk patients, preoperative spirometry should be performed with and without bronchodilators in order to identify patients who may

benefit from preoperative treatment with inhaled b 2 agonists and steroids. These patients include those with a history of chronic cough or dyspnea, evidence of pulmonary abnormalities by either physical examination or chest radiograph, and a history of chronic obstructive pulmonary disease, as well as patients with a significant history of smoking. In addition to the preoperative spirometric evaluation, an arterial blood gas assessment should be performed. The spirometric abnormalities most often associated with postoperative atelectasis and pneumonia are shown in Table 19.14.

Table 19.14. Predictors of Postoperative Pulmonary Complications a

Young, healthy patients rarely have abnormal chest radiographic examination results. Therefore, chest radiographs should not be performed routinely in these patients. Most patients with abnormal chest radiographs have history or physical examination findings suggestive of pulmonary disease ( 214). Chest radiographs should be limited to patients older than 40 years, patients with a history of smoking, patients with a history of pulmonary disease, and patients who have evidence of cardiopulmonary disease.

Asthma The prevalence of bronchial asthma is increasing worldwide, and approximately 10% of people have suffered an asthma attack ( 215). Asthma is a disease that is characterized by a history of episodic wheezing, physiologic evidence of reversible obstruction of the airways, either spontaneously or following bronchodilator therapy, and pathologic evidence of chronic inflammatory changes in the bronchial submucosa. Asthma is not a disease of airway physiology in which hypertrophy and increased contractility of bronchial smooth muscle is the dominant lesion; rather, it is an inflammatory disease affecting the airways that secondarily results in epithelial damage, leukocytic infiltration, and increased sensitivity of the airways to a number of different stimuli. The treatment of asthma is directed toward relaxing the airways and alleviating inflammation with glucocorticoids. Despite advances in pharmacologic management, morbidity and mortality from asthma have been increasing in recent years ( 216). This most likely cause has been the result of underdiagnosis and undertreatment of this disease ( 217). Multiple stimuli have been noted to precipitate or exacerbate asthma, including environmental allergens or pollutants, respiratory tract infections, exercise, cold air, emotional stress, use of b-adrenergic blockers, and aspirin ( 218). Management of asthma includes removal of the inciting stimuli as well as use of appropriate pharmacologic therapy. The severity of clinical asthma correlates with measurements of the severity of the inflammatory response in the lung ( 219). Some investigators have referred to asthma as a chronic eosinophilic bronchitis ( 217). Numerous mediators, including interleukin-3, interleukin-5, granulocyte-macrophage colony-stimulating factors, tumor necrosis factor-a, and interferon-g, are released in the lungs by eosinophils, macrophages, and T cells. The mediators induce microvascular leakage, bronchoconstriction, and epithelial damage, which block the distal airways. The optimal therapy for asthma involves not only managing the acute symptoms but also long-term management of the inflammatory component of the disease. Pharmacotherapy of Asthma The recognition of asthma as an inflammatory condition that should be treated with antiinflammatory agents has led to the use of glucocorticoids for treatment. Glucocorticoids have become the first-line therapy for chronic asthma because they inhibit mediator release from eosinophils and macrophages, inhibit the late response to allergens, and reduce hyperresponsiveness of the bronchioles ( 217). Inhaled steroids have greatly reduced the steroid dose required to achieve optimal results. The steroid effect is dose related, but many patients with asthma can achieve control using low-dose inhaled steroids (1,000 g/day). Onset of action is slow (several hours), and up to 3 months of steroid therapy may be required for optimal improvement of bronchial hyperresponsiveness. Even with acute exacerbation of asthma, steroid treatment can enhance the beneficial effect of b-adrenergic treatment. During acute exacerbations of asthma, a short course of oral steroids may be necessary in addition to inhaled steroids. For adults with chronic asthma, however, only a minority will require chronic oral steroid therapy. Patients taking oral steroids should receive intravenous steroid support perioperatively. Until recently, b 2-adrenergic agonists were considered the first-line drugs for asthma. These drugs, inhaled 4 to 6 times daily, rapidly relax smooth muscle in the airways and are effective for up to 6 hours. Studies of b 2 agonists in chronic asthma, however, have failed to show any influence of these agents on the inflammatory component of asthma. Furthermore, it has been suggested that the long-term use of this class of drugs can lead to a worsening of asthma ( 217). Thus b 2 agonists are now recommended for use for short-term relief of bronchospasm or as first-line treatment for patients with very infrequent symptoms or symptoms provoked solely by exercise (220). Methylxanthines, such as theophylline, have been relegated to third-line status in the management of asthma. It is doubtful whether these drugs have any additional benefit in patients who are using maximal inhaler therapy. The xanthines are limited by their narrow therapeutic window. It is necessary to achieve a serum concentration of at least 10 g/ml; at levels higher than 20 g/ml significant toxicity develops, including nausea, tremor, and central nervous system excitation. Xanthines have a limited antiinflammatory effect and no effect on bronchial hyperresponsiveness or eosinophilic degranulation. In addition, plasma concentrations can be altered by drugs or environmental factors, requiring an adjustment in the theophylline dose. Smoking and phenobarbital use, for example, increase clearance of theophylline by the liver, whereas clearance of theophylline is decreased with hepatic disease and cardiac failure or with the concomitant use of certain drugs, including ciprofloxacin, cimetidine, erythromycin, and troleandomycin. Anticholinergic agents are weak bronchodilators that work via inhibition of muscarinic receptors in the smooth muscle of the airways. The quaternary derivatives such as ipratropium bromide (Atrovent) are available in an inhaled form that is not absorbed systemically. Anticholinergic drugs may provide additional benefit in conjunction with standard steroid and bronchodilator therapy but should not be used as single-agent therapy because they do not inhibit mast cell degranulation, do not have any effect on the late response to allergens, and do not have an antiinflammatory effect. Cromolyn sodium is highly active in the treatment of seasonal allergic asthma in children and young adults. It is usually not as effective in older patients or in patients in whom asthma is not caused by allergy (220). The drug is taken by inhalation but has a relatively short duration of action (3 to 4 hours). It has a mild antiinflammatory effect but is less effective than inhaled cortical steroids, and its role as a single agent is limited. Perioperative Management of Asthma In patients with asthma, elective surgery should be postponed whenever possible until pulmonary function and pharmacotherapeutic management are optimized. The preoperative evaluation may include pulmonary function testing and arterial blood gas assessment, depending on the severity of the symptoms and concern regarding ventilation and oxygenation. Preoperative chest physiotherapy, bronchodilator therapy, systemic hydration, and appropriate antibiotics will improve the reversible components of asthma (221). For mild asthma, the use of inhaled b-adrenergic agonists preoperatively may be all that is required. For chronic asthma, optimization of steroid therapy will greatly decrease alveolar inflammation and bronchiolar hyperresponsiveness. Inhaled b 2 agonists should be added to therapy as needed for further control of asthma. Each drug prescribed should be used in maximal dosage before adding an additional agent. For patients undergoing emergent surgery who

have significant bronchoconstriction, a multimodal approach should be instituted, including aggressive bronchodilator inhalation therapy, intravenous aminophylline, as well as steroid therapy. Ideally, steroid therapy can be instituted 3 to 6 days preoperatively. In all patients with asthma, pharmacotherapeutic response can be demonstrated by an improvement in the peak expiratory flow rate based on pulmonary function testing ( 220). Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) is the greatest risk factor for the development of postoperative pulmonary complications. The term COPD has been used to encompass both chronic bronchitis and emphysema, disease entities that often occur in tandem. Cigarette smoke is implicated in the pathogenesis of both, and any treatment plan must include cessation of smoking ( 222). Chronic bronchitis is defined as the presence of productive cough on most days for at least 3 months per year and for at least 2 successive years ( 223). It is characterized by chronic airway inflammation and excessive mucus production. The histologic changes of emphysema include destruction of alveolar septa and distension of airspaces distal to terminal alveoli. The destruction of alveolar septa is most likely caused by serine elastase, released by neutrophils exposed to cigarette smoke ( 222). The destruction of alveoli results in air trapping, loss of pulmonary elastic recoil, collapse of the airways in expiration, increased work of breathing, significant ventilation–perfusion mismatching, and an ineffective cough ( 219). The impaired ability to cough effectively and clear secretions predisposes patients with COPD to atelectasis and pneumonia in the postoperative period. COPD and a history of heavy smoking account for the majority of postoperative pulmonary complications in gynecologic surgical patients. The severity of COPD can be determined preoperatively via a thorough history, physical examination, pulmonary function tests, and arterial blood gas assessments. Preoperative evaluation should be performed to assess reversible components of COPD, such as bronchospasm or infection. Several studies have suggested that preoperative pulmonary preparation of patients with preexisting lung disease can decrease the incidence of postoperative pulmonary complications by 50% to 70% ( 224,225,226 and 227). The severity of COPD can be quantitated with pulmonary function testing ( 206,208,228). Typically, patients with COPD demonstrate impaired expiratory air flow, manifested by diminished forced expiratory volume (FEV 1), forced vital capacity (FVC), FEV 1/FVC, and maximal expiratory flow rate (MEFR). In one study, patients with abnormal pulmonary function test results had a 70% incidence of postoperative pulmonary complications, as compared with a 3% incidence of complications in patients who had normal spirography results ( 208). In patients considered to be at high risk, the incidence of complications was highest in those undergoing abdominal surgery (92%) or thoracic surgery (78%) and lowest in those undergoing surgery outside the abdomen (26%). Guidelines for preoperative spirometry include the following: lung resection; coronary artery bypass or upper abdominal surgery in a patient with a positive smoking history or dyspnea; lower abdominal surgery in a patient with uncharacterized pulmonary symptoms or history of pulmonary disease without recent spirometry within 60 days, especially if the surgery will be extensive, prolonged, or require strenuous postoperative rehabilitation ( 229). Arterial blood gas measurement may show varying degrees of hypoxemia and hypercapnia and can be used for prognostic purposes; Pa O2 levels lower than 70 mm Hg and Pa CO2 levels higher than 45 mm Hg are associated with an increase in the risk of postoperative pulmonary complications and the need for mechanical ventilation postoperatively ( 230). PaCO2 levels higher than 50 mm Hg are associated with increased postoperative respiratory failure and should caution against elective surgery (221). The preoperative preparation of the patient at risk for postoperative pulmonary complications should include cessation of smoking for as long as possible preoperatively. Whereas 2 to 3 days of smoking abstinence are sufficient for carboxyhemoglobin levels to return to normal ( 231), 2 months of smoking abstinence is required to significantly lower the risk of postoperative pulmonary complications ( 232). Longer periods of abstinence can thus be considered in patients undergoing elective surgery. In patients with severe COPD, maximal improvement in airflow limitation can be achieved with a therapeutic trial of high-dose oral glucocorticoids followed by a 2-week trial of high-dose inhaled steroid ( beclomethasone 1.5 mg/day or the equivalent) in addition to inhaled bronchodilator therapy. Ideally, oral and inhaled steroid therapy should be initiated 1 to 2 weeks preoperatively. Inhaled steroids, in particular, address the inflammatory component of COPD. Oral steroid therapy initiated preoperatively should be maintained throughout the perioperative period and then tapered postoperatively. b-Adrenergic agonist therapy can be initiated at least 72 hours preoperatively and is beneficial in patients who have demonstrated either clinical or spirometric improvement with bronchodilator therapy. Patients with COPD and an active bacterial infection, as suggested by purulent sputum, should undergo a full course of antibiotic therapy prior to surgery. The antibiotic used should cover the most likely etiologic organisms, Streptococcus pneumoniae and Haemophilus influenzae. In any patient with acute upper respiratory infection, surgery should be delayed if possible. In the absence of evidence of an acute infection, the use of antibiotics to sterilize the sputum should be avoided because this practice may lead to bacterial resistance. Instruction in deep breathing maneuvers and chest physical therapy are easily instituted, and these measures can be started the evening before surgery ( 232). Steps to improve skeletal muscle strength include good nutrition and treatment of hypokalemia ( 221). Prophylactic measures, such as smoking cessation, pharmacotherapy administration, and aggressive pulmonary toilet, should be instituted preoperatively and continued postoperatively to minimize the incidence of atelectasis and pneumonia. Postoperative Pulmonary Management Atelectasis Atelectasis accounts for more than 90% of all postoperative pulmonary complications. The pathophysiology involves a collapse of the alveoli resulting in ventilation–perfusion mismatching, intrapulmonary venous shunting, and a subsequent drop in the Pa O2. Collapsed alveoli are susceptible to superimposed infection, and if managed improperly atelectasis will progress to pneumonia. Patients with atelectasis have a decreased FRC as well as decreased lung compliance, resulting in increased work during breathing. Despite the decrease in Pa O 2, the PCO2 remains unaffected unless atelectatic changes progress to large volumes of the lung or there is preexisting lung disease. Physical findings associated with atelectasis may include a low-grade fever. Auscultation of the chest may reveal decreased breath sounds at the bases or dry rales upon inspiration. Percussion of the posterior thorax may suggest elevation of the diaphragm. Radiologic findings include the presence of horizontal lines or plates noted on the posteroanterior chest radiographs, occasionally with adjacent areas containing hyperinflation. These changes are most pronounced during the first 3 postoperative days. Therapy for atelectasis should be aimed at expanding the alveoli and increasing the functional residual capacity. The most important maneuvers are those that promote maximal inspiratory pressure, which is maintained for as long as possible. This exercise promotes not only an expansion of the alveoli but also secretion of surfactant, which stabilizes alveoli. It can be achieved with aggressive supervised use of incentive spirometry, deep breathing exercises, coughing and, in some cases, the use of positive expiratory pressure with a mask (continuous positive airway pressure). Oversedation should be avoided, and patients should be encouraged to ambulate and change positions frequently. Fiberoptic bronchoscopy for removal of mucopurulent plugs should be reserved for patients who fail to improve with the usual measures. Cardiogenic (High-pressure) Pulmonary Edema Cardiogenic pulmonary edema can result from myocardial ischemia, myocardial infarction, or from intravascular volume overload, particularly in patients who have low cardiac reserve or renal failure. The process usually begins with an increase in the fluid in the alveolar septa and bronchial vascular cuffs, ultimately seeping into the alveoli. Complete filling of the alveoli impairs secretion and production of surfactant. Concomitant with alveolar flooding, there is a decrease in lung compliance, impairment of the oxygen diffusion capacity, and an increase in the arteriolar–alveolar oxygen gradient. Ventilation–perfusion mismatching in the lung results in a decrease in the Pa O 2, resulting eventually in decreased oxygenation of the tissues and impairment of cardiac contractility. Symptoms may include tachypnea, dyspnea, wheezing, and use of the accessory muscles of respiration. Clinical signs may include distention of the jugular veins, peripheral edema, rales upon auscultation of the lungs, and an enlarged heart. Radiographic findings may include the presence of bronchiolar cuffing as well as increased interstitial fluid markings extending to the periphery of the lung. The diagnosis can be further confirmed with the use of central hemodynamic monitoring,

which will denote an elevated central venous pressure and, more specifically, an elevation in the pulmonary–capillary wedge pressure. The patient's volume status should be evaluated thoroughly. In addition, myocardial ischemia or infarction should be ruled out by performing ECG and analyzing cardiac enzyme levels. The management of cardiogenic pulmonary edema includes oxygen support, aggressive diuresis, and afterload reduction to increase the cardiac output. In the absence of myocardial infarction, an inotropic agent may be used. Mechanical ventilation should be reserved for cases of acute respiratory failure. Noncardiogenic Pulmonary Edema (Adult Respiratory Distress Syndrome) In contrast to cardiogenic pulmonary edema, in which alveolar flooding is a result of an increase in the hydrostatic pressure of the pulmonary capillaries, alveolar flooding in patients with adult respiratory distress syndrome (ARDS) is the result of an increase in pulmonary capillary permeability. The primary pathophysiologic process is one of damage to the capillary side of the alveolar–capillary membrane. This damage results in rapid movement of fluid containing high concentrations of protein from the capillaries to the pulmonary parenchyma and alveoli. Lung compliance decreases and oxygen diffusion capacity is impaired, resulting in hypoxemia. If not managed aggressively, respiratory failure may result. Even if managed aggressively, the mortality rate associated with ARDS is 60% to 70% ( 221). There are a number of causes as well as several distinct states of ARDS. The causes of ARDS include shock, sepsis, massive nonlung trauma (as from fractures or burns), multiple red blood cell transfusions, aspiration injury, inhalation injury, pneumonia, pancreatitis, DIC, and fat emboli ( 221). Irrespective of the cause, which should be identified and treated if possible, the evolving clinical findings and management are very similar. Clinically, ARDS passes through several stages. Initially, patients develop tachypnea and dyspnea with no remarkable findings on clinical evaluation or on chest radiograph. Chest radiographs will eventually reveal bilateral diffuse pulmonary infiltrates. As lung compliance becomes impaired, functional residual capacity, tidal volume, and vital capacity decrease. The Pa O 2 decreases and, characteristically, increases only marginally with oxygen supplementation. An attempt should be made to maintain the arterial oxygen level above 90%. This may be achievable initially by administering oxygen by mask. For patients with severe hypoxemia, endotracheal intubation with positive-pressure ventilation should be instituted. Guidelines for initial ventilatory support are changing, and new lung-protective ventilation strategies are being advocated. One strategy advocates the use of high positive end-expiratory pressure (PEEP), low tidal volume, permissive hypercapnia, and pressure-limited ventilatory modes. The low-tidal-volume strategy may confer a survival advantage, and available data support its use in patients with ARDS ( 233). Multicenter trials are currently under way to assess differences in PEEP and F IO 2 levels, and the use of glucocorticoids. Attempts to manage and treat the cause of ARDS also must include aggressive efforts toward hemodynamic and circulatory resuscitation in patients with shock. Nosocomial pneumonia is present in 50% of patients with ARDS, and broad-spectrum antibiotic therapy should be administered as appropriate for patients with suspected pneumonia or sepsis. Patients who have DIC may require replacement with cryoprecipitate or FFP. Other measures for general care should include the placement of a nasogastric tube, gastric acid suppression with H 2 blockers, and administration of steroids in patients with the fat emboli syndrome. Hemodynamic monitoring is invaluable and should be initiated early in the course of the disease process. Patients with any evidence of fluid overload should receive aggressive diuresis, whereas others may require fluid resuscitation for maintenance of tissue perfusion while the pulmonary–capillary wedge pressure is maintained below 15 mm Hg. Pulmonary wedge pressure may be falsely elevated when PEEP is being applied. The goal of management is to maintain the lowest pulmonary–capillary wedge pressure, with acceptable cardiac output and blood pressure. In the presence of hypotension and oliguria, inotropic support with dopamine or dobutamine is helpful. With aggressive management, particularly if the inciting cause is identified and treated, ARDS can be reversed during the first 48 hours with few sequelae. After the first 48 hours, however, progression of the ARDS will cause lung damage that may leave residual pulmonary fibrosis. With progression beyond 10 days, multiple organ system failure occurs and the mortality rate is higher than 80% ( 234).

Renal Disease The need for surgical intervention in patients with renal impairment has resulted in the development of a very specialized medical approach to their care. Special precautions are necessary to compensate for the kidney's impaired ability to regulate fluids and electrolytes and excrete metabolic waste products. Equally important are the unique problems that develop in patients with chronic renal impairment, including an increased risk of sepsis, coagulation defects, impaired immune function and wound healing, and a propensity to develop specific acid-base abnormalities. Special consideration must be given to a variety of different medications, anesthetic agents, and numerous hematologic and nutritional factors that are important in the successful surgical care of patients with renal insufficiency. Management of fluid levels and cardiovascular hemodynamics in patients with acute or chronic renal impairment is paramount. Intravascular fluid volume changes that lead to hypertension or hypotension are very common in these patients and are often difficult to manage secondary to autonomic dysfunction, acidosis, and other problems that are inherent to the underlying kidney disease. Patients undergoing dialysis for whom major abdominal or pelvic surgery is contemplated should be treated using a Swan-Ganz catheter intraoperatively and postoperatively. The results of physical examination and central venous pressure monitoring correlate poorly with left cardiac filling pressures. Swan-Ganz catheter measurements will help guide fluid replacement and avoid volume overload. Invasive hemodynamic monitoring should be continued as needed throughout the first postoperative week because third spacing will occur during this period. Postoperative dialysis is usually necessary to avoid problems associated with fluid overload and hyperkalemia. Dialysis-dependent patients should undergo dialysis approximately 24 hours following surgery. A short-lived but rather significant fall in the number of platelets occurs during dialysis, and heparin is used in hemodialysis equipment to prevent clotting. Because of these factors and concerns about postoperative bleeding, dialysis is usually avoided during the first 12 to 24 hours following surgery. Although ischemic heart disease is the most common cause of death in patients with renal insufficiency, it is not a major cause of perioperative mortality (235). A large percentage of perioperative deaths of patients with renal insufficiency are associated with hyperkalemia that is controlled most effectively by dialysis (236). Patients with chronic renal failure are at an increased risk for postoperative infections resulting from abnormalities in neutrophil and monocyte function ( 237). Appropriate preoperative antibiotic prophylaxis and an accurate assessment of nutritional status will lower the incidence of postoperative infectious complications. The major hematologic concern in patients with chronic renal insufficiency is the increased incidence of bleeding. These bleeding problems are secondary to abnormal bleeding times and, in particular, disorders of platelet function related to a decreased amount of factor VIII and von Willebrand antigen in the serum of uremic patients. Anemia, which is common in patients with renal insufficiency, can contribute to prolonged bleeding times ( 238). Abnormalities in arachidonic acid metabolism, acquired platelet storage pool deficiency, and disturbed regulation of platelet calcium content all account for an increased tendency for uremic patients to have significant bleeding during surgery ( 239). Therefore, the bleeding time should be routinely checked preoperatively in these patients and abnormalities should be corrected before surgery. Options for the correction of bleeding time in uremic patients include infusion of desmopressin or cryoprecipitate, both of which act to increase plasma levels of factor VIII and von Willebrand antigen ( 240,241). Normal renal function is essential for maintenance of acid-base balance in the body. Patients with renal insufficiency can have a normal anion gap or an elevated anion gap acidosis. When mild renal insufficiency develops, a normal anion gap can be seen, whereas in more significant and severe renal dysfunction, an elevated anion gap acidosis occurs. Hemodialysis corrects metabolic acidosis. If a patient is severely acidotic (pH less than 7.15) and emergency surgery is planned, correction of the blood pH to 7.25 using intravenous sodium bicarbonate is indicated. Correction of metabolic acidosis should be carried out slowly, however, because in patients with hypocalcemia seizures may be precipitated ( 241). It is also important to exclude other causes of elevated anion gap acidosis, such as ketoacidosis secondary to diabetes, lactic acidosis secondary to infection or, in rare instances, poisoning with ethylene glycol, methanol, or aspirin. Impaired kidney function causes phosphate retention by the kidney and impaired vitamin D metabolism. Therefore, hypocalcemia is common in patients with renal insufficiency, but tetany and other signs of hypocalcemia are relatively uncommon because metabolic acidosis raises the level of ionized calcium. Oral phosphate binders such as aluminum hydroxide (1 to 2 g per meal) and dietary phosphate restriction (1 g per day) is the usual treatment for hypocalcemia-hyperphosphatemia in patients with renal insufficiency. In chronic situations, because of central nervous system toxicity associated with elevated aluminum levels, it is preferable to treat hypocalcemia-hyperphosphatemia with large doses of calcium carbonate (6 to 12 g per day) rather than with the standard aluminum-containing antacids ( 242). Approximately 20% of patients with renal insufficiency will exhibit clinical evidence of protein calorie malnutrition. Vitamin deficiencies, most notably with water-soluble

vitamins, also occur with dialysis. Nutritional disturbances in patients with chronic renal insufficiency arise secondary to deficiencies in protein intake, and studies have shown that, in patients with chronic renal insufficiency, their kidneys are hyperfiltrating ( 243). Postoperatively, both protein and caloric intake may need to be increased dramatically to meet catabolic demands in surgical patients. As much as 1.5 g/kg of protein and 45 kcal/kg of calories may be needed ( 243). Wound healing is impaired in patients with chronic renal failure, and wound dehiscence and evisceration are potential problems. Wound healing is most appropriately aided by nutritional assessment preoperatively and maintenance of adequate caloric and protein intake in the perioperative setting. Antibiotic prophylaxis should be used in these patients, and uremia should be treated with dialysis as indicated. A running mass-closure of the midline vertical incision with continuous monofilament sutures should be used to further decrease the risk of wound dehiscence and evisceration ( 244). Patients with chronic renal disease have an altered ability to excrete drugs and are prone to significant metabolic derangements secondary to the altered bioavailability of many commonly used medications. Because of this, as well as the effect of dialysis on drug pharmacokinetics, the gynecologic surgeon and nephrologist must be aware of the lowered metabolism and bioavailability of narcotics, barbiturates, muscle relaxants, antibiotics, and other drugs that require renal clearance. Of particular note is the inability of patients with renal insufficiency to clear the neuromuscular blockade caused by pancuronium (245). Care must be taken with D-tubocurarine, especially if repeated doses are given ( 246). Midazolam, propofol, vecuronium, and atracurium have been safely used in patients with renal failure (241). Succinylcholine has been reported to cause significant hyperkalemic responses in patients with renal failure ( 247). Succinylcholine can be used safely in patients with chronic renal insufficiency. Careful monitoring of the serum potassium level is necessary ( 248). Perioperative acute renal failure in previously normal patients may be caused by decreased renal perfusion, nephrotoxins, or both. Patients with impaired cardiac function, intravascular volume depletion, sepsis, or hypotension fall under the first category. Nephrotoxic medications such as aminoglycosides, chemotherapeutic agents such as cisplatin, or iodinated contrast agents fall under the second category ( 249,250 and 251). The risk of renal impairment becomes cumulative if more than one of these factors exist at the same time, and especially if a variety of factors are associated with intervascular volume depletion ( 252). Several measurements should be used to avoid acute renal failure. All nephrotoxic drugs should be discontinued when possible; when it is not practical to withdraw medication, strict attention should be paid to the pharmacokinetic characteristics of each drug as well as to the regular measurements of the serum creatinine. Patients with diabetes should be given reduced doses of radiocontrast agents and should be well hydrated because they are particularly susceptible to renal injury from these materials (253). Volume repletion is essential to lower the incidence of renal impairment ( 254).

Liver Disease Management of perioperative problems in gynecologic patients with liver disease requires a comprehensive understanding of normal liver physiology and the pathophysiology underlying diseases of the liver that may complicate surgery or recovery. Patients with liver disease often have numerous complicated problems involving nutrition, coagulation, wound healing, encephalopathy, and infection. History and Physical Examination Patients with a history of alcohol abuse, drug use, hepatitis, jaundice, blood product exposure, or a family member with liver disease should undergo biochemical evaluation. During the physical examination, note should be made of any jaundice, signs of muscle wastage, ascites, right upper quadrant tenderness, or hepatomegaly. Laboratory Testing The biochemical profile (alkaline phosphatase, calcium, lactic acid dehydrogenase, bilirubin, serum glutamic-oxaloacetic transaminase, cholesterol, uric acid, phosphorous, albumin, total protein, and glucose) has not been shown to be useful for routine preoperative evaluation ( 255). Mild abnormalities lead to further extensive testing that require consultation, delays in surgery, and increased cost without net benefit. A possible exception is selected use of biochemical testing when the history or physical examination reveals abnormalities. Patients with known liver disease should undergo albumin and bilirubin testing using the Child's risk classification (Table 19.15). This system was originally designed to predict mortality following portosystemic shunt surgery. It divides patients into three classes of severity based on five easily assessed clinical parameters. Measurement of prothrombin time may also be helpful in patients with significant histories of liver disease. If a history of hepatitis is ascertained, the patient should be tested for serum aminotransferase, alkaline phosphatase, bilirubin, and albumin levels. Serologic documentation of hepatitis is also important. If a patient has a known malignancy, there may be some benefit from biochemical testing of the liver as a screen for metastatic disease, although this has not been proved conclusively.

Table 19.15. Child's Classification of Liver Dysfunction

Anesthesia With few exceptions, most anesthetic agents, including those administered by epidural or spinal routes, reduce hepatic blood flow and decrease oxygenation of the liver. Other perioperative factors—hemorrhage, intraoperative hypotension, hypercarbia, congestive heart failure, and intermittent positive pressure ventilation, especially in critically ill patients—lead to decreased hepatic perfusion and hypoxia ( 256). Drug Metabolism Patients with altered liver function should be carefully monitored because of the prolonged action of many medications used during surgery. In addition to impaired metabolism, hypoalbuminemia decreases drug binding, which alters serum levels and biliary clearance rates. The degree of hepatic metabolism varies greatly, depending on the type of medication being considered. For inhalation anesthetics, isoflurane is preferred because it undergoes minimal hepatic metabolism in comparison with halothane or enflurane. Narcotics, induction agents, sedatives, and neuromuscular blocking agents all undergo abnormal metabolism in patients with decompensated liver disease. Diazepam, meperidine, and phenobarbital cause prolonged depression of consciousness and may precipitate hepatic encephalopathy because of their altered rates of clearance. Sufentanil and oxazepam are the preferred narcotics, and benzodiazepine should be used for patients with altered liver function. Muscle relaxants, such as D-tubocurarine, pancuronium, and vecuronium, cause prolonged neuromuscular blockade in patients with impaired liver function and are not ideal drugs to use in this situation. Atracurium is not metabolized by the liver and, therefore, is the preferred muscle relaxant for patients with abnormal hepatic function. Succinylcholine metabolism is greatly prolonged in patients with hepatic dysfunction and must be used with great caution ( 257). Determination of Operative Risk Although it is well known that acute hepatobiliary damage results in increased morbidity and mortality in the surgical patient, estimating the operative risk in patients with hepatic dysfunction is troublesome, because it is often difficult to determine which patients are at risk based on the history and physical examination. The most accurate method for risk assessment of surgery in patients with hepatic dysfunction is Child's classification ( Table 19.15). Using this system, accurate assessment of

morbidity and mortality can be directly related to the degree of liver dysfunction ( 258). The Child's classification has been shown to be useful for patients undergoing a variety of different types of abdominal surgery. Operative mortalities of 10%, 31%, and 76% have been reported for each of the three Child's classifications, respectively (259). The major cause of perioperative death was sepsis. This classification correlated significantly with postoperative complications such as bleeding, renal failure, wound dehiscence, and sepsis. Acute Viral Hepatitis Acute viral hepatitis poses an increased risk of operative complications and perioperative mortality and, therefore, elective surgery is contraindicated ( 260). Elective surgery should be delayed for approximately 1 month after the results of all biochemical tests have returned to normal ( 261). In patients with ectopic pregnancy, hemorrhage, or bowel obstruction secondary to malignancy, however, surgical intervention must take place before normalization of serum transaminase ( 260). In these situations, the perioperative morbidity (12%) and mortality (9.5%) rates are much higher than when they are performed under ideal situations ( 257). Chronic Hepatitis Chronic hepatitis is a group of disorders characterized by inflammation of the liver for at least 6 months. The disease is divided by morphologic and clinical criteria into chronic persistent hepatitis and chronic active hepatitis. A liver biopsy is usually required to establish the extent and type of injury. The surgical risk in these patients correlates most closely with the disease severity. The risk of surgery in patients with asymptomatic or mild disease is minimal, in contrast to a significant risk for those patients who have symptomatic chronic active hepatitis ( 262). Elective surgery is contraindicated in symptomatic patients, and nonelective surgery is associated with significant morbidity ( 261). In the nonelective situation, patients taking long-term glucocorticoid therapy should be given appropriate stress coverage with a higher dose of glucocorticoids during the perioperative period. Preoperatively, patients who are not taking steroids should receive prednisone and azathioprine, which have been shown to reduce the perioperative risk of complications and may result in remission in up to 80% of patients ( 263). More recently, a controlled randomized trial of prednisone and interferon-a has documented regression of the hepatitis B core antigen and hepatitis B viral DNA replication in approximately 30% of patients (264). Interferon-a has also been used in the treatment of hepatitis C. Consideration should be given to using these medications for patients in whom surgery cannot be avoided but is not emergent. Asymptomatic carriers of the hepatitis B virus (individuals who test positive for the hepatitis B surface antigen) are not at increased risk for postoperative complications in the absence of elevated aminotransferase levels and liver inflammation. There is, however, a significant risk to the health care professional when operating on these individuals. In cases of needle stick in which the patient's hepatitis status is unknown, both the health care worker and the patient should be tested for HCV antibody and HBV serologic markers. If markers for HBV infection are present, hepatitis B immune globulin should be administered to unvaccinated medical personnel. A vaccination series should then be initiated during the early postoperative period. If the health care worker is immune (surface antibody positive), no treatment is necessary (257). All medical personnel, and especially those in the surgical subspecialties, should receive a full course of recombinant hepatitis B vaccine as recommended by the Centers for Disease Control and Prevention ( 265). Alcoholic Liver Disease Alcoholic liver disease encompasses a spectrum of diseases including fatty liver, acute alcoholic hepatitis, and cirrhosis. Elective surgery is not contraindicated in patients with fatty liver because liver function is preserved. If nutritional deficiencies are discovered, they should be corrected prior to elective surgery. Acute alcoholic hepatitis is characterized on biopsy by hepatocyte edema, polymorphonuclear leukocyte infiltration, necrosis, and the presence of Mallory bodies. Elective surgery in these patients is contraindicated ( 266). Abstinence from alcohol for approximately 6 to 12 weeks along with clinical resolution of the biochemical abnormalities are recommended before surgery is considered. Severe alcoholic hepatitis may persist for several months despite abstinence and, if any question of continued activity exists, a liver biopsy should be repeated ( 267). In cases of urgent or emergent surgery on patients with alcohol dependence, a benzodiazepine taper is appropriate as prophylaxis against alcohol withdrawal. Cirrhosis Cirrhosis is an irreversible liver lesion characterized histologically by parenchymal necrosis, nodular degeneration, fibrosis, and a disorganization of hepatic lobular architecture. The most serious complication of cirrhosis is portal venous hypertension that ultimately leads to bleeding from esophageal varices, ascites, and hepatic encephalopathy. Conventional liver biochemical test results correlate poorly with the degree of liver impairment in patients with cirrhosis. Hepatic dysfunction, however, may be somewhat quantitated by low albumin levels and prolonged prothrombin times. Surgical risk is clearly increased in patients with cirrhosis, although it is substantially greater in emergency surgery than in elective surgery. Perioperative mortality correlates with the severity of cirrhosis and can be estimated through the use of the Child's classification ( Table 19.15). Surgery in patients with Child's class A cirrhosis can usually be performed without significant risk, whereas surgery in patients with Child's class B or C poses a major risk and requires careful preoperative consideration. Meticulous preoperative preparation may improve the surgical outcome ( 268).

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Chapter 20. Incontinence, Prolapse, and Disorders of the Pelvic Floor Novak’s Gynecology

Chapter 20

Incontinence, Prolapse, and Disorders of the Pelvic Floor Shawn A. Menefee L. Lewis Wall

Pelvic Floor Anatomy Pelvic Support Lower Urinary Tract Function Colorectal Function Lower Urinary Tract Dysfunction Urinary Incontinence Mixed Incontinence Functional or Transient Incontinence Disorders of Bladder Emptying, Storage, and Contents Voiding Difficulty Disorders of Bladder Sensation Pelvic Organ Prolapse Definition and Classification Symptoms of Prolapse Examination Treatment Colorectal Dysfunction Anal Incontinence Rectal Prolapse Constipation References

The genital and urinary tracts are intimately associated anatomically and embryologically from the earliest stages of their development. The bladder is located directly above the anterior vaginal wall, and the urethra is fused to it. Both of these structures, as well as other structures of the pelvic floor, are placed at risk during pregnancy and childbirth. Each organ system in the pelvic floor—urinary, genital, intestinal—traverses the pelvis and exits through its own orifice. Thus, these systems are intricately related in function and anatomic support ( 1). Disorders of each of these components should be evaluated in light of their impact on the function of the surrounding structures and the functional anatomy of the pelvic floor. The term urogynecology has been coined to describe the area of gynecology that deals with disorders of the female lower urinary tract; however, it has become apparent that urinary tract disorders are only one facet of a wide range of pelvic floor disorders that afflict women. As part of this growing recognition, the American Board of Obstetrics and Gynecology and the American Board of Urology have recently agreed to begin the process of jointly accrediting fellowship programs in Female Pelvic Medicine and Reconstructive Surgery. This effort to train both urologists and gynecologists in the treatment of all aspects of pelvic floor dysfunction is a positive step toward improving the care of patients afflicted with these common conditions.

Pelvic Floor Anatomy The striated muscles of the pelvic floor, in combination with their fascial attachments, work together across the entire pelvis to prevent pelvic organ displacement, to maintain continence, and to control expulsive activities. An appreciation of the fact that these organ systems have complex interrelationships should help clinicians realize that patients' problems are not necessarily limited to a single organ; rather, each disturbance of pelvic support or continence exists within a complex pelvic “ecosystem” and, as a result, may be linked to problems in other organ systems.

Pelvic Support The bony pelvis surrounds and protects its contents but, by itself, actually provides them with little support. The pelvic organs are supported primarily by the muscular activity of the pelvic floor, aided by ligamentous attachments. Rather than functioning as a rigid structure, the pelvic floor muscles provide dynamic support through constant activity, functioning more like a self-regulating trampoline that continually adjusts its tension in response to changing circumstances ( 2,3). The functional anatomy of the muscles of the pelvic floor (the levator ani) has been studied for many years but remains poorly understood ( 4). The pelvic floor muscles contract to maintain urinary and fecal incontinence and relax to permit bowel and bladder emptying. The pelvic floor plays a role in normal female sexual responsiveness (5). It must distend tremendously to allow the delivery of a term infant but must contract again during the postpartum period to allow its varied functions to continue. Because the urethra, bladder, rectum, and supporting structures of the pelvis are all part of the pelvic floor, the functions of these organs cannot really be understood without an understanding of the pelvic musculature (see Chapter 5) (6,7). Levator Ani Muscle The nomenclature of the pelvic muscles has long been subject to debate. The levator ani muscle (the broad general term for most of the muscles of the pelvic floor) has been described as consisting of a diaphragmatic portion (iliococcygeus) and the more important pubovisceral portion ( 8). The iliococcygeus portion of the levator ani consists of a thin muscular sheet that arises from the pelvic sidewall on either side of the arcus tendineus and ischial spine and inserts into a midline raphe behind the rectum. The pubovisceral (pubococcygeus) portion of the levator ani muscle consists of a thick U-shaped band of muscle arising from the pubic bone and attaching to the lateral walls of the vagina and rectum ( Fig. 20.1). Therefore, the rectum is supported by a muscular sling that pulls it toward the pubic bones when these muscles contract. This muscular band is often called the puborectalis or the pubococcygeus muscle, but a more accurate term is the pubovisceral muscle because these muscles arise from the pubic bone and insert directly onto pelvic viscera or provide a supporting sling for them.

Figure 20.1 The levator ani muscles, as seen from below. (From Goss CM, ed. Gray's anatomy of the human body. 28th ed. Philadelphia, Lee & Febiger, 1966:447, with permission.)

When the pubovisceral muscle contracts, it pulls the rectum, vagina, and urethra anteriorly toward the pubic bone and constricts the lumens of these pelvic organs (Fig. 20.2). It is this contractile property that is so important in maintaining urinary and fecal continence and in providing support for the genital organs (vagina, cervix, uterus) that lie upon and are supported by the levator plate. The medial portions of the pubovisceral muscle (levator ani) pass laterally to the arcus tendineus fasciae of the pelvis and attach to the endopelvic fascia surrounding the vaginal wall at a point opposite the upper half of the urethra ( 9,10 and 11) (Fig. 20.3). The pubovisceral muscle attaches to a web of endopelvic fascia rather than directly to the urethra in this area. This portion of the muscle (puborectalis) contains large quantities of type I (“slow-twitch”) muscle fibers that are tonically contracted. This baseline level of muscular activity provides constant resilient support for the urethra. At the same time, type II (“fast-twitch”) fibers allow the pubovisceral muscle to respond quickly to rapid changes in intraabdominal pressure (coughing, sneezing) and to maintain urethral closure under such conditions ( 12). Reflex contraction of both types of muscle fibers helps support all of the contents of the pelvis.

Figure 20.2 A: The “pubovisceral” muscle at rest. B: Contraction of the pubovisceral muscle constricts the lumens of the urethra, vagina, and rectum, augmenting closure of all three organs.

Figure 20.3 Frontal section of the cadaver of a 21-year-old woman at the vesical neck showing the supportive layer formed by the vaginal wall (VW) and the endopelvic fascia (E) attached to the pelvic wall at the arcus tendineus fasciae pelvis (ATFP) on the inner surface of the levator ani (LA) at the level of the proximal urethral and internal urinary meatus (IUM). The area where the pubic bones were removed is shaded (PB). The image is reconstructed from a specimen made from the left side of the body by reflecting it across the midline. (From Delancey J. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170:1715, with permission.)

As with the external anal sphincter, the levator ani muscles exhibit constant baseline tone in addition to their ability to contract and offset increases in intraabdominal pressure that would force pelvic contents downward. The phenomenon of constant baseline tone is separate from the ability of these muscles to contract forcefully. This aspect of pelvic muscle function is poorly understood, but it is critical for proper pelvic support because closure of the pelvic floor allows the pelvic viscera to rest on a muscular shelf. The constant adjustments in muscle activity maintain pelvic floor closure in response to changing circumstances and keep the pelvic ligaments from stretching. Pelvic Ligaments It is often erroneously believed that the various pelvic ligaments are the most important factors in pelvic support. Ligaments are poorly suited to maintaining support over time because fibrous tissues elongate when subjected to constant tension. The pelvic ligaments serve mainly to keep structures in positions where they can be supported by muscular activity rather than acting as weight-bearing structures themselves. The loss of normal muscular support leads to sagging and widening of the urogenital hiatus and predisposes patients to the development of pelvic organ prolapse ( 13) (Fig. 20.4).

Figure 20.4 Supportive role of the levator plate. Note how muscle tone in the levator muscle complex keeps the urogenital hiatus constricted and relatively closed

(top). As muscle tone is lost, the levator plate sags, gradually widening the levator hiatus and predisposing the patient to the development of prolapse ( bottom).

Although fascia and ligaments are believed to be essential for support of the pelvic organs, this belief comes more from the amount of attention given to these structures in the performance of gynecologic surgery than from any empiric evidence regarding their role in pelvic support. However, the pelvic ligaments (i.e., the round, infundibulopelvic, and cardinal) are loose condensations of areolar tissue, blood vessels, and muscle fibers. By themselves, they have little supportive strength; rather, they function as “moorings” to hold the uterus and vagina in place. The pelvic ligaments and the endopelvic fascia attach the uterus and vagina to the pelvic sidewalls so that these structures can be supported by the muscles of the pelvic floor. The entire complex then rests on the levator plate, where it can be closed by increases in intraabdominal pressure by a flap-valve effect ( 14). Connective Tissue Connective tissue is the “glue” of the body. It is composed primarily of elastin and collagen fibers in a polysaccharide ground substance. The composition of connective tissue is not constant but varies in different sites throughout the body. Connective tissue forms capsules to help maintain the structural integrity of organs. It forms the fascia that covers muscles and the tendons and allows them to attach to other structures in the body. If connective tissue fails, muscular support is weak because the attachments that permit muscles to exercise their functions are unreliable ( 15). Connective tissue is not static; instead, it is a dynamic tissue that undergoes constant turnover and remodeling in response to stress. Connective tissue turnover and repair are especially important in relation to wound healing and recovery from surgery. Hormonal changes appear to have significant effects on collagen, and these effects are probably of great importance during pregnancy and parturition, as well as in aging ( 16,17 and 18). Exercise appears to increase collagen turnover, as measured by increased proline hydroxylase activity in 69-year-old women who exercised for 8 weeks (19). Nutrition has an important role in the maintenance of connective tissue integrity. Vitamin C deficiency (scurvy) produces defects in collagen synthesis and repair that can result in the breakdown of seemingly normal connective tissue, even including the reopening of old, previously healed wounds (20). Studies suggest that connective tissue abnormalities are a significant factor contributing to prolapse and related conditions. For example, joint hypermobility is a common clinical marker for abnormal collagen levels. Several studies have now shown an association between joint hypermobility and pelvic floor prolapse (21,22). Studies evaluating patients with a history of Ehlers-Danlos syndrome, a disorder of collagen synthesis, have revealed an increased incidence of urinary incontinence associated with this disorder ( 23,24). Fibroblasts grown in tissue culture from the fascia of women with recurrent genital prolapse have an imbalance of collagen types, with excessive synthesis of weaker type III collagen ( 25). Both collagen content and collagen strength appear to be decreased in the fascia of women with stress incontinence ( 26,27). However, pelvic support defects are affected by many different factors, and the ultimate clinical presentation (and perhaps the surgical solution) may be different for each patient ( 28).

Lower Urinary Tract Function The bladder is a complex organ that has a relatively simple function: to store urine effortlessly, painlessly, and without leakage and to discharge urine voluntarily, effortlessly, completely, and painlessly. To meet these demands, the bladder must have normal anatomic support as well as normal neurophysiologic function. Normal Urethral Closure Normal urethral closure is maintained by a combination of intrinsic and extrinsic factors. The extrinsic factors include the levator ani muscles, the endopelvic fascia, and their attachments to the pelvic sidewalls and the urethra. This forms a hammock beneath the urethra that responds to increases in intraabdominal pressure by remaining tense, allowing the urethra to be closed against the posterior supporting shelf ( Fig. 20.5). When this supportive mechanism becomes faulty for some reason—the endopelvic fascia has detached from its normal points of fixation, muscular support has weakened, or a combination of these two processes—normal support is lost, and anatomic hypermobility of the urethra and bladder neck develops. For many women, this loss of support is severe enough to cause loss of closure during periods of increased intraabdominal pressure, and stress incontinence results. However, many women remain continent in spite of loss of urethral support ( 11).

Figure 20.5 Lateral view of the pelvic floor drawn from a three-dimensional reconstruction with the urethra, vagina, and fascial tissues transected at the level of the vesical neck. Note how the urethra is compressed against the underlying supportive tissues by the downward force (arrow) generated by a cough or sneeze. (From Delancey J. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994;170:1718, with permission.)

The intrinsic factors contributing to urethral closure include the striated muscle of the urethral wall, vascular congestion of the submucosal venous plexus, the smooth muscle of the urethral wall and associated blood vessels, the epithelial coaptation of the folds of the urethral lining, urethral elasticity, and the tone of the urethra as mediated by a-adrenergic receptors of the sympathetic nervous system. The intrinsic competence of the urethral closure mechanism can be affected by congenital developmental defects, scarring from trauma or multiple unsuccessful surgical procedures, estrogen deficiency, and neurologic injury. Stress incontinence resulting from intrinsic sphincteric deficiency is more difficult to correct than that occurring from loss of proper anatomic support. Urethral support alone, however, is not responsible for ensuring the integrity of the closure mechanism. The bladder is an autonomic organ under voluntary control, and neurophysiology plays a role in its function, although our understanding of these complex processes is limited ( 29). The Bladder The bladder is a bag of smooth muscle that stores urine and contracts to expel urine under voluntary control. It is a low-pressure system that expands to accommodate increasing volumes of urine without an appreciable rise in pressure. This function appears to be mediated primarily by the sympathetic nervous system. During bladder filling, there is an accompanying increase in outlet resistance. This action is manifest as increasing muscle fiber recruitment, as seen with electromyography of the pelvic floor and urethra while performing filling cystometry. The bladder muscle (the detrusor) should remain inactive during bladder filling, without involuntary contractions. When the bladder has filled to a certain volume, fullness is registered by tension-stretch receptors, which signal the brain to initiate a micturition reflex. This reflex is permitted or not permitted by cortical control mechanisms, depending on the social circumstances and the state of the patient's nervous system. Normal voiding is accomplished by voluntary relaxation of the pelvic floor and urethra, accompanied by sustained contraction of the detrusor muscle, leading to complete bladder emptying. Innervation The lower urinary tract receives its innervation from three sources: (a) the sympathetic and (b) parasympathetic divisions of the autonomic nervous system

and (c) the neurons of the somatic nervous system (external urethral sphincter). The autonomic nervous system consists of all efferent pathways with ganglionic synapses that lie outside the central nervous system. Although knowledge of the norepinephrine of the autonomic nervous system is incomplete, it appears that the sympathetic system primarily controls bladder storage and that the parasympathetic nervous system controls bladder emptying. The somatic nervous system plays only a peripheral role in neurologic control of the lower urinary tract through its innervation of the pelvic floor and external urethral sphincter. The sympathetic nervous system originates in the thoracolumbar spinal cord, principally T11 through L2 or L3. The ganglia of the sympathetic nervous system are located close to the spinal cord and use acetylcholine as the preganglionic neurotransmitter. The postganglionic neurotransmitter in the sympathetic nervous system is norepinephrine, and it acts on two types of receptors: a receptors, located principally in the urethra and bladder neck, and b receptors, located principally in the bladder body. Stimulation of a receptors increases urethral tone and thus promotes closure. a-Adrenergic receptor blockers have the opposite effect. Stimulation of b receptors decreases tone in the bladder body. The parasympathetic nervous system controls bladder motor function—bladder contraction and bladder emptying. The parasympathetic nervous system originates in the sacral spinal cord, primarily in S2 to S4, as does the somatic innervation of the pelvic floor, urethra, and external anal sphincter. Sensation in the perineum is also controlled by sensory fibers that connect with the spinal cord at this level. For this reason, examination of perineal sensation, pelvic muscle reflexes, and pelvic muscle or anal sphincter tone is relevant to clinical evaluation of the lower urinary tract. The parasympathetic neurons have long preganglionic neurons and short postganglionic neurons, which are located in the end organ. Both the preganglionic and postganglionic synapses use acetylcholine as their neurotransmitter, acting on muscarinic receptors. Because acetylcholine is the main neurotransmitter used in bladder muscle contraction, virtually all drugs used to control detrusor muscle overactivity have anticholinergic properties. Unfortunately, cholinergic stimulants appear to be ineffective in promoting bladder emptying, even though they cause bladder muscle strips to contract in a laboratory setting, thus making medical treatment of voiding dysfunction unsuccessful in most cases. Bladder storage and bladder emptying involve the interplay of the sympathetic and parasympathetic nervous systems. The modulation of these activities appears to be influenced by a variety of nonadrenergic, noncholinergic neurotransmitters and neuropeptides, which fine-tune the system at various facilitative and inhibitory levels in the spinal cord and higher areas of the central nervous system ( 30,31 and 32). Thus, neuropathology at almost any level of the neurourologic axis can have an adverse effect on lower urinary tract function. Micturition Micturition is triggered by the peripheral nervous system controlled by the central nervous system. It is useful to consider this event as occurring at a micturition threshold, a bladder volume at which reflex detrusor contractions occur. The threshold volume is not fixed but instead is variable, and it can be altered depending on the contributions made by sensory afferents from the perineum, bladder, colon, and rectum as well as input from the higher centers of the nervous system. The micturition threshold is, therefore, a floating threshold that can be altered or reset by various influences. The spinal cord and higher centers of the nervous system have complex patterns of inhibition and facilitation. The most important facilitative center above the spinal cord is the pontine-mesencephalic gray matter of the brain stem, often called the pontine micturition center, which serves as the final common pathway for all bladder motor neurons. Transection of the tracts below this level leads to disturbed bladder emptying, whereas destruction of tracts above this level leads to detrusor hyperreflexia. The cerebellum serves as a major center for coordinating pelvic floor relaxation and the rate, force, and range of detrusor contractions, and there are multiple interconnections between the cerebellum and the brain-stem reflex centers. Above this level, the cerebral cortex and related structures exert inhibitory influences on the micturition reflex. Thus, the upper cortex exerts facilitative influences that release inhibition, permitting the anterior pontine micturition center to send efferent impulses down the complex pathways of the spinal cord, where a reflex contraction in the sacral micturition center generates a detrusor contraction that causes bladder emptying.

Colorectal Function The sigmoid (S-shaped) colon begins at the pelvic brim and straightens as it enters the pelvis to become the rectum. Below the cul-de-sac, it expands into the rectal ampulla, filling the posterior pelvis from the left side. An anorectal angle of 90 degrees is formed at this point by the action of the puborectalis portion of the levator ani muscle complex, separating the anal canal below from the rectum above. The anorectal angle is believed to be one factor among several that are important in the maintenance of normal anal continence. The puborectalis muscle maintains this angle through its normal tone, and during normal defecation, it relaxes to depress the pelvic floor and then contracts to elevate the pelvic floor during and after bowel emptying. The anorectal continence mechanism consists of an internal sphincter composed of smooth muscle and an external sphincter composed of striated muscle. The internal sphincter is a visceral muscle under autonomic control and normally has a high resting tone. The external sphincter is a striated muscle under voluntary control. In addition, there are sensory nerves in the rectum and pelvic floor. Continence is maintained at the level of the internal anal sphincter by gradual increases in the level of tonic contraction of the internal anal sphincter. This seal works only if the anal lining is sufficiently bulky to permit closure, and it is maintained by a combination of vascularity and infolding of the anal lining. The contractile efficiency of the internal sphincter is aided by contraction of the external anal sphincter. Rapid rectal distention causes a reflex relaxation of the internal anal sphincter. Under these circumstances, continence is maintained by contraction of the external sphincter. The efficiency of this process is closely linked to rectal sensation. Afferent sensation from the rectum appears to travel with the parasympathetic nerves to sacral segments S2 to S4. Sensation from the anal canal also travels to these sacral segments through the inferior hemorrhoidal branches of the pudendal nerve. The sensory apparatus of the rectum allows patients to distinguish between solid feces, liquid stool, and flatus. Impairment of this ability can have serious social consequences. Innervation The innervation of the gut is similarly complex. There are two ganglionic complexes in the bowel wall: (a) a myenteric plexus between the longitudinal and circular muscle coats, and (b) a submucosal plexus. The innervation of the smooth muscle of the bowel involves excitatory and inhibitory nonadrenergic, noncholinergic neurotransmitters and cotransmitters, primarily acetylcholine, substance P, and vasoactive intestinal polypeptide. The sphincters appear to be under separate neuronal control from nonsphincteric smooth muscle of the bowel. Sympathetic stimulation (norepinephrine) appears to cause contraction of the internal anal sphincter, whereas parasympathetic stimulation causes relaxation of the internal anal sphincter. The internal anal sphincter receives sympathetic innervation by the hypogastric nerves from L5, and the parasympathetic innervation comes from sacral segments S1 to S3. The external anal sphincter is innervated by branches of the pudendal nerve, originating in the sacral segments S2 to S4, with some branches from the coccygeal nerve plexus (S4 to S5). Like the bladder, the colon and rectum undergo a filling and emptying cycle; unlike the bladder, the lower end of the gastrointestinal tract is not a closed viscus but rather a one-way conduit through which waste matter passes ( 33). Like the bladder, colorectal function can be categorized into storage (continence) and emptying (defecation) components. Anal Continence Anal continence is maintained by a combination of colonic compliance and mechanisms for retention in the rectosigmoid that keep the distal rectum collapsed and empty. The forces of retention are both mechanical and physiologic. The mechanical forces promoting retention of stool involve the S-shaped anteroposterior angulations of the sigmoid colon and the spiral folds in the lumen formed by the valves of Houston. Also, the puborectalis muscle creates a sharp angulation of the anorectum, which is accentuated by contraction of this muscle. Increases in intraabdominal pressure accentuate these angulations. These pressure increases have been postulated to create a flap-valve effect, which helps occlude the upper anal canal during periods of increased intraabdominal pressure ( 34); however, the principal mechanism of action may actually be a sphincter-like function exerted by puborectalis contraction ( 35). A flutter-valve effect may also be created in the collapsed anorectum (33,36). Retention of stool is further helped by a reverse pressure gradient between the rectum and the rectosigmoid colon. Waves of muscle contraction are both more frequent and of higher amplitude in the rectum than they are in the sigmoid. The most important factors in maintaining fecal continence are sphincteric factors. The anus has both internal and external sphincters. Both of these sphincters are tonically contracted in the resting state, with the internal sphincter more so than the external sphincter. The external sphincter contains both slow-twitch and fast-twitch fibers. It remains tonically contracted even during sleep. In addition to its tonic baseline contractility, the external anal sphincter can respond with a quick, forceful contraction during periods of stress to maintain anal control, and its degree of contraction varies with posture and activity. The internal sphincter is at or near its state of maximal contraction all of the time. It relaxes only to allow the passage of stool when the rectum reaches a threshold of distention. When this occurs, relaxation of

the internal sphincter allows the passage of matter into the distal anal canal. This stimulates multiple nerve endings to give warning of an impending movement of matter, which is detected as solid, liquid, or gaseous in nature. Continence is maintained by a reflex contraction of the external anal sphincter, which occurs concurrently with internal sphincter relaxation. Voluntary contraction of the anal sphincter, in conjunction with rectal compliance, allows the individual to withhold a bowel movement until it is appropriate to release it. Defecation Defecation is the emptying phase of the colonic cycle. This may occur involuntarily in certain pathologic states or as a response to prolonged overdistention of the rectum, but defecation usually is a voluntary process. Voluntary defecation begins with closure of the glottis, which helps increase intraabdominal pressure, and by closure of the muscles of the pelvic floor. The diaphragm descends, and the muscles of the abdominal wall are contracted, raising intraabdominal pressure. The anal sphincter also contracts, further increasing intraabdominal pressure. Segmental contractions in the colon are inhibited. When the bolus of feces reaches the upper rectum, the muscles of the pelvic floor relax, the pelvic floor descends, and the acute rectal angle that existed at rest is straightened. Constriction of the distal muscles allows pressure to build up in the rectum, and when the internal sphincter relaxes, the bolus of stool is expelled. As the bolus passes, there is complete inhibition of electrical activity in the external sphincter, which contracts again only after the stool has been passed. The act of defecation represents the only known condition in which the external sphincter responds to increased intraabdominal pressure by relaxation rather than by contraction. At the end of defecation, the pelvic floor is elevated to its normal position, and the sphincters return to their tonically contracted resting state (“the closing reflex”). The complex intricate mechanisms involved in maintenance of continence and defecation are poorly understood, grossly undervalued, and generally taken for granted until impairment occurs (34). The same is undoubtedly true for all aspects of pelvic floor function.

Lower Urinary Tract Dysfunction Symptoms arising in the lower urinary tract account for a significant number of patient visits to gynecologists. Disturbances in bladder function produce a wide variety of urinary tract symptoms. To help the clinician organize an initial patient evaluation, these symptoms can be classified according to whether they are disturbances of storage, emptying, sensation, or bladder contents ( Table 20.1).

Table 20.1. Classification and Definition of Lower Urinary Symptoms in Women

Urinary Incontinence Urinary incontinence is defined as involuntary loss of urine that is a social or hygienic problem and that is objectively demonstrable ( 37). Urinary incontinence is a symptom, not a diagnosis. It is not a normal part of aging, although the prevalence of the problem increases with age, and it is not a trivial complaint. Urinary incontinence affects 13 million Americans, with an estimated 1 million new cases diagnosed each year. The total annual cost to care for patients with incontinence in the United States is estimated at $11.2 billion in the community and $5.2 billion in nursing homes ( 38). The differential diagnosis of urinary incontinence is extensive (Table 20.2); however, urinary incontinence is almost always treatable. It can almost always be improved and frequently can be cured, often using relatively simple, nonsurgical interventions.

Table 20.2. Differential Diagnosis of Urinary Incontinence

Principles of Investigation The initial evaluation of most patients with incontinence is not difficult, but it requires a systematic approach to consider all possible causes. The following items should be part of the basic evaluation: 1. 2. 3. 4. 5.

History Physical examination Urinalysis, with urine culture and cytology as appropriate Measurement of postvoid residual urine Frequency/volume bladder chart

When these steps have been completed, some patients benefit from urodynamic studies to create a more comprehensive bladder biophysical profile before treatment. History Every incontinent patient should undergo a thorough history, including a review of symptoms, general medical history, review of past surgery, and current medications. It is helpful to write down the patient's chief complaint in her own words and expand the history from this point. The patient's most troubling symptoms must be ascertained—how often she leaks urine, how much urine she leaks, what provokes urine loss, what helps the problem or makes it worse, and what treatment (if any) she has had in the past. The general medical history often reveals systemic illnesses that have a direct bearing on urinary incontinence, such as diabetes mellitus (which produces osmotic

diuresis if glucose control is poor), vascular insufficiency (which can lead to incontinence at night when peripheral edema is mobilized into the vascular system, resulting in increased diuresis), chronic pulmonary disease (which can lead to stress incontinence from chronic coughing), or a wide variety of neurologic conditions that can affect the neurourologic axis at any point from the cerebral cortex to the peripheral nervous system. Many medications affect the lower urinary tract ( 39,40). 1. Sedatives such as the benzodiazepines may accumulate in the patient's system and cause confusion and secondary incontinence, particularly for elderly patients. 2. Alcohol may have similar effects to benzodiazepines and also impairs mobility as well as produces diuresis. 3. Anticholinergic drugs may impair detrusor contractility and may lead to voiding difficulty and overflow incontinence. Drugs with anticholinergic properties are widespread and include antihistamines, antidepressants, antipsychotics, opiates, antispasmodics, and drugs used to treat Parkinson's disease. 4. a-Adrenergic agents may have a profound effect on the lower urinary tract. a-Agonists, which are often found in over-the-counter cold remedies, increase outlet resistance and may lead to voiding difficulty. 5. a-Blockers, which are often used in the treatment of hypertension (e.g., prazosin, terazosin), may decrease urethral closure and lead to stress incontinence ( 41). 6. Calcium-channel blockers may reduce bladder smooth muscle contractility and lead to voiding problems or incontinence; they may also cause peripheral edema, which may lead to nocturia or nighttime urine loss. 7. Angiotensin-converting enzyme inhibitors may result in a chronic and bothersome cough that can result in increasing stress urinary incontinence in an otherwise asymptomatic patient (42). Physical Examination The physical examination of the patient with incontinence should include detection of general medical conditions that may affect the lower urinary tract. Such conditions include cardiovascular insufficiency, pulmonary disease, occult neurologic processes (e.g., multiple sclerosis, stroke, Parkinson's disease, and anomalies of the spine and lower back), as well as abnormalities of genitourinary development. The pelvic examination, including an evaluation of urethral support, is of crucial importance. 1. Patients with urinary incontinence should be examined with a full bladder, particularly if stress incontinence is a complaint. 2. The patient should stand with her feet separated to shoulder width and cough several times to see if the physical sign of stress incontinence can be demonstrated. If urine loss occurs, confirm with the patient that this is the problem that has been bothering her. Many multiparous women may lose a small amount of urine during such an examination but not be bothered by it. 3. Many women with urge incontinence caused by detrusor overactivity may demonstrate urine loss during a cough stress test, but this finding may not be relevant to their real complaint. The physical findings must be set within the context of the patient's history to be relevant. 4. The patient's complaint should be reproduced by the physician and confirmed with the patient, particularly if surgery is contemplated. Urinalysis Examination of the urine by dipstick testing and microscopy is necessary to exclude infection, metabolic abnormalities, and kidney disease. 1. Urine culture will help rule out infection, which can be associated with incontinence. 2. Urine cytology is useful as a screening test for urinary tract malignancy, but the utility of the test depends greatly on the accuracy of the laboratory performing the cytology. Routine urinary cytology is not helpful, but testing should be performed in women older than 50 years of age with irritative urinary tract symptoms, particularly if those symptoms are of sudden onset. 3. Hematuria should be evaluated with cytology, intravenous urography, and cystoscopy. Bladder biopsy should be performed by the surgeon who will treat the patient in the event that a malignancy is discovered. Measurement of Postvoid Residual Urine Incomplete bladder emptying is a frequent cause of incontinence. Patients with a large postvoid residual urine have a diminished functional bladder capacity because of the dead space occupied in the bladder by retained urine. This stagnant pool of urine is also a frequent source of urinary tract infections, because the major defense of the bladder against infection is frequent, complete emptying. A large postvoid residual can contribute to urinary incontinence in two ways. If the bladder is overdistended, increases in intraabdominal pressure can force urine past the urethral sphincter, causing stress incontinence. In some cases, bladder overdistention may provoke an uninhibited contraction of the detrusor muscle, leading to incontinence. Both conditions may exist together, further complicating the problem. Patients with an elevated postvoid residual urine should begin a regimen of clean, intermittent self-catheterization to improve bladder emptying. In many cases, this technique may be the only therapy needed to correct the incontinence and eliminate recurrent urinary tract infections. The recent development of sacral nerve root neuromodulation for nonobstructive voiding dysfunction now offers an additional treatment option for some of these women ( 43). Frequency/Volume Bladder Chart A frequency/volume bladder chart is an invaluable aid in the evaluation of patients with urinary incontinence, but use of this tool often is neglected ( 44,45). A frequency/volume chart is a voiding record kept by the patient for several days. Use of a plastic measuring “hat” that fits over the patient's toilet bowl is very helpful in keeping accurate records. Patients should be instructed to write down the time of every void on the chart and measure the amount of urine voided. The time of any incontinent episodes should be recorded, and it is also helpful to maintain an annotated record of symptoms or activities associated with urine loss. If desired, the patient can also be instructed to keep a record of fluid intake, although in most cases intake can be estimated with some accuracy from the amount of urine produced. A frequency/volume bladder chart gives an accurate record of 24-hour urinary output, the total number of daily voids, the average voided volume, and the functional bladder capacity (largest volume voided in normal daily life). This information allows the clinician to confirm complaints of urinary frequency with objective data and to determine whether part of the patient's problem is an abnormally high (or low) urinary output. For example, incontinence is a common complaint of many patients with diabetes, and the first step in the management of such patients is to control their blood glucose levels and decrease their urinary output rather than using medications or surgery, which often is ineffective. Conversely, many patients with incontinence decrease their fluid intake dramatically in an attempt to control their urine loss, not realizing that the resulting highly concentrated urine is often much more irritating to their bladders than a higher volume of a more diluted urine. As a rule, daily urine output should be 1,500 to 2,500 mL, with an average voided volume of about 250 mL, a functional bladder capacity (largest voided volume) of 400 to 600 mL, and seven or eight voids per day. The frequency/volume chart is the foundation for conservative management of urinary incontinence based on fluid manipulation and behavioral management of voiding habits. Urodynamic Studies At its most basic level, a urodynamic study is anything that provides objective evidence about lower urinary tract function ( 46). In this sense, measurement of a patient's voided urine volume and catheterization to determine her postvoid residual urine are urodynamic studies. A frequency/volume chart is also a valuable urodynamic study. Obtaining clinically useful information does not always require the use of expensive, complex technology. Bladder Filling Test If a patient with a complaint of urinary incontinence comes for her examination without a full bladder, a great deal of information can be obtained by a simple bladder filling test ( 47). The patient should urinate and measure the volume she voids. The residual urine can be measured by draining it through a 10- or 12-Fr. red rubber catheter placed into the bladder. Once the residual urine has been drained out, a bag of sterile water or saline attached to the catheter can be used to fill the patient's bladder at a rate of 60 to 75 mL/min until her functional bladder capacity is reached. If the patient experiences urgency with accompanying urine loss during bladder filling, it is highly likely that she has motor urge incontinence caused by detrusor overactivity. If the patient leaks an isolated spurt of urine each time she coughs, and this leakage is demonstrated repetitively and confirmed as the problem for which she is seeking help, she has stress incontinence. Further evaluation is required for patients who exhibit mixed incontinence (the presence of both stress and urge

incontinence), who exhibit prolonged leakage with coughing (suggestive of a cough-induced detrusor contraction), who have marked incontinence with a nearly empty bladder or with minimal effort, who develop incontinence after their prolapse is treated, or who report incontinence that cannot be verified by simple testing. Multichannel Urodynamic Studies Multichannel urodynamic studies produce a biophysical profile of a patient's bladder and urethral function, but such studies are helpful only if they are interpreted with reference to the patient's history and the results of her physical examination. Clinicians who recommend that patients undergo urodynamic studies without first taking a careful history and performing a thorough physical examination are likely to obtain useless or irrelevant information from these expensive investigations. A detailed history and a thorough physical examination often can predict reliably the type of incontinence when these findings are combined with those derived from some simple urodynamic tests (48,49 and 50). A wide variety of sophisticated studies of bladder and urethral function have been developed to measure various aspects of bladder storage and bladder emptying. These studies include uroflowmetry, filling cystometry, pressure-flow voiding studies (with and without simultaneous electromyography of the pelvic floor), urethral pressure profilometry, and determination of leak-point pressure. The bladder is affected by neural impulses running along afferent and efferent sensory pathways and generates a pressure–volume relationship in the cycle of micturition (Fig. 20.6). As bladder volume increases, tension-stretch receptors in the bladder wall are activated, and the afferent sensory impulses gradually lead to a desire to void. Normally, this occurs between 150 and 250 mL. Normally, a patient is able to suppress a micturition reflex until an appropriate time. She should then be able to relax the pelvic floor and generate a sustained contraction of the bladder detrusor muscle until emptying is complete, after which the detrusor relaxes and the cycle begins again.

Figure 20.6 Pressure–volume relationship of the micturition cycle. (1) The normal bladder accommodates increasing urine volumes without a significant increase in pressure. (2) At about 200 mL, the first sensation of bladder fullness is appreciated. (3) The micturition reflex can be suppressed until a socially acceptable time and place for urination presents itself. (4) At this time, a voluntary detrusor contraction is initiated, in conjunction with pelvic floor relaxation. (5) There is a brief isometric pressure rise before the bladder neck is open and flow starts. (6) Normal voiding is accomplished by a sustained detrusor contraction until bladder emptying is complete. (7) The detrusor muscle then relaxes and the process of filling begins anew. (From Wall LL, Addison WA. Basic cystometry in gynecologic practice. Postgrad Obstet Gynecol 1988;26[2]:2, with permission.)

Cystometry Cystometry is the technique by which the pressure–volume relationship of the bladder is measured. It can be divided into two phases: (a) filling cystometry and (b) voiding cystometry (also called a pressure-flow study). Simple cystometry is carried out when bladder pressure only is measured during filling. Because the bladder is an intraabdominal organ, however, the pressure recorded in the bladder is a combination of several other pressures, most notably the pressure created by the activity of the detrusor muscle itself and the pressure exerted on the bladder by the weight of the surrounding intraabdominal contents (e.g., uterus, intestines, straining, or exertion). For this reason, the technique of subtracted cystometry is used. Subtracted cystometry is an attempt to measure the pressure exerted in the bladder by the activity of the detrusor muscle. Subtracted cystometry is carried out by measuring total intravesical pressure (Pves) with a bladder pressure catheter, approximating intraabdominal pressure (Pabd) by measuring either rectal or vaginal pressure, and using an electronic instrument to subtract the latter from the former to give the true detrusor pressure (P det) or the subtracted pressure:

Measurements can be made using either expensive electronic microtip transducer pressure catheters or inexpensive fluid-filled pressure lines. The technique for such a study is shown in Figure 20.7.

Figure 20.7 Subtracted filling cystometry. Pressure catheters are in place in the bladder and rectum. An additional filling catheter has been placed in the bladder. Volume infused, total bladder pressure, rectal (abdominal) pressure, and subtracted detrusor pressure (intrinsic bladder pressure) are recorded. (From Wall LL, Addison WA. Basic cystometry in gynecologic practice. Postgrad Obstet Gynecol 1988;26(2):3).

1. Fluid (usually sterile water or saline, sometimes radiographic contrast dye) is infused at a rate of 50 to 100 mL/min. The volume infused and the pressure measurements are recorded continuously. The patient's bladder may be filled with her lying supine, in a modified lithotomy position, sitting, or standing. When possible, standing cystometry is usually preferable because most patients with incontinence complain of this problem when they are erect. 2. The point at which any leakage occurs should be noted carefully. 3. During filling, the point at which the first desire to void is experienced should be noted, along with the point at which the patient experiences a strong desire to void, urgency, and her cystometric capacity. 4. Provocative maneuvers are performed, such as coughing, heel-bouncing, and listening to the sound of running water in an attempt to produce urinary incontinence and to provoke any uninhibited detrusor contractions, which may be the cause of the patient's symptoms. Normal cystometric values for women are shown in Table 20.3.

Table 20.3. Approximate Normal Values of Female Bladder Function

At cystometric capacity (ideally, the same as the patient's functional bladder capacity), the filling catheter should be removed, leaving only the pressure measurement lines in place ( Fig. 20.8). If the pressures are allowed to equilibrate for 1 minute, bladder compliance can be calculated by dividing the bladder volume in milliliters by the pressure of water in centimeters. The patient should then void. The urine flow rate can be measured and correlated with the detrusor pressure. This technique allows a better assessment of voiding function than measurement of urine flow rate alone.

Figure 20.8 Pressure–flow voiding study. The filling catheter has been removed. Volume voided, urine flow rate, total bladder pressure, rectal (abdominal) pressure, and subtracted detrusor pressure are recorded. (From Wall LL, Addison WA. Basic cystometry in gynecologic practice. Postgrad Obstet Gynecol 1988;26[2]:3, with permission).

Urethral Pressure Profile In addition to an assessment of filling and emptying, specific urodynamic tests allow some quantitative assessment of sphincteric integrity. The urethral pressure profile is a test designed to measure urethral closure. Because continence requires the pressure in the urethra to be higher than the pressure in the bladder, it was believed that measuring the pressure differential between the two would provide useful clinical information. The urethral pressure profile is generated by slowly pulling a pressure-sensitive catheter through the urethra from the bladder, which is usually filled with a standardized volume of fluid ( Fig. 20.9). The urethral closure pressure (Pclose) is the difference between the urethral pressure (P ure) and the bladder pressure (P ves):

Figure 20.9 Parameters normally measured during urethral pressure profile studies (International Continence Society).

Although this pressure can be used to differentiate groups of normal women from groups of those with stress incontinence (women with stress incontinence tend to have higher urethral pressure levels than those who do not), there is considerable overlap between the two groups. It has also been suggested that women with stress incontinence with low urethral closure pressure ( Pessary

Conservative management of prolapse usually involves fitting the patient with a pessary. A wide variety of shapes and sizes of pessaries are available. The use of pessaries is an important part of gynecologic practice that has been neglected in contemporary gynecologic residency training programs ( 181). Each patient should be fitted individually with her pessary, much as each individual is fitted for a contraceptive diaphragm. The patient who is using a pessary should have a well-estrogenized vagina. Postmenopausal women should be given hormone replacement therapy, or alternatively, they should use intravaginal estrogen cream on a regular basis. For women who are past menopause, it is preferable to use intravaginal estrogen cream 4 to 6 weeks before the pessary is inserted because this makes the pessary more comfortable to wear, dramatically increases compliance, and promotes long-term use. Complications of pessary use include chronic irritation and erosion of a pessary into the bladder, creating a vesicovaginal fistula ( 182,183). All such cases are caused by neglect rather than the pessary itself. Patients who are using pessaries, particularly older women, should be examined on a regular basis. Some pessaries, such as the silicone doughnut pessary, can be left in place for months at a time without removal or inspection. Other pessaries, such as the cube pessary, which provides vaginal support through a gentle suction effect, ideally should be removed by the patient at bedtime each night and replaced in the morning to avoid erosions. The exact schedule of care should be based on individual circumstances. At the initial fitting, the patient should be encouraged to insert and remove the pessary herself. If the pessary fits and the patient is comfortable, it is helpful to reexamine her within 1 week and at least every 4 to 6 months thereafter. Surgery Traditionally, prolapse has been treated by surgery, the nature of which depends on the type of prolapse. The goal of surgery should be to relieve the patient of her symptoms by repairing each aspect of abnormal pelvic support in a durable and long-lasting manner. A detailed description of the various operations for managing pelvic support defects is beyond the scope of this chapter and can be obtained elsewhere ( 184,185); however, a few general remarks are in order. Most patients with prolapse have defects in more than one location; thus, attention should be paid to correcting all defects during the same operation. Operations for prolapse are generally, but not always, carried out through the vaginal route rather than through the abdominal surgical route. Some conditions, such as stress urinary incontinence, are more reliably handled by an abdominal operation. Operations for Vaginal Prolapse Vaginal Hysterectomy Uterine prolapse is generally treated with vaginal hysterectomy, which may be accomplished by several different techniques. The advantage of vaginal hysterectomy is that it allows other vaginal surgery (e.g., anterior and posterior colporrhaphy or enterocele repair) to be performed at the same time, without the need for a separate incision or for repositioning the patient. At the time of hysterectomy for prolapse, special attention should be paid to closing the cul-de-sac using a McCall culdoplasty and to reattaching the endopelvic fascia and the uterosacral ligaments to the vaginal cuff to provide additional support ( 186). These same steps should be performed with abdominal hysterectomy (187). This reattachment to the uterosacral ligaments can be used both as a prophylactic procedure to prevent future posthysterectomy vaginal vault prolapse and as treatment for uterine prolapse. A modification to the standard plication, the high lateral fixation of the vaginal apex bilaterally without midline plication of the uterosacral ligaments, recreates normal anatomy with durable results ( 188,189). With any reconstructive procedure that requires plication or suspension to the uterosacral complex, care must be taken to avoid the ureters and ensure their postoperative patency (190). Manchester/Fothergill Operation An alternative to hysterectomy for patients with uterine prolapse is the Manchester operation, originally described in 1888 by Donald and subsequently modified by Fothergill. In this operation, the bladder is dissected off the cervix, which is then amputated. The cardinal ligaments are sewn to the anterior cervical stump, and the posterior vagina is closed over the rest of the opening. This operation is usually performed in conjunction with an anteroposterior colporrhaphy, and it is usually done for the sake of expediency in patients who are poor surgical risks and who do not desire future fertility. Uteropexy Occasionally, marked uterine prolapse may develop in a young nulliparous patient who desires to retain her fertility. If prolapse cannot be managed successfully with a pessary, such patients present a surgical challenge. The older abdominal uterine suspension operations (Baldy-Webster, Gilliam, ventrofixation, or hysteropexy) do not work for patients with significant uterine prolapse. There is anecdotal evidence of success in such patients using sacrospinous ligament fixation or retroperitoneal abdominal uterosacropexy, suturing mesh or fascia to the uterosacral ligaments and then to the anterior longitudinal ligament of the sacrum. There is little information available regarding long-term follow-up of such patients. Paravaginal Defect Repair Operation Anterior vaginal prolapse has been treated with anterior colporrhaphy, plicating the endopelvic fascia in the midline under the bladder neck. If the anterior vaginal prolapse results from a lateral detachment of the endopelvic fascia from the lateral pelvic sidewall, however, better results will be obtained by performing a lateral repair. In this technique, the endopelvic fascia is reattached to the arcus tendineus fasciae pelvis through what is referred to as a paravaginal defect repair operation (91,92,177,178). Although generally this procedure is performed through an abdominal incision, operating in the space of Retzius, some surgeons are now performing it through a vaginal incision. In patients with severe or recurrent anterior defects, the traditional repair is now being reinforced with fascia lata or another graft material ( 191,192). Posterior Colporrhaphy Repair of posterior vaginal prolapse for rectocele and enterocele is also performed vaginally using posterior colporrhaphy. In a rectocele repair, the posterior vagina is opened, the rectum is dissected away from the pararectal fascia, and the levator ani muscles are plicated over the rectum in the midline, after which the vaginal epithelium is closed. Because of concern over postoperative dyspareunia, recent modifications of posterior colporrhaphy have included site-specific repair. In this technique, the posterior vaginal epithelium is opened in the traditional fashion, and breaks in vaginal muscularis or Denonvillier's fascia are identified by using a finger in the rectum to demonstrate the defect. The traumatic separations may occur in various directions and be of varying magnitude; however, it is usually possible to identify and repair these defects ( 193,194). The site-specific repair technique for posterior compartment relaxation offers a more logical correction than the standard plication procedure and appears to have success rates similar to those of traditional approaches but with less vaginal narrowing. An enterocele is a peritoneal hernia, usually seen over the rectum, often appearing as a second bump higher up in the vaginal canal on examination. The peritoneal sac should be carefully identified, opened, and closed with several pursestring sutures of permanent material; the sac should be excised, and the vagina should be closed once more over the defect. If the perineal body is noted to be deficient and the patient has a gaping introitus, this deficit may be repaired by a perineorrhaphy or perineoplasty, in which the vaginal fourchette is opened and the base of the levator ani muscle is pulled together in the midline, providing renewed support for the lateral vagina at its outlet. Operations for Complete Eversion of the Vagina Among the most challenging cases are those involving complete eversion of the vagina in patients who have had a previous hysterectomy. This condition virtually always requires surgical correction because of the large size of the prolapse, its propensity to enlarge over time because of increases in intraabdominal pressure, and the rare danger of vaginal evisceration if it is not treated. Colpectomy and Colpocleisis For some patients, particularly elderly women who are not sexually active and who lead a sedentary lifestyle, the condition can be managed by surgically removing the vagina and closing off the space (colpectomy and colpocleisis). The correction of a significant and bothersome pelvic prolapse in elderly patients can often be completed using this technique with local anesthesia. These operations have proved very successful in preventing recurrent prolapse if patients are selected properly ( 195). The surgeon must consider both the patient's future coital activity as well as underlying issues relating to self-image if consideration is given to an obliterative procedure. Colpopexy A different procedure is required for younger women and for women who wish to retain sexual function. For these women, the condition can be managed transvaginally or transabdominally. With the transvaginal approach, vaginal eversion is corrected by suturing one or both sides of the vaginal apex (usually the right side) to the sacrospinous ligament with one or two sutures—a transvaginal sacrospinous colpopexy. Other transvaginal reconstructive procedures for the management of advanced posthysterectomy vaginal vault prolapse (stage 3 to 4) include enterocele ligation and uterosacral ligament suspension or vaginal vault suspension using the iliococcygeal fascia on the pelvic sidewall. These procedures are performed transvaginally and have demonstrated effectiveness in restoring normal vaginal anatomy (197,198). In the transabdominal approach, the vaginal apex is suspended from the anterior longitudinal ligament along the sacrum using a graft of fascia or artificial mesh that is sutured to the vagina and to the sacrum in a retroperitoneal position—a transabdominal sacral colpopexy. The vaginal suspension should always be combined with a meticulous culdoplasty to repair the enterocele that coexists with vaginal eversion. All these operations are highly successful in resuspending the vaginal apex ( 196,197,198 and 199). Because the lines of force produced by increases in intraabdominal pressure are directed across the vagina differently after the two operations, patients who have recurrent prolapse postoperatively tend to have different problems. As a rule, recurrent anterior

vaginal prolapse is more common in patients with vaginal eversion if they have had a sacrospinous ligament fixation, whereas recurrent posterior vaginal prolapse is more common if they have undergone an abdominal sacral colpopexy. Some authors have suggested that recurrent posterior relaxation can be prevented by a colpoperineopexy in which mesh is attached all the way down to the perineal body during the suspension operation ( 200). It is unclear which is the best route for correcting posthysterectomy vaginal vault prolapse, and there are few clinical data comparing the vaginal or abdominal approaches ( 201,202). The most appropriate procedure must be individualized to each patient's clinical findings and the operating surgeon's expertise in reconstructive pelvic surgery.

Colorectal Dysfunction Pelvic floor disorders span all three anatomic compartments of the pelvis: urinary, genital, and colorectal. Any approach to pelvic floor dysfunction that ignores colonic and rectal problems will not meet the needs of these women. Disorders of colonic and rectal function are disproportionately prevalent among women and represent a major area of continuing clinical neglect in women's health care ( 1). Although gynecologists and urologists have made great strides in jointly evaluating and treating urinary incontinence, to date neither specialty has done a creditable job of incorporating the treatment of posterior compartment problems into patient care. Because they are often the first physicians that women see for pelvic floor disorders, gynecologists have an obligation to become knowledgeable about common colorectal complaints. Not only can many of these problems be evaluated and treated initially by gynecologists, but a familiarity with colorectal conditions and a good working relationship with a colon and rectal surgeon or an interested gastroenterologist will also help educate practitioners of these specialties about the genitourinary complaints that frequently accompany disorders of the posterior pelvis. Among the more common conditions with which gynecologists should be familiar are anal incontinence, rectal prolapse, constipation, fecal impaction, and irritable bowel syndrome (see Chapter 14).

Anal Incontinence Anal incontinence refers to involuntary passage of flatus or feces (either liquid or formed stool) through the anal canal. The term anal incontinence is therefore a more comprehensive term than fecal incontinence, which refers only to the involuntary passage of stool ( 203,204). Many women have disabling loss of gas, even though they are able to control feces. Although it is becoming more acceptable socially to talk about urinary incontinence, discussion of fecal loss still remains a taboo subject. Even patients with severe anal incontinence often will refuse to bring this problem to the attention of their doctor because of the extreme embarrassment involved. Physicians must ask patients directly (but sensitively) about loss of bowel control in order to elicit this complaint. The problem is more prevalent than most people realize: in one large household survey, 7.1% of the general population reported some degree of anal incontinence ( 205). Diagnosis Normal anal continence depends on the harmonious integration of many factors, including anal sphincter function, anorectal sensation and reflexes, colonic transit, rectal distensibility (compliance), stool consistency, stool volume, and the patient's level of mental functioning. As in the case of urinary incontinence, there are multiple potential causes of anal incontinence ( 203,204,205,206,207,208 and 209) (Table 20.8).

Table 20.8. Causes of Fecal Incontinence

History A thorough history regarding bowel function should delineate the nature and frequency of anal loss. Loss of flatus alone is usually (but not necessarily) less troublesome than frequent loss of formed stool. The presence of liquid stool or diarrhea often represents a challenge that a decompensated sphincter cannot withstand, and this condition may respond favorably to bulking agents. If the history is uncertain, administration of a normal saline enema often is helpful in determining the diagnosis. The patient who can retain 1,000 to 1,500 mL of normal saline without leakage is unlikely to have a significant problem with anal incontinence (207). Important pieces of information include changes in stool frequency or consistency, history of blood in the stool, associated medical conditions (especially diabetes and related neurologic problems), medication use, obstetric history, and any history of pelvic or perianal surgery. It is also important to determine whether the patient ever notices anything protruding from the anus because rectal prolapse often is associated with anal incontinence. Examination The perineum should be carefully inspected to determine the state of hygiene, the presence of fissures, and the status of the anal sphincter. Pelvic muscle reflexes should be checked in all patients with anal incontinence, and a vaginal and bimanual examination should be performed. The possibility of a disrupted sphincter or a rectovaginal fistula must be considered. The patient should be examined while straining to check for the presence of rectal prolapse. All patients should undergo a digital rectal examination with testing of the stool for occult blood: at least 50% of rectal carcinomas lie within reach of the examiner's finger. Many patients with fecal incontinence have a fecal impaction, which should be removed ( 210,211). The puborectalis muscle should be palpated through the posterior rectum. When the patient contracts this muscle, the examiner's finger should move anteriorly. Poor sphincter tone is indicated by gaping of the rectum when the puborectalis muscle is depressed. Direct inspection of the large intestine through the use of flexible sigmoidoscopy or colonoscopy should be considered in all patients. Tests The American Gastroenterological Association has recently reviewed the major tests currently available for the evaluation of anorectal function ( 212). Anorectal manometry, endoanal ultrasonography, and evacuation proctography (defecography) are the most useful diagnostic tests; there are others, but they are less useful in clinical decision making. Anorectal Manometry Anorectal manometry is a test performed to evaluate anorectal sensation, resting and squeeze pressures, compliance (distensibility), and reflexes. The test may be performed with solid-state transducers or water-perfusion techniques. In anorectal manometry, the pressure-measuring device is slowly withdrawn through the rectum and anal canal at rest and during intermittent squeeze maneuvers. Pressure gradients are calculated, and the response of the anus and rectum to distention with an air-filled balloon is evaluated. Specific resting and squeeze values cannot distinguish continent from incontinent patients, but patients with low squeeze pressures are more likely, as a group, to be incontinent than those who have higher values. Patients with low anal compliance (often due to radiation fibrosis or proctitis) tend to have urgency symptoms; when these patients undergo anorectal surgery, they tend to have less successful operative outcomes. Measurement of sensory thresholds is important in patients with anal incontinence because one of the most effective interventions is biofeedback training to improve anorectal sensation (213). Endoanal Ultrasonography Endoanal ultrasonography is performed using a rotating ultrasound probe inserted into the anal canal that produces a circumferential view of the anatomy of the internal and external anal sphincters. It is currently the procedure of choice for evaluating sphincter damage, particularly from obstetric causes. Endoanal ultrasonography performed after vaginal childbirth has revealed a very high rate of occult sphincter injury in women who did not have a known perineal laceration at delivery ( 214). Although many of these women do not have symptoms in the immediate postpartum period, the long-term consequences of

occult sphincter injury are unclear. Such an injury may play an important role in the development of anal incontinence in later life. Endoanal ultrasonography is important in helping the clinician decide whether surgical repair will aid patients who have anal incontinence. Evacuation Proctography Evacuation proctography is a radiographic test in which stoollike contrast material (usually a barium paste) is instilled into the rectum. The utility of the test can be enhanced by putting additional contrast in the bladder and vagina and by having the patient ingest contrast material before the study to opacify the small bowel. Cinefluoroscopic images are then taken with the patient sitting on a radiolucent commode so that the mechanism of rectal evacuation can be studied. The test is useful for evaluating puborectalis muscle function, detecting the presence of occult enteroceles, and evaluating patients for the presence of rectal prolapse and intussusception. These studies are most useful if done collaboratively by a pelvic floor physician and radiologist with special interest in this area ( 215). Because the external anal sphincter is innervated by the pudendal nerve, assessment of pudendal nerve function would appear to have a role in the evaluation of patients with anal incontinence. Unfortunately, the pudendal nerve is hidden in the pelvis and traverses a tortuous pathway from the sacral spinal cord to the perineum, which varies significantly among different individuals. To date, it has not been possible to measure the length of the pudendal nerve accurately in individual patients; therefore, precise measurement of pudendal nerve conduction velocity (time of impulse transmission/length of pudendal nerve) is not possible. Numerous attempts have been made to correlate the time (latency) between a stimulus applied to the pudendal nerve at the ischial spine and its appearance at the anal sphincter, but the studies that correlate these results with clinical findings and surgical outcome are conflicting and their utility is questionable. The American Gastroenterology Association does not recommend this test in the evaluation of patients with fecal incontinence ( 212). Treatment Effective treatment of anal incontinence depends on its cause ( 204). The first step in treating fecal incontinence is usually bowel management, especially in patients with fecal impaction and resulting “overflow” incontinence. These patients respond well to disimpaction and the subsequent regular use of stool softeners and laxatives. Diarrhea can be evaluated and treated with bulking agents, often with surprisingly successful results. Antiflatulence preparations such as Beano (AK Pharma, Pleasantville, NJ) are often very helpful. High-fiber diets and stool-bulking agents will help the patient develop a more consistent stool that can be controlled more easily by the sphincter muscles. Antidiarrheal agents, such as loperamide or diphenoxylate with atropine, are also helpful. Daily tap water enemas can be used to help keep the rectum empty and to schedule predictable daily bowel movements. Biofeedback training is useful in helping patients regain control of sphincteric activity, especially when they have impaired rectal sensation. This technique allows patients to strengthen the muscles of the pelvic floor, to sense smaller volumes of stool in the rectum, and to improve their control over the anal sphincter mechanism, often with surprisingly good results ( 216). Surgical repair should be considered in patients who have a demonstrable sphincter defect. The best results appear to be obtained using an overlapping sphincteroplasty rather than an end-to-end reapproximation of the torn sphincter ( 217). Although restoration of complete continence in most patients with an old sphincter injury is unlikely, the chance for substantial improvement is great enough that all patients should be offered the option of surgical repair if they are otherwise suitable candidates, irrespective of age ( 204). Patients with a rectovaginal fistula will obviously benefit from fistula closure. For some patients, construction of an anal neosphincter using transplanted gracilis muscle driven by an implanted pacemaker may be of benefit ( 218). Patients who have severe persistent incontinence after biofeedback therapy, medical management, and surgical treatment may be candidates for colostomy. An algorithm for the evaluation and treatment of fecal incontinence is given in Fig. 20.21 (204).

Figure 20.21 Treatment algorithm for fecal incontinence. (From Soffer EE, Hull T. Fecal incontinence: a practical approach to evaluation and treatment. Am J Gastroentererol 2000;95:1879, with permission.) PNTML, pudendal nerve terminal motor latency

Rectal Prolapse Rectal prolapse is relatively uncommon but nonetheless is a significant clinical problem for those unfortunate enough to experience it. About 90% of patients with rectal prolapse are women (219). Normally, the rectum is attached firmly to the levator ani muscle complex through an extensive interweaving of longitudinal muscle fibers. This attachment is important because the rectum undergoes multiple changes in position and location during the normal act of defecation. Without this attachment, the rectum would slip down through the levator muscle hiatus during defecation. In rectal prolapse, this actually occurs. An intussusception of the rectum develops (for reasons not totally clear). Gradually, over time, the intussusception pulls the rectum away from its sacral attachments, ultimately allowing it to appear at or beyond the anal verge. Predisposing factors associated with rectal prolapse are summarized in Table 20.9 (219).

Table 20.9. Factors Associated with or Predisposing to Rectal Prolapse

Diagnosis Most patients with rectal prolapse consider the presence of the prolapse itself as the major problem. Many patients have constipation; however, fecal incontinence also is commonly associated with rectal prolapse. Stretch injury of the pudendal and pelvic nerves may cause denervation injury to the rectum and resultant incontinence, but this finding is not always present. As the prolapse worsens, patients must replace the rectum manually to defecate. Occasionally, a rectal prolapse may become incarcerated; rarely, there is a transanal evisceration of small bowel from a ruptured rectal prolapse. Patients with rectal prolapse should be examined while straining. If their sphincter tone is poor and the anus is patulous, subsequent surgical repair may not be satisfactory. If the tone of the pelvic muscles is good, however, the prognosis is more favorable. An important point is whether the prolapse is a full-thickness prolapse of the rectum or whether it is only a prolapse of the rectal mucosa. Examination of patients with rectal prolapse should include both digital examination and a thorough proctosigmoidoscopic or colonoscopic examination because a colonic cancer or sigmoidal polyp may form at the point at which an intussusception develops. Changes associated with the solitary rectal ulcer syndrome are frequently seen in patients with early rectal prolapse. The value of evacuation proctography in the evaluation of

rectal prolapse is well established ( 215,220,221). Treatment Partial or incomplete rectal mucosal prolapse generally can be treated with anal surgery, often involving only excision of the affected area. Complete rectal prolapse is a more complicated problem, with more than 200 operations having been described for the treatment of this condition. The proposed operations include or combine several modes of therapy, such as narrowing the anal orifice, obliteration of the cul-de-sac, restoration of the pelvic floor, resection of bowel, and suspension or fixation of the rectum. In general, some form of rectopexy appears to have the highest success rate, the lowest recurrence rate, and an acceptable level of complications. Several concise but comprehensive reviews of this subject have recently been prepared ( 222,223 and 224).

Constipation Constipation is a common patient concern, yet there is no generally accepted definition of the term ( 225). Commonly used definitions include frequent straining at stool (more than 25% of the time) or fewer than three bowel movements per week. Nearly 95% of normal individuals have between three bowel movements per day and three bowel movements per week. In surveys of patients not seeking medical care for gastrointestinal disorders, between 10% to 20% appear to have symptoms of constipation; most of these individuals are female ( 226,227). Constipation is less frequent among the young and increases to its highest prevalence in old age. Because there is no generally accepted definition of constipation, the physician must generally take the patient's reports of this problem at face value and then attempt to understand what she means by this term. Constipation is a symptom, rather than a disease, produced by many different factors ( 228) (Table 20.10). Most patients who describe themselves as constipated can be treated with laxatives, increased fiber intake, and the development of regular dietary habits. Only a small percentage of patients have “intractable” constipation, but these patients should undergo an appropriate evaluation.

Table 20.10. Causes of Constipation

Diagnosis Because of its high prevalence among women, physicians should be well versed in the treatment of constipation. The goal of treatment for patients with chronic constipation is restoration of normal frequency and consistency of stools without the need to strain during defecation ( 229). Restoration should be accomplished with as little artificial intervention as possible, and it should result in the diminution of any associated symptoms such as crampy abdominal pain or bloating. Because stool of normal consistency is about 70% water, the mainstays in the treatment of constipation are water and fiber. The fiber serves as a bulking agent that can trap water and promote an increased mass of stool. The normal dietary fiber intake should be 14 g/d. Unprocessed bran is the most readily available fiber supplement. If it is not available, psyllium can also be used. The type of fiber is not nearly as important as adequate fiber intake. One inexpensive and highly useful dietary recipe for use by constipated patients involves mixing about 1 cup of Miller's bran, ½ cup of applesauce, and ¼ cup of prune juice to desired consistency, storing it under refrigeration, and taking 1 to 2 tablespoons per day. This can be taken straight, or mixed with fruit or cereal, and titrated to the desired results. Treatment Laxatives are an important adjunct to fiber and water in the treatment of constipation. Literally hundreds of laxative preparations are available. They can be divided into two main groups: stimulant laxatives and mechanical laxatives. Stimulant laxatives (e.g., cascara, senna, castor oil, bisacodyl, and diphenylmethane) cause increased peristaltic activity in the colon. Stimulant laxatives may be used occasionally, but chronic use should be avoided because the bowel may become dependent on them. Side effects of stimulant laxatives can include cramps and urgent, explosive defecation. The mechanical laxatives include salts such as sodium phosphate or magnesium sulfate, mineral oil, and surfactants such as docusate sodium. These agents increase peristalsis by changing stool consistency or increasing stool bulk. Agents such as lactulose produce an osmotic catharsis. Oral agents such as mineral oil work by decreasing water absorption from the stool, thereby keeping it soft. If taken orally, mineral oil should be used with caution because inhalation can lead to serious aspiration pneumonia, particularly in elderly or debilitated patients. Enemas and suppositories are also useful. An enema is particularly helpful in removing an acute fecal impaction. The best enemas are usually the simplest: warm tap water or equal parts of water, glycerin, and mineral oil. The use of these agents is preferable to soap enemas or hypertonic phosphate enemas, which are particularly irritating. Injudicious use of enemas can cause electrolyte imbalances or colonic perforation. Suppositories are helpful in the periodic evacuation of the lower bowel. Insertion of a simple glycerin suppository will usually initiate defecation within 1 hour without chemical stimulation of the colon. Attention should always be paid to other factors influencing the normal action of the gut. Patients should be taught not to suppress defecation but to make use of the normal gastrocolic reflex that promotes a call to stool about 30 minutes after a meal (usually breakfast). Regular meals help promote regular bowel movements. Regular exercise, even exercise as simple as a brisk walk, has an important influence on regular defecation, as well as on general fitness and well-being. Attention to good bowel habits, adequate fiber intake, and occasional laxative use should help prevent fecal impaction. Although this condition can occur at any age, elderly and institutionalized patients are at particular risk for impaction ( 210). Continued passage of stool does not rule out impaction. Many impacted patients develop diarrhea and anal incontinence, as well as nausea, anorexia, vomiting, and abdominal pain, as loose bowel contents bypass the point of impaction. The diagnosis of fecal impaction can usually be established by rectal examination, although a fecal impaction is sometimes located high in the colon. The impacted stool may be hard or soft and may be a single mass or multiple pellets. If the patient's presentation suggests an impaction but one cannot be detected on rectal examination, it may be useful to obtain an x-ray of the abdomen. Fecal masses or unusual air-fluid levels may be detected with this technique. Once diagnosed, the impaction should be removed by fragmenting the fecal mass manually and removing it piecemeal. This usually can be accomplished using local anesthesia ( lidocaine jelly) and liberal amounts of lubricant, combined with pressure on the posterior vagina. After the mass has been broken up, tap water enemas and bisacodyl suppositories will help finish expelling it. The patient should then be placed on a bowel regimen thereafter to prevent the recurrence of future impactions. Conservative measures, including adequate fluid intake, a high-fiber diet, and occasional laxative use, should allow most women with constipation to regain normal bowel habits of at least three movements per week. If a trial of 3 to 6 months of conservative therapy in a compliant patient is unsuccessful in relieving the constipation, further evaluation should be undertaken. Constipation is not a diagnosis but rather is a symptom that may be associated with many different pathologic states. The major concerns in the evaluation of intractable constipation are ruling out an underlying colonic pathology (i.e., carcinoma, intussusception) and picking up those patients with altered colonic motility (“slow-transit” constipation) or a nonrelaxing puborectalis muscle (“spastic pelvic floor syndrome”). Gynecologists in particular should be on guard against the common assumption that all women with constipation and a rectocele have a condition that is correctable by surgery. Concomitant pathology often is present. The further examination of patients with constipation should include endoscopic examination of the colon and rectum and referral to a colorectal physiology laboratory for more sophisticated studies, including segmental colonic transit studies, anorectal manometry, pelvic floor electromyography, and defecography (225). If blood is present in the stool, if the constipation is painful, if constipation is the result of a sudden change in bowel habits, or if the clinician is otherwise suspicious of a more serious disease process, these studies should be performed earlier in the course of treatment. When the usual sets of studies reveal no cause, constipation is considered functional or nonorganic ( 226). Most patients with severe functional constipation are young women

(227,228 and 229). Many of these women appear to have disordered colonic motility of unknown etiology, and many of them exhibit paradoxical contraction (rather than relaxation) of the pelvic floor during defecation, resulting in fecal outflow obstruction. This condition has been termed the spastic pelvic floor syndrome. Although they are refractory to treatment by fiber supplementation and laxatives, some of these patients appear to benefit from biofeedback therapy that enables them to learn normal patterns of defecation and to relax the pelvic floor during a bowel movement ( 230). The possibility that they may have been victims of sexual abuse should always be considered in the differential diagnosis of such patients.

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A clinical study of patients with fecal incontinence and diarrhea. Gastroenterology 1979;76:747–756. Wrenn K. Fecal impaction. N Engl J Med 1989;321:658–662. Read NW, Abouzekry L. Why do patients with faecal impaction have faecal incontinence? Gut 1986;27:283–287. Diamant NE, Kamm MA, Wald A, et al. AGA position paper on anorectal testing techniques. Gastroenterology 1999;116:735–760. Sun WM, Read NW, Miner PB. Relationship between rectal sensation and anal function in normal subjects and patients with faecal incontinence. Gut 1990;31:1056–1061. Sultan AH, Kamm MA, Hudson CN, et al. Anal-sphincter disruption during vaginal delivery. N Engl J Med 1993;329:1905–1911. Kelvin FM, Maglinte DDT, Benson JT. Evacuation proctography (defecography): an aid to the investigation of pelvic floor disorders. Obstet Gynecol 1994;83:307–314. Enck P. Biofeedback training in disordered defecation: a critical review. Dig Dis Sci 1993;38:1953–1960. Parks AG, McPartlin JF. 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Chapter 21. Gynecologic Endoscopy Novak’s Gynecology

Chapter 21

Gynecologic Endoscopy Malcom G. Munro Andrew I. Brill

Laparoscopy Diagnosis Therapy Manipulation of Fluid and Tissue Complications Hysteroscopy Diagnostic Hysteroscopy Operative Hysteroscopy Patient Preparation Equipment and Technique Complications References

Endoscopy is a procedure that uses a narrow telescope to view the interior of a viscus space. Although the first medical endoscopic procedures were performed more than 100 years ago, the potential of this method has only recently been realized. Endoscopes are currently used to perform a variety of operations. In gynecology, endoscopes are used most often to diagnose conditions by direct visualization of the peritoneal cavity (laparoscopy) or the inside of the uterus (hysteroscopy). When used appropriately, endoscopic surgery offers the benefits of reduced pain, improved cosmesis, lower cost, and faster recovery. The indications for endoscopic surgery are outlined here and detailed in the appropriate chapters. The technology, potential uses, and complications of laparoscopy and hysteroscopy are summarized here.

Laparoscopy The past three decades have witnessed rapid progress and technologic advances in laparoscopy ( 1,2,3,4,5,6,7,8,9,10,11 and 12). Operative laparoscopy was developed in the 1970s; and in the early 1980s, laparoscopy was first used to direct the application of electrical or laser energy for the treatment of advanced stages of endometriosis (6 and 7). The use of high-resolution, lightweight video cameras in operative laparoscopy has made it easier to view the pelvis during the performance of complex procedures (7,8,9 and 10). Subsequently, many other procedures that were previously performed using traditional techniques, such as hysterectomy, became feasible with the laparoscope (11). However, the endoscopic approach may have drawbacks in some patients. Although some laparoscopic procedures appear to reduce the cost and morbidity associated with surgery, others have not been shown to be effective replacements for more traditional operations. The techniques and indications for operative endoscopy are evolving.

Diagnosis The objective lens of a laparoscope can be positioned to allow wide-angle or magnified views of the peritoneal cavity. Laparoscopy is the standard method for the diagnosis of endometriosis and adhesions because no other imaging technique provides the same degree of sensitivity and specificity. There are limitations to laparoscopy, however. The view is restricted, and if tissue or fluid becomes attached to the lens, vision may be obscured. Also, soft tissues or the inside of a hollow viscus cannot be palpated. For assessment of soft tissue, an imaging modality, such as ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) scans, is superior. Because of its ability to view soft tissue, ultrasonography is more accurate than laparoscopy for the evaluation of the inside of adnexal masses. The intraluminal contour of the uterus can be demonstrated only by hysteroscopy or contrast imaging. Ultrasonography, in combination with serum assays of b-human chorionic gonadotropin (b-hCG) and progesterone, can be used to diagnose ectopic pregnancy, usually allowing medical therapy to be given without laparoscopic confirmation ( 12). As a result of the advances in blood tests and imaging technology, laparoscopy is more often used to confirm a clinical impression than for initial diagnosis. Laparoscopy may disclose abnormalities that are not necessarily related to the patient's problem. Although endometriosis, adhesions, leiomyomas, and small cysts in the ovaries are common, they are frequently asymptomatic. Thus, diagnostic laparoscopy must be performed prudently, interpreting findings in the context of the clinical problem and other diagnoses.

Therapy The role of laparoscopy in the operative management of gynecologic conditions is still being defined. Many procedures previously in the domain of traditional abdominal and vaginal operations are feasible with laparoscopy. In addition to the benefits of endoscopic procedures in general, laparoscopic surgery is less likely than laparotomy to form adhesions. Because sponges are not used, the amount of direct peritoneal trauma is reduced substantially, and contamination of the peritoneal cavity is minimized. The lack of exposure to air allows the peritoneal surface to remain more moist and, therefore, less susceptible to injury and adhesion formation. Despite these advantages, there are potential limitations: exposure of the operative field can be reduced, manipulation of the pelvic viscera is limited, and the caliber of the suture required may be larger than otherwise desired. In many cases, the cost of hospitalization increases, despite a shortened stay, because of prolonged operating room time and the use of more expensive surgical equipment and supplies. Efficacy may be reduced because surgeons may not adequately replicate the abdominal operation. In some patients, there is an increased risk for complications, which can be attributed to the innate limitations of laparoscopy, the level of surgical expertise, or both. With an adequate combination of ability, training, and experience, however, operative time and complications are comparable to those of traditional abdominal surgery. Tubal Surgery Sterilization Laparoscopic sterilization has been extensively used since the late 1960s and can be performed under local or general anesthesia. The tubes may be occluded by suture, clips, or Silastic rings, but electrosurgical desiccation with bipolar energy is the technique used most often (see Chapter 10). If an operative laparoscope is used, only one incision is required. Otherwise, a second port is needed for the introduction of the occluding instrument. Patients remain in the hospital

for several hours, even when general anesthesia is used. Postoperative pain is usually minor and related to the effects of the anesthesia, gas that remains in the peritoneal cavity (shoulder pain, dyspnea), and in the case of occlusive devices, pain at the surgical site. These effects normally disappear within a few days. The failure rate is about 5.4 per 1,000 woman-years ( 13,14). Ectopic Gestation Ectopic gestation can be managed using laparoscopy to perform the same procedures done with laparotomy, including salpingostomy, salpingectomy, and segmental resection of a portion of the oviduct (see Chapter 17) (15). Salpingostomy is performed with scissors, a laser, or an electrosurgical electrode after carefully injecting the mesosalpinx with a dilute vasopressin-containing solution (20 units per 100 mL of normal saline). For salpingectomy, the vascular pedicles are usually secured with electrosurgical desiccation, ligatures, clips, or a combination thereof. Tissue is removed from the peritoneal cavity through one of the laparoscopic ports. When salpingostomy is performed by any route, there is about a 5% chance that trophoblastic tissue remains. In such instances, medical treatment with methotrexate is considered appropriate (see Chapter 17). Consequently, b-hCG levels should be measured weekly until there is confidence that complete excision has occurred (16,17). Ovarian Surgery Ovarian Masses Laparoscopic removal of selected ovarian masses is a well-established procedure ( 18,19). However, controversy exists regarding the selection of tumors that can be removed by laparoscopy, because of concerns about an adverse effect on prognosis with malignant tumors ( 20). Preoperative ultrasonography is mandatory. Sonolucent lesions with thin walls and no solid components are at very low risk for malignancy and, therefore, are suitable for laparoscopic removal. For postmenopausal women, the measurement of CA125 may be useful in identifying candidates for laparoscopic management ( 21,22). Lesions with ultrasonographic findings suggestive of mature teratoma (dermoid) may also be suitable for endoscopic management ( 23). The ovarian tumors should be assessed by frozen histologic section, and any malignancy should be managed expeditiously by laparotomy ( 22,24). Oophorectomy and cystectomy are performed similar to those for laparotomy (16). For cystectomy, scissors are used to separate the cyst from the ovary; if oophorectomy is performed, the vascular pedicles are ligated with sutures, clips, linear cutting staplers, electrosurgical desiccation, or a combination thereof. Most cysts are drained before extraction, through either a laparoscopic cannula or a posterior colpotomy. If there is concern about the impact of spilled cyst contents, the specimen can be removed in a retrieval bag inserted into the peritoneal cavity. Although in the past the ovary has routinely been closed after cystectomy, this practice may be unnecessary and could contribute to the formation of adhesions ( 25). However, complete disruption of the ovarian cortex may make closure necessary. If so, the edges of the ovarian incision can be sutured. Other Ovarian Surgery Many cases of ovarian torsion previously treated by laparotomy and oophorectomy can be managed laparoscopically ( 26,27). If there is no apparent necrosis, the adnexa should be untwisted. Otherwise, adnexectomy is indicated. Polycystic ovarian syndrome can be treated laparoscopically using electrosurgery and laser vaporization ( 28,29 and 30). Although such procedures have been shown to be successful, the occurrence of postoperative adhesions in 15% to 20% of patients underscores the need first to exhaust medical treatment ( 31,32). Uterine Surgery Myomectomy Laparoscopic myomectomy, although feasible, is rarely performed, in part because its efficacy is yet to be established, especially as it relates to the treatment of infertility and menorrhagia ( 33,34). Also, laparoscopic myomectomy requires more technical skills than many other endoscopic procedures. Unless the myoma involves the endometrial cavity, it is unlikely to contribute to heavy menstrual bleeding. Leiomyomas that cause pressure are often large and located in or near vital vascular structures. Myomectomy should be performed only when indicated (as opposed to expectant or medical management), and laparotomy should be used if there are technical limitations ( 35). The only leiomyomas that are clearly appropriate candidates for laparoscopic excision are those pedunculated or subserosal lesions that cause pain in association with torsion (16,36). Hysterectomy In many patients, hysterectomy can be performed under laparoscopic direction. Laparoscopic hysterectomy encompasses a variety of procedures, including the facilitation of vaginal hysterectomy with variable extents of endoscopic dissection, supracervical hysterectomy by dissection, amputation and mechanical removal of the fundus, and the removal of the entire uterus with the assistance of the laparoscope (37). The procedure is performed with scissors, sutures, electricity, clips, and, in some instances, linear cutting and stapling devices to dissect or ligate pedicles. Laparoscopic hysterectomy offers no advantage for women in whom vaginal hysterectomy is possible because the endoscopic approach is more expensive and has a higher risk for postoperative morbidity ( 38,39). Infertility Operations Laparoscopic treatment of infertility includes operations used to reconstruct the normal anatomic relationships altered by an inflammatory process: fimbrioplasty, adhesiolysis, and salpingostomy for distal obstruction ( 40). Fimbrioplasty is distinguished from salpingostomy because it is performed in the absence of preexisting complete distal obstruction. Endometriosis associated with adnexal distortion can be treated by laparoscopic adhesiolysis. There is no known additional benefit of laparoscopic (or medical) treatment to coexistent active endometriosis. Laparoscopy has been superseded by ultrasound for the retrieval of oocytes for in vitro fertilization but is still used for procedures in which gametes (gamete intrafallopian transfer) or zygotes (zygote intrafallopian transfer) are placed into the fallopian tube. Adhesiolysis may be accomplished by blunt or sharp dissection with scissors, laser, or an electrosurgical electrode. These instruments are usually passed through an ancillary port; those who use laser energy frequently use the channel of the operating laparoscope. Although there has been controversy regarding the most appropriate modality, both methods are probably equally effective in appropriately trained hands. Laparoscopic operations for the treatment of mechanical infertility are probably equally effective to similar procedures performed by laparotomy. In patients with extensive adhesions, however, the effectiveness of all procedures is limited. Assisted reproductive technologies such as in vitro fertilization and embryo transfer are necessary in these situations ( 16,41). Endometriosis The laparoscopic management of endometriomas parallels that of adnexal masses, although the ultrasonographic complexity of endometriomas may make it difficult to distinguish them preoperatively from a neoplasm. The relationship of the endometrioma to the ovarian cortex and stroma makes it difficult to find surgical dissection planes. There is a tendency either to compromise the function of the remaining ovary by attempting complete removal or to leave part of the endometrioma in place. Therefore, for women who want to retain their fertility, electrosurgical or laser ablative techniques may be used to treat endometriotic tissue that is adherent to the remaining ovary. Multifocal endometriosis may be treated by mechanical excision or ablation, the latter using coagulation or vaporization with either electrical or laser energy. With proper use, each energy source creates about the same amount of thermal injury ( 42,43). Endometriosis is frequently deeper than appreciated, making excisional techniques valuable in many instances (16,41). Pelvic Floor Disorders

Laparoscopy can be used to guide procedures to treat pelvic floor prolapse, including enterocele repair, vaginal vault suspension, paravaginal repair, and retropubic cystourethropexy for urinary stress incontinence. Although these conditions can be treated vaginally, the abdominal approach may offer benefits, particularly with retropubic urethropexy. There is some evidence that this procedure is effective when compared with the traditional approaches ( 44,45). The laparoscopic treatment of enterocele and vault prolapse may be useful in patients who require abdominal approaches after failure of a previous vaginal procedure. Gynecologic Malignancies The role of laparoscopy in the management of gynecologic malignancy has not been clearly established ( 24,46,47). However, a number of ongoing research protocols relating to cervical, endometrial, and ovarian cancer should help document this role. Lymph node biopsies performed by laparoscopy can be coupled with vaginal hysterectomy for the management of early-stage endometrial cancer. The potential for laparoscopic lymphadenectomy has fostered a resurgence of interest in vaginal radical hysterectomy for stage I carcinoma of the cervix. Laparoscopy is also being investigated for the staging of early ovarian malignancy and for second-look surgery. Patient Preparation and Communication The prospective patient must understand the rationale, alternatives, risks, and potential benefits of the selected approach. She should know what would probably happen if the procedure were not done and expectant management were used. The expectations and risks of diagnostic laparoscopy, as well as those of any other procedures that may be needed, must be explained. The risks of laparoscopy include those associated with anesthesia, infection, bleeding, and injury to the abdominal and pelvic viscera. Infection is uncommon with laparoscopic surgery. For procedures involving extensive dissection, there is a higher risk for visceral injury. The potential for these risks should be clearly presented. The patient should be given realistic expectations regarding postoperative disability. Because pain and visceral dysfunction normally continue to improve after uncomplicated laparoscopy, the patient should be instructed to communicate immediately any regression in her recovery. After diagnostic or brief operative procedures, patients can be discharged on the day of surgery and usually require 24 to 72 hours away from work or school. If extensive dissection is performed or the surgery lasts longer than 2 hours, hospital admission may be necessary, and the period of disability may be longer. If the colon may be involved, mechanical bowel preparation should be performed to help improve visualization and minimize the need for a colostomy if the colon is entered. The patient should arrange for a friend or family member to discuss the results of the procedure and to drive her home if she is discharged the same day. Mild analgesia is often necessary. Technique Laser and electrical sources of energy manifest their effect by conversion to thermal energy. Highly focused energy produces vaporization or cutting, whereas less focused energy causes desiccation and tissue coagulation. Animal studies fail to demonstrate differences in injury characteristics ( 41,42 and 43). Randomized controlled studies have shown no differences in fertility outcomes in women undergoing CO 2 laser surgery and electrosurgery ( 48). Therefore, differences in results are more likely to be caused by other factors, such as patient selection, extent of disease, and degree of surgical expertise. With proper education, modern equipment, and adherence to safety protocols, these techniques can be used safely. To facilitate the discussion of laparoscopic equipment, supplies, and techniques, it is useful to divide procedures into “core competencies,” which are as follows: 1. 2. 3. 4. 5. 6. 7. 8.

Patient positioning Operating room organization Peritoneal access Visualization Manipulation of tissue and fluid Cutting, hemostasis, and tissue fastening Tissue extraction Incision management

Patient Positioning Proper positioning of the patient is essential for safety, comfort of the operator, and optimal visualization of the pelvic organs. Laparoscopy is performed on an operating table that can be rotated around the patient's long axis and tipped to create a steep, head-down (Trendelenburg) position. The footrest can be dropped to allow access to the perineum. The patient is placed in the low lithotomy position, with the legs supported in stirrups and the buttocks protruding slightly from the lower edge of the table ( Fig. 21.1). The thighs are usually kept in the neutral position to preserve the sacroiliac angle, reducing the tendency of bowel to slide into the peritoneal cavity. The feet should rest flat, and the lateral aspect of the knee should be protected with padding or a special stirrup to avoid peroneal nerve injury. The knees should be kept in at least slight flexion to minimize stretching of the sciatic nerve and to provide more stability in the Trendelenburg position. The arms are positioned at the patient's side by adduction and pronation to allow freedom of movement for the surgeon and to lower the risk for brachial plexus injury (Fig. 21.2). Care must be exercised to protect the patient's fingers and hands from injury when the foot of the table is raised or lowered. After the patient is properly positioned, the bladder should be emptied with a catheter and a uterine manipulator attached to the cervix.

Figure 21.1 Patient positioning: the low lithotomy position. The patient's buttocks are positioned so that the perineum is at the edge of the table. The legs are well supported with stirrups, with the thighs in slight flexion. Too much flexion may impede the manipulation of laparoscopic instruments while in the Trendelenburg (head-down) position.

Figure 21.2 Operating room organization. The patient's arms are at the sides. The right-handed surgeon stands on the patient's left. Instruments and equipment are distributed around the patient within view of the surgeon. For pelvic surgery, the monitor should be located between the patient's legs. For upper abdominal surgery, or when operating from below, a monitor should be placed near the patient's head.

Operating Room Organization The arrangement of instruments and equipment is important for safety and efficiency. The orientation depends on the operation, the instruments used, and whether the surgeon is right- or left-handed. An orientation for a right-handed operator is shown in Fig. 21.2. For pelvic surgery, the monitor should be placed at the foot of the table within the angle formed by the patient's legs. If a second monitor is used, one should be positioned at each foot of the patient. If upper abdominal surgery is also to be performed, the additional monitor should be moved to the head of the operating table. The surgeon stands by the patient's left side, at an angle facing the patient's contralateral foot. The nurse or technician and instrument table are positioned near the foot of the operating table to avoid obscuring the video monitor. The insufflator is placed on the patient's right side, in front of the surgeon, to allow continuous monitoring of the inflation rate and intraabdominal pressure. The electrosurgical generator is also positioned on the patient's right side to permit visualization of the power output. When a laser is used through a second puncture site, it is also placed to the patient's right. When the laser is passed through the channel of an operating laparoscope, however, it is situated on the patient's left side, beside the surgeon. Peritoneal Access Before inserting the laparoscope, a cannula or port must be positioned in the abdominal wall to establish access to the peritoneal cavity. The closed technique is a blind approach in which the cannula is introduced with a sharp trocar used to penetrate the abdominal layers. In open laparoscopy, entry into the peritoneal cavity is achieved by a minilaparotomy, with the cannula fixed into position with sutures or other suitable techniques. Gynecologists have generally favored a closed technique, preinflating the peritoneal cavity with CO 2 through a hollow needle. In either case, additional cannulas are inserted by sharp trocars under direct vision to allow the use of laparoscopic hand instruments such as scissors, probes, and other manipulating devices. Cannula insertion is aided by an understanding of the normal anatomy, especially the location of vessels ( Fig. 21.3). A “safety zone” exists inferior to the sacral promontory in the area bounded cephalad by the bifurcation of the aorta, posteriorly by the sacrum, and laterally by the iliac vessels ( 49). In women placed in the Trendelenburg position, the great vessels are situated more cephalad and anterior, making them more vulnerable to injury unless appropriate adjustments are made in the angle of insertion ( Fig. 21.4). Therefore, positioning of the insufflation needle, the initial trocar, and the cannula is best accomplished with the patient in a horizontal position. This approach also facilitates the evaluation of the upper abdomen, which is limited if the intraperitoneal contents are shifted cephalad by the head-down position.

Figure 21.3 Vascular anatomy of the anterior abdominal wall. Location of the vessels that can be traumatized when inserting trocars into the anterior abdominal wall.

Figure 21.4 Vascular anatomy. Location of the great vessels and their changing relationship to the umbilicus with increasing patient weight ( from left to right).

Insufflation Needles Virtually all insufflation needles are modifications of the hollow needle designed by Verres ( Fig. 21.5). In cases uncomplicated by previous pelvic surgery, the preferred site for insertion is as close as possible to (or within) the umbilicus, where the abdominal wall is the thinnest.

Figure 21.5 Insufflation needle (Ethicon Endosurgery, Inc., Cincinnati, OH). When pressed against tissue such as fascia or peritoneum, the spring-loaded blunt obturator is pushed back into the hollow needle, revealing its sharpened end. When the needle enters the peritoneal cavity, the obturator springs back into position, protecting the intraabdominal contents from injury. The handle of the hollow needle allows the attachment of a syringe or tubing for insufflation of the distention gas.

1. A 3-mm incision adequate for the needle is made with a small scalpel, and the abdominal wall is elevated by gripping it in the midline below the umbilicus. Safe insertion of the insufflation needle mandates that the instrument be maintained in a midline, sagittal plane while the operator directs the tip between the iliac vessels, anterior to the sacrum but inferior to the bifurcation of the aorta and the proximal aspect of the vena cava. Therefore, in women of average weight, the insufflation needle is directed at a 45-degree angle to the patient's spine. In heavy to obese individuals, this angle may be increased incrementally to nearly 90 degrees, accounting for the increasing thickness of the abdominal wall and the tendency of the umbilicus to gravitate caudad with increasing abdominal girth ( 49). The needle's shaft is held by the tips of the fingers and steadily but purposefully guided into position only far enough to allow the tip's entry into the peritoneal cavity. The tactile and visual feedback created when the needle passes through the facial and peritoneal layers of the abdominal wall may provide guidance and help prevent overaggressive insertion attempts. This proprioceptive feedback is less apparent with disposable needles than with the classic Verres needle. With the former, the surgeon must listen to the “clicks” as the needle obturator retracts when it passes through the rectus fascia and the peritoneum. The needle should never be forced. 2. In instances in which known or suspected intraabdominal adhesions surround the umbilicus, alternative sites for insufflation needle insertion should be used. These include the pouch of Douglas, the fundus of the uterus, and the left upper quadrant, most often at the left costal margin ( Fig. 21.6). The left upper quadrant is preferred if there has been no previous surgery in this area. In such patients, the stomach must be decompressed with a nasogastric or orogastric tube before the puncture.

Figure 21.6 Insufflation needle and cannula insertion sites. In most instances, both the insufflation needle, if used, and the primary cannula are inserted through the umbilicus. When subumbilical adhesions are known or suspected, the insufflation needle may be placed through the pouch of Douglas or in the left upper quadrant after evacuation of the gastric contents with an orogastric tube.

3. Before insufflation, the operator should try to detect whether the insufflation needle has been malpositioned in the omentum, mesentery, blood vessels, or hollow organs such as the stomach or bowel. Using a syringe attached to the insufflation needle, blood or gastrointestinal contents may be aspirated. This examination may be facilitated by injecting a small amount of saline into the syringe. If the needle is appropriately positioned, negative intraabdominal pressure is created by lifting the abdominal wall. This negative pressure may be demonstrated by aspiration of a drop of saline placed over the open, proximal end of the needle or, preferably, by using the digital pressure gauge on the insufflator. 4. Additional signs of proper placement may be sought after starting insufflation. The intraabdominal pressure reading should be low, reflecting only systemic resistance to the flow of CO 2. Consequently, there should be little deviation from a baseline measurement, generally less than 10 mm Hg. The pressure varies with respiration and is slightly higher in obese patients. The earliest reassuring sign is the loss of liver “dullness” over the lateral aspect of the right costal margin. However, this sign may be absent if there are dense adhesions in the area, usually the result of previous surgery. Symmetric distention is unlikely to occur when the needle is positioned extraperitoneally. Proper positioning can also be shown by lightly compressing the xiphoid process, which increases the pressure measured by the insufflator. 5. The amount of gas transmitted into the peritoneal cavity should depend on the measured intraperitoneal pressure, not the volume of gas inflated. Intraperitoneal volume capacity varies significantly between individuals. Many surgeons prefer to insufflate to 20 mm Hg for positioning of the cannulas. This level usually provides enough counterpressure against the peritoneum, facilitating trocar introduction and potentially reducing the chance of bowel or posterior abdominal wall and vessel trauma. After placement of the cannulas, the pressure should be dropped to 10 to 12 mm Hg, which essentially eliminates hypercarbia or decreased venous return of blood to the heart. Laparoscopic Cannulas Laparoscopic cannulas are necessary to allow the insertion of laparoscopic instruments into the peritoneal cavity while maintaining the pressure created by the distending gas ( Fig. 21.7 and Fig. 21.8). Cannulas are hollow tubes with a valve or sealing mechanism at or near the proximal end. The cannula may be fitted with a Luer-type port that allows attachment to tubing connected with the CO 2 insufflator. Larger-diameter cannulas (8 to 12 mm) may be fitted with adapters or specialized valves that allow the insertion of smaller-diameter instruments without loss of intraperitoneal pressure.

Figure 21.7 Primary laparoscopic cannulas. Left to right: a nondisposable 10-mm cannula with the obturator removed (Olympus America, Inc., Woodbury, NY), a disposable 5- to 12-mm cannula with a “safety” sheath (Autosuture, Inc, Norwalk, CT), and a Hasson cannula used in open laparoscopy (Ethicon Endosurgery, Inc., Cincinnati, OH).

Figure 21.8 Ancillary laparoscopic cannulas: 5-mm laparoscopic cannulas for ancillary instruments. Top: Apple Medical, Boston, MA (disposable). Middle: Wolf, Laguna Niguel, CA (nondisposable). These cannulas neither have nor require ports or safety sheaths and are therefore less expensive than other cannulas. Bottom: Core Surgical Inc. (Jacksonville, FL).

The trocar is a longer instrument of slightly smaller diameter that is passed through the cannula, exposing its tip. Most trocars have sharp tips, allowing penetration of the abdominal wall after a small skin incision. Many disposable trocar-cannula systems are designed with a safety mechanism—usually a pressure-sensitive spring that either retracts the trocar or deploys a protective sheath around its tip after passage through the abdominal wall. None of these protective devices has been shown to make the procedure safer; however, they all increase the cost. Cannulas can be inserted following minilaparotomy (open laparoscopy), after the successful creation of a pneumoperitoneum (secondary puncture), or without previously instilling intraperitoneal gas (primary puncture). With open laparoscopy, there is less risk for injury to blood vessels and abdominal viscera. However, open laparoscopy cannot prevent all insertion accidents because intestine can be entered inadvertently no matter how small the laparotomy. There is little evidence that secondary puncture is necessary, at least when there are no preexisting abdominal wall adhesions. Therefore, in women with no previous surgery, the primary puncture can be performed with a sharp-tipped trocar-cannula system, which lowers the cost by eliminating the need for the insufflation needle and by reducing operating time. The first, or primary, cannula must be of sufficient caliber to permit passage of the laparoscope and is usually inserted in or at the lower border of the umbilicus. The incision should be extended only enough to allow insertion of the cannula; otherwise, leakage of gas may occur around the sheath. For the primary puncture, an assistant should elevate the abdominal wall. For the secondary puncture, it is unnecessary to lift the abdominal wall during insertion. Both hands can be positioned on the device, using one to provide counterpressure and control to prevent “overshoot” and resultant injury to bowel or vessels. The angle of insertion is the same as for the insufflation needle; adjustments are made according to the patient's weight and body habitus. The laparoscope should be inserted to confirm proper intraperitoneal placement before the insufflation gas is allowed to flow. Laparoscope cannulas can become dislodged and slip out of the incision during a procedure. There are a variety of cannula attachments designed to prevent slippage. Previous abdominal surgery increases the incidence of adhesions of the bowel to the anterior abdominal wall, frequently near the umbilicus and in the path of the primary trocar. In such patients, another primary insertion site should be selected, even if it is used solely for conveying a narrow “scout” laparoscope, some types of which can be inserted through an insufflation needle ( Fig. 21.9). Using such a laparoscope, the presence of adhesions under the incision can be confirmed or excluded, and the umbilical cannula can be inserted under direct vision. Alternate insertion sites for primary cannulas are shown in Fig. 21.6. Of these locations, the left upper quadrant is the most useful because adhesions are rarely present. Nasogastric or orogastric suction must be applied preceding insertion to improve vision and reduce the risk for gastric injury.

Figure 21.9 Scout laparoscopes. Top: the 2.7-mm-diameter Olympus/Ethicon Endosurgery system. The Imagyn outer sheath is introduced with a standard diameter 15-cm insufflation needle, and the Olympus/Ethicon system is inserted with a 3-mm needle. Bottom: the 2-mm-diameter Imagyn laparoscope (Imagyn, Inc., Laguna Niguel, CA).

Ancillary Cannulas Ancillary cannulas are necessary to perform most diagnostic and operative laparoscopic procedures. Most of the currently available disposable ancillary cannulas are identical to those designed for insertion of the primary cannula. However, many of the integrated design features of the primary cannula are unnecessary for ancillary cannulas. Consequently, simple cannulas without safety sheaths and insufflation ports are sufficient ( Fig. 21.8). Proper positioning of these cannulas depends on a sound knowledge of the abdominal wall vascular anatomy. They should always be inserted under direct vision because injury to bowel or major vessels can occur. Before insertion, the bladder should be drained with a urethral catheter. The insertion sites depend on the procedure, the disease, the patient's body habitus, and the surgeon's preference. The most useful and cosmetically acceptable site for an ancillary cannula is usually in the midline of the lower abdomen, about 2 to 4 cm above the symphysis. The ancillary cannula should not be inserted too close to the symphysis because it limits the mobility of the ancillary instruments and access to the cul-de-sac. Lower-quadrant cannulas are useful for operative laparoscopy, but the inferior epigastric vessels must be located in order to avoid injury ( Fig. 21.3). Transillumination of the abdominal wall from within permits the identification of the superficial inferior epigastric vessels in most thin women. However, the deep inferior epigastric vessels cannot be identified by this mechanism because of their location deep to the rectus sheath. The most consistent landmarks are the medial umbilical ligaments (obliterated umbilical arteries) and the exit point of the round ligament into the inguinal canal. At the pubic crest, the deep inferior epigastric vessels begin their cephalad course between the medially located umbilical ligament and the laterally positioned exit point of the round ligament. The trocar should be inserted medial or lateral to the vessels if they are visualized. If the vessels cannot be seen and it is necessary to position the cannula laterally, the cannula should be placed 3 to 4 cm lateral to the medial umbilical ligament or lateral to the lateral margin of the rectus abdominis muscle. If the insertion is placed too far laterally, it will endanger the deep circumflex epigastric artery. The risk for injury can be minimized by placing a 22-gauge spinal needle through the skin at the desired location, directly observing the entry through the laparoscope. This provides reassurance that a safe location has been identified and allows visualization of the peritoneal needle hole, which provides a precise target for inserting the trocar. Even after a proper incision, the abdominal wall vessels can be injured if the trocar is directed medially. Large-diameter trocars are more likely to cause injury; therefore, the smallest cannulas necessary to perform the procedure should be used. Ancillary cannulas should not be placed too close together because this results in “knitting” of the hand instruments, which compromises access and maneuverability. Visualization

During endoscopy, the image must be transferred through an optical system. Although direct optical viewing is feasible and often used for diagnostic purposes, virtually all operative laparoscopy is performed using video guidance. Operative versus Diagnostic Equipment Laparoscopes used for operative purposes have a straight channel, parallel to the optical axis, for the introduction of operating instruments. An advantage of such an endoscope is that it provides an additional port for the insertion of instruments and the tangential application of laser energy. However, operative endoscopes are of relatively larger caliber than diagnostic laparoscopes and have smaller fields of view and increased electrosurgical risks. Diagnostic laparoscopes permit better visualization at a given diameter and are associated with fewer electrosurgical risks. Dimeter Narrow-diameter laparoscopes allow limited transfer of light both into and out of the peritoneal cavity; therefore, they require a more sensitive camera or a more powerful light source for adequate illumination. Ideal illumination is provided by 10-mm diagnostic laparoscopes, but improvements in optics are making more procedures feasible with smaller-caliber devices ( Fig. 21.10).

Figure 21.10 Laparoscopes. Top to bottom: 5-mm diameter (Olympus, Inc., Woodbury, NY), 10-mm diameter (Karl Storz, Agoura Hills, CA), and 2-mm diameter (Imagyn, Inc., Laguna Niguel, CA) laparoscopes. The 2-mm laparoscope can be inserted by a very narrow cannula passed through an insufflation needle.

Lenses Most laparoscope lenses are made of optical-quality glass. The use of fibers is necessary for very-small-caliber laparoscopes (3 ng/ml), a low 17a-hydroxyprogesterone level (150 ng/dl), fasting insulin levels of greater than 25 µIU/ml (normal 2 µg/dl). Reduction in hair growth rate has been reported ( 72), as well as significant improvement in acne associated with adrenal hyperandrogenism.

Ketoconazole Ketoconazole inhibits the key steroidogenic cytochromes. Administered at a low dose (200 mg/day), it can significantly reduce the levels of androstenedione, testosterone, and calculated free testosterone ( 73). Spironolactone Spironolactone is a specific antagonist of aldosterone, which competitively binds to the aldosterone receptors in the distal tubular region of the kidney. It is, therefore, an effective potassium-sparing diuretic, which was originally used for treatment of hypertension. The effectiveness of spironolactone in the treatment of hirsutism is based on the following mechanisms: 1. 2. 3. 4.

Competitive inhibition at the intracellular receptor level for DHT ( 74). Suppression of testosterone biosynthesis by a decrease in the CYP enzymes ( 75). Increase in androgen catabolism (with increased peripheral conversion of testosterone to estrone). Inhibition of skin 5a-reductase activity ( 74).

Although total and free testosterone levels are significantly reduced in patients with both PCOS and idiopathic hirsutism (hyperandrogenism with regular menses) after treatment with spironolactone, total and free testosterone levels in patients with PCOS remain higher than those with idiopathic hirsutism (hyperandrogenism with regular menses) (76). In both groups, SHBG levels are unaltered. The reduction in circulating androgen levels observed within a few days of spironolactone treatment partially accounts for the progressive regression of hirsutism. At least a modest improvement in hirsutism can be anticipated in 70% to 80% of women using at least 100 mg of spironolactone per day for 6 months (77). Spironolactone reduces the daily linear growth rate of sexual hair, hair shaft diameters, and daily hair volume production ( 78). The most common dosages is 25 to 100 mg twice daily. Women treated with 200 mg/day show a greater reduction in hair shaft diameter than women receiving 100 mg/day (79). Maximal effect on hair growth is noted between 3 and 6 months but continues for 12 months. Electrolysis can be recommended 9 to 12 months after the initiation of spironolactone for permanent hair removal. The most common side effect of spironolactone is menstrual irregularity (usually metrorrhagia), which may occur in over 50% of patients with a dosage of 200 g/day (79). Normal menses may resume with reduction of the dosage. Infrequently, other side effects such as urticaria, mastodynia, or scalp hair loss occur ( 79). Nausea and fatigue can occur with high doses ( 77). Because spironolactone can increase serum potassium levels, its use is not recommended in patients with renal insufficiency or hyperkalemia. Periodic monitoring of potassium and creatinine levels is suggested. Return of normal menses in amenorrheic patients is reported in up to 60% of cases ( 76). Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus. Cyproterone Acetate Cyproterone acetate is a synthetic progestin derived from 17-OHP that has potent antiandrogenic properties. The primary mechanism of cyproterone acetate is competitive inhibition of testosterone and DHT at the level of androgen receptors ( 80). This agent also induces hepatic enzymes and may increase the metabolic clearance rate of plasma androgens ( 81). The combination of ethinyl estradiol with cyproterone acetate, which was commonly used in Europe for many years, significantly reduces plasma testosterone and androstenedione levels, suppresses gonadotropins, and increases SHBG levels ( 82). Cyproterone acetate also shows mild glucocorticoid activity ( 83) and may reduce DHEAS levels (84). Administered in a reverse sequential regimen (cyproterone acetate 100 g/day on days 5 to 15, and ethinyl estradiol 30 to 50 mg/day on cycle days 5 to 26), this cyclic schedule allows regular menstrual bleeding, provides excellent contraception, and is effective in the treatment of even severe hirsutism and acne (85). When a desired clinical response is achieved, the dose of cyproterone acetate may be tapered gradually at 3- to 6-month intervals. Side effects of cyproterone acetate include fatigue, weight gain, decreased libido, irregular bleeding, nausea, and headaches. These symptoms occur less often when ethinyl estradiol is added. Cyproterone acetate administration has been associated with liver tumors in beagles and is not approved by the U.S. Food and Drug Administration for use in the United States. Flutamide Flutamide, a pure nonsteroidal antiandrogen, is approved for treatment of advanced prostate cancer. Its mechanism of action is inhibition of nuclear binding of androgens in target tissues. Although it has a weaker affinity to the androgen receptor than spironolactone or cyproterone acetate, larger doses (250 mg given 2 or 3 times daily) may compensate for the reduced potency. Flutamide is also a weak inhibitor of testosterone biosynthesis. In a single, 3-month study of flutamide alone, most patients demonstrated significant improvement in hirsutism with no change in androgen levels ( 86). Significant improvement in hirsutism with a significant drop in androstenedione, DHT, LH, and FSH levels was observed in an 8-month follow-up of flutamide and low-dose OCs in women who did not respond to OCs alone (87). The side effects of flutamide treatment combined with a low-dose OC included dry skin, hot flashes, increased appetite, headaches, fatigue, nausea, dizziness, decreased libido, liver toxicity, and breast tenderness ( 88). Many patients taking flutamide (50% to 75%) report dry skin or a blue-green discoloration of urine. The risk of liver toxicity precludes flutamide as a routine option for the treatment of hirsutism. Cimetidine Cimetidine is a histamine H2 receptor antagonist that has demonstrated a weak antiandrogenic effect as a result of its ability to occupy androgen receptors and inhibit DHT binding at the level of the hair follicles. Although cimetidine has been reported to reduce hair growth in women with hirsutism ( 89), two later studies show no beneficial effect ( 90,91). Finasteride Finasteride is a specific inhibitor of type 2 5a-reductase enzyme activity that has been approved in the United States at a 5-mg dose for the treatment of benign prostatic hyperplasia and at a 1-mg dose to treat male-pattern baldness. In a study in which finasteride (5 mg daily) was compared with spironolactone (100 mg daily) (92), both drugs resulted in similar significant improvement in hirsutism despite differing effects on androgen levels. Most of the improvement in hirsutism occurred after 6 months of therapy with 7.5 mg of finasteride daily (93). The improvement in hirsutism in the presence of rising testosterone levels serves as convincing evidence that it is the binding of DHT and not testosterone to the androgen receptor that is responsible for hair growth. Finasteride does not prevent ovulation or cause menstrual irregularity. The increase in SHBG caused by OCs further decreases free testosterone levels; OCs in combination with finasteride are more effective in reducing hirsutism than finasteride alone. As with spironolactone, finasteride could theoretically feminize a male fetus; therefore, both of these agents are used only with additional contraception. Ovarian Wedge Resection Bilateral ovarian wedge resection is associated with only transient reduction in androstenedione levels and a prolonged minimal decrease in plasma testosterone (94,95). In patients with hirsutism and PCOS who have had wedge resection, hair growth was reduced by approximately 16% ( 96,97). Although Stein's original report cited a pregnancy rate of 85% following wedge resection and maintenance of ovulatory cycles, subsequent reports show lower pregnancy rates and a concerning incidence of periovarian adhesions ( 98). Laparoscopic Electrocautery

Laparoscopic ovarian electrocautery is used as an alternative to wedge resection in patients with severe PCOS whose condition is resistant to clomiphene citrate. In a recent series (99), ovarian drilling was achieved laparoscopically with an insulated electrocautery needle, using 100-W cutting current to aid in entry and 40-W coagulating current to treat each microcyst over 2 seconds (8-mm needle in ovary). In each ovary, 10 to 15 punctures were created. This led to spontaneous ovulation in 73% of patients, with 72% conceiving within 2 years. Of those who had undergone a follow-up laparoscopy, 11 of 15 were adhesion free. To reduce adhesion formation, a technique that cauterized the ovary only in four points led to a similar pregnancy rate ( 100), with a miscarriage rate of 14% (much lower than the usual miscarriage rate of 30% to 40% for patients with PCOS). Most series report a decrease in both androgen and LH concentrations and an increase in FSH concentrations (101,102). Unilateral diathermy has been shown to result in bilateral ovarian activity ( 103). Further studies are anticipated to define candidates who may benefit most from such a procedure. The risk of adhesion formation should be discussed with the patient. Physical Methods of Hair Removal Depilatory creams remove hair only temporarily. They break down and dissolve hair by hydrolyzing disulfide bonds. Although depilatories can have a dramatic effect, many women cannot tolerate these irritative chemicals. The topical use of corticosteroid cream may prevent contact dermatitis. Eflornithine hydrochloride cream also know as difluoromethylornithine (DMFO), irreversibly blocks ornithine decarboxylase (ODC), the enzyme in hair follicles that is important in regulating hair growth. It also has proved effective in the treatment of unwanted facial hair ( 104). Shaving is effective. Contrary to common belief, it does not change the quality, quantity, or texture of hair ( 105). However, plucking, if done unevenly and repeatedly, may cause inflammation and damage to hair follicles and render them less amenable to electrolysis. Waxing is a grouped method of plucking in which hairs are plucked out from under the skin surface. The results of waxing last longer (up to 6 weeks) than shaving or depilatory creams ( 105). Bleaching removes the hair pigment through the use of hydrogen peroxide (usually 6% strength), which is sometimes combined with ammonia. Although hair lightens and softens during oxidation, this method is frequently associated with hair discoloration, or skin irritation, and is not always effective ( 104). Electrolysis and laser hair removal are the only permanent means recommended for hair removal. Under magnification, a trained technician destroys each hair follicle individually. When a needle is inserted into a hair follicle, galvanic current, electrocautery, or both used in combination (blend) destroy the hair follicle. After the needle is removed, a forceps is used to remove the hair. Hair regrowth ranges from 15% to 50%. Problems with electrolysis include pain, scarring, and pigmentation. Cost can also be an obstacle ( 106). Laser hair removal destroys the hair follicle through photoablation. Insulin Sensitizers Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities. Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used extensively in Europe for non–insulin-dependent diabetes. Given its category B status, there has been limited use of the drug in pregnant women with diabetes. Preliminary studies evaluating metformin use in pregnancy suggest no teratogenicity and a reduced miscarriage rate but a potential increased risk of preeclampsia and perinatal mortality ( 107,108). Metformin lowers blood glucose mainly by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake. Metformin enhances insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal ( 109). The hyperandrogenism of PCOS is substantially relieved with metformin therapy, which leads to a drop in insulin levels and improved reproductive function ( 110,111 and 112). Metformin (500 mg 3 times daily) increases ovulation rates both spontaneously and when used in combination with clomiphene citrate in obese patients with PCOS. In this group, a 90% ovulation rate has been achieved ( 113). The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, bloating, and flatulence. Because the drug has caused fatal lactic acidosis in men with diabetes who have renal insufficiency, baseline renal function testing is suggested. The drug should not be given to women with elevated serum creatinine levels (109). Troglitazone, another insulin sensitizer, has been reported to enhance the number of ovulatory cycles when used alone or with clomiphene citrate ( 114). The drug has been withdrawn from the market because of liver toxicity and other adverse effects. A step-by-step approach to ovulation induction in women with PCOS has been suggested ( 109). This algorithm offers a practical way to integrate insulin sensitizers and ovulation induction in the treatment of PCOS. This regimen may need to be modified as knowledge of the disorder and its treatment continues to evolve. The step approach is: If body-mass index is elevated, loss of at least 5% of current body weight, Ovulation induction with clomiphene (with or without glucocorticoid if DHEAS is elevated), Insulin sensitizer as a single agent, Insulin sensitizer in combination with clomiphene citrate, Gonadotropin therapy, Insulin sensitizer in combination with gonadotropin therapy, Ovarian surgery, and In vitro fertilization (IVF). Current concepts regarding the role of obesity and insulin resistance/hyperinsulinemia in PCOS suggest that the primary intervention should be to recommend and assist with weight loss (5–10% of body weight). In those with an elevated BMI, orlistat has proven to be helpful in initiating and maintaining weight loss. A percentage of PCOS patients will respond to weight loss with spontaneous ovulation. In those who do not respond to weight loss alone or who are unable to lose weight, the sequential addition of chomiphene citrate followed by an insulin sensitizer alone, followed by the combination of these agents may promote ovulation without the need to proceed to injectable gonadotropins. A prevailing concern over the increased incidence of spontaneous abortions in women with PCOS and the potential reduction afforded by insulin sensitizers suggest that insulin sensitizers may be beneficial in combination with gonadotropin therapy for ovulation induction or in vitro fertilization (115).

Cushing's Syndrome The adrenal cortex produces three classes of steroid hormones—glucocorticoids, mineralocorticoids, and sex steroids (androgen and estrogen precursors). Hyperfunction of the adrenal gland can produce clinical signs of increased activity of any or all of these hormones. Increased glucocorticoid action results in nitrogen wasting and a catabolic state. This causes muscle weakness, osteoporosis, atrophy of the skin with striae, nonhealing ulcerations and ecchymoses, reduced immune resistance that increases the risk of bacterial and fungal infections, and glucose intolerance resulting from enhanced gluconeogenesis and antagonism to insulin action. Although most patients with Cushing's syndrome gain weight, some lose it. Obesity is typically central, with characteristic redistribution of fat over the clavicles around the neck and on the trunk, abdomen, and cheeks. Cortisol excess may lead to insomnia, mood disturbances, depression, and even overt psychosis. With overproduction of sex steroid precursors, women may develop some degree of masculinization (hirsutism, acne, oligomenorrhea or amenorrhea, thinning of scalp hair), and men may manifest some degree of feminization (gynecomastia and impotence). With overproduction of mineralocorticoids, patients may manifest arterial hypertension and hypokalemic alkalosis. The associated fluid retention may cause pedal edema. The characteristic laboratory findings associated with hypercortisolism are confined mainly to a complete blood count showing evidence of granulocytosis and reduced levels of lymphocytes and eosinophils. Increased urinary calcium secretion may be present. Causes The six recognized noniatrogenic causes of Cushing's syndrome can be either ACTH dependent or ACTH independent (Table 25.3). The ACTH-dependent causes can result from ACTH secreted by pituitary adenomas or from an ectopic source. The hallmark of ACTH-dependent forms of Cushing's syndrome is

the presence of normal or high plasma ACTH concentrations with increased cortisol levels. The adrenal glands are hyperplastic bilaterally. Pituitary ACTH-secreting adenoma, or Cushing's disease, is the most common cause of Cushing's syndrome. These pituitary adenomas are usually microadenomas (3 mm) nodules, which often are pigmented and secrete sufficient cortisol to suppress pituitary ACTH. This condition can be sporadic or familial. Surgical removal of a neoplasm is the treatment of choice (127,128). If a unilateral, well-circumscribed adenoma is identified by MRI or CT scanning, the flank approach may be the most convenient. The cure rate following surgical removal of adrenal adenomas approaches 100%. Several months of corticosteroid replacement therapy usually is required. Treatment of Cushing's Disease The treatment of choice for Cushing's disease is transsphenoidal resection. The cure rate is approximately 80% in patients with microadenomas who undergo surgery by an experienced surgeon ( 120) and is less than 50% in patients with macroadenomas (121). Transient diabetes insipidus is common (122). Radiation Therapy High-voltage external pituitary radiation (4,200 to 4,500 cGy) is given at a rate not exceeding 200 cGy/day. Although only 15% to 25% of adults show total improvement (122), approximately 80% of children respond ( 123). Medical Therapy Mitotane can be used to induce medical adrenalectomy during or after pituitary radiation ( 124). The role of medical therapy is to prepare the severely ill patient for surgery and to maintain normal cortisol levels while a patient awaits the full effect of radiation. Occasionally, medical therapy is used for patients who respond to therapy with only partial remission. Adrenal enzyme inhibitors include aminoglutethimide, metyrapone, trilostane, and etomidate. A combination of aminoglutethimide and metyrapone may cause a total adrenal enzyme block requiring corticosteroid-replacement therapy. Ketoconazole, an FDA-approved antifungal agent, also inhibits adrenal steroid biosynthesis at the side arm cleavage and 11b-hydroxylation steps. The dose of ketoconazole for adrenal suppression is 600 to 800 mg/day for 3 months to 1 year (125). Ketoconazole is effective for long-term control of hypercortisolism of either pituitary or adrenal origin. Nelson's syndrome is an ACTH-secreting pituitary adenoma that develops after bilateral adrenalectomy for Cushing's disease ( 126). This syndrome reportedly complicates 10% to 50% of bilateral adrenalectomy cases. Nelson's syndrome is less common today because bilateral adrenalectomy is less frequently used as initial treatment. Present medical management produces such an effective block to steroid overproduction that it is used primarily as well as after the failure of surgical and radiation therapy. This syndrome is usually caused by a macroadenoma that produces sellar pressure symptoms of headaches, visual field disturbances, and ophthalmoplegia. Extremely high ACTH levels are associated with severe hyperpigmentation (melanocyte-stimulating hormone activity). The treatment is surgical removal or radiation.

Congenital Adrenal Hyperplasia CAH is transmitted as an autosomal recessive disorder. Several adrenocortical enzymes necessary for cortisol biosynthesis may be affected. Failure to synthesize the fully functional enzyme has the following effects: 1. 2. 3. 4.

A relative decrease in cortisol production A compensatory increase in ACTH levels Hyperplasia of the zona reticularis of the adrenal cortex An accumulation of the precursors of the affected enzyme in the bloodstream.

21-Hydroxylase Deficiency Deficiency of 21-hydroxylase is responsible for over 90% of all cases of CAH. The disorder produces a spectrum of conditions. Salt-wasting CAH, which is the most severe form, affects 75% of patients in whom, during the first 2 weeks of life, a hypovolemic salt-wasting crisis is manifest, accompanied by hyponatremia, hyperkalemia, and acidosis. The salt-wasting crisis results from ineffective aldosterone synthesis. The condition is usually diagnosed earlier in affected women than in men because it causes genital virilization (e.g., clitoromegaly, labioscrotal fusion, and abnormal urethral course). In simple virilizing CAH, affected patients are diagnosed as virilized newborn females or as rapidly growing masculinized boys at 3 to 7 years of age. 1. 2. 3. 4.

Basal follicular phase 17-OHP 500 ng/dl establishes the diagnosis; there is no need for further testing ( 125). Basal 17-OHP >200 ng/dl and 1,000 ng/dl ( 129) (Fig. 25.3).

Figure 25.3 Basal and stimulated 17-hydroxyprogesterone concentration.

5. Individuals who are heterozygous (carriers) for both adult-onset adrenal hyperplasia and CAH reveal stimulated 17-OHP values 1.5) was used instead of one CA125 level ( 157). More recent studies reported that the value of CA125 in diagnosis of endometriosis is limited but higher for moderate to severe disease, especially if serum CA125 concentrations are measured during the midfollicular phase ( 159,160). Serial CA125 determinations may be useful to predict the recurrence of endometriosis after therapy (161,162). CA125 levels decrease after combined medical and surgical therapy or during medical treatment of endometriosis with danazol, gonadotropin-releasing hormone (GnRH) analogues, or gestrinone, but not with medroxyprogesterone acetate (MPA) or placebo (163,164 and 165). CA125 levels have been reported to increase to pretreatment levels as early as 3, 4, or 6 months after the cessation of therapy with danazol, GnRH analogs, or gestrinone ( 153,164,165,167 and 168). Posttreatment increases in CA125 levels have been reported to correlate with endometriosis recurrence ( 152,162,169). However, other studies have not substantiated a correlation between posttreatment CA125 levels and disease recurrence (163,166,170). Laparoscopic Findings During diagnostic laparoscopy, the pelvic and abdominal cavity should be systematically investigated for the presence of endometriosis. This examination should include a complete inspection and palpation in a clockwise or counterclockwise fashion with a blunt probe of the bowel, bladder, uterus, tubes, ovaries, cul-de-sac, and broad ligament ( Fig. 26.1).

Figure 26.1 Pelvic localization of endometriosis.

Characteristic findings include typical (“powder-burn,” “gunshot”) lesions on the serosal surfaces of the peritoneum. These are black, dark brown, or bluish nodules or small cysts containing old hemorrhage surrounded by a variable degree of fibrosis ( Fig. 26.2). Endometriosis can appear as subtle lesions ( Fig. 26.3), including red implants (petechial, vesicular, polypoid, hemorrhagic, red flamelike), serous or clear vesicles, white plaques or scarring, yellow-brown discoloration of the peritoneum, and subovarian adhesions ( 89,90 and 91,171,172). Histologic confirmation of the laparoscopic impression is essential for the diagnosis of endometriosis (173), not only for subtle lesions but also for typical lesions reported to be histologically negative in 24% of cases ( 174).

Figure 26.2 Subtle and typical endometriotic lesions. A: Clear translucent vesicle on pelvic peritoneum. B: Red polypoid lesions and petechial and hemorrhagic areas on pelvic peritoneum. C: Typical black-puckered lesions on uterosacral ligaments. D: Combination of typical black-puckered lesions on left uterosacral ligament and red polypoid lesions in cul-de-sac.

Figure 26.3 Ovarian endometriosis: endometriotic cyst (endometrioma) on the left ovary.

Mild forms of deep endometriosis may only be detected by palpation under an endometriotic lesion or by discovery of a palpable mass beneath visually normal peritoneum, most notably in the posterior cul-de-sac ( 141) (Fig. 26.4). Reduced Douglas depth and volume in women with deep endometriosis suggest that such lesions develop not in the rectovaginal septum but intraperitoneally and that burial by anterior rectal wall adhesions creates a false bottom, giving an erroneous impression of xtraperitoneal origin ( 175).

Figure 26.4 Laparoscopic excision of deep endometriosis from the cul-de-sac.

The diagnosis of ovarian endometriosis is facilitated by careful inspection of all sides of both ovaries, which may be difficult when adhesions are present in more advanced stages of disease (Fig. 26.5). With superficial ovarian endometriosis, lesions can be both typical and subtle. Larger ovarian endometriotic cysts (endometrioma) are usually located on the anterior surface of the ovary and are associated with retraction, pigmentation, and adhesions to the posterior peritoneum. These ovarian endometriotic cysts often contain a thick, viscous dark brown fluid (“chocolate fluid”) composed of hemosiderin derived from previous intraovarian hemorrhage. Because this fluid may also be found in other conditions, such as in hemorrhagic corpus luteum cysts or neoplastic cysts, biopsy and preferably removal of the ovarian cyst for histologic confirmation are necessary for the diagnosis in the revised endometriosis classification of the American Society for Reproductive Medicine. If that is not possible, the presence of an ovarian endometriotic cyst should be confirmed by the following features: cyst diameter of less than 12 cm, adhesion to pelvic sidewall or broad ligament, endometriosis on surface of ovary, and tarry, thick, chocolate-colored fluid content ( 176). Ovarian endometriosis appears to be a marker for more extensive pelvic and intestinal disease. Exclusive ovarian disease is found in only 1% of endometriosis patients, with the remaining patients having mostly extensive pelvic or intestinal endometriosis ( 177).

Figure 26.5 Revised American Fertility Society Classification, 1985. (From the America Fertility Society.Revised American Fertility Society classification of endometriosis. Fertil Steril 1985;43:351–235, with permission.)

Histologic Confirmation Histologic confirmation is essential in the diagnosis of endometriosis. In a study of 44 patients with chronic pelvic pain, endometriosis was laparoscopically diagnosed in 36%, but histologic confirmation was obtained in only 18%. This resulted in a low diagnostic accuracy of laparoscopic inspection with a positive predictive value of only 45%, explained by a specificity of only 77% ( 178). Microscopically, endometriotic implants consist of endometrial glands and stroma with or without hemosiderin-laden macrophages ( Fig. 26.6). It has been suggested, however, that using these stringent and unvalidated histologic criteria may result in significant underdiagnosis of endometriosis ( 2). Furthermore, problems in obtaining biopsies (especially small vesicles) and variability in tissue processing (step or partial instead of serial sectioning) may contribute to false-negative results. Endometrioid stroma may be more characteristic of endometriosis than endometrioid glands ( 179). Stromal endometriosis, which contains endometrial stroma with hemosiderin-laden macrophages or hemorrhage, has been reported in women ( 173,174) and in baboons (97) and may represent a very early event in the pathogenesis of endometriosis. Isolated endometrial stromal cell nodules, immunohistochemically positive for vimentin and estrogen receptor, can be found without endometrial glands along blood or lymphatic vessels ( 180).

Figure 26.6 Histologic appearance of endometriosis: endometrial glandular epithelium, surrounded by stroma in (A) typical lesion and (B) clear vesicle.

Different types of lesions may have different degrees of proliferative or secretory glandular activity ( 179). Vascularization, mitotic activity, and the three-dimensional structure of endometriosis lesions are key factors ( 181,182 and 183). Deep endometriosis has been described as a specific type of pelvic endometriosis characterized by proliferative strands of glands and stroma in dense fibrous and smooth muscle tissue ( 110). However, smooth muscles are also frequent components of endometriotic lesions on the peritoneum, ovary, rectovaginal septum, and uteroasacral ligaments ( 184). Microscopic endometriosis is defined as the presence of endometrial glands and stroma in macroscopically normal pelvic peritoneum. It is believed to be important in the histogenesis of endometriosis and its recurrence after treatment ( 185,186). The clinical relevance of microscopic endometriosis is controversial because it has not been observed uniformly. Using undefined criteria for what constitutes normal peritoneum, peritoneal biopsy specimens of 1 to 3 cm were obtained during laparotomy from 20 patients with moderate to severe endometriosis ( 186). Examination of the biopsy results with low-power scanning electron microscopy revealed unsuspected microscopic endometriosis in 25% of cases not confirmed by light microscopy. Peritoneal endometriotic foci have been demonstrated by light microscopy in areas that show no obvious evidence of disease (187). In serial sections of laparoscopic biopsies of normal peritoneum, 10% to 15% of women were shown to have microscopic endometriosis, and endometriosis was found in 6% of those without macroscopic disease ( 172,188,189). In contrast, other studies have been unable to detect microscopic endometriosis in 2-mm biopsy specimens of visually normal peritoneum ( 88,190,191 and 192). Examination of larger samples (5 to 15 mm) of visually normal peritoneum has revealed microscopic endometriosis in only 1 of 55 patients studied ( 193). Similarly, a histologic study of serial sections through the entire pelvic peritoneum of visually normal peritoneum from baboons with and without disease indicated that microscopic

endometriosis is a rare occurrence ( 194). Therefore, it appears that macroscopically appearing normal peritoneum rarely contains microscopic endometriosis ( 193).

Classification The current classification system of endometriosis is the former American Fertility Society (AFS) system ( Fig. 26.5), which has been revised without major changes (121). It is based on the appearance, size, and depth of peritoneal and ovarian implants; the presence, extent, and type of adnexal adhesions; and the degree of cul-de-sac obliteration. In the new classification system, the morphology of peritoneal and ovarian implants should be categorized as red (red, red-pink, and clear lesions), white (white, yellow-brown, and peritoneal defects), and black (black and blue lesions). This system reflects the extent of endometriotic disease but has considerable intraobserver and interobserver variability ( 195,196). Because the revised classification of endometriosis is the only internationally accepted system, it appears to be the best available tool to describe objectively the extent of endometriosis and relate it to spontaneous evolution and to therapeutic outcomes (pain relief, enhancement of fertility). The classification system has also been criticized because several investigators failed to find a correlation between it and endometriosis-related pain or infertility, as will be reviewed in the section, Results of Surgical Treatment.

Spontaneous Evolution Endometriosis appears to be a progressive disease in a significant proportion (30% to 60%) of patients. During serial observations, deterioration (47%), improvement (30%), or elimination (23%) was documented over a 6-month period (197). In another study, endometriosis progressed in 64%, improved in 27%, and remained unchanged in 9% of patients over 12 months (198). A third study of 24 women reported 29% with disease progression, 29% with disease regression, and 42% with no change over 12 months. Follow-up studies in both baboons and women ( 200,201) with spontaneous endometriosis over 24 months have demonstrated disease progression in all baboons and in 6 of 7 women. Several studies have reported that subtle lesions and typical implants may represent younger and older types of endometriosis, respectively. In a cross-sectional study, the incidence of subtle lesions decreased with age ( 203). This was recently confirmed by a 3-year prospective study that reported that the incidence, overall pelvic area involved, and volume of subtle lesions decreased with age, but in typical lesions, these parameters and the depth of infiltration increased with age ( 100). Remodeling of endometriotic lesions (transition between typical and subtle subtypes) has been reported to occur in women and in baboons, indicating that endometriosis is a dynamic condition ( 202,204). Several studies in women, cynomolgus monkeys, and rodents have shown that endometriosis is ameliorated after pregnancy ( 204,205). The characteristics of endometriosis are variable during pregnancy, and lesions tend to enlarge during the first trimester but regress thereafter (208). Studies in baboons have revealed no change in the number or surface area of endometriosis lesions during the first two trimesters of pregnancy ( 209). These results do not exclude a beneficial effect that potentially may occur during the third trimester or in the immediate postpartum period. Establishment of a “pseudopregnant state” with exogenously administered estrogen and progestins was based on the belief that symptomatic improvement may result from decidualization of endometrial implants during pregnancy (210). This hypothesis, however, has not been substantiated.

Treatment Prevention No strategies to prevent endometriosis have been uniformly successful. Although a reduced incidence of endometriosis has been reported in women who engaged in aerobic activity from an early age ( 16), the possible protective effect of exercise has not been investigated thoroughly. There also is insufficient evidence that oral contraceptive use offers protection against the development of endometriosis. In contrast, a recent report ( 211) showed an increased risk for endometriosis development in a select population of women taking oral contraceptives. Regardless of the clinical profile (subfertility, pain, asymptomatic findings), treatment of endometriosis may be justified because endometriosis appears to progress in 30% to 60% of patients within a year of diagnosis and because it is not possible to predict in which patients it will progress ( 198). Unfortunately, elimination of the endometriotic implants by surgical or medical treatment often provides only temporary relief. Therefore, the goal should be to eliminate the endometriotic lesions and, more importantly, to treat the sequelae (pain and subfertility) often associated with this disease.

Surgical Treatment In most women with endometriosis, preservation of reproductive function is desirable. Therefore, the least invasive and least expensive approach that is effective should be used. The goal of surgery is to excise or coagulate all visible endometriotic lesions and associated adhesions—peritoneal lesions, ovarian cysts, deep rectovaginal endometriosis—and to restore normal anatomy. Laparoscopy can be used in most women, and this technique decreases cost, morbidity, and the possibility of recurrence of adhesions postoperatively. Laparotomy should be reserved for patients with advanced-stage disease who cannot undergo a laparoscopic procedure and for those in whom fertility conservation is not necessary. Peritoneal Endometriosis Endometriosis lesions can be removed during laparoscopy by surgical excision with scissors, bipolar coagulation, or laser methods (CO 2 laser, potassium-titany-phosphate laser, or argon laser). Although some surgeons claim that the CO 2 laser is superior because it causes only minimal thermal damage, no evidence is available to show that one technique is better than the other. Comparable cumulative pregnancy rates have been reported after treatment of mild endometriosis with laparoscopic excision and electrocoagulation ( 212). Ovarian Endometriosis Superficial ovarian lesions can be vaporized. Small ovarian endometrioma (3 cm in diameter) ovarian endometrioma should be aspirated, followed by incision and removal of the cyst wall from the ovarian cortex. To prevent recurrence, the cyst wall of the endometrioma must be removed, and normal ovarian tissue must be preserved. Although as little as one tenth of an ovary is enough to preserve function and fertility ( 214), there is increasing concern that ovarian cystectomy with concomitant removal or destruction of primordial follicles may reduce ovarian volume and reserve and diminish fertility. A recent study reported reduced follicular response in natural and clomiphene citrate-stimulated cycles, but not in gonadotropin-stimulated cycles, in women younger than 35 years of age who underwent cystectomy compared with controls of similar age with normal ovaries ( 215). Therefore, it has been proposed to replace cystectomy by fenestration and coagulation of the inner wall of the endometriotic ovarian cyst. In one study, cumulative clinical pregnancy rates and recurrence rates were comparable in women treated with cystectomy and with fenestration and coagulation after 36 months, but conception occurred more quickly in the fenestration and coagulation group ( 216). A more recent case-control study in 231 patients reported a lower cumulative reoperation rate in the cyst excision group than in the fenestration and coagulation group after 18 (6% versus 22%) and 42 (24% versus 59%) months of follow-up ( 217). A randomized controlled trial demonstrated that pain and subfertility caused by ovarian endometrioma were improved more by cystectomy than by fenestration and coagulation ( 218). A reduced recurrence of pain after 2 years [odds ratio (OR), 0.2; confidence interval (CI), 0.05 to 0.77], an increased pain-free interval after operation (19 months versus 9.5 months), and an increased pregnancy rate (67% versus 23%) were found in the cystectomy group when compared with the fenestration and coagulation group ( 218). Therefore, based on the current evidence, ovarian cystectomy appears to be the method of choice. Adhesiolysis The removal of endometriosis-related adhesions (adhesiolysis) should be performed carefully as described in Chapter 21. Routine use of pharmacologic or liquid agents to prevent postoperative adhesions after fertility surgery cannot be recommended based on evidence from randomized controlled trials (219). Preoperative Hormonal Treatment In patients with severe endometriosis, it has been recommended that surgical treatment be preceded by a 3-month course of medical treatment to reduce vascularization and nodular size ( 141). However, a recent randomized study comparing 3 months of preoperative treatment with GnRH and no treatment in 75 women with moderate to severe endometriosis failed to show a significant difference in ease of surgery between the two groups ( 220). Deep Rectovaginal and Rectosigmoidal Endometriosis The surgical excision of deep rectovaginal and rectosigmoidal endometriosis is difficult and can be

associated with major complications. Postoperative bowel perforations with peritonitis have been reported in 2% to 3% of cases ( 221). Preoperative investigations, including gynecologic ultrasound, intravenous pyelography (to exclude ureteral endometriosis), and colon contrast radiography (to exclude transmural rectosigmoidal endometriosis), are essential. Preoperative laxatives, starch-free diet, and full bowel preparation are needed to allow perioperative bowel suturing, if needed. To allow complete excision of rectovaginal endometriosis, 6% of patients needed bowel wall resection, and 14% required partial resection of the posterior vaginal fornix ( 221). Segmental rectosigmoid resection can be performed by laparotomy, laparoscopy with intracorporeal suturing, or by laparoscopically assisted vaginal technique ( 222). The latter technique appears to be faster than laparoscopy with intracorporeal suturing and cheaper than laparotomy because of decreased hospital stay and lower operating room charges ( 222). Ureter stents may be required before excision of peritoneal endometriosis surrounding the ureter. A multidisciplinary approach involving gynecologic and gastroenterologic surgeons and urologists is desirable. Oophorectomy and Hysterectomy Radical procedures such as oophorectomy or total hysterectomy are indicated only in severe situations and can be performed either laparoscopically or, more commonly, by laparotomy. However, it is important to note that women aged 30 years or younger at the time of hysterectomy for endometriosis-associated pain are more likely than older women to have residual symptoms, to report a sense of loss, and to report more disruption from pain in different aspects of their lives ( 223). Postoperative Hormone Replacement Postoperative hormone replacement with estrogen is required after bilateral oophorectomy, and there is a negligible risk for renewed growth of residual endometriosis. To reduce this risk, hormone replacement therapy should be withheld until 3 months after surgery. The addition of progestins to this regimen protects the endometrium. Some cases of adenocarcinoma have been reported, presumably arising from endometriosis lesions left in women treated with unopposed estrogen (214).

Results of Surgical Treatment Pain The outcome of surgical therapy in patients with endometriosis and pain is influenced by many psychological factors relating to personality, depression, and marital and sexual problems. There is a significant placebo response to surgical therapy: diagnostic laparoscopy without complete removal of endometriosis may alleviate pain in 50% of patients (224,225 and 226). Similar results have been reported using oral placebos ( 227). Although some reports have claimed pain relief with laser laparoscopy in 60% to 80% of patients with very low morbidity, none was prospective or controlled and, thus, did not allow a definitive conclusion regarding treatment efficacy (141,228,229,230 and 231). Endometriosis Stage and Pain Relief after Surgery In patients with pain, the endometriosis stage was not related to pain symptoms in several studies (232,233). However, more recent studies reported a positive correlation between endometriosis stage and endometriosis-related dysmenorrhea or chronic pelvic pain (234,235). In a prospective, controlled, randomized, double-blind study, surgical therapy has been shown to be superior to expectant management 6 months after treatment of mild and moderate endometriosis (224). In women with mild and moderate disease treated with laser, 74% achieved pain relief. Treatment was least effective in women with minimal disease. There were no reported operative or laser complications ( 224). One year later, symptom relief was still present in 90% of those who initially responded ( 199). Patients with severe disease were not included because it had previously been shown that surgery resulted in pain relief in 80% of patients who did not respond to medical therapy ( 236). These results suggest that laser laparoscopy may be effective for the treatment of pain associated with mild to severe endometriosis. In women with minimal endometriosis, laser treatment may limit progression of disease. Effects of Postoperative Hormonal Treatment on Pain Substantial evidence from randomized controlled trials supports the postoperative medical treatment of endometriosis-associated pain for 6 to 12 months. Postoperative GnRH treatment resulted in reduced pain scores and in a delay of pain recurrence for more than 12 months if the agonists were given for 6 months but not if they were only administered for 3 months ( 237,238 and 239). Similarly, postoperative hormonal treatment with danazol, 100 mg/d (low dose), for 12 months after surgery for moderate to severe endometriosis resulted in a significantly lower pain score in the treated group when compared with the placebo group. In contrast, postoperative high-dose danazol, 600 mg/d for 3 months, was not superior to expectant management with respect to pain recurrence in an identical patient population ( 240). Subfertility Endometriosis Stage and Pregnancy Outcome after Surgery When endometriosis causes mechanical distortion of the pelvis, surgery should be performed if reconstruction of normal pelvic anatomy can be achieved. The success of surgery in relieving infertility is probably related to the severity of endometriosis. A recent retrospective multicenter analysis ( 241) reported cumulative pregnancy rates of 39%, 31%, 30%, and 25% in patients with endometriosis stages I, II, III, and IV, respectively, 12 months after surgical treatment. Although there appeared to be a negative correlation between stage of endometriosis and fertility outcome, no significant difference was found between the four groups in this study. However, the study had many limitations, including retrospective design, lack of well-defined definition of male factor infertility as potential bias, multicenter data with significant interobserver variability, inclusion of only a limited number of patients with substantial adhesive disease, variable infertility treatment after 6 months of follow-up, and absence of a control group. A somewhat higher cumulative intrauterine pregnancy rate has been reported in 30 women with deep uterosacral endometriosis after surgery: 48% after 12 months (47% for AFS stages I to II and 46% for AFS stages III to IV) (242). A cumulative pregnancy rate of 24% was reported in patients 9 months after undergoing reoperation for stage III to IV endometriosis ( 243). Other investigators reported a negative correlation between stage of endometriosis and fertility after surgical treatment. In an older study, using an older classification system, a significant decrease in fecundability was seen in women with severe or extensive endometriosis compared with women with mild or moderate disease (244,245). Other studies have reported a significant negative correlation between endometriosis stage and pregnancy rate and decreased pregnancy rates when the revised scores exceeded 70 (246,247). Preoperative and Postoperative Medical Treatment Preoperative medical treatment with danazol, GnRH agonists, or progestins may be useful to reduce the extent of endometriosis in patients with advanced disease. Postoperative medical treatment is rarely indicated because it does not work based on randomized trials, because it prevents pregnancy, and because the highest pregnancy rates occur during the first 6 to 12 months after conservative surgery ( 238,239). If pregnancy does not occur within 2 years of surgery, there is little chance of subsequent fertility ( 248). Minimal to Mild Endometriosis and Fertility after Surgery Surgical management of infertile women with minimal to mild endometriosis is controversial. The cumulative pregnancy rate after 5 years without therapy has been reported to be as high as 90% in women with minimal or mild endometriosis ( 249). This is comparable to the 93% rate reported in women who do not have endometriosis. Laparoscopic destruction of endometriosis has been reported to improve fertility in patients with minimal to mild disease (250,251 and 252), but not all investigators share this conclusion ( 253,254 and 255). It has been hypothesized that the MFR is higher during the first 6 to 12 months after laparoscopic surgery than with expectant management ( 256,257). Two randomized controlled studies have evaluated the effect of surgical treatment of endometriosis on fertility parameters ( 133,134). Marcoux and coworkers (133) reported that laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis. They studied 341 infertile women, 20 to 39 years of age, with minimal or mild endometriosis. During diagnostic laparoscopy, the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy. The study objects were recruited among infertile women scheduled for diagnostic laparoscopy with strict eligibility criteria. There was no previous surgical treatment for endometriosis and no medical treatment for endometriosis in the previous 9 months. There was no other medical or surgical treatment for infertility in the previous 3 months. They had no history of pelvic inflammatory disease and no severe pelvic pain precluding expectant management. The diagnosis of endometriosis required the presence of one or more typical bluish or black lesions. The stage of endometriosis was determined according to the revised AFS classification. During the diagnostic laparoscopy, the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They found that resection or ablation of minimal and mild endometriosis increased the likelihood of pregnancy in infertile women. In the treated group, 31% of the patients became pregnant, compared with 18% in the nontreated group ( p = 0.006). In a multicenter Italian study, a similar study design was used to compare the effect of diagnostic laparoscopy with surgical resection and ablation of visible

endometriosis (on fertility parameters) in infertile women with minimal to mild endometriosis ( 134). Eligible patients were women aged less than 36 years who were trying to conceive and had a laparoscopically confirmed diagnosis of minimal or mild endometriosis, according to the revised AFS classification system. None of the women had had therapy for endometriosis or infertility. Treatment was randomly allocated during laparoscopy. There was a follow-up period of 1 year after the laparoscopy. The results of this study did not show a beneficial effect of surgery regarding fertility. During the follow-up period after laparoscopy, no statistically significant differences in conception and live-birth rates were observed in the treated group (24% and 20%, respectively) and in the control group (29% and 22%, respectively). Based on these studies, and taking into account the larger patient population in the Canadian multicenter study, surgical treatment of minimal to mild endometriosis appears to offer a small but significant benefit with regard to fertility outcome. Furthermore, the surgical removal of peritoneal endometriosis may also be important to prevent progression of endometriosis. However, care is needed to prevent adhesion formation that could result as a consequence of overenthusiastic excision of minimal to mild endometriosis.

Medical Treatment Because estrogen is known to stimulate the growth of endometriosis, hormonal therapy has been designed to suppress estrogen synthesis, thereby inducing atrophy of ectopic endometrial implants or interrupting the cycle of stimulation and bleeding. Implants of endometriosis react to gonadal steroid hormones in a manner similar but not identical to normally stimulated ectopic endometrium. Ectopic endometrial tissue displays histologic and biochemical differences from normal ectopic endometrium in characteristics such as glandular activity (proliferation, secretion), enzyme activity (17b-hydroxysteroid dehydrogenase), and steroid (estrogen, progestin, and androgen) hormone receptor levels. The use of diethylstilbestrol, methyltestosterone, or other androgens is no longer advocated because they lack efficacy, have significant side effects, and pose risks to the fetus if pregnancy occurs during therapy. A new generation of aromatase inhibitors, estrogen receptor modulators, and progesterone antagonists may offer new hormonal treatment options in the future. Recent progress in the understanding of the pathogenesis of endometriosis has led to the expectation that new pharmaceutical agents affecting inflammation, angiogenesis, and MMP activity may prevent or inhibit the development of endometriosis. Oral Contraceptives Continuous Administration Manipulation of the endogenous hormonal milieu is the basis for the medical management of endometriosis. The treatment of endometriosis with continuous low-dose monophasic combination contraceptives (one pill per day for 6 to 12 months) was originally used to induce pseudopregnancy caused by the resultant amenorrhea and decidualization of endometrial tissue ( 210). Kistner was the first to introduce the concept of an adynamic endometrium through elimination of the normal cyclic hormonal changes characteristic of the menstrual cycle ( 258). This induction of a pseudopregnancy state with combination oral contraceptive pills has been shown to be effective in reducing dysmenorrhea and pelvic pain. In addition, the subsequent amenorrhea induced by oral contraceptives could potentially reduce the amount of retrograde menstruation (one of the many risk factors proposed in the etiology of endometriosis), decreasing the risk for disease progression. Pathologically, oral contraceptive use is associated with decidualization of endometrial tissue, necrobiosis, and possibly absorption of the endometrial tissue ( 259). Unfortunately, there is no convincing evidence that medical therapy with oral contraceptives offers definitive therapy. Instead, the endometrial implants survive the induced atrophy and, in most patients, reactivate after termination of treatment. Any low-dose combination oral contraceptive containing 30 to 35 mg of ethinyl estradiol used continuously can be effective in the management of endometriosis. The objective of the treatment is the induction of amenorrhea, which should be continued for 6 to 12 months. Symptomatic relief of dysmenorrhea and pelvic pain is reported in 60% to 95% of patients ( 260,261). After a first-year recurrence rate of 17% to 18%, a 5% to 10% annual recurrence rate has been observed. In addition, a posttreatment pregnancy rate of up to 50% can be expected. Although oral contraceptives are effective in inducing a decidualized endometrium, the estrogenic component in oral contraceptives may potentially stimulate endometrial growth and increase pelvic pain in the first few weeks of treatment. The long-term significance of this effect remains to be determined. Oral contraceptives are less costly than other treatments and may be helpful in the short-term management of endometriosis with potential long-term benefits in some women. Cyclic Administration There is no convincing evidence that cyclic use of combination oral contraceptives provides prophylaxis against either the development or recurrence of endometriosis. Estrogens in oral contraceptives potentially may stimulate the proliferation of endometriosis. The reduced menstrual bleeding that often occurs in women taking oral contraceptives may be beneficial to women with prolonged, frequent menstrual bleeding, which is a known risk factor for endometriosis (16). Further research is warranted to assess the effect of low-dose oral contraceptives in preventing endometriosis and in treating associated pain. In a recent randomized controlled study, a cyclic 2-day oral contraceptive ( ethinyl estradiol 20 gamma + desogestrel 0.15 mg) combined with very-low-dose danazol (50 mg/d) was less effective in relief of dysmenorrhea than depot medroxyprogesterone acetate (150 mg every 3 months) (262). Progestins Progestins may exert an antiendometriotic effect by causing initial decidualization of endometrial tissue followed by atrophy. They can be considered as the first choice for the treatment of endometriosis because they are as effective as danazol or GnRH analogues and have a lower cost and a lower incidence of side effects than these agents (263). There is no evidence that any single agent or any particular dose is preferable to another. The effective doses of several progestins are summarized in Table 26.1. In most studies, the effect of treatment has been evaluated after 3 to 6 months of therapy. MPA has been the most studied agent. It is effective in relieving pain starting at a dose of 30 mg/d and increasing the dose based on the clinical response and bleeding patterns ( 264,265). However, a recent randomized placebo controlled study reported a significant reduction in stages and scores of endometriosis in both the placebo group and the group treated with MPA, 50 mg/d, and placebo at laparoscopy within 3 months after cessation of therapy ( 266). These findings raise questions about the need for medical therapy.

Table 26.1. Medical Treatment of Endometriosis-Associated Pain: Effective Regimens (Usual Duration: 6 Months)

Medroxyprogesterone acetate (150 mg) given intramuscularly every 3 months is also effective for the treatment of pain associated with endometriosis, but it is not indicated in infertile women because it induces profound amenorrhea and anovulation, and a varying length of time is required for ovulation to resume after discontinuation of therapy. Megestrol acetate has been administered in a dose of 40 mg/d with good results ( 276). Other treatment strategies have included dydrogesterone (20 to 30 mg/d, either continuously or on days 5 to 25) and lynestrenol (10 mg/d). The effectiveness of natural progesterone has not been evaluated. Side effects of progestins include nausea, weight gain, fluid retention, and breakthrough bleeding due to hypoestrogenemia. Breakthrough bleeding, although common, is usually corrected by short-term (7-day) administration of estrogen. Depression and other mood disorders are a significant problem in about 1% of women taking these medications. Local progesterone treatment of endometriosis-associated dysmenorrhea with a levonorgestrel-releasing intrauterine system for 12 months has resulted in a

significant reduction in dysmenorrhea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules ( 267,268). Although the results are promising, none of these pilot studies included a control group. Further randomized evidence is needed to determine whether intrauterine progesterone treatment is effective in the suppression of endometriosis. Progesterone Antagonists Progesterone antagonists and progesterone receptor modulators may suppress endometriosis based on their antiproliferative effects on the endometrium, without the risk for hypo-estrogenism or bone loss that occurs with GnRH treatment. These products are soon to be introduced in the United States, but their clinical effectiveness remains to be proved. Mifepristone Mifepristone (RU-486) is a potent antiprogestagen with a direct inhibitory effect on human endometrial cells and, in high doses, an antiglucocorticoid action (269). The recommended dose for endometriosis is 25 to 100 g/d. In uncontrolled studies, mifepristone, 50 to 100 mg/d, reduced pelvic pain and induced 55% regression of the lesions without significant side effects ( 270,271). In an uncontrolled pilot study, mifepristone, 5 mg/d, resulted in pain improvement, but there was no change in endometriosis lesions, suggesting that this dosage is probably too low ( 272). Onapristone Progesterone antagonists onapristone (ZK98299) and ZK136799, used in the treatment of rats with surgically induced endometriosis, resulted in a remission in 40% to 60% of treated animals. In animals with persistent endometriosis, growth inhibition was obtained in 48% and 85% of endometriotic lesions after therapy with onapristone and ZK136799, respectively (273). Other Progesterone Antagonists The chemical synthesis and pharmacologic characterization of a highly potent progesterone antagonist, ZK230211, have been reported, with little or no other endocrinologic effects. ZK230211 is active on both progesterone receptors A and B (274). In primates, this drug has been reported to block ovulation and menstruation at all effective doses ( 275), whereas another progesterone antagonist, ZK137316, allowed ovulation but blocked menstruation in a dose-dependent fashion. All progesterone antagonist–treated animals maintained normal follicular phase concentration of estradiol and returned to menstrual cyclicity within 15 to 41 days after treatment (275). Both progesterone antagonists block unopposed estrogen action on the endometriosis through their antiproliferative effect. Gestrinone Gestrinone is a 19-nortestosterone derivative with androgenic, antiprogestagenic, antiestrogenic, and antigonadotropic properties. It acts centrally and peripherally to increase free testosterone and reduce sex hormone–binding globulin levels (androgenic effect), reduce serum estradiol values to early follicular phase levels (antiestrogenic effect), reduce mean LH levels, and obliterate the LH and follicle-stimulating hormone (FSH) surge (antigonadotropic effect). Gestrinone causes cellular inactivation and degeneration of endometriotic implants but not their disappearance ( 277). Amenorrhea occurs in 50% to 100% of women and is dose dependent. Resumption of menses generally occurs 33 days after discontinuing the medication ( 278,279). An advantage of gestrinone is its long half-life (28 hours) when given orally. The standard dose has been 2.5 mg twice a week. Although it has been reported that 1.25 mg twice weekly is equally effective ( 280), a more recent randomized study demonstrated in women with mild to moderate endometriosis that 2.5 mg gestrinone, twice weekly for 24 weeks, is more effective and has a better effect on bone mass (+7% versus –7%) when compared with 1.25 mg gestrinone, 2 times weekly for 24 weeks (281). The clinical side effects of gestrinone are dose dependent and similar to but less intense than those caused by danazol (278). They include nausea, muscle cramps, and androgenic effects such as weight gain, acne, seborrhea, and oily hair and skin. In a multicenter, randomized, double-blind study, gestrinone was as effective as GnRH for the treatment of pelvic pain associated with endometriosis ( 282). However, gestrinone has fewer side effects and has the added advantage of twice-weekly administration. Pregnancy is contraindicated while taking gestrinone because of the risk for masculinization of the fetus. Danazol Danazol is not more effective than other available medications to treat endometriosis. Recognized pharmacologic properties of danazol include suppression of GnRH or gonadotropin secretion, direct inhibition of steroidogenesis, increased metabolic clearance of estradiol and progesterone, direct antagonistic and agonistic interaction with endometrial androgen and progesterone receptors, and immunologic attenuation of potentially adverse reproductive effects ( 283,284). The multiple effects of danazol produce a high-androgen, low-estrogen environment (estrogen levels in the early follicular to postmenopausal range) that does not support the growth of endometriosis, and the amenorrhea that is produced prevents new seeding of implants from the uterus into the peritoneal cavity. The immunologic effects of danazol have been studied in women with endometriosis and adenomyosis and include a decrease in serum immunoglobulins, a decrease in serum C3, a rise in serum C4 levels, decreased serum levels of autoantibodies against various phospholipid antigens, and decreased serum levels of CA125 during treatment (152,153,165,166,167 and 168,285,286). Danazol inhibits peripheral blood lymphocyte proliferation in cultures activated by T-cell mitogens but does not affect macrophage-dependent T-lymphocyte activation of B lymphocytes ( 284). Danazol inhibits interleukin-1 and TNF production by monocytes in a dose-dependent manner, and suppresses macrophage- and monocyte-mediated cytotoxicity of susceptible target cells in women with mild endometriosis ( 287). These immunologic findings may be important in the remission of endometriosis with danazol treatment and may offer an explanation of the effect of danazol in the treatment of a number of autoimmune diseases, including hereditary angioedema ( 289), autoimmune hemolytic anemia (290), systemic lupus erythematosus (291), and idiopathic thrombocytopenic purpura (292,293). Doses of 800 mg/d are frequently used in North America, whereas 600 mg/d is commonly prescribed in Europe and Australia. It appears that the absence of menstruation is a better indicator of response than drug dose. A practical strategy for the use of danazol is to start treatment with 400 mg daily (200 mg twice a day) and increase the dose, if necessary, to achieve amenorrhea and relieve symptoms ( 279). The significant adverse side effects of danazol are related to its androgenic and hypoestrogenic properties. The most common side effects include weight gain, fluid retention, acne, oily skin, hirsutism, hot flashes, atrophic vaginitis, reduced breast size, reduced libido, fatigue, nausea, muscle cramps, and emotional instability. Deepening of the voice is another potential side effect that is nonreversible. Although danazol can cause increased cholesterol and low-density lipoprotein levels and decreased high-density lipoproteins levels, it is unlikely that these short-term effects are clinically important. Danazol is contraindicated in patients with liver disease because it is largely metabolized in the liver and may cause hepatocellular damage. Danazol is also contraindicated in patients with hypertension, congestive heart failure, or impaired renal function because it can cause fluid retention. The use of danazol is contraindicated in pregnancy because of its androgenic effects on the fetus. Because the many side effects of oral danazol limit its use, alternative routes of administration have been studied. In an uncontrolled pilot study, local danazol treatment using a vaginal danazol ring (1,500 mg) has been shown to be effective for pain relief in deeply infiltrative endometriosis without the classic danazol side effects, or detectable serum danazol levels, while allowing ovulation and conception ( 294). Gonadotropin-releasing Hormone Agonists GnRH agonists bind to pituitary GnRH receptors and stimulate LH and FSH synthesis and release. However, the agonists have a much longer biologic half-life (3 to 8 hours) than endogenous GnRH (3.5 minutes), resulting in the continuous exposure of GnRH receptors to GnRH agonist activity. This causes a loss of pituitary receptors and downregulation of GnRH activity, resulting in low FSH and LH levels. Consequently, ovarian steroid production is suppressed, providing a medically induced and reversible state of pseudomenopause. A direct effect of GnRH agonists on ectopic endometrium is also possible because expression of the GnRH receptor gene has been documented in ectopic endometrium and because direct inhibition of endometriosis cells has been demonstrated in vitro (295). Furthermore, in rat models for surgical adhesion formation and endometriosis, GnRH agonist therapy decreased activity of plasminogen activators and matrix MMPs and increased the activity of their inhibitors, suggesting potential GnRH agonist–regulated mechanisms for reducing adhesion formation ( 296). Various GnRH agonists have been developed and used in treating endometriosis. These agents include leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, and triptorelin. These drugs are inactive orally and must be administered intramuscularly, subcutaneously, or by intranasal absorption. The best therapeutic effect is often associated with an estradiol dose of 20 to 40 pg/mL (75 to 150 pmol/L). These so-called depot formulations are attractive because of the reduced frequency of administration and because nasal administration can be complicated by variations in absorption rates and problems with patient compliance ( 279). The results with

GnRH agonists are similar to those with danazol or progestin therapy. Although GnRH agonists do not have an adverse effect on serum lipids and lipoproteins, their side effects are caused by hypoestrogenism and include hot flashes, vaginal dryness, reduced libido, and osteoporosis (6% to 8% loss in trabecular bone density after 6 months of therapy). Reversibility of bone loss is equivocal and therefore of concern ( 297,298), especially because treatment periods of longer than 6 months may be required. The goal is to suppress endometriosis and maintain serum estrogen levels of 30 to 45 pg/mL. More extreme estradiol suppression will induce bone loss ( 297). The dose of daily GnRH agonist can be regulated by monitoring estradiol levels, by the addition of low-dose progestin or estrogen-progestin in an add-back regimen, or by draw-back therapy. The goal of add-back therapy is to treat endometriosis and endometriosis-associated pain effectively, while preventing vasomotor symptoms and bone loss related to the hypoestrogenic state induced by GnRH analogues. Add-back therapy can be achieved by administering progestogens only, including norethisterone, 1.2 mg, and norethindrone acetate, 5 mg, but bone loss is not prevented by medrogestone, 10 mg/d (298,299 and 300). Add-back therapy can also be achieved by tibolone, 2.5 mg/d ( 301,302), or by an estrogen-progestin combination (i.e., conjugated estrogens, 0.625 mg, combined with medroxyprogesterone acetate, 2.5 mg, or with norethindrone acetate, 5 mg, estradiol, 2 mg, and norethisterone acetate, 1 mg) (299,300,301,302 and 303). However, some concern remains about the long-term effects of GnRH analogues on bone loss. In one report, bone mineral density reduction occurred during long-term GnRH agonist use and was not fully recovered up to 6 years after treatment (304). Use of add-back therapy (2 mg estradiol and 1 mg norethisterone acetate) did not affect this process ( 304). Draw-back therapy has recently been suggested as an alternative in a study showing that 6 months of intake of 400 µg/d of nafarelin was as effective as a draw-back regimen consisting of 1 month of intake of 400 µg/d of nafarelin followed by 5 months of 200 µg/d of nafarelin, with similar estradiol levels (30 pg/mL) but less loss of bone mineral density (305). Aromatase Inhibitors Treatment of rats with induced endometriosis using the nonsteroidal aromatase inhibitor fadrozole hydrochloride (306) or YM511 (307) resulted in a dose-dependent volume reduction of endometriosis transplants, but these products have so far not been used in published human studies. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor, anastrozole, 1 mg/d, and elemental calcium, 1.5 g/d for 9 months, resulted in hypoestrogenism, pain relief after 2 months, and after 9 months a 10-fold reduction in the 30-mm diameter size of red, polypoid vaginal lesions, along with remodeling to gray tissue. No other data are available, except this case report (308). Selective Estrogen Receptor Modulators Raloxifen In animal models, raloxifene therapy resulted in regression of endometriosis. The effect was seen in both a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure ( 309). Nonhormonal Medical Therapy Modulation of Cytokines In rats with experimental endometriosis, recombinant human TNF-a–binding protein can reduce 64% of the size of endometriosis-like peritoneal lesions ( 310). Similarly, a recent prospective randomized placebo- and drug-controlled study in baboons showed that recombinant human TNF-a–binding protein effectively inhibits the development of endometriosis and endometriosis-related adhesions ( 311). In mice with experimental endometriosis, a placebo-controlled double-blind study showed that intraperitoneal or subcutaneous injection of recombinant interferon-a2B resulted in smaller endometriotic lesions when compared with the placebo control group ( 312). In rats with experimental endometriosis, regression of endometrial explants was observed after treatment with immune-enhancing modulators loxoribine and levamisole (313). Antiinflammation In the future, leukotriene receptor antagonists could be of use in patients with endometriosis who do not respond to prostaglandin synthetase inhibitors (314). In humans, a randomized placebo-controlled trial of oral pentoxifylline, 800 mg/d for 12 months,reported after life-table analysis a similar overall pregnancy rate in treated patients (31%) and in controls (18.5%) ( 315). Inhibition of Matrix Metalloproteinase In nude mice, suppression of MMPs by progesterone or by a natural inhibitor slows the establishment of ectopic lesions by human endometrium (316). Thus far, no clinical reports have been published. Efficacy of Medical Treatment Pain Medical treatment with progestins, danazol, gestrinone, or GnRH agonists is effective in treating pain associated with endometriosis, as shown in several prospective, randomized, placebo-controlled double-blind studies ( 197,226,317,318). Based on published studies, medroxyprogesterone acetate, danazol, gestrinone, and GnRH agonists have similar efficacy in resolution of the laparoscopically documented disease and in pain alleviation ( 278). Postoperative medical therapy may be required in patients with incomplete surgical resection and persistent pain. Treatment should last at least 3 to 6 months, and pain relief may be of short duration, presumably because endometriosis recurs. Disadvantages of medical therapy over surgical therapy include the high cost of hormone preparations, the high prevalence of side effects, and the higher recurrence rate of endometriosis. Subfertility Conception is either impossible or contraindicated during medical treatment of endometriosis. There is no evidence that medical treatment of minimal to mild endometriosis leads to better chances of pregnancy than expectant management ( 197,249, 317,318,319,320,321,322 and 323). Adolescent Endometriosis The incidental finding of minimal to mild endometriosis in a young woman without immediate interest in pregnancy is a common clinical problem. Seventy percent of girls with chronic pelvic pain unresponsive to oral contraceptives (OAC) or nonsteroidal antiinflammatory drugs are affected by endometriosis (324). Mild disease can be treated by surgical removal of implants at the time of diagnosis, followed by administration of continuous low-dose combination oral contraceptives to prevent recurrence. More advanced disease can be treated medically for 6 months, followed by continuous oral contraceptives to prevent progression of disease. GnRH agonists with add-back therapy can be considered for adolescents older than 16 years of age who have completed pubertal maturation (324).

Recurrence Endometriosis tends to recur unless definitive surgery is performed. The recurrence rate is about 5% to 20% per year, reaching a cumulative rate of 40% after 5 years. The rate of recurrence increases with the stage of disease, the duration of follow-up, and the occurrence of previous surgery ( 325,326,327,328 and 329). The likelihood of recurrence appears to be lower when endometriosis is located only on the right side of the pelvis than when the left side is involved ( 330). In a recent randomized controlled trial, postoperative low-dose cyclic oral contraceptive use resulted in a significantly lower cumulative recurrence rate after 1 year, but not after 2 to 3 years (331). In women treated with a second operation for recurrent endometriosis, the cumulative recurrence rate was comparable to those rates after laparoscopy or laparotomy (332). The recurrence rates reported in women 5 years after therapy with various GnRH agonists were 37% for minimal disease and 74% for severe disease ( 325). In women treated with GnRH agonists or danazol for endometriosis associated with pelvic pain, the recurrence rates of endometriosis were similar, and associated pain symptoms usually returned after cessation of therapy ( 333). Pain recurs within 5 years in about one in five patients with pelvic pain treated by complete laparoscopic excision of visible endometriotic lesions ( 334).

Assisted Reproduction and Endometriosis The treatment of endometriosis-related infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms, and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means, and the expected results. Assisted reproduction, including controlled ovarian hyperstimulation with

intrauterine insemination, IVF, and gamete intrafallopian transfer, may be options for infertility treatment in addition to surgical reconstruction and expectant management. IVF is the method of choice when distortion of the tuboovarian anatomy contraindicates the use of superovulation with intrauterine insemination or gamete intrafallopian transfer. Intrauterine Insemination Endometriosis-associated infertility can be successfully treated with intrauterine insemination. A recent randomized study ( 335) compared controlled ovarian hyperstimulation with FSH and intrauterine insemination with no treatment during 311 cycles in 103 couples with minimal to mild endometriosis as the only infertility factor. This study reported a significantly higher live-birth rate per cycle in the treated group (11%) than in the control group (2%) (OR, 5.6; 95% CI, 1.8 to 17.4). However, there is clear evidence that the pregnancy rate in an insemination program is lower in women with endometriosis than in women with unexplained infertility (336,337). In a recent metaanalysis of 5,214 cycles by stepwise logistic regression ( 338), evaluating the effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility, the OR for pregnancy associated with endometriosis was 0.45 (95% CI, 0.27 to 0.76) and for male factor was 0.48 (95% CI, 0.37 to 0.61). In Vitro Fertilization Based on several retrospective studies, several investigators ( 130,135) have suggested that the pregnancy rate after IVF may be lower in women with endometriosis than in women without the disease. In earlier studies, this had been ascribed to a reduced oocyte quality and decreased fertilization rate in women with endometriosis. However, these findings were not confirmed in more recent studies that reported a normal fertilization rate but a reduced implantation rate per embryo transferred also in women obtaining oocytes from oocyte donors with endometriosis (339,340). This reduced implantation rate could possibly be related to increased interleukin-6 levels in follicular fluid of women with endometriosis when compared with controls ( 341). However, in a more recent case-control study in an IVF egg-donation program comparing oocyte receptors in patients with endometriosis stage III or IV (cases) with oocyte receptors in patients without endometriosis (controls), a similar implantation rate, miscarriage rate, and pregnancy rate was observed in cases and controls, suggesting that there is no endometrial implantation problem in women with endometriosis stage III or IV treated with IVF ( 342). In another case-control study, the cumulative pregnancy rate and live-birth rate was comparable after five cycles of IVF in women with ovarian endometriosis and those with tubal infertility: 63% versus 63% (CPR) and 47% versus 51% (CLBR), but women with ovarian endometriosis had poorer responses and needed higher gonadotropin therapy ( 343). When endometriosis was assigned a stage, the pregnancy rate after IVF was decreased in patients with stage IV endometriosis but normal in women with less advanced disease (344,345,346,347,348,349 and 350). However, some studies have been unable to demonstrate a significant negative correlation between either the presence or stage of endometriosis and the pregnancy rate per cycle ( 351,352). The use of danazol, gestrinone, or GnRH agonists in women with endometriosis before IVF has been reported to improve the pregnancy rate by some ( 350,354) but not all investigators ( 352). Intracytoplasmic Sperm Injection A recent well-controlled study in intracytoplasmic sperm injection (ICSI) patients ( 353) reported a reduced number of oocytes recovered after ovarian aspiration but a normal fertilization rate, implantation rate, and pregnancy rate in women with endometriosis when compared with controls. These normal fertilization, implantation, and pregnancy rates also were reported in another recent ICSI study ( 355). Gamete Intrafallopian Transfer The use of gamete intrafallopian transfer in patients with endometriosis is reported to result in a higher monthly fecundity rate (25%) than with IVF (14%), but this difference may be related to selection bias because less severe forms of endometriosis may have been more likely to be treated with gamete intrafallopian transfer, reserving IVF for more advanced stages of disease ( 257). In one study, the gamete intrafallopian transfer pregnancy rate in patients with a primary diagnosis of endometriosis (32.5%) was lower than in matched controls (356). The current evidence suggests that patients with endometriosis have a poorer ovarian response and need a higher dose of gonadotropin therapy in IVF or ICSI programs, but no reduced endometrial implantation. It remains unclear whether the presence or degree of endometriosis is associated with impaired oocyte quality, fertilization rate, and implantation rate. Future studies evaluating the association between endometriosis and reproductive outcome after assisted reproduction should be prospective and should include the following components ( 131): Accurate and recent laparoscopic description of the stage of endometriosis Date, number of procedures, and interval between surgery Ultrasonographic evidence of endometriosis, confirmed by cytology or histology when endometriotic cysts are aspirated during oocyte aspiration Effectiveness of interim suppressive therapy between diagnosis and treatment with assisted reproduction Reliability and date of negative diagnosis Clear definition of implantation rate, pregnancy rate, abortion rate, and live-birth rate per started cycle, per oocyte aspiration, and per embryo transfer

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J In Vitro Fertil Embryo Transf 1988;5:248–256. 349. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent of recurrent disease. Fertil Steril 1991;56:628–634. 350. Dicker D, Goldman JA, Levy T, et al. The impact of long-term gonadotrophin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer. Fertil Steril 1992;57:597–600. 351. Inoue M, Kobayashi Y, Honda I, et al. The impact of endometriosis on the reproductive outcome of infertile patients. Am J Obstet Gynecol 1992;167:278–282. 352. Tummon IS, Colwell KA, Mackinnon CJ, et al. Abbreviated endometriosis-associated infertility correlates with in vitro fertilization success. J In Vitro Fertil Embryo Transf 1991;8:149–153. 353. Wardle PG, Foster PA, Mitchell JD, et al. Endometriosis and IVF: effect of prior therapy. Lancet 1986:276–277. 354. Minguez Y, Rubio C, Bernal A, et al. The impact of endometriosis in couples undergoing intracytoplasmic sperm injection. Hum Reprod 1997;12:2282–2285. 355. Bukulmez O, Yarali H, Gurgan T. The presence and extent of endometriosis do not effect clinical pregnancy rate and implantation rates in patients undergoing ICSI. Eur J Obstet Gynecol Reprod Biol 2001;96:102–107. 356. Guzick DS, Yao YAS, Berga SL, et al. Endometriosis impairs the efficacy of gamete intrafallopian transfer: results of a case-control study. Fertil Steril 1994;62:1186–1191. 357. Metzger DA, Olive DL, Stohs GF, et al. Association of endometriosis and spontaneous abortion: effect of control group selection. Fertil Steril 1986;45:18–22. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 27. Infertility Novak’s Gynecology

Chapter 27

Infertility Mylene W. M. Yao Daniel J. Schust

Epidemiology The Infertile Couple Initial Visit Causes of Infertility Male Factor Age and Decreased Ovarian Reserve Ovulatory Factor Tubal, Paratubal, and Peritoneal Factors Cervical and Immunologic Factors Uterine Factors Infectious Factors Systemic Illness Unexplained Infertility Treatment Options Gonadotropin Therapy Assisted Reproductive Technologies Complications of ART Other Considerations Preservation of Fertility in Cancer Patients References

Infertility is defined as 1 year of unprotected intercourse without pregnancy. This condition may be further classified as primary infertility, in which no previous pregnancies have occurred, and secondary infertility, in which a prior pregnancy, although not necessarily a live birth, has occurred. Fecundability is the probability of achieving pregnancy within a single menstrual cycle, and fecundity is the probability of achieving a live birth within a single cycle. The fecundability of a normal couple has been estimated at 20% to 25% (1). On the basis of this estimate, about 90% of couples should conceive after 12 months of unprotected intercourse. Infertility affects about 10% to 15% of reproductive-age couples in the United States. Despite the relatively stable prevalence of infertility in the United States, the use of infertility services has increased significantly. Between 1968 and 1984, the number of office visits for infertility increased nearly threefold to the current 1.6 million visits annually (2). There are several reasons for this increase. Recent media coverage of assistive reproductive technology (ART) and other fertility treatments has heightened awareness of the problem and its treatment; the aging of the post–World War II “baby boomers” has led to an increase in the number of reproductive-age women; and sociologic changes have led to delayed marriage with a consequent postponement of childbearing. Still, despite an increased awareness of available therapies, only 43% of infertile couples seek treatment, and only 24% seek specialized care. Fewer than 2% use in vitro fertilization (IVF) or other ART methods. The women most likely to obtain specialized treatment are 30 years of age or older, white, married, and of relatively high socioeconomic status ( 3).

Epidemiology Data from the U.S. National Survey of Family Growth indicate that the prevalence of infertility among women who had not been surgically sterilized was 13.3% in 1965, 13.9% in 1982, and 13.7% in 1988 ( 4). In 1990, about 1 in 3 women in the United States reported 12 consecutive months of unprotected coitus without pregnancy at some time in her life (5). A number of demographic variables, including age and socioeconomic status, have been associated with infertility. The delay in childbearing in the United States population has led to attempts to conceive by a higher percentage of women in the older reproductive age groups. As a result, although the overall prevalence of infertility has not changed in the United States since 1965, the percentage of women with primary infertility has increased significantly. In 1965, only one of six infertile women was nulliparous, whereas in 1988, more than half of infertile women had never been pregnant ( 6). The prevalence of infertility does not differ significantly among racial and ethnic groups. Although patients seeking treatment for infertility are predominantly of high socioeconomic status, infertility is more common among groups of relatively low socioeconomic status ( 6). Improved familiarity with and access to infertility services among the affluent and better-educated patients probably accounts for their greater use of these medical resources.

The Infertile Couple Initial Visit The physician's initial encounter with the infertile couple is the most important one because it sets the tone for subsequent evaluation and treatment. The male partner should be present at this first visit because his history is a key component in the selection of diagnostic and therapeutic plans. It cannot be overemphasized that infertility is a problem of the couple. The presence of the male partner beginning with the initial evaluation involves him in the therapeutic process. This essential involvement demonstrates that the physician is receptive to the male partner's needs as well as to those of the female partner, while allowing the male partner an opportunity to ask questions and to voice any concerns. The physician should obtain a complete medical, surgical, and gynecologic history from the woman. Specifically, information regarding menstrual cyclicity, pelvic pain, and obstetric history is important. Risk factors for infertility, such as a history of pelvic inflammatory disease (PID), intrauterine device use, or pelvic surgery, should be reviewed. A history of intrauterine exposure to diethylstilbestrol (DES) is significant. In addition, questions should be asked about pituitary, adrenal, and thyroid function. A directed history, including past genital surgery, infections (including mumps orchitis), and previous genital trauma, should be obtained from the male partner. A history of occupational exposures that might affect the reproductive function of either partner is also important. Additionally, the interviewer should obtain information about coital frequency, dyspareunia, and sexual dysfunction. The initial interview provides the physician with the opportunity to assess the emotional impact of infertility on the couple. It further gives the physician a chance to emphasize the emotional support available to the couple as they proceed with the diagnostic evaluation and suggested treatments. In some cases, referral to a trained social worker or psychologist at this point may be beneficial.

The physical examination of the female should be thorough, with particular attention given to height, weight, body habitus, hair distribution, thyroid gland, status with regard to galactorrhea, and findings of the pelvic examination. Referral of the male to a urologist for examination is often beneficial if historic information or subsequent evaluation suggests an abnormality. The initial encounter also gives the doctor the opportunity to outline the general causes of infertility and to discuss subsequent diagnostic and treatment plans. ( Fig. 27.1, Fig. 27.2, Fig. 27.3, Fig. 27.4 and Fig. 27.5).

Figure 27.1 Diagnostic and treatment algorithm: infertility. (From eries Yao M. Clinical management of infertility.Washington, DC: The Advisory Board: 2000, with permission.

Figure 27.2 Diagnostic and treatment algorithm: anovulation. (From eries Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.

Figure 27.3 Diagnostic and treatment algorithm: ovarian disorders. (From eries Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.

Figure 27.4 Diagnostic and treatment algorithm: polycystic ovarian syndrome. (From eries Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.)

Figure 27.5 Diagnostic and treatment algorithm: tubal factor. (From eries Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.)

Causes of Infertility The main causes of infertility include the following: 1. 2. 3. 4. 5. 6. 7. 8.

Male factor Decreased ovarian reserve Ovulatory disorders (ovulatory factor) Tubal injury, blockage, or paratubal adhesions (including endometriosis with evidence of tubal or peritoneal adhesions) Cervical and immunologic factors Uterine factors Conditions such as immunologic aberrations, infections, and serious systemic illnesses Unexplained factors (including endometriosis with no evidence of tubal or peritoneal adhesions)

Factors from either or both partners may contribute to difficulties in conceiving; therefore, it is important to consider all possible diagnoses before pursuing invasive treatment. In some cases, no specific cause is detected despite an extensive and complete evaluation. The relative prevalence of the different causes of infertility varies widely among patient populations ( Table 27.1).

Table 27.1. Causes of Infertility

Very few couples have absolute infertility, which can result from congenital or acquired irreversible loss of functional gametes in either partner or the absence of a uterus in the female. These specific couples should be counseled regarding their options of adoption, the use of donor gametes, or surrogacy. Rather, most couples who have difficulty conceiving have subfertility. According to this fundamental concept, most ouples could conceive spontaneously in time, but because of known or unidentifiable causes, their spontaneous fecundity rate is so low that medical management is warranted. Another reason to seek medical attention, particularly among older women, is that as time passes during unsuccessful spontaneous attempts, fecundability will be further compromised by increasing age and concomitantly decreasing ovarian reserve. Although identification of apparent causes of subfertility (such as anovulation or oligospermia) allows treatment to be targeted, effective empiric treatments greatly increase the chance of a pregnancy even when no distinct cause is identified. Overall, these treatments aim at increasing the probability of conception and implantation by optimizing gamete (sperm and oocyte) and uterine factors. The next section of this chapter outlines causes of male and female infertility, their methods of diagnosis, and the specific treatments for these conditions. The basic investigations that should be performed before starting any infertility treatment are semen analysis, confirmation of ovulation, and the documentation of tubal patency by hysterosalpingography (HSG). Some treatments, especially ART, are indicated for more than one diagnosis and are discussed in greater detail. Often, more than one cause is identified in a couple. For this reason, multiple directions of investigation and treatment may be undertaken in parallel.

Male Factor The combined effects of our increased understanding of genetic causes in male factor infertility and the efficacy of intracytoplasmic sperm injection (ICSI) in ART have revolutionized modern treatment of male factor infertility. For men, semen analysis as the initial step in their diagnostic evaluation for infertility is a fairly simple one. Semen analysis is inexpensive and noninvasive, and it should be included at the initiation of every infertility workup. The assessment of semen parameters, however, is confounded by controversies regarding the proper range of normal values. Semen parameters in normal fertile men vary considerably over time and may even drop below established norms; this situation makes evaluation of the male patient more difficult. The value and interpretation of the semen analysis and other tests for male infertility should be considered within the context of male reproductive physiology. Physiology The male reproductive tract consists of the testis, epididymis, vas deferens, prostate, seminal vesicles, ejaculatory duct, bulbourethral glands, and urethra. The testes contain two cell types: the Sertoli cells, which line the seminiferous tubules (the site of spermatogenesis), and the Leydig cells (the site of androgen synthesis). In the male, the pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act on the testes. LH stimulates the synthesis and secretion of testosterone by the Leydig cells, and FSH stimulates the Sertoli cells to secrete inhibin. FSH and testosterone act on the seminiferous tubules to stimulate spermatogenesis. In humans, it takes about 75 days for spermatogonia to develop into mature sperm cells. The immature spermatogonia undergo mitotic division, giving rise to spermatocytes. These spermatocytes subsequently undergo meiosis, or reduction division, which gives rise to spermatids containing 23 (rather than 46) chromosomes. Upon maturation, spermatids become spermatozoa, which enter the epididymis, where they continue to mature and become progressively more motile during the 12 to 21 days that is required to traverse this tortuous structure. During ejaculation, mature spermatozoa are released from the vas deferens along with fluid from the prostate, seminal vesicles, and bulbourethral glands. The semen released is a gelatinous mixture of spermatozoa and seminal plasma; however, it thins out 20 to 30 minutes after ejaculation by a process called liquefaction. Liquefaction occurs secondary to the presence of proteolytic enzymes within the prostatic fluid. The released spermatozoa are not usually capable of fertilization. Instead, a series of complex biochemical and electrical events, termed capacitation, must take place within the sperm's outer surface membrane before fertilization can occur. Normally, capacitation occurs in the cervical mucus; however, it can occur in physiologic media in vitro. Finally, as part of fertilization, the sperm must undergo the acrosome reaction, in which the release of enzymes of the inner acrosomal membrane results in the breakdown of the outer plasma membrane and its fusion with the outer acrosomal membrane (7). Several of the enzymes within the acrosome appear to be important to the sperm's penetration of the egg's zona pellucida. As the sperm penetrates the egg, it initiates a hardening of the zona pellucida (cortical reaction), which prevents penetration by additional sperm ( 8). Semen Analysis The basic semen analysis measures semen volume, sperm concentration, sperm motility, and sperm morphology. In addition, many laboratories measure pH, fructose levels, and white blood cell counts within the semen. Normal values suggested by the World Health Organization (WHO) are listed in Table 27.2 (18). These values represent only general guidelines, and normal values should be separately established by individual andrology laboratories.

Table 27.2. Normal Values for a Semen Analysis

Specimen Collection The method used for semen specimen collection is important to the achievement of accurate results. The optimal period of abstinence before semen collection is unknown; however, because a decrease in sperm concentration is associated with frequent ejaculation, a period of 2 to 3 days usually is recommended. The specimen should be obtained by masturbation and collected in a clean container. Because of the presence of spermicidal agents, collection into condoms is generally unacceptable, although special sheaths that do not contain spermicides are available for semen collection. All semen specimens should be taken to the laboratory within 1 to 2 hours of collection. Even when collection is done under optimal circumstances, interpretation of the results of the semen analysis is complicated by wide differences in normal semen parameters ( 9), seasonal variability ( 10), variations among laboratories or technicians ( 11), and inconsistent correlation with fertility outcome. Semen parameters also may vary widely from one man to another and among men with proven fertility. In many circumstances, several specimens are necessary to verify an abnormality. Sperm Volume The normal ejaculated volume of semen is 2 to 6 mL. Volumes may be abnormally low in cases of retrograde ejaculation, and high volumes usually reflect relatively long periods of abstinence or inflammation of the accessory glands. Absence of fructose or high pH may be associated with ejaculatory tract obstruction or seminal vesicle dysfunction. Sperm Concentration Sperm concentration or density is defined as the number of sperm per milliliter in the total ejaculate. Establishing a lower limit of normal for sperm concentration is difficult. Historically, cutoffs of 60 million sperm per milliliter for normal fertility have been advocated, but most WHO laboratories recognize the value of 20 million sperm per milliliter as a lower limit of normal ( 12). Some have advocated concentrations of 5 million sperm per milliliter as a lower limit of normal (13,14). Sperm Motility An equally important parameter in the semen analysis is sperm motility, which is defined as the percentage of progressively motile sperm in the ejaculate. Lower limits of normal vary considerably and depend on the local laboratory's experience. The WHO and many laboratories use a cutoff of 50% motility as the lower limit of normal; whereas others requires 40% motility as a criterion for defining male factor infertility ( 15). Computer-assisted semen analysis, in which computer-generated images of sperm specimens quantitate both sperm counts and sperm motility, may yield results very different from those of nonautomated semen analyses. Regardless of how motility is assessed, the interpretation of sperm motility—as with sperm concentration—is hampered by both significant variability among repeat samples obtained from a single individual and poor correlation of motility with fertility. Sperm Morphology The WHO uses a fairly permissive visual assessment of sperm within a semen specimen to assess morphology values; greater than 30% normal forms is defined as acceptable. More stringent criteria have evolved from other sources. The strict Tygerberg criteria were introduced by Kruger and Menkveld in 1986 to assess sperm morphology (16). Using this system, the entire spermatozoon—including the head, midpiece, and tail—is assessed, and even mild abnormalities in head forms are classified as abnormal. Most sperm from normal men exhibit minor abnormalities when subjected to Tygerberg standards. One advantage of these strict criteria, however, is that the Tygerberg classification correlates with prognosis in IVF treatment. For example, greater than 14% normal morphology is associated with normal rates of fertilization in IVF programs; 4% to 14% normal morphology is associated with a “good prognosis.” Values of less than 4% normal sperm morphology are associated with poor prognosis for fertilization and pregnancy in IVF ( 17). In some studies, this sperm morphology classification has also been found to be predictive of pregnancy outcomes after intrauterine insemination (IUI) treatment, especially when the total motile sperm count is less than 1 × 10 6 (18). The disparity in assessment criteria for semen morphology mandates that to interpret semen analysis results properly, the clinician must thoroughly understand the methodology used by the local andrology laboratory. White Blood Cells Although measurements of semen volume, sperm concentration, sperm motility, and sperm morphology make up the standard semen analysis, some laboratories also report numbers of round cells. These cells, which may be lymphocytes, can signify the presence of prostatitis or, alternatively, may actually be immature germ cells. These two cell types can be distinguished by an immunoperoxidase staining technique that identifies leukocytes (Endtz test) ( 19). The WHO views ejaculates with more than5 million round cells per milliliter or more than 1 million leukocytes per milliliter as abnormal ( 20); however, the prognostic significance of leukocytes in the semen is controversial. The presence of immature sperm cells in the ejaculate suggests a defect in spermatogenesis and, therefore, may signify a relatively poor prognosis for fertilization ( 21). Although the standard semen analysis and associated tests provide a fairly reasonable picture of semen quality, they yield little information about sperm function. Consequently, several tests of sperm function have been devised in an effort to assess the physiologic properties of sperm and thereby predict the likelihood of fertilization of normal oocytes. Sperm Penetration Assay The most commonly used test of sperm function is the sperm penetration assay (SPA), or hamster egg penetration test (22). This test attempts to measure the ability of an individual patient's sperm to undergo capacitation (i.e., the acrosome reaction), to fuse with and penetrate the oocyte membrane, and to undergo nuclear decondensation. In the SPA, golden hamsters are superovulated, and their eggs are collected and treated with enzymes to remove the cumulus and zona pellucida. Meanwhile, sperm are isolated from the patient's semen and placed in a protein-rich environment that promotes capacitation. Sperm from normal fertile men are used as positive controls. After this incubation, the zona-free eggs are exposed to patient and control sperm. The presence of one or more swollen sperm heads within the hamster oocyte after exposure to sperm demonstrates penetration. Most laboratories report the percentage of eggs successfully penetrated; however, some laboratories count the number of penetrations per egg (usually two or more is considered normal). Cutoff values for the lower limit of normal in the SPA differ remarkably among laboratories. The prognostic value of the SPA has been controversial almost since its inception. On the basis of a metaanalysis of the SPA, the test does not discriminate between fertile and infertile men ( 23). The value of the test as a predictor of success in IVF has been no less controversial. In most evaluations of the male partner, the SPA offers little definitive information; however, it may uncover sperm abnormalities in couples with otherwise unexplained infertility. Several other tests attempt to correlate sperm function with fertility prognosis. The human zona-binding assay (the Hemizona test) examines the ability of the sperm to bind to zona. In this assay, human zona are bisected; half of the zona is exposed to the patient's sperm, and half is exposed to sperm from a known fertile donor control (24). Results compare the binding ability of samples of patients to those of controls. The hypoosmotic swelling test examines the normality of the sperm tail. When placed in a hypoosmotic solution of sodium citrate and fructose, the normal sperm tail swells and coils; when there is an abnormality in fluid transport across the tail membrane, the sperm tail fails to swell (25). To detect the acrosome reaction, some investigators have used monoclonal antibodies ( 26), whereas others have measured adenosine triphosphate (ATP) content in the semen ( 27). These functional tests should be considered experimental until more definitive evidence demonstrates their utility in clinical settings. Further Evaluation If abnormalities in the semen are detected, further evaluation of the male partner by a urologist is indicated to diagnose the defect. Table 27.3 lists the differential diagnoses for male factor infertility ( 40). Several groups have attempted to assess the distribution of male infertility diagnoses; two such distributions are shown in Table 27.4 (24,28). The first is the result of a WHO study of 7,057 men with complete diagnoses based on the WHO standard investigation of the infertile couple ( 28). The figures include data from cases in which the male partner was normal and the presumed cause of the couple's infertility was a female factor. The second distribution is the result of a study of 425 subfertile male patients ( 24). Although the two studies represent different populations (one is from a study of couples, the other from a urologic practice) and differ in their distribution of male infertility diagnoses, idiopathic male factor and varicocele predominate. Other anatomic and endocrine causes occur less frequently.

Table 27.3. Etiologic Factors in Male Infertility

Table 27.4. Frequency of Some Etiologies in Male Factor Infertility

The widely accepted concept of a global decline in sperm counts needs to be reassessed ( 9,30). A number of recent analyses reported no decrease in sperm counts over time (31,32 and 33). Geographic differences in the results of semen analyses do seem to exist, but a global trend toward decreasing semen quality does not (34,53 and 36). Furthermore, the rate of male factor infertility has not increased significantly in recent decades. Thus, even if semen characteristics are changing, these changes do not appear to be having a dramatic clinical effect. Nevertheless, exposures to environmental toxins may certainly be harmful to sperm, and the incidence of some exposures (e.g., phytoestrogens) may be on the rise. Marijuana and cocaine use can reduce sperm concentration ( 37,38). Certain drugs, such as anabolic steroids, chemotherapeutic agents, cimetidine, erythromycin, nitrofurans, spironolactone, sulfasalazine, and tetracycline, also may reduce semen parameters. Finally, commonly ingested agents present in cigarettes and coffee have been associated with diminished semen quality ( 39). Treatment Treatment of male factor infertility may be classified as medical, surgical, orART-related therapies. Further, the diagnosis and treatment of azoospermia(no sperm on semen analysis) will be discussed separately from other forms ofmale factor infertility. Medical therapies for male factor infertility are severely limited. Medical correction of underlying treatable endocrine or infectious causes of subfertility tends to be efficacious. These conditions may include sexually transmitted diseases, thyroid disorders, and other rare causes of male infertility. Clomiphene citrate, an estrogen agonist and partial antagonist, has often been used to treat male infertility of idiopathic origin. Clomiphene citrate acts on the hypothalamic–pituitary axis and, in men, increases serum levels of LH, FSH, and testosterone ( 41). Although efficacy of clomiphene for male factor infertility is controversial, most studies have shown little improvement in semen parameters and no improvement in pregnancy rates (42). However, severe idiopathic male factor infertility has been treated with pure FSH, with no notable improvement in semen parameters but a significant increase in fertilization rates during ART ( 43). Surgical approaches to male factor infertility include procedures to correct varicocele, artificial insemination, and ART. Varicocele A varicocele is an abnormal dilation of the veins within the spermatic cord. Varicoceles nearly always occur on the left side, presumably because of the direct insertion of the spermatic vein into the renal vein on that side. The pathophysiologic effects of varicocele on testicular function are uncertain but appear to be mediated by an associated rise in testicular temperature or a reflux of toxic metabolites from the left adrenal or renal veins ( 44). In either event, the effect on sperm production is bilateral. Our understanding of the role of varicoceles in infertility is complicated by two issues: the prevalence of varicoceles in the normal male population and the efficacy of varicocele repair in infertile men. One WHO study found varicocele to be present in 25.4% of men with abnormal semen analyses, as opposed to 11.7% of men with normal semen (45). This study failed to demonstrate a difference in the frequency of spontaneous pregnancies among couples in which the men did or did not have varicoceles. The presence of a varicocele was, however, associated with decreased testicular volume, impaired semen quality, and a reduction in serum testosterone levels. Varicocele repair involves interruption of the internal spermatic vein and is commonly performed in the 40% of infertile men with clinically evident varicoceles. Currently, it is performed as an outpatient procedure and may involve laparoscopy, open surgery, or the injection of embolizing agents. Despite its widespread use, the therapeutic benefits of varicocele repair have remained controversial. Two multicenter trials have shown that pregnancy rates are significantly increased after varicocelectomy (46,47). However, the validity of the control groups in each of these trials has been criticized ( 48). A more recent metaanalysis on four randomized, controlled trials involving a total of 385 patients failed to demonstrate significantly altered pregnancy rates after varicocelectomy ( 48,49,50,51 and 52). Artificial Insemination Artificial insemination encompasses a variety of procedures. All involve the placement of whole semen or processed sperm into the female reproductive tract, which permits sperm–oocyte interaction in the absence of intercourse. The placement of whole semen into the vagina as a mode of fertility treatment is now rarely performed. Exceptions include cases of severe coital dysfunction, including those involving severe hypospadias, retrograde ejaculation, erectile abnormalities, and psychosocial dysfunction precluding intercourse. Currently, all of the common forms of artificial insemination involve processed sperm obtained from the male partner or a donor before its use. Artificial insemination has mainly been used to treat unexplained infertility (usually combined with superovulation) and male factor infertility. The efficacy of each type of insemination method should be assessed separately for each of these two diagnoses. Types of Insemination for Unexplained Infertility Many techniques for artificial insemination have been described. Of intracervical, intrauterine, intraperitoneal, and intrafollicular insemination and fallopian tube sperm perfusion, only the first two methods have been routinely employed. Intrauterine insemination (IUI) is the best studied and most widely practiced of all the insemination techniques. It involves placement of about 0.3 mL of washed, processed, and concentrated sperm into the intrauterine cavity by transcervical catheterization. In contrast with IUI, intracervical insemination may be performed either with unwashed or with processed specimens. The success rates with intracervical insemination are consistently lower than those with IUI ( 53). Fallopian tube sperm perfusion (FSP) differs from IUI in that a large volume of washed sperm (about 4 mL) is injected into the intrauterine cavity. This is a more expensive procedure because larger volumes of media are required during sperm processing. Technical performance of FSP may be complicated by efflux of sperm through the vagina during the intrauterine injection of such large volumes of fluid. Among several techniques of efflux prevention, use of an intrauterine Foley catheter with balloon inflation is most commonly described. Although many have demonstrated that fallopian sperm perfusion does not offer any general advantage over IUI (54,55,56 and 57), its benefit in the treatment of unexplained infertility remains controversial. Several prospective randomized trials have reported higher pregnancy

rates among patients with unexplained infertility in cycles treated with FSP compared with those using IUI ( 58,59,60 and 61). One recent metaanalysis found that FSP significantly improves pregnancy rates in patients with unexplained infertility undergoing controlled ovarian hyperstimulation (COH)/insemination with an odds ratio (OR) of 1.9 and a 95% confidence interval (CI) of 1.2 to 3 ( 60) (see Controlled Ovarian Hyperstimulation). Direct intraperitoneal insemination involves the injection of washed, processed sperm into the intraperitoneal cavity by puncture of the posterior vaginal cul-de-sac. Evidence from prospective randomized trials showed that direct intraperitoneal insemination offers no advantage over IUI ( 62,63,64 and 65). Intrafollicular insemination as a treatment of male factor infertility has also been reported ( 66), but in a series of 50 patients with unexplained infertility, only one intrauterine pregnancy resulted (67). Its low efficacy has deterred further investigation of this technique. In summary, IUI is the best-studied insemination technique, with proven superiority to intracervical insemination in the treatment of unexplained infertility ( 53). FSP appears to be a viable alternative to IUI with COH/insemination in couples with unexplained infertility. However, the potential increase in pregnancy rates using FSP over IUI is unlikely to be as great as that of IVF/ICSI over IUI. Therefore, although COH/FSP may be chosen instead of COH/IUI in a center where FSP gives a higher pregnancy rate, there is no benefit to switch from COH/IUI to COH/FSP after three cycles of failed COH/IUI in patients with unexplained infertility. IVF/ICSI remains the best available treatment option in patients with unexplained infertility who have not become pregnant with COH/IUI treatment. Processing Semen Two important issues regarding the use of artificial insemination procedures are the mode of semen processing and the number and timing of inseminations. Many protocols have been developed for sperm preparation. Seminal fluid usually is prevented from reaching the intrauterine cavity and intraabdominal space by the cervical barrier. The introduction of seminal fluid past this barrier may be associated with severe uterine cramping or anaphylactoid reactions, possibly mediated by seminal factors such as prostaglandins. Thus, protocols for processing whole semen include the washing of specimens to remove seminal factors and to isolate pure sperm. Some semen preparation methods attempt to enhance sperm motility or morphology further by using additional separation protocols. These methods include centrifugation through density gradients, sperm migration protocols, and differential adherence procedures. Finally, phosphodiesterase inhibitors, such as pentoxiphylline, have been used during semen processing in an attempt to enhance sperm motility, fertilization capacity, and acrosome reactivity for IVF procedures ( 68). IUI as Treatment of Male Factor Infertility Studies of the efficacy of IUI in the treatment of male factor infertility have been generally difficult to assess because of variations in inclusion criteria. Further, sperm function tests are not consistently used in these studies, nor is their use standardized. Considering these limitations, the benefits of IUI in male factor infertility have been accepted because IUI appears to result in higher pregnancy rates than natural intercourse or intracervical insemination (OR, 2.20;95% CI, 1.43 to 3.39) ( 69). However, the IUI pregnancy rates are generally lower in couples with male factor infertility than in couples with unexplained infertility (4.8% versus 11.6%) ( 69). In a retrospective analysis of 1,841 couples undergoing 4,056 cycles of IUI for male factor infertility, pregnancy rates were found to be related to total motile sperm count. Optimal pregnancy rates (>8.2% per cycle) were reached with initial total motile sperm counts of greater than or equal to 5.0 × 106. Higher counts did not necessarily yield higher pregnancy rates. The minimal total motile sperm count that resulted in a pregnancy was 1.6 × 10 6 (70). Some couples with male factor infertility fail treatment with artificial insemination, and some have initial semen parameters that make insemination a suboptimal approach. In these couples, use of ART, especially with ICSI, may be superior treatment options. The efficacy of ICSI in ART allows almost all cases of male factor infertility to be highly treatable. ICSI only requires that viable sperm be present. Therefore, ICSI should be considered if the total motile sperm count is less than 0.5 × 106 because the IUI success rates are extremely low with such sperm counts (71). Finally, ICSI should be recommended after a maximum of three IUI cycles have failed in a couple with male factor infertility. Azoospermia: Classification and Treatment Azoospermia is the absence of spermatozoa in the ejaculate. Azoospermia is found on semen analysis in about 5% of all couples being investigated for infertility (72), and its incidence is 10% to 20% among infertile men who have abnormal semen analysis (73). Traditionally, azoospermia has been classified as obstructive or nonobstructive. However, an increased understanding of the various etiologies of azoospermia and treatment advances using surgical sperm retrieval and ART have prompted a reclassification. The new classification system, advocated by Sharif and others, may better reflect the etiology, prognosis, and treatment of azoospermia (74,75 and 76). It separates azoospermic patients into those with pretesticular, testicular, and posttesticular causes. Pretesticular Azoospermia Pretesticular azoospermia represents those conditions in which the hypothalamic–pituitary axis fails to stimulate spermatogenesis within the testis. Congenital, acquired, and idiopathic etiologies of hypogonadotropic hypogonadism are included in this category. A full endocrine history, including information on puberty and growth and a review of endocrine systems, should guide the physician in the evaluation of the hypogonadotropic hypogonadal patient. Laboratory investigations of particular benefit in this population include measurement of serum LH, FSH, testosterone, and prolactin levels and imaging of the pituitary gland. Low levels of gonadotropins (LH and FSH) and low serum levels of testosterone are characteristic. Hormonal treatment of hypogonadotropic hypogonadism has been conclusively demonstrated to be efficacious. In fact, pulsatile gonadotropin-releasing hormone (GnRH) therapy is both conceptually indicated and effective in infertile men with hypothalamic dysfunction ( 77), including those patients with Kallmann's syndrome. Infertile males with hypogonadotropic hypogonadism secondary to panhypopituitarism also may respond to GnRH therapy ( 78). An alternative treatment uses human chorionic gonadotropin (hCG), 1,000 to 2,500 IU twice a week, with the dose titrated to maintain serum testosterone and estradiol levels within the normal range. Treatment with hCG is then combined with human menopausal gonadotropin (hMG), which is given at a dose of 150 IU three times weekly ( 79,80). Spermatogenesis and pregnancy can be achieved in up to 80% to 88% of patients after 1 year of therapy ( 79,80). Testicular Azoospermia Gonadal failure is the hallmark of testicular azoospermia. Causes of this condition may be congenital or genetic (e.g., Klinefelter's syndrome, microdeletion of Y chromosome), acquired (e.g., radiation therapy, chemotherapy, testicular torsion, or mumps orchitis), or developmental (e.g., testicular maldescent). The latter disorder may be associated most closely with male factor infertility in the absence of complete testicular azoospermia. A large observational cohort study suggested that infertility was, in fact, associated with congenital bilaterally maldescended testes, but that men with congenital unilaterally maldescended testes did not have decreased fertility when compared with controls ( 81). Men with hypergonadotropic hypogonadism (elevated levels of LH and FSH with low serum levels of testosterone) generally have primary gonadal failure. A karyotype should be obtained in such cases to detect chromosomal abnormalities such as Klinefelter's syndrome (47, XXY). Acquired causes of primary gonadal failure are usually evident on history, but they should be confirmed by assessment of the serum hormonal profile and biopsy. If the diagnosis of gonadal failure is confirmed on biopsy, endocrine therapy is contraindicated. It is becoming increasingly evident that some cases of male factor infertility that have previously been categorized as idiopathic are actually the result of genetic defects on the Y chromosome. The two most commonly implicated candidate gene families are the RNA-binding motif (RBM) and the “deleted in azoospermia” (DAZ) families, but microdeletions at various loci on the Y chromosome have been described. For example, microdeletions in Yq11.23 have been found in 10% to 20% of men with idiopathic azoospermia or severe oligospermia ( 82,83). In another study involving 200 infertile men, 7% were found to have microdeletions in the Y chromosome (84). Semen analyses in affected men varied between oligospermia and azoospermia. Interestingly, 2% of fertile men also have microdeletions in the Y chromosome. These microdeletions can be transmitted to the male offspring, who may then also suffer from infertility. Therefore, screening for genetic causes is indicated in nonacquired cases of testicular azoospermia so that proper genetic counseling can be provided before treatment. Treatment is focused on surgical retrieval of spermatozoa with subsequent fertilization of the oocyte by ICSI. These approaches have made fertility possible for some men with testicular azoospermia. Intracytoplasmic Sperm Injection ICSI is a micromanipulation technique commonly used in some ART procedures. It was first reported to result in human pregnancies in 1992 (85). ICSI is performed to increase the fertilization rate of oocytes retrieved during ART. The procedure involves stripping the aspirated cumulus complex of all surrounding granulosa cells, so that micromanipulation can be performed on the egg itself. A holding pipette is used to stabilize the egg while an injection pipette is used to insert a viable sperm into the cytoplasm of the egg (ooplasm). This procedure is thought to bypass some of the physiologic events, such as capacitation and the acrosome reaction, that are normally required for fertilization in vivo. In general, ICSI has allowed couples with male factor infertility to achieve ART pregnancy outcomes that are comparable with those of couples with non–male factor infertility using conventional IVF treatment. The indications of ICSI have evolved since its introduction. They will most likely continue to evolve as more is learned

about risks and benefits of ICSI. One absolute indication for ICSI is severe male factor infertility as demonstrated by total progressively motile sperm counts (0.5 × 106/mL and 40 years) and abnormal day 3 FSH or CCCT results to strictly limit the number of IVF cycle attempts because of their overall poor prognosis. These tests should not, however, be used as the sole basis to exclude women from IVF treatment (142). Recently, serum inhibin B has also been proposed as a potential screening test for ovarian reserve. Inhibin B is produced by ovarian granulosa cells predominantly during the follicular phase of the menstrual cycle. Inhibin B suppresses the production of FSH by the pituitary gland. The normal rise in circulating levels of FSH associated with menopause is thought to be secondary to the decrease in inhibin B production accompanying the age-related depletion of functional ovarian follicles. In fact, in the CCCT, the main mechanism by which FSH is normally suppressed is via inhibin B production by granulosa cells. Women with decreased ovarian reserve have a lower rise in the day 10 serum inhibin B levels in response to the CCCT ( 147). In addition, women who have clinical evidence of diminished ovarian reserve and normal day 3 FSH levels have been found to have decreased day 3 inhibin B levels. This observation suggests that a decrease in day 3 serum inhibin B

levels may precede detectable changes in day 3 FSH levels ( 140). Although the degree of elevation in serum inhibin B levels 24 hours after administration of exogenous FSH appears to be positively predictive of good ovarian response ( 148), clinical application of serum inhibin B still requires further evaluation. In particular, basal inhibin B levels do not provide additional age-independent prognostic value for predicting pregnancy outcomes after ART ( 128). One possible reason for this is that levels of inhibin B may reflect granulosa cell function and thereby only forecast ovarian response in ART. Although granulosa cell competence is certainly associated with oocyte quality, clinical application of serum inhibin B testing will also depend on whether levels are predictive of normal meiotic division of the oocyte because fetal karyotype is an important determinant of pregnancy outcome ( 149). Spontaneous Abortion Another factor contributing to the decreased fecundity among older reproductive-age women is the increased risk for spontaneous abortion in this population. A large study based on the Danish national registry estimated the rates of clinically recognized spontaneous abortion for various age groups to be 13.3% (12 to 19 years), 11.1% (20 to 24 years), 11.9% (25 to 29 years), 15.0% (30 to 34 years), 24.6% (35 to 39 years), 51.0% (40 to 44 years), and 93.4% (>45 years) ( 150). In addition, using sensitive hCG assays in women during their reproductive years, 22% of all pregnancies were found to be lost before they could be clinically diagnosed ( 151). One might predict that this proportion would be increased among older women attempting pregnancy, making subclinical spontaneous pregnancy loss a significant consideration among older women who are thought to be having difficulty conceiving. One major cause for the increase in spontaneous losses among older women is their increased incidence of chromosomally abnormal fetuses. A cytogenetic analysis of 750 spontaneous abortions revealed that the increase in chromosomally abnormal conceptuses seen with increased maternal age was mainly due to an increase in chromosomal trisomies. In particular, the incidence of trisomies 16, 21, 22, 18, and 20 were significantly increased, with 18 and 20 being the most dramatic. In contrast, the risk for monosomy X and polypoidy did not increase with advanced maternal age ( 152). In conclusion, an increased spontaneous loss rate, coupled with a reduced conception rate, significantly decreases the chance of a live birth among women older than 40 years of age. Age of Male Partner There is little doubt that increasing age is accompanied by reduced female fecundity; however, the age-related decline in fecundity for men is more controversial. Male fertility peaks at about 35 years of age and declines sharply after 45 years of age; however, men have reportedly fathered children into their 80s (6). Also, the risk for chromosomal trisomies appears to be related, at least in part, to increased paternal age ( 153). Recent observations have demonstrated an increase in the rate of autosomal recessive disorders among the progeny of men 35 years of age and older ( 154,155). These findings suggest an age-related decline in gamete quality among men, albeit one that is more subtle than that experienced by women.

Ovulatory Factor Disorders of ovulation account for about 30% to 40% of all cases of female infertility. These disorders are generally among the most easily diagnosed and most treatable causes of infertility. The normal length of the menstrual cycle in reproductive-age women varies from 25 to 35 days; most women have cycle lengths of 27 to 31 days. Figure 27.7 showsthe fluctuations of estradiol, progesterone, FSH and LHin a normal, 28-day ovulatory cycle. Women who have regular monthly menses (about every 4 weeks) with moliminal symptoms, such as premenstrual breast swelling and dysmenorrhea, almost invariably have ovulatory cycles. Because ovulation is an obligatory prerequisite to conception, ovulation must be documented as part of the basic assessment of the infertile couple. Initial diagnoses among women with ovulatory factor infertility may include anovulation (complete absence of ovulation) or oligoovulation (infrequent ovulation).

Figure 27.7 Relative hormonal fluctuations in a normal, ovulatory, 28-day menstrual cycle.

Methods to Document Ovulation Luteinizing Hormone Monitoring Documentation of the LH surge represents a remarkably reproducible method of predicting ovulation. Ovulation occurs 34 to 36 hours after the onset of the LH surge and about 10 to 12 hours after the LH peak (156,157). Commercially available kits for documenting the LH surge are generally accurate, quick, convenient, and relatively inexpensive enzyme-linked immunosorbent assays (ELISAs) using 40 mIU/mL as the threshold for detection (158,159). The positive and negative predictive values of these kits have been described to be 90% and 96%, respectively ( 160). A 100% correlation between urinary LH prediction of ovulation and transvaginal ultrasound diagnosis of ovulation has further confirmed the value of urine LH detection kits for home ovulation detection (161). Still, there may be up to 5% to 10% of women for whom this ELISA test cannot detect urinary LH, probably either because of failed recognition by the antibody used or because their peak urinary LH concentration does not rise above the threshold set by the kit manufacturers. Serum LH measurements may be necessary to predict ovulation in such cases. Basal Body Temperature The least expensive method of confirming ovulation is for the patient to record her temperature each morning on a basal body temperature (BBT) chart. The oral or rectal temperature should be determined before the patient arises, eats, or drinks. Smoking is forbidden before temperature measurement, and irregular sleep patterns can interfere with the test results. Patients monitoring BBT record their temperature daily but also record times when coitus occurs. Use of a BBT is preferred to use of a conventional thermometer because of the BBT instrument's precision in the temperature range under consideration. The principle behind temperature charting as a means to document ovulation is simple. Significant progesterone secretion by the ovary generally occurs only after ovulation. Progesterone is a thermogenic hormone. The secretion of progesterone causes a temperature increase of about 0.58°F over the baseline temperature of 97° to 98.8°F typically recorded during the follicular phase of the menstrual cycle. Charting of daily BBTs produces a characteristic biphasic pattern in women with ovulatory cycles. Frequently, a nadir in charted BBT is noted at the time of the LH surge, but this finding is inconsistent. A normal luteal phase is characterized by a documented temperature elevation lasting at least 10 days. BBT charting for documentation of ovulation, although simple, has several drawbacks. Presumptive ovulation can be identified only retrospectively (i.e., the test merely confirms rather than predicts ovulation). Even retrospectively, the exact time of ovulation is difficult to determine using BBTs, although in most instances, it is probably 1 day before documented temperature elevation. An unequivocal temperature rise generally occurs 2 days after the LH surge and correlates with serum progesterone levels of 0.4 ng/mL (162). Also, in a small percentage of patients, BBT charts are monophasic, despite the documentation of ovulation by other methods. Further, BBT charting is correlated with transvaginal ultrasound evidence of ovulation in only 30.4% of cases ( 161). Despite its limitations, for many patients, BBT charting is a simple way to document ovulation, and unequivocal biphasic cycles are almost certainly ovulatory. Patients with monophasic cycles require confirmation of ovulation using alternative methods. Midluteal Serum Progesterone Elevations in serum levels of progesterone constitute indirect evidence of ovulation. When used to document ovulation, serum progesterone measurement should coincide with peak progesterone secretion in the midluteal phase (typically on days 21 to 23 of an ideal 28-day cycle). The lower limit of progesterone levels in the luteal phase varies among laboratories, but a level above 3 ng/mL (10 nmol/L) typically confirms ovulation. However, an appropriate interpretation of isolated luteal-phase measurements of serum progesterone is complicated by the frequent pulses that characterize the secretion of this hormone (163). Although ovulatory levels are often considerably higher than 3 ng/mL, low midluteal serum levels of progesterone are not necessarily diagnostic of anovulation.

Ultrasound Monitoring Ovulation can also be documented by monitoring the development of a dominant follicle by ultrasound until ovulation takes place. Ovulation is characterized both by a decrease in the size of a monitored ovarian follicle and by the appearance of fluid in the cul-de-sac ( 164). It most often occurs when follicular size reaches about 21 to 23 mm, although it may occur with follicles as small as 17 mm or as large as 29 mm ( 165,166). Because of the inconvenience and expense of serial measurements, routine use of ultrasound for documenting ovulation is discouraged. Instead, it is recommended that its use be confined to the monitoring of ovulation induction. Follow-up Tests If tests confirm that a patient is anovulatory or oligoovulatory, then diagnoses such as hypothalamic–pituitary disorder, hypothyroidism, anorexia nervosa, polycystic ovarian syndrome (PCOS), and premature ovarian failure need to be considered. In addition to history and physical examination, the basic investigations typically used to assess further these potential diagnoses include serum FSH, prolactin, and thyroid-stimulating hormone (TSH) testing. These three investigations are often sufficient to guide the initial management plan. Polycystic Ovarian Syndrome PCOS is the most common cause of oligoovulation and anovulation—both in the general population and among women presenting with infertility. The diagnosis of PCOS is determined by a history of oligoovulation or anovulation in conjunction with physical evidence of hyperandrogenism. The exclusion of pregnancy, hypothalamic–pituitary disorders, or other causes of hyperandrogenism (e.g., androgen-secreting tumors or nonclassical congenital adrenal hyperplasia) may be indicated in some patients presenting with presumptive ovulatory disorders and infertility. However, once other causes of oligoovulation or anovulation have been excluded, biochemical evidence consistent with PCOS—including serum LH-to-FSH ratios and hyperinsulinemia—is not required before initiation of infertility treatment. Because oligomenorrheic women with PCOS are at risk for endometrial hyperplasia, it may be prudent to perform an endometrial biopsy before beginning ovulation induction therapy. Ovulation Induction in Women with PCOS Despite the use of similar medications, the indications and goals of ovulation induction should be distinguished from those of superovulation. Ovulation induction refers to the therapeutic restoration of the release of one egg per cycle in a woman who either has not been ovulating regularly or has not been ovulating at all. Although it is usually acceptable for ovulation induction to result in the release of two eggs, one should avoid the ovulation of more than two eggs in an effort to minimize the risk for ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. In contrast, superovulation is indicated for the treatment of women with unexplained infertility who have been unable to conceive despite regular, monthly ovulation. The explicit goal of superovulation is to cause more than one egg to be ovulated, thereby increasing the probability of conception. Ovulation induction can be achieved either medically or surgically in women with PCOS. There is no fixed protocol on how to approach ovulation induction in these patients, although there exists a reasonable tendency to progress from the least to the most invasive therapies. Appropriate patient selection for various therapies can be a significant determinant of successful ovulation induction among PCOS patients. Regardless of which treatment is employed, one important concept to convey to couples is that pregnancy is a cumulative probability. Once ovulation has been documented for a particular treatment, patients should be mentally prepared to continue with that regimen for at least three cycles because, for most treatments, the rate of a pregnancy occurring per therapeutic cycle is the same for each of the first three cycles. When counseling patients, it is often helpful to remind them that even a couple with no fertility problems has a fecundity rate of only 20% to 25% per cycle (1). A good rule of thumb involves review of the patient management plan at least once every 3 cycles and more frequently if side effects are present. This plan should be explicitly discussed with patients, thereby promoting education, communication, and informed compliance. Weight Loss A body mass index (BMI) above 27 kg/m2 is considered excessive; moreover, an increase in BMI is associated with an increased risk for insulin resistance. There are several excellent reasons for recommending weight loss among overweight infertile patients. Using hypocaloric diets, weight loss of 20 kg (mean pretreatment weight, 77 kg) in one study and 10 kg (mean pretreatment BMI, 32 kg/m 2) in another study, resulted in a decrease in plasma testosterone, androstenedione, LH, and fasting insulin levels ( 167,168). Significant improvement in these parameters, which are thought to play a role in the pathogenesis of PCOS, helps restore spontaneous ovulation in many patients. In a study of67 overweight women who had a mean weight loss of 10.2 kg/m 2, spontaneous ovulation and pregnancy occurred in 90% and 30%, respectively ( 169). Obese patients are at increased risk for medical conditions such as diabetes, hypertension, and cardiovascular disease. Because obesity also is a risk factor for obstetric complications, there should be tremendous incentive for the infertile patient to reduce weight (170). As with any other lifestyle change, promotion of weight loss can be difficult and frustrating for both patient and practitioner. Weight loss often requires multidisciplinary efforts, including the involvement of an experienced dietitian and promotion of an effective exercise program. Many women may be discouraged by the time it takes to reduce their weight and the uncertainty of successful weight reduction; thus, it is reasonable to pursue medical options in parallel with lifestyle changes. Clomiphene Citrate Traditionally, clomiphene citrate (Clomid, Serophene) has been the first-line intervention for medical induction of ovulation in PCOS patients. Clomiphene citrate is a weak synthetic estrogen, but it mimics the activity of an estrogen antagonist when given at typical pharmacologic doses for the induction of ovulation. A functional hypothalamic–pituitary–ovarian axis is required for appropriate clomiphene citrate activity. More specifically, clomiphene citrate is thought to bind and block estrogen receptors in the hypothalamus for prolonged periods, thereby decreasing the normal ovarian–hypothalamic estrogen feedback loop ( 171). This blockade increases GnRH pulse amplitude in some anovulatory women ( 172). Increases in GnRH then feed forward to cause increased gonadotropin secretion by the pituitary, promoting ovarian follicular development. Clomiphene citrate also may affect ovulation through direct action on the pituitary ( 173) or the ovary (174,175). Unfortunately, the antiestrogenic effects of clomiphene citrate at the level of the endometrium (176) or the cervix (177) may have adverse effects on fertility in a minority of individuals ( 178,179). Use of clomiphene citrate for ovulation induction is generally associated with excellent outcomes. In fact, in some populations, 80% to 85% of treated women will ovulate and 40% will conceive (180,181). Discrepancies between ovulatory rates and conception rates are most likely associated with the number of cycles attempted or are secondary to the presence of additional, nonovulatory infertility factors among treated women. Most pregnancies resulting from induction of ovulation with clomiphene citrate occur during the first 6 months of therapy ( 180). Side effects of clomiphene citrate therapy include infrequent OHSS, vasomotor flushes, nausea, pelvic discomfort, and breast pain ( 173). In the presence of visual abnormalities, clomiphene citrate should be promptly discontinued. Use of clomiphene citrate is associated with a 35% to 60% incidence of multiple follicular recruitments ( 182); however, the incidence of multiple gestation with this agent is only about 5% to 8%. Most of these multiple gestations are twin pregnancies; triplet pregnancies occur infrequently. Rates of spontaneous abortion and teratogenicity in humans are not increased with the use of clomiphenecitrate (183). Clomiphene citrate is typically used for ovulation induction in the following manner: 1. The drug is supplied in 50-mg tablets; the usual starting dosage is 50 mg/d. Therapy is typically begun on the fifth day after the onset of a spontaneous or progesterone-induced menses and is continued through day 9 of the menstrual cycle. Treatment on days 2 to 6 after onset of menses has also been advocated (184). Some patients respond to a dosage as low as 25 mg/d. 2. Ovulation should be documented using a home urine LH kit. This information is valuable for future therapeutic planning because failure to conceive despite successful ovulation has different implications than failure to conceive because of failed ovulation induction. If ovulation does not occur at the initial dosage of clomiphene citrate, the dosage is increased in each subsequent cycle by 50 mg/d. The U.S. Food and Drug Administration recommends a maximum dosage of 100 mg/d; however, in patients who ovulate as a result of clomiphene citrate treatment, 11.8% do so only at doses of 150 mg/d or more (180). Considerable clinical experience with clomiphene citrate indicates that a dosage of up to 250 mg/d is safe. 3. Ovulation is expected to occur 5 to 10 days after the last day of therapy; thus, with standard clomiphene citrate regimens, ovulation testing should begin on day 12 or 13 and continued daily until results are positive. Once a pattern is established, ovulation testing can be confined to a 5-day period in subsequent months. Intercourse every other day for 1 week beginning a day or two before anticipated ovulation is recommended. Alternatively, daily intercourse for 3 days beginning on the day of a positive urine LH test will also maximize the chance of a pregnancy. 4. If ovulation cannot be induced despite the use of increasing amounts of clomiphene citrate, ultrasound can be used to monitor follicular development during the treatment cycle. If a dominant follicle develops, but there is no spontaneous LH surge, hCG (10,000 units given intramuscularly) can be used for final follicular maturation/ovulation, followed by timed intercourse or IUI. The number of clomiphene citrate–treated and ovulatory cycles should not exceed six cycles because the maximum cumulative pregnancy rate has been achieved by that point, and further treatment with clomiphene citrate would have minimal predicted benefit.

Despite the high therapeutic success rates of clomiphene citrate in most anovulatory women, treatment has relatively low success in inducing ovulation in women with PCOS and insulin resistance, in whom obesity or elevated BMI also is evident. Before initiating therapeutic changes in such women, differential diagnoses should be reviewed and endocrinologic investigations repeated if necessary. Dexamethasone, 0.5 mg/d at bed time, combined with typical clomiphene citrate regimens may induce ovulation in patients who have elevated serum dihydroepiandrosterone sulfate (DHEAS) ( 185). At this low dosage, dexamethasone therapy is associated with minimal adverse effects. Alternatively, there is now increasing evidence that insulin sensitizers are particularly effective in inducing ovulation in PCOS women with insulin resistance. Insulin Sensitizers PCOS is currently viewed as a disease that can result from different genetic causes with possible modification by environmental factors ( 186). Insulin resistance is thought to play a central role in the pathogenesis of PCOS in the subset of patients characterized by increased BMI, hyperinsulinemia, and significant hyperandrogenism ( Table 27.5)(186). It is also thought that a different form of insulin resistance intrinsic to PCOS is part of the underlying disease mechanism in thin women with PCOS (187,188). Metformin and troglitazone are the best-studied of the insulin sensitizers used for ovulation induction.

Table 27.5. Clinical Findings That Suggest Insulin Resistance and Hyperinsulinemia

Metformin is an oral biguanide that is approved for the treatment of non–insulin-dependent diabetes. Metformin acts by several mechanisms, including inhibition of gluconeogenesis in the liver and an increase in the uptake of glucose in the periphery ( 189). When women with PCOS, hyperandrogenism, and hyperinsulinemia are treated with metformin for 12 weeks, their fasting insulin and total testosterone levels, free testosterone index, BMI, waist-to-hip ratio, hirsutism, and acne all decrease significantly (190). Moreover, among women who have PCOS, a BMI greater than 28 kg/m2, and hyperandrogenemia, 89% ovulate after treatment with a combination of metformin and clomiphene citrate. This rate is significantly higher than the 12% of patients who ovulated during combined treatment with placebo and clomiphene citrate (191). Although metformin alone has also been reported to induce spontaneous ovulation, this monotherapy has not been compared with metformin plus clomiphene citrate or placebo in a prospective, randomized trial ( 187). Similarly, troglitazone, an insulin sensitizer under the category of thiazolidinediones, has beneficial effects on plasma androgen and fasting insulin levels, and increases the rate of spontaneous ovulation in obese women with hyperandrogenemia and insulin resistance, even in the absence of weight loss ( 192,193). Troglitazone, however, has recently been withdrawn from the market because it carries a 1 in 50,000 chance of fatal liver failure. In contrast, metformin has an excellent safety profile. Gastrointestinal complaints are its most common side effects, although isolated cases of fatal lactic acidosis have been reported in patients with underlying renal compromise. Metformin is typically discontinued once pregnancy has been established; however, it is a category B drug and its administration during pregnancy is not known to confer specific risk to the fetus. Two new insulin sensitizers have recently been approved for treatment of diabetes: rosiglitazone and pioglitazone. The safety and efficacy of these medications has not yet been assessed for use in ovulation induction. A typical treatment regimen using metformin with or without clomiphene citrate for ovulation induction in PCOS patients follows (187): 1. Select PCOS patients. Failure of ovulation induction with clomiphene citrate alone is an indication but not a requirement for the use of metformin. 2. Confirm normal liver and renal function (serum creatinine 40 IU/L are consistent with complete cessation of ovarian function. However, ovarian function can wax and wane over several years, and levels can fluctuate accordingly. Therefore, women with amenorrhea and FSH >40 IU/L may resume menstruating for a short time in the future and occasionally may achieve pregnancy ( 70). Luteinizing Hormone Evaluation of luteinizing hormone (LH) levels appears to be of somewhat less value than other hormone assessments during the menopausal transition. Prior to menopause, LH levels are usually in the range of 5 to 20 IU/L. Although LH levels increase during the menopausal transition in a manner similar to those of FSH, LH is also significantly elevated during the midcycle surge and in cases of chronic anovulation. Because individuals rarely may have amenorrhea as a result of

gonadotropin-secreting pituitary adenomas, it is reasonable to check both LH and FSH in women, especially young patients, with apparent loss of ovarian function (71).

Symptoms Amenorrhea The most obvious symptom of cessation of cyclic ovarian function is prolonged amenorrhea. The cessation of menstruation indicates that the amount of estrogen produced by the ovaries is no longer enough to promote endometrial proliferation, and the absence of cyclic progesterone production is accompanied by the absence of withdrawal bleeding. This is an advantageous situation for several reasons. First, the sometimes-disabling discomfort and anemia suffered by many women as a result of cyclic bleeding is no longer a problem. Second, any abnormal bleeding that may occur later serves as a warning for potential malignancy and is obvious to both the patient and her physician. Unfortunately, hormone replacement therapy results in vaginal bleeding in most women (72). Not only is this effect a common reason for discontinuing hormone replacement therapy, but bleeding that would normally be interpreted as a warning sign is attributed to the hormone therapy, potentially delaying diagnosis of a malignancy. Hot Flashes The classic symptom associated with estrogen deficiency is the hot flash, also known as a hot flush. This symptom is described as “recurrent, transient periods of flushing, sweating, and a sensation of heat, often accompanied by palpitations, feelings of anxiety, and sometimes followed by chills” ( 73). The entire episode usually lasts no more than 1 to 3 minutes and may recur as many as 30 times per day, although 5 to 10 times per day is probably more common ( 8). Hot flashes are experienced by at least one-half of all women during natural menopause and by even more women after surgical menopause ( 73,74). Although most women do not report these events as particularly disturbing, as many as 25% complain of severe or frequent hot flashes, especially after surgical menopause. In these cases, hot flashes may be accompanied by fatigue, nervousness, anxiety, irritability, depression, and memory loss ( 75). These sensations may result in part from hot flashes that occur at night, referred to as night sweats, which are believed to exert their effect by the interruption of sleep patterns. Early in the menopausal transition, vasomotor instability may manifest as an intermittent sleep disturbance in the absence of obvious hot flashes. Physiologically, hot flashes correspond to marked, episodic increases in the frequency and intensity of gonadotropin-releasing hormone (GnRH) pulses from the hypothalamus. Although it has not been firmly established, it is believed that these symptoms are not the result of increased GnRH secretion. Instead, the increased pulsatile activity is a marker for the same central disturbance of the body temperature regulation center that is responsible for the hot flashes ( 76). Estrogen replacement therapy results in the resolution of hot flashes in most women in a matter of days. In some women, especially after oophorectomy, a higher dose of estrogen is commonly needed. In the case of women without risk factors for cardiovascular disease, low-dose oral contraceptives can be used with excellent results. Alternatively, the daily estrogen dose can be increased stepwise to as high as the equivalent of 2.5 mg of conjugated estrogens to resolve persistent hot flashes. The estrogen dose should be tapered slowly over a period of months to no more than 1.25 mg of conjugated estrogen per day, because the risk of cardiovascular disease actually may be increased in women taking larger doses ( 77). In women for whom hormone replacement is contraindicated, multiple alternative treatments for hot flashes have been developed. Somewhat effective alternatives may be progestins such as medroxyprogesterone (10 to 30 mg daily orally) (78) or megestrol acetate (20 to 40 mg daily orally) (79). If either of these progestins results in intolerable side effects, the use of alternative progestins may be considered, although few data exist regarding their efficacy. In addition to the progestins, other nonsteroidal treatments for hot flashes have been developed. One of the best studied is the b 2-adrenergic agonist, clonidine. This drug probably works through both central and peripheral mechanisms and can be given either orally (0.05 mg twice daily) or by transdermal patch (0.1 mg weekly) (80). In the past, night sweats were treated with a formulation that contained a combination of phenobarbital, ergotamine, and belladonna However, this combination has a marked sedative effect and potentially can be habit forming. In addition, controlled studies show little long-term effectiveness of this treatment ( 81). For these reasons, this formulation is not currently recommended as a treatment for hot flashes. Many women have mild hot flashes that they do not feel require therapy. The patients can be advised that, without treatment, the symptoms usually subside slowly over 3 to 5 years (73). Sleep Disturbances Changes in sleep patterns occur in both sexes with age. However, during the menopausal transition, many women experience increasing sleep difficulties and insomnia that appear to be related to estrogen deficiency ( 38). Hot flashes may disrupt sleep and sleep patterns, a problem that may be markedly improved by hormone therapy (82).

Long-term Health Problems Associated with the Menopause Low estrogen levels have a cumulative effect on many tissues. Prolonged estrogen deficiency may contribute to the development of potentially reversible conditions, such as genitourinary atrophy, or more life-threatening and irreversible conditions, such as cardiovascular disease and osteoporosis. Prevention and early detection remain the cornerstones of health maintenance in this age group. Vaginal and Urinary Tract Changes Vaginal tissue and the tissues of the urethra and bladder base are known to be estrogen sensitive. Within 4 to 5 years of menopause, approximately one-third of women who are not taking hormone therapy develop symptomatic atrophy (83). Vaginal symptoms include dryness, dyspareunia, and recurrent vaginal infections. Fortunately, these symptoms are reversible with estrogen therapy ( 84). Urinary symptoms may include dysuria, urgency, and recurrent urinary tract infections ( 44). In addition, genuine stress urinary incontinence may be related to estrogen deficiency. Urethral shortening associated with postmenopausal atrophic changes may result in urinary incontinence. Estrogen therapy may improve or cure stress urinary incontinence in more than 50% of treated women, presumably by exerting a direct effect on urethral mucosa ( 85). A trial of hormone therapy should be undertaken prior to a surgical approach in any woman with vaginal atrophy. Central Nervous System Estrogen deficiency appears to have effects on the central nervous system that have only recently been appreciated. Perimenopausal women often experience difficulty concentrating and loss of short-term memory. These symptoms have been attributed to either the effects of aging alone or subtle sleep deprivation associated with hot flashes ( 86). Estrogen appears to have direct effects on mental function, and replacement therapy has been shown to improve both short-term and long-term memory in postmenopausal women (87,88). One of the most intriguing areas of research is the potential role of estrogen therapy in the prevention or treatment of Alzheimer's disease. Evidence suggests that the risk of developing Alzheimer's disease can be decreased by estrogen therapy ( 89,90), but prospective trials to verify this are lacking. Although the precise role of

estrogen deficiency in Alzheimer's disease has yet to be defined, the implications of this finding for the aging population are readily apparent. Cardiovascular Disease Cardiovascular disease, including coronary artery disease and cerebrovascular disease, continues to be the leading public health problem in this country. Combined, these diseases account for more than 50% of all deaths in women over 50 years of age ( 91). Cardiovascular disease has been associated with multiple causes, the most important of which may be age. The risk of cardiovascular disease increases for men and women throughout their lifetimes (91). Although the risk of death from coronary artery disease is at least 3 times as great for men as for women before menopause, the relative risk for women increases significantly after menopause. It is essential to be aware of preventable risk factors for cardiovascular disease and to encourage women to minimize these risk factors. One of the most pervasive and treatable risk factors after the menopause is hypoestrogenemia. In the past, it was believed that age alone explained the increased risk of cardiovascular disease observed after menopause ( 92). Recent data have indicated that estrogen deficiency significantly increases the risk of cardiovascular disease and that this risk may be reduced by hormone replacement therapy ( 93). Postmenopausal women taking estrogen replacement therapy have less than one-half the risk of either myocardial infarction or stroke as women who are not taking estrogen therapy ( 77,91,94). However, long-term prospective trials of the cardiovascular benefits and risks of estrogen replacement therapy are lacking. This potentially substantial but controversial benefit of estrogen therapy should be made known to patients, especially those who may be reluctant to take estrogens for other reasons. On the other hand, a short-term trial suggested no overall decrease in mortality and an increase in early venous thrombotic events in women with preexisting cardiovascular disease ( 95). Although hypoestrogenemia is apparently a major contributing factor to cardiovascular disease in women, other risk factors that are amenable to change may be equally important. Probably the most significant risk factors are hypertension and cigarette smoking ( 55). Studies suggest that hypertension increases the risk of cardiovascular disease by 10-fold and cigarette smoking increases the risk by at least threefold ( 96). Other risk factors include diabetes mellitus, hypercholesterolemia, and a sedentary lifestyle. To decrease cardiovascular disease in postmenopausal women, screening for these risk factors must be performed and lifestyle changes must be recommended. Osteoporosis The association between both natural and surgical menopause and osteoporosis has been clearly established. By definition, osteoporosis is the reduction in the quantity of bone. Because this definition may be too broad to be clinically useful, some authors have narrowed the definition to include only bone loss that has progressed to a point that specific parts of the skeleton are so thin that they have an enhanced susceptibility to fractures or that fractures are actually present (97). The degree of cortical and trabecular bone loss necessary to meet this criterion is uncertain in those who have not yet had a bone fracture. The numbers of elderly women who have osteoporosis-related crush fractures of spinal vertebrae or fractures of either the radius or the neck of the femur have reached epidemic proportions ( 98). With the aging of the population, the problem is likely to increase. Although the rate of bone loss significantly increases at the time of menopause, the maximal incidence of osteoporosis-related fractures appears to occur several decades later. It is estimated that more than 30% of all women older than 90 years will experience hip fractures ( 99), and approximately 20% of these women will die within 3 months, most commonly from complications related to prolonged immobilization (100). By the time signs of osteoporosis become apparent, treatment is difficult. Pathophysiology The cause of osteoporosis is multifactorial. The primary factors associated with osteoporosis include heredity, age, estrogen status, and dietary calcium intake. Age is the most important factor associated with bone loss (101). All women begin losing bone mass in their early 30s, and this loss continues throughout their lives. Before menopause, the rate of loss is less than 1% of total bone tissue per year. After menopause, the rate of bone loss increases to as high as 5% per year in estrogen-deficient women. Evidence suggests that this may be related to the gradual decrease in growth hormone levels associated with age ( 102). Heredity plays a role primarily by determining the peak bone mass that a woman will attain during her life and the subsequent rate of bone loss. On average, African American women have a higher bone mass than white women, and this may explain the low risk of osteoporosis-related fractures observed in African Americans (103). A family history of osteoporosis is a strong risk factor ( 104). A third factor associated with bone loss is estrogen status. For women not taking hormone replacement, bone loss after menopause is accelerated to a rate of 3% to 5% per year (105). This loss is most rapid during the first 5 years after menopause, when up to 20% of the expected lifetime loss from the femoral neck may occur (106). Depending on the age at surgery, surgical menopause poses a higher risk than natural menopause because a woman experiences a longer period with low estrogen levels (107). Hypoestrogenemia has a direct effect on osteoblast function and appears to exert its adverse effects by altering calcium balance ( 108,109). A fourth factor affecting bone loss is dietary calcium. Dietary intake of calcium, primarily in the form of dairy products, has been shown to be associated with decreased bone loss in premenopausal women ( 110). In postmenopausal women taking estrogen therapy, calcium supplementation of 1,000 mg/day appears to be sufficient to decrease bone loss ( 111). Combined with the average dietary intake of calcium in the United States of only 500 mg/day for adults ( 110), the total requirement of 1,500 mg/day is provided by diet plus supplementation. Calcium therapy can be given as calcium carbonate (oyster shell) tablets or as calcium citrate. Fortunately, this amount of calcium supplementation does not appear to increase the risk of kidney stones ( 112). However, it may be associated with gastrointestinal complaints such as constipation or increased flatus. Other factors that preserve bone density and decrease the risk of osteoporosis include physical activity ( 113) and avoidance of cigarette smoking ( 114). There have been no controlled studies of these factors to determine their impact on osteoporosis-related fractures in later life. Methods for Detection After a prolonged period of hypoestrogenemia, bone loss is only partially reversible. For these reasons, it is more practical and effective in most women to implement therapy to prevent bone loss at the time of menopause than to screen for early signs of osteoporosis. In some women, hormone replacement therapy may be contraindicated or not desired by the patient. In these women, an alternative approach would be to screen for bone loss at set intervals and institute therapy if a defined threshold of osteopenia is reached ( Table 29.1). No standard guideline for significant osteopenia has been established, but recommendations for screening have been published ( 115).

Table 29.1. Radiographic Techniques to Screen for Osteoporosis

Hormone Replacement Therapy Estrogen deficiency has been considered by many to be a physiologic rather than a pathologic condition, probably because ovarian failure is genetically programmed. With the increased life expectancy of women, however, the negative impact of prolonged estrogen deficiency becomes more significant. Although estrogen deficiency is treatable, fewer than 20% of postmenopausal women take estrogen ( 116). Although hormone replacement therapy is not completely risk free, the health benefits appear to outweigh the risks for most women.

Benefits Hormone replacement therapy is indicated for any woman with signs or symptoms of hypoestrogenemia (Table 29.2). Because of the health risks associated with estrogen deficiency, replacement therapy should be offered to all postmenopausal women who have no contraindications. Women with known risk factors for osteoporosis should be encouraged to consider taking estrogen to minimize their risks. Some of the benefits of estrogen are felt immediately, but the long-term benefits may not be apparent for several decades.

Table 29.2. Indications and Contraindications for Estrogen Replacement Therapy

Hot Flashes Relief of hot flashes is the most common reason motivating women to start and continue hormone replacement. Hot flashes may interfere with the normal sleep cycle resulting in insomnia ( 86) and, in severe cases, they may also interfere with concentration ( 73). Although oral estrogen therapy usually is effective in reducing the severity and frequency of hot flashes within a few days, patients should be advised that it might be several weeks before maximal relief is achieved. Osteoporosis Hormone replacement therapy helps maintain bone mass and skeletal integrity, thereby protecting against osteoporosis (117). Estrogen conserves calcium by both enhancing the efficiency of intestinal absorption and by improving renal calcium conservation ( 108). In addition, estrogen appears to have a direct effect on osteoclast function ( 109). Estrogen can effectively slow bone loss and, to a limited degree, it can reverse the bone loss associated with osteoporosis ( 118). For this reason, hormone replacement therapy should be initiated at menopause and should be given for a long term, although the optimal duration is unclear. Recent evidence has suggested that progesterone also has a role in maintaining bone density ( 119). Progesterone appears to promote bone formation by increasing osteoblast activity, either directly or indirectly, by inhibiting the corticosteroid effect on osteoblasts. This finding supports the use of a progestin alone in women who are unable to take estrogen therapy. Cardiovascular Disease Estrogen replacement therapy may protect against cardiovascular disease, including coronary artery disease and stroke, although the issue has not been settled. Multiple cohort and case-control studies have suggested that estrogen decreases the risk of both myocardial infarction and stroke by 50% ( 76,90,93). Even when there is angiographic evidence of coronary artery disease, estrogen enhances survival ( 120). However, carefully controlled prospective trials to rule out the possibility of selection bias and other confounding factors must be completed to fully understand the cardiovascular benefits and risks of hormone replacement therapy. There are several mechanisms by which estrogen could protect the heart. The most important mechanism appears to be the effect of estrogen on serum lipids and lipoproteins. Estrogen decreases circulating levels of low-density lipoproteins ( 121,122) and increases levels of high-density lipoproteins. Both the absolute decrease in total cholesterol and the increase in the high-density to low-density lipoprotein ratio appear to retard progression of coronary artery disease. Although these effects are attenuated by concomitant progestin use, this effect appears to decrease over time ( 123). It has been estimated that estrogen accounts for 20% to 50% of the total protective effect for cardiovascular disease. The degree to which progestins may diminish this effect, if any, is unknown. Estrogen also exerts an antiarteriosclerotic effect on blood vessels ( 124). This appears to result, in part, from a direct effect on blood vessels that is not reversed by progestin. Estrogen appears to be an antioxidant that decreases the formation of lipid peroxidases, which may prevent arteriosclerosis by minimizing the oxidation of low-density lipoprotein cholesterol, a potent inducer of plaque formation in vessels ( 125). A third beneficial effect is that of vasodilation ( 126). There appears to be a direct effect on blood vessel endothelial cells that results in immediate vasodilation, perhaps mediated by estrogen receptors ( 127). A final beneficial effect is on coagulation. Low-dose estrogen therapy (i.e., 0.625 mg daily of conjugated estrogens) results in a subclinical decrease in coagulability by decreasing platelet aggregation and fibrinogen and by inhibiting plasminogen formation ( 128). This effect appears to be lost with higher doses of estrogen (i.e., 1.25 mg of conjugated estrogens). At even higher doses, equivalent to those used in oral contraceptives, there is an increase in coagulability. Therefore, doses of estrogen equivalent to 0.625 mg of conjugated estrogens should be used for long-term therapy.

Potential Health Risks The risks of estrogen therapy appear to be dose related. Many of the side effects of high-dose oral contraceptives have not occurred with the lower doses of estrogen used for hormone replacement therapy. Because of the sensitivity of some tissues to estrogen, the potential risks of estrogen for postmenopausal women must be considered. Breast Cancer Numerous retrospective and prospective observational studies have evaluated whether exogenous estrogens in the form of either oral contraceptives or estrogen replacement therapy have an impact on the incidence of breast cancer. Although some recent meta-analyses have concluded that there is no increased risk of this malignancy among women who receive hormone replacement (129,130), others have demonstrated a significant increase in breast cancer risk that may be related to the duration of estrogen use ( 24,131,132). One of these studies showed a relative risk for the development of breast cancer of 1.46 in women who took postmenopausal estrogens for 5 years or longer ( 24). However, large prospective clinical trials are incomplete and the benefits of hormone replacement may outweigh

this potential risk in some patients. Endometrial Cancer A well-established risk of estrogen replacement therapy is endometrial hyperplasia and endometrial cancer. Early observational studies found that women who used estrogen alone were 4 to 7 times more likely to develop endometrial cancer than women who did not ( 53). The simultaneous use of progestins effectively prevents this problem in most cases (133,134). However, it should be kept in mind that even women taking progestin therapy can develop endometrial cancer, especially if they have used unopposed estrogens in the past ( 135). Therefore, endometrial evaluation remains an important part of management for all women with irregular vaginal bleeding. Gallbladder Disease The risk of symptomatic gallbladder disease is increased by the use of oral contraceptives ( 135). In a recent questionnaire study of postmenopausal women, hormone replacement therapy doubled the risk of gallbladder disease compared with women taking no hormones ( 136). However, in two case-control studies, no increased risk could be appreciated (135,137). Thrombophlebitis There is no increased risk of thrombophlebitis associated with hormone replacement therapy, despite the well-established association with the use of oral contraceptives. With the standard doses of conjugated estrogens normally used, there is no increased risk of either venous thrombosis or pulmonary embolism in healthy women (138), although there appears to be some increased risk in women with preexisting cardiovascular disease ( 95). Hormone replacement therapy does not significantly alter clotting factors ( 139). No study has specifically addressed the risk of recurrent thrombophlebitis for women taking estrogen. Therefore, women who have a history of thrombophlebitis should be offered hormone replacement therapy with the understanding that it is unlikely, but uncertain, that this therapy alters the risk of recurrent thrombophlebitis (140). Hypertension Hypertension has been one of the relative contraindications to oral contraceptives because the higher-dose formulations were found to further increase blood pressure (141). In contrast, at the dosages used for hormone replacement therapy, conjugated estrogens appear to have little effect on blood pressure ( 142). Because chronic hypertension is a well-established risk factor for myocardial infarction and stroke, women with this disorder should be encouraged to maintain low blood pressure levels and to consider the potential protective effect of hormone replacement therapy for cardiovascular disease. Side Effects Vaginal Bleeding Any vaginal bleeding may be distressing; therefore, hormone replacement regimens associated with amenorrhea are preferable. Daily use of estrogen and cyclic use of progestin produces cyclic bleeding in most women. In an effort to avoid cyclic bleeding, the daily use of estrogen and progestin has been advocated. After several months, daily progestin therapy will result in amenorrhea in more than one-half of women with minimal risk of hyperplasia ( 72). Irregular bleeding may be an early warning sign of endometrial hyperplasia or malignancy. More commonly, it is a sign of endometrial atrophy or asynchronous shedding. Because of the known association of estrogen replacement therapy with endometrial cancer, endometrial biopsy is indicated when irregular uterine bleeding occurs postmenopausally. Breast Tenderness Breast tenderness can occur with hormone replacement therapy (143). This effect may be related to both estrogen and progesterone stimulation of breast tissue. The symptoms of fibrocystic breast changes may be increased (143,144). The initial approach to relieving breast symptoms is to decrease the daily estrogen dose to the equivalent of 0.625 mg of conjugated equine estrogen, and reduce progestin to the equivalent of 2.5 mg of medroxyprogesterone. If this is ineffective, the type of estrogen may be changed. Mood Changes Progestins are known to cause mood disturbances similar to those of premenstrual syndrome, including anxiety, irritability, or depression ( 145,146). Because of the significant protective effect of progestins against endometrial cancer, a dose or formulation of progestin that has the fewest side effects should be sought. Weight Gain and Water Retention Some women are extremely sensitive to exogenous estrogens and experience symptoms such as weight gain or water retention (147). Although few data are available regarding these problems, alternative doses and formulations of both estrogen and progestins should be used to find the combination with the fewest side effects.

Special Cases In some women, the standard approach to hormone replacement therapy may not be appropriate or sufficient. Despite the benefits of estrogen administration after menopause, for some this therapy is contraindicated ( Table 29.2). History of Breast Cancer One of the most controversial subjects concerning hormone replacement therapy is whether a woman with a history of successfully treated breast cancer can receive estrogen. Because it appears that estrogen replacement therapy may increase the risk of breast cancer, there has been a fear that estrogen may increase the risk of recurrent breast cancer. The limited data available suggest no increased risk of recurrent breast cancer among postmenopausal estrogen users ( 148,149). Until more long-term data are available, estrogen should be used with caution in women with a history of breast cancer. In a woman with nonmetastatic (node-negative) estrogen receptor–negative breast cancer, particularly one who has a strong family history of osteoporosis and heart disease, the benefits of estrogen may outweigh the low theoretic risk that the hormone will predispose her to the development of recurrent cancer. History of Endometrial Cancer Although, theoretically, estrogen and progestin therapy should not increase the risk of recurrent endometrial cancer, there are few data regarding estrogen or progestin therapy in women who have been treated for endometrial cancer ( 150). Progestins have been used to treat recurrent endometrial cancer ( 151). One study of women successfully treated for stage I endometrial cancer revealed that a combination of estrogen and progestin therapy does not increase the risk of recurrence (152). Because of the limited information available, any woman with a history of endometrial cancer should be informed of the unknown risk of recurrence with hormone therapy. Endometriosis

There have been anecdotal reports of recurrent endometriosis ( 153,154) or malignant transformation of endometriosis in women with endometriosis who take hormone replacement therapy following bilateral oophorectomy ( 155). Therefore, such women should be treated with continuous estrogen and progestin. In women with severe endometriosis, especially when the bowel, bladder, or ureter is involved, a hormone-free period for up to 6 months immediately after surgery may also be advisable prior to instituting combined estrogen and progestin therapy. Liver Disease Hormone replacement therapy has not been associated with the development of liver disease. However, estrogens are metabolized in the liver, and women with normal ovarian function and chronic liver disease are known to have significantly elevated levels of circulating estrogens ( 156). Likewise, normal doses of conjugated estrogens could lead to a substantially higher level of circulating estrogens than expected in these women. Therefore, hormone replacement therapy should be avoided in women with active or chronic liver disease.

Replacement Hormones and Regimens The mainstay of hormone replacement in the absence of ovarian function is estrogen, usually with the addition of a progestin. Standard replacement therapy has consisted of concurrent estrogen and progestin in anyone with an intact uterus. Estrogen only was given to women who had had hysterectomies. Better understanding of the effects hormones have on the body has altered these classic approaches to therapy. Types of Estrogen and Progesterone Estrogens are available in oral and parenteral forms ( Table 29.3). The most commonly prescribed oral estrogen preparation is conjugated equine estrogen, a combination of estrone (50%), equilin (23%), 17a-dihydroequilin (13%), and various other estrogens extracted from the urine of pregnant mares ( 157). This formulation has been available in the United States for more than 50 years; thus, most of the data regarding the safety and efficacy of estrogen replacement therapy have been gathered from women taking conjugated estrogens. Several other estrogen preparations have been developed, and data are accumulating regarding their comparable effectiveness. There is, at present, no compelling reason to recommend one preparation over others based on risks or side effects. If side effects become a problem with one formulation, a woman should be encouraged to try a different dose or estrogen formulation rather than abandon estrogen replacement altogether.

Table 29.3. Standard Dosages Used for Hormone Replacement Therapy

Estrogens are used orally as the first line of therapy in most women. Transdermal estradiol patches have also been found to be an effective method for hormone administration. However, there are several potential drawbacks to this approach. On a physiologic level, it is uncertain whether the same benefit is achieved in terms of reduction of cardiovascular disease risks, because changes in lipoprotein profiles do not occur as rapidly as with oral therapy ( 158). Transdermal patches are more expensive than oral preparations and result in some skin irritation at the site of placement in one-third of users ( 159). In women in whom oral estrogen therapy does not alleviate symptoms or is poorly tolerated or in whom oral preparations create a problem with hypertriglyceridemia, estrogen patches may offer some advantage (121). A special situation is the vaginal use of conjugated estrogens. Apparently, the rate of vaginal absorption of estrogen is similar to that of oral absorption ( 160). This has two important implications. First, when women who have contraindications to oral estrogen therapy use vaginal estrogen for atrophic vaginitis, the amount of systemically absorbed estrogen must be considered. In these women, it is recommended that the smallest dose needed to maintain the vaginal tissue effect be used. This is usually approximately one-third of an applicator (0.2 mg) used 2 to 3 times weekly. Second, women who desire estrogen therapy but are unable to take oral estrogen can try vaginal administration. This route of administration appears to be less effective in resolving symptoms of estrogen deficiency ( 161) and may not alter serum lipids to the same degree as oral estrogens ( 162). Progestins are also available in several different formulations ( Table 29.3). The most common progestin used is medroxyprogesterone given orally. In the doses prescribed to protect the endometrium (2.5 to 10 mg daily), some women experience psychological effects such as anxiety, irritability, or depression ( 142,143). Although these problems may be associated to some degree with all progestins, few studies have evaluated them. Many progestin formulations have been evaluated for the treatment of irregular bleeding and have been found to be effective. No single progestin is clearly superior to another. If a woman has significant side effects with one progestin dose, a lower dose or a different progestin formulation should be given. Estrogen Alone Whenever possible, unopposed estrogen therapy should be avoided in a woman with a uterus ( 163). However, some women experience intolerable side effects from progestin therapy. If no dose or formulation of progestin can be found that has acceptable side effects, estrogen alone may be given. A reasonable approach is the use of the lowest effective dose of estrogen daily coupled with yearly surveillance of the endometrium by endometrial biopsy. The use of vaginal ultrasonography for endometrial surveillance may prove ultimately to be effective for this use. Daily estrogen alone has been recommended for women after hysterectomy. Progestins have been avoided because they may partially reverse the beneficial effects of oral estrogens on serum lipids. However, the effects of progestins on lipids appear to be short term ( 122), and only part of the protective effect of estrogens on the cardiovascular system are derived from lipid effects. Therefore, it is controversial whether progestins should be used in combination with estrogen for these women (24). Estrogen plus Cyclic Progesterone Methods have been sought to avoid the risks of estrogen therapy while retaining the benefits. The addition of a progestin to estradiol minimizes the risk of endometrial hyperplasia and cancer ( 164). The use of 12 to 14 days per month of medroxyprogesterone results in a risk of endometrial cancer less than that for the population at large. Initially, in the United States, estrogen was given for only 21 to 25 days per month and progestins were given for the last 7 to 10 days of the estrogen therapy ( 164), followed by a monthly period of 6 to 8 days when no hormones were given. Although this had the theoretic advantage of giving all hormonally responsive tissue a rest, no study has ever shown a benefit to this hormone-free period. However, data from Great Britain suggest that 10 days of progestin therapy per month may not be enough to prevent endometrial hyperplasia in some women (165). Therefore, when cyclic progestins are used, they should be given for 12 to 14 days per year. With 14 days of therapy (10 mg medroxyprogesterone or equivalent), endometrial hyperplasia is uncommon ( 166).

Estrogen plus Continuous Progesterone Although cyclic progestins given at appropriate doses can protect the endometrium from hyperplasia, this approach also results in cyclic endometrial shedding and menstruation in most women (167). Vaginal bleeding is one of the most common reasons that women discontinue hormone replacement therapy ( 168). In addition, the relatively high dose of progestin used may result in significant symptoms in some women ( 142). These may include physical symptoms such as breast tenderness, fluid retention, and edema and psychological symptoms such as anxiety, irritability, or depression. Therefore, regimens using lower daily doses of progestins have been developed (164,169). Daily progestin therapy (2.5 to 5.0 mg medroxyprogesterone acetate or equivalent) protects against endometrial hyperplasia to a degree similar to that of cyclic administration at higher doses (Fig. 29.2) (166).

Figure 29.2 Administration of hormone replacement therapy.

More than 50% of women who take a daily combination of estrogen and progestin will experience irregular bleeding, even after 1 year of therapy ( 72). This group of women may be better served by continuous estrogen accompanied by cyclic progesterone. For many women, regular bleeding may be preferable to unpredictable bleeding. Selective Estrogen Receptor Modulators In 1995, an estrogen receptor, ER-b, was cloned ( 170). This receptor displayed similar but distinct ligand-binding specificities to that of ER-a but had a different tissue distribution. With this discovery came the search for the optimal long-term female hormone replacement for women. It resulted in the development of selective estrogen-receptor modulators known as SERMS. Raloxifene, a benzothiopene compound is of particular interest ( 171). This SERM binds with higher affinity to the estrogen receptor a than b. Clinically, raloxifene produces a effect similar to estrogen on the skeletal and cardiovascular system while behaving as an estrogen antagonist in the uterus and the breast. Raloxifene maintains a favorable lipid profile and does not exert a proliferative effect on the endometrium. More importantly, effects on bone remodeling are similar to those of estrogen. Unfortunately, raloxifene does not relieve hot flushes. Raloxifene may be particularly useful for decreasing the risk of osteoporosis in women who are unwilling or unable to take hormone replacement therapy because of persistent benign bleeding, a history of severe endometriosis, or a high risk for primary or recurrent breast cancer (172). Testosterone Testosterone has been used in women, especially after surgical menopause, to alleviate specific symptoms ( 173). In the United States, testosterone is available in an injectable form (testosterone enanthate 75 to 150 mg intramuscular every month), and as a combined oral formulation ( methyltestosterone 2.5 to 5 mg, plus conjugated or esterified estrogens 0.625 to 1.25 mg). In Great Britain, a subcutaneous testosterone implant is also available. The most common indication for androgens is loss of libido ( 174). Studies of testosterone administration have shown mixed results in terms of libido improvement (173,174,175,176,177 and 178). One 6-month study of the oral preparation showed an adverse effect on the estrogen-induced changes in lipoproteins ( 176). Because of a lack of long-term studies of any of these agents, the effects on heart disease and other organ systems are unknown. Until studies establish a benefit for this type of therapy, androgens should be prescribed with caution. For women who experience decreased sexual responsiveness, appropriate counseling appears to be the most effective therapy (177,180).

Patient Monitoring Continued monitoring of patients taking hormone replacement therapy relies heavily on self-reporting of symptoms and bleeding patterns. Postmenopausal women also should undergo routine assessments that should include evaluation and counseling regarding risk factors. Symptoms In women for whom the standard doses of estrogen do not seem to be sufficient to control hot flashes, doses as high as 2.5 mg of conjugated estrogens per day can be used. In premenopausal women who have undergone oophorectomy, oral contraceptives may offer relief in difficult cases ( 65), but they have more side effects than hormone replacement therapy (61). Vaginal dryness responds somewhat slower than hot flashes to hormone replacement therapy. Even at the lowest therapeutic doses, however, complete resolution of vaginal dryness is usually seen after 3 to 6 weeks ( 181). Any symptoms of atrophic vaginitis will decrease over the same period. Vaginal Bleeding The bleeding patterns associated with estrogen therapy depend on the type of hormone protocol used. The most common pattern with unopposed estrogen is amenorrhea (72). If breakthrough bleeding occurs, endometrial biopsy should be performed. Even with no vaginal bleeding, yearly endometrial evaluation is recommended for women taking unopposed estrogen because of the risk of endometrial cancer. With continuous estrogen and cyclic medroxyprogesterone, cyclic estrogen withdrawal bleeding almost always occurs monthly ( 167). If irregular or intermenstrual bleeding occurs, endometrial biopsy should be performed ( Fig. 29.2). Although endometrial hyperplasia or cancer occurs only rarely, risk is not completely eliminated with progestin therapy. When continuous estrogen and continuous progestins are used, the bleeding pattern is more variable. Many women taking this therapy will develop amenorrhea ( 72). One-half of women will have some degree of irregular bleeding even after 1 year. The best method for evaluation of the endometrium has not been determined. Although the bleeding is almost always light, the significance of it cannot be determined without endometrial evaluation. It is reasonable to consider a baseline endometrial biopsy for anyone taking this agent who has irregular bleeding. If irregular bleeding persists for 6 months, further evaluation with ultrasonography and possibly hysteroscopy may be of benefit.

Nonhormonal Drugs In addition to estrogen, calcium, vitamin D, calcitonin, and bisphosphonates (especially etidronate and alendronate ) have been used for the treatment of

postmenopausal osteoporosis. Calcium can slow bone loss but does not increase bone mass ( 182), and calcium intake of 1,500 mg daily is considered a mainstay of both prevention and treatment of osteoporosis in postmenopausal women. Fluoride is the only known agent that can stimulate bone formation and substantially increase bone density (183), but the bone formed is actually more fracture prone, and fluoride is not recommended therapy. Calcitonin is probably as effective as estrogen in reducing fracture risk and is a consideration for women who cannot take oral medication ( 184). Calcitriol, a vitamin D analog, can increase lumbar bone mass and decrease the rate of vertebral fractures ( 185) in women with low vitamin D levels despite adequate daily intake of 400 IU vitamin D. Although raloxifene does not appear to slow bone loss as effectively as conventional hormone replacement therapy, it does appear to be effective in reducing fracture risk ( 186). Of the bisphosphonates, alendronate is approximately 1,000 times more potent than etidronate in terms of the inhibition of bone resorption. Newer bisphosphonates, pamidronate and risedronate, are being evaluated and appear to be equally effective in increasing bone mineral density and reducing fracture risk with fewer side effects. In a randomized study, alendronate was given orally 5 to 20 mg/day for 3 years, or 20 mg/day for 2 years followed by 5 mg/day for the third year, along with 500 mg/day of calcium (187). Compared with placebo, the rate of vertebral fracture was approximately one-half: 3.2% for those receiving alendronate versus 6.2% for the placebo group. In general, all women with documented osteoporosis, either by densitometry or previous fracture, are candidates for aggressive antiresorptive therapy in addition to calcium and vitamin D replacement.

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165. Whitehead MI, King RJ, McQueen J, et al. Endometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. J R Soc Med 1979;72:322–327. 166. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994;170:1213–1223. 167. MacLennan AH, MacLennan A, O'Neill S, et al. Oestrogen and cyclical progestogen in postmenopausal hormone replacement therapy. Med J Aust 1992;157:167–170. 168. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332–1334. 169. Marslew U, Riis BJ, Christiansen C. Bleeding patterns during continuous combined estrogen-progestogen therapy. Am J Obstet Gynecol 1991;164:1163–1168. 170. Kuiper GG, Enmark E, Pelto-Huikko M, et al. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996;93:5925–5930. 171. Plouffe L Jr. Selective estrogen receptor modulators (SERMs) in clinical practice. J Soc Gynecol Invest 2000;7[Suppl 1]:S38–46. 172. Mincey BA, Moraghan TJ, Perez EA. Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc 2000;75:821–829. 173. Sherwin BB, Gelfand MM. The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 1987;49:397–409. 174. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 1985;10:325–335. 175. Sherwin BB, Gelfand MM. Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 1985;151:153–160. 176. Dow MG, Gallagher J. A controlled study of combined hormonal and psychological treatment for sexual unresponsiveness in women. Br J Clin Psychol 1989;28:201–212. 177. Dow MG, Hart DM, Forrest CA. Hormonal treatments of sexual unresponsiveness in postmenopausal women: a comparative study. Br J Obstet Gynaecol 1983;90:361–366. 178. Myers LS, Dixen J, Morrissette D, et al. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J Clin Endocrinol Metab 1990;70:1124–1131. 179. Hickok LR, Toomey C, Speroff L. A comparison of esterified estrogens with and without methyltestosterone: effects on endometrial histology and serum lipoproteins in postmenopausal women. Obstet Gynecol 1993;82:919–924. 180. Whitehead A, Mathews A. Factors related to successful outcome in the treatment of sexually unresponsive women. Psychol Med 1986;16:373–378. 181. Semmens JP, Tsai CC, Semmens EC, et al. Effects of estrogen therapy on vaginal physiology during menopause. Obstet Gynecol 1985;66:15–18. 182. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995;98:331–335. 183. Riggs BL, O'Fallon WM, Lane A, et al. Clinical trial of fluoride therapy in postmenopausal osteoporotic women: extended observations and additional analysis. J Bone Miner Res 1994;9:265–275. 184. Overgaard K, Hansen MA, Jensen SB, et al. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. BMJ 1992;305:556–561. 185. Tilyard MW, Spears GFS, Thomson J, et al. Treatment of postmenopausal osteoporosis with calcitrol or calcium. N Engl J Med 1992;326:357–362. 186. Ettinger B, Black DM, Mitlak BH, et al. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637–645. 187. Liberman UA, Weiss ST, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437–1443. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 30. Uterine Cancer Novak’s Gynecology

Chapter 30

Uterine Cancer John R. Lurain

Epidemiology and Risk Factors Endometrial Cancer Screening Endometrial Hyperplasia Endometrial Cancer Clinical Features Diagnosis Pathology Pretreatment Evaluation Clinical Staging Prognostic Variables Treatment Postoperative Adjuvant Therapy Recurrent Disease Treatment Results Follow-up after Treatment Estrogen Replacement Therapy after Treatment of Endometrial Cancer Uterine Sarcoma Classification Treatment of Uterine Sarcomas References

Endometrial carcinoma is the most common malignancy of the female genital tract, accounting for almost half of all gynecologic cancers in the United States. About 39,300 new cases are diagnosed annually, resulting in more than 6,600 deaths. Endometrial carcinoma is the fourth most common cancer, ranking behind breast, lung, and bowel cancers, and the seventh leading cause of death from malignancy in women. Overall, about 2% to 3% of women develop endometrial cancer during their lifetime (1). In recent years, certain factors have led to an increasing awareness of and emphasis on diagnosis and treatment of endometrial cancer. These factors include the declining incidence of cervical cancer and related deaths in the United States, prolonged life expectancy, postmenopausal use of hormone replacement therapy, and earlier diagnosis. The availability of easily applied diagnostic tools and a clearer understanding of premalignant lesions of the endometrium have led to an increase in the number of women diagnosed with endometrial cancer. Although endometrial carcinoma usually presents as early-stage disease and can generally be managed without radical surgery or radiotherapy, deaths from endometrial carcinoma now exceed those from cervical carcinoma in the United States. Endometrial cancer is a disease that occurs primarily in postmenopausal women and is increasingly virulent with advancing age. The role of estrogen in the development of most endometrial cancers has clearly been established; any factor that increases exposure to unopposed estrogen increases the risk for endometrial cancer. During the past several decades, the histopathology, spread patterns, and prognostic factors that affect the prognosis of endometrial cancers have been better defined. Management of endometrial cancer has evolved from a program of preoperative intrauterine radium packing or external pelvic irradiation followed in 6 weeks by hysterectomy, to a single brachytherapy session using an intrauterine tandem and colpostats followed immediately by hysterectomy, to an individualized approach using hysterectomy as primary therapy and employing additional postoperative treatment depending on surgical and pathologic findings. Further analysis and investigation are needed to determine whether this initial operative approach to treatment and staging, followed by targeted postoperative therapy, will translate into improved survival rates and lower morbidity.

Epidemiology and Risk Factors There appear to be two different pathogenetic types of endometrial cancer (2). The most common type occurs in younger, perimenopausal women with a history of exposure to unopposed estrogen, either endogenous or exogenous. In these women, tumors begin as hyperplastic endometrium and progress to carcinoma. These “estrogen-dependent” tumors tend to be better differentiated and have a more favorable prognosis than tumors that are not associated with hyperestrogenism. The other type of endometrial carcinoma occurs in women with no source of estrogen stimulation of the endometrium. These spontaneously occurring cancers are not associated pathologically with endometrial hyperplasia, but may arise in a background of atrophic endometrium. They are less differentiated and associated with a poorer prognosis than estrogen-dependent tumors. These “estrogen-independent” tumors tend to occur in older, postmenopausal, thin women and are present disproportionately in African American and Asian women. Several risk factors for the development of endometrial cancer have been identified ( 3,4,5,6,7 and 8) (Table 30.1). Most of these risk factors are related to prolonged, unopposed estrogen stimulation of the endometrium. Nulliparous women have 2 to 3 times the risk of parous women. Infertility and a history of irregular menses as a result of anovulatory cycles (prolonged exposure to estrogen without sufficient progesterone) increase the risk. Natural menopause occurring after 52 increases the risk for endometrial cancer 2.4 times compared with that in women whose menopause occurred before 49 years of age, probably as a result of prolonged exposure of the uterus to progesterone-deficient menstrual cycles. The risk for endometrial cancer is increased 3 times in women who are 21 to 50 pounds overweight and 10 times in those more than 50 pounds overweight (excess estrone as a result of peripheral conversion of adrenally derived androstenedione by aromatization in fat).

Table 30.1. Risk Factors for Endometrial Cancer

Other factors leading to long-term estrogen exposure, such as polycystic ovary syndrome and functioning ovarian tumors, also are associated with an increased risk for endometrial cancer. Menopausal estrogen replacement therapy without progestins increases the risk for endometrial cancer 4 to 8 times. This risk is greater with higher doses and with more prolonged use and can be reduced to essentially baseline levels by the addition of progestin ( 7). It has been noted that the use of the antiestrogen tamoxifen for treatment of breast cancer is associated with a twofold to threefold increased risk for the development of endometrial caner ( 8,9). Diabetes mellitus increases a women's risk for endometrial cancer by 1.3 to 2.8 times. Other medical conditions, such as hypertension and hypothyroidism, have been associated with endometrial cancer, but a causal relationship has not been confirmed.

Endometrial Hyperplasia Endometrial hyperplasia represents a spectrum of morphologic and biologic alterations of the endometrial glands and stroma, ranging from an exaggerated physiologic state to carcinoma in situ. Clinically significant hyperplasias usually evolve within a background of proliferative endometrium as a result of protracted estrogen stimulation in the absence of progestin influence. Endometrial hyperplasias are important clinically because they may cause abnormal bleeding, be associated with estrogen-producing ovarian tumors, result from hormonal therapy, and precede or occur simultaneously with endometrial cancer. The most recent classification scheme endorsed by the International Society of Gynecological Pathologists is based on architectural and cytologic features as well as long-term studies that reflect the natural history of the lesions ( 10) (Table 30.2). Architecturally, hyperplasias are either simple or complex; the major differing features are complexity and crowding of the glandular elements. Simple hyperplasia is characterized by dilated or cystic glands with round to slightly irregular shapes, an increased glandular-to-stromal ratio without glandular crowding, and no cytologic atypia. Complex hyperplasia has architecturally complex (budding and infolding), crowded glands with less intervening stroma without atypia. Atypical hyperplasia refers to cytologic atypia and can be categorized as simple or complex, depending on the corresponding glandular architecture. Criteria for cytologic atypia include large nuclei of variable size and shape that have lost polarity, increased nuclear-to-cytoplasmic ratios, prominent nucleoli, and irregularly clumped chromatin with parachromatin clearing ( Fig. 30.1).

Table 30.2. Classification of Endometrial Hyperplasias

Figure 30.1 Atypical hyperplasia (complex hyperplasia with severe nuclear atypia) of endometrium. A: The proliferative endometrial glands reveal considerable crowding and papillary infoldings. The endometrial stroma, although markedly diminished, can still be recognized between the glands. B: Higher magnification demonstrates disorderly nuclear arrangement and nuclear enlargement and irregularity. Some contain small nucleoli. (Reproduced or modified from Berek JS, Hacker NF. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

The risk of endometrial hyperplasia progressing to carcinoma is related to the presence and severity of cytologic atypia. Kurman and colleagues retrospectively studied endometrial curettings from 170 patients with untreated endometrial hyperplasia followed a mean of 13.4 years ( 11). They found that progression to carcinoma occurred in 1% of patients with simple hyperplasia, 3% of patients with complex hyperplasia, 8% of patients with atypical simple hyperplasia, and 29% of patients with atypical complex hyperplasia. Most of the hyperplasias seemed to remain stable (18%) or regress (74%). The premalignant potential of hyperplasia is influenced by age, underlying ovarian disease, endocrinopathy, obesity, and exogenous hormone exposure ( 12,13). Of patients with atypical hyperplasia detected in an endometrial biopsy or curettage specimen, about 25% have an associated, usually well-differentiated, endometrial carcinoma seen at hysterectomy. Marked cytologic atypia, a high mitotic rate, and marked cellular stratification are features of atypical endometrial hyperplasia most often associated with the finding of an undiagnosed carcinoma at hysterectomy. In a report of 85 menopausal women with endometrial hyperplasia treated with medroxyprogesterone acetate (10 to 20 mg per day), 84% of 65 who did not have cytologic atypia had complete reversal of the lesions, 6% developed recurrent hyperplasia, but none developed cancer, at a mean follow-up of 7 years ( 14). By contrast, of 20 patients with cytologic atypia, only 50% responded to progestin, 25% developed recurrent hyperplasia, and 25% developed adenocarcinoma. In another study, hyperplasia resolved in 94% of 32 patients with atypical endometrial hyperplasia who were treated with megestrol acetate (20 to 40 mg/d); however, relapse occurred in all 7 patients who discontinued progestin therapy ( 15). Progestin therapy is very effective in reversing endometrial hyperplasia without atypia but is less effective for endometrial hyperplasia with atypia. For

women with endometrial hyperplasia without atypia, ovulation induction, cyclical progestin therapy (e.g., medroxyprogesterone acetate, 10 to 20 mg/d for 14 days per month), or continuous progestin therapy (e.g., megestrol acetate, 20 to 40 mg/d) all appear to be effective. Continuous progestin therapy with megestrol acetate (40 mg/d) is probably the most reliable treatment for reversing complex or atypical hyperplasia. Therapy should be continued for 2 to 3 months, and endometrial biopsy should be performed 3 to 4 weeks after completion of therapy to assess response. Periodic endometrial biopsy or transvaginal ultrasound is advisable in patients being followed after progestin therapy for atypical hyperplasia, because of the presence of undiagnosed cancer in 25% of cases, the 29% progression rate to cancer, and the high recurrence rate after treatment with progestins.

Endometrial Cancer Screening Screening for endometrial cancer should currently not be undertaken because of the lack of an appropriate, cost-effective, and acceptable test that reduces mortality (16,17 and 18). Routine Papanicolaou's (Pap) test is inadequate and endometrial cytology is too insensitive and nonspecific to be useful in screening for endometrial cancer even in a high-risk population. A progesterone challenge test reveals whether the endometrium has been primed by estrogen, but it does not identify abnormal endometrial pathology. Transvaginal ultrasound examination of the uterus and endometrial biopsy are too expensive to be employed as screening tests. Although many risk factors for endometrial cancer have been identified, screening of high-risk individuals could at best detect only half of all cases of endometrial cancer. Furthermore, no controlled trials have been carried out to evaluate the effectiveness of screening for endometrial cancer. Screening for endometrial cancer or its precursors may be justified for certain high-risk women, such as those receiving postmenopausal estrogen replacement therapy without progestins and members of families with hereditary nonpolyposis colorectal cancer. Conversely, women taking tamoxifen receive no benefit from routine screening with transvaginal ultrasound or endometrial biopsy (19,20). Fortunately, most patients who have endometrial cancer present with abnormal perimenopausal or postmenopausal uterine bleeding early in the development of the disease, when the tumor is still confined to the uterus. Application of an appropriate and accurate diagnostic test in this situation usually results in early diagnosis, timely treatment, and a high cure rate.

Endometrial Cancer Clinical Features Symptoms Endometrial carcinoma most often occurs in women in the sixth and seventh decades of life, at an average age of 60 years; 75% of cases occur in women older than 50 years of age. About 90% of women with endometrial carcinoma have vaginal bleeding or discharge as their only presenting complaint. Most women recognize the importance of this symptom and seek medical consultation within 3 months. Some women experience pelvic pressure or discomfort indicative of uterine enlargement or extrauterine disease spread. Bleeding may not have occurred because of cervical stenosis, especially in older patients, and may be associated with hematometra or pyometra, causing a purulent vaginal discharge. This finding is often associated with a poor prognosis ( 21). Less than 5% of women diagnosed with endometrial cancer are asymptomatic. In the absence of symptoms, endometrial cancer is usually detected as the result of investigation of abnormal Pap test results, discovery of cancer in a uterus removed for some other reason, or evaluation of an abnormal finding on a pelvic ultrasound or computed tomography (CT) scan obtained for an unrelated reason. Women who are found to have malignant cells on Pap test are more likely to have a more advanced stage of disease ( 22). Abnormal perimenopausal and postmenopausal bleeding should always be taken seriously and be properly investigated, no matter how minimal or nonpersistent. Causes may be nongenital, genital extrauterine, or uterine ( 23). Nongenital tract sites should be considered based on the history or examination, including testing for blood in the urine and stool. Invasive tumors of the cervix, vagina, and vulva are usually evident on examination, and any tumors discovered should be biopsied. Traumatic bleeding from an atrophic vagina may account for up to 15% of all causes of postmenopausal vaginal bleeding. This diagnosis can be considered if inspection reveals a thin, friable vaginal wall, but the possibility of a uterine source of bleeding must first be eliminated. Possible uterine causes of perimenopausal or postmenopausal bleeding include endometrial atrophy, endometrial polyps, estrogen replacement therapy, hyperplasia, and cancer or sarcoma (24,25,26 and 27) (Table 30.3). Uterine leiomyomas should never be accepted as a cause of postomenopausal bleeding. Endometrial atrophy is the most common endometrial finding in women with postmenopausal bleeding, accounting for 60% to 80% of such bleeding. Women with endometrial atrophy have usually been menopausal for about 10 years, endometrial biopsy often yields insufficient tissue or only blood and mucus, and there is usually no additional bleeding after biopsy. Endometrial polyps account for 2% to 12% of postmenopausal bleeding. Polyps are often difficult to identify with office endometrial biopsy or curettage. Hysteroscopy, transvaginal ultrasonography, or both may be useful adjuncts in identifying endometrial polyps. Unrecognized and untreated polyps may be a source of continued or recurrent bleeding, leading eventually to unnecessary hysterectomy.

Table 30.3. Causes of Postmenopausal Uterine Bleeding

Estrogen therapy is an established risk factor for endometrial hyperplasia and cancer. The risk for endometrial cancer is 4 to 8 times greater in postmenopausal women receiving unopposed estrogen replacement, and the risk increases with time and higher estrogen doses. This risk can be decreased by the addition of a progestin to the estrogen, either cyclically or continuously. Endometrial biopsy should be performed as indicated to assess unscheduled bleeding or annually in women not taking a progestin. Endometrial hyperplasia occurs in 5% to 10% of patients with postmenopausal uterine bleeding. The source of excess estrogen should be considered, including obesity, exogenous estrogen, or an estrogen-secreting ovarian tumor. Only about 10% of patients with postmenopausal bleeding have endometrial cancer. Premenopausal women with endometrial cancer invariably have abnormal uterine bleeding, which is often characterized as menometrorrhagia or oligomenorrhea, or cyclical bleeding that continues past the usual age of menopause. The diagnosis of endometrial cancer must be considered in premenopausal women when abnormal bleeding is persistent or recurrent or if obesity or chronic anovulation is present. Signs Physical examination seldom reveals any evidence of endometrial carcinoma, although obesity and hypertension are commonly associated constitutional factors. Special attention should be given to the more common sites of metastasis. Peripheral lymph nodes and breasts should be assessed carefully. Abdominal examination

is usually unremarkable except in advanced cases in which ascites or hepatic or omental metastases may be palpable. On gynecologic examination, the vaginal introitus and suburethral area, as well as the entire vagina and cervix, should be carefully inspected and palpated. Bimanual rectovaginal examination should be performed specifically to evaluate the uterus for size and mobility, the adnexa for masses, the parametria for induration, and the cul-de-sac for nodularity.

Diagnosis Office endometrial aspiration biopsy is the accepted first step in evaluating a patient with abnormal uterine bleeding or suspected endometrial pathology (28). The diagnostic accuracy of office-based endometrial biopsy is 90% to 98% when compared with subsequent findings at dilation and curettage (D & C) or hysterectomy (29,30 and 31). The narrow plastic cannulas are relatively inexpensive, can often be used without a tenaculum, cause less uterine cramping, resulting in increased patient acceptance, and are successful in obtaining adequate tissue samples in more than 95% of cases. If cervical stenosis is encountered, a paracervical block can be performed, and the cervix can be dilated. Premedication with an antiprostaglandin agent can reduce uterine cramping. Complications following endometrial biopsy are exceedingly rare; uterine perforation occurs in only 1 to 2 cases per 1,000. Endocervical curettage may also be performed at the time of endometrial biopsy if cervical pathology is suspected. A Pap test is an unreliable diagnostic test because only 30% to 50% of patients with endometrial cancer have abnormal Pap test results (32). Hysteroscopy and D & C should be reserved for situations in which cervical stenosis or patient tolerance does not permit adequate evaluation by aspiration biopsy, bleeding recurs after a negative endometrial biopsy, or the specimen obtained is inadequate to explain the abnormal bleeding. Hysteroscopy is more accurate in identifying polyps and submucous myomas than endometrial biopsy or D & C alone ( 33,34). Transvaginal ultrasound may be a useful adjunct to endometrial biopsy for evaluating abnormal uterine bleeding and selecting patients for additional testing ( 35,36 and 37). Transvaginal ultrasound, with or without endometrial fluid instillation (ultrasonohysterography), may be helpful in distinguishing between patients with minimal endometrial tissue whose bleeding is due to perimenopausal anovulation or postmenopausal atrophy and patients with significant amounts of endometrial tissue or polyps who are in need of further evaluation. The finding of an endometrial thickness greater than 4 mm, a polypoid endometrial mass, or a collection of fluid within the uterus requires further evaluation. Although most studies agree that an endometrial thickness of 5 mm or less in a postmenopausal woman is consistent with atrophy, more data are needed before ultrasound findings can be considered to eliminate the need for endometrial biopsy in a patient who has symptoms.

Pathology The histologic classification of carcinoma arising in the endometrium is shown in Table 30.4 (10,38).

Table 30.4. Classification of Endometrial Carcinomas

Endometrioid Adenocarcinoma The endometrioid type accounts for about 80% of endometrial carcinomas. These tumors are composed of glands that resemble normal endometrial glands; they have columnar cells with basally oriented nuclei, little or no intracytoplasmic mucin, and smooth intraluminal surfaces ( Fig. 30.2). As tumors become less differentiated, they contain vadjust solid areas, less glandular formation, and more cytologic atypia. The well-differentiated lesions may be difficult to separate from atypical hyperplasia.

Figure 30.2 Well-differentiated adenocarcinoma of endometrium. The glands and complex papillae are in direct contact with no intervening endometrial stroma, the so-called back-to-back pattern. (Reproduced or modified from Berek JS, Hacker NF. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

Criteria that indicate the presence of invasion and are used to diagnose carcinoma are desmoplastic stroma, glands back-to-back without intervening stoma, extensive papillary pattern, and squamous epithelial differentiation. These changes, with the exception of the infiltrating pattern with desmoplastic reaction, require an area of involvement equal to or exceeding half of a low-power microscopic field (LPF) (>1 LPF; 4.2 mm in diameter) ( 39,40). The differentiation of a carcinoma, expressed as its grade, is determined by architectural growth pattern and nuclear features (Table 30.5). In the International Federation of Gynecology and Obstetrics (FIGO) grading system proposed in 1989, tumors are grouped into three grades: grade 1, 5% or less of the tumor shows a solid growth pattern; grade 2, 6% to 50% of the tumor shows a solid growth pattern; and grade 3, more than 50% of the tumor shows a solid growth pattern. In addition, notable nuclear atypia that is inappropriate for the architectural grade increases the tumor grade by one.

Table 30.5. FIGO Definition for Grading of Endometrial Carcinoma

Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component. This FIGO system is applicable to all endometrioid carcinomas, including its variants, and to mucinous carcinomas. In serous and clear cell carcinomas, nuclear grading takes precedence; however, most investigators believe that these two carcinomas should always be considered high-grade lesions, making grading unnecessary. About 15% to 25% of endometrioid carcinomas have areas of squamous differentiation (Fig. 30.3). In the past, tumors with benign-appearing squamous areas were called adenoacanthomas, and tumors with malignant-looking squamous elements were called adenosquamous carcinomas. It is now recommended that the term endometrial carcinoma with squamous differentiation be used to replace these two designations because the degree of differentiation of the squamous component parallels that of the glandular component and the behavior of the tumor is largely dependent on the grade of the glandular component ( 41,42).

Figure 30.3 Adenocarcinoma with squamous differentiation of endometrium. This lesion is also classified as adenoacanthoma. Squamous cells with eosinophilic cytoplasm and distinct cell borders form solid clusters in the lumina of neoplastic glands. (Reproduced or modified from Berek JS, Hacker NF. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

A villoglandular configuration is present in about 2% of endometrioid carcinomas ( 43,44). In these tumors, the cells are arranged along fibrovascular stalks, giving a papillary appearance but maintaining the characteristics of endometrioid cells. The villoglandular variants of endometrioid carcinomas are always well-differentiated lesions that behave like the regular endometrioid carcinomas, and they should be distinguished from papillary serous carcinomas. Secretory carcinoma is a rare variant of endometrioid carcinoma that accounts for about 1% of cases ( 45,46). It occurs mostly in women in their early postmenopausal years. The tumors are composed of well-differentiated glands with intracytoplasmic vacuoles similar to early secretory endometrium. These tumors behave as regular well-differentiated endometrioid carcinomas and generally have an excellent prognosis. Secretory carcinoma may be an endometrioid carcinoma that exhibits progestational changes, but a history of progestational therapy is rarely elicited. Secretory carcinoma must be differentiated from clear cell carcinoma because both tumors have predominately clear cells. These two tumors can be distinguished by their structure: secretory carcinomas have uniform glandular architecture, uniform cytology, and low nuclear grade, whereas clear cell carcinomas have more than one architectural pattern and a high nuclear grade. Mucinous Carcinoma About 5% of endometrial carcinomas have a predominant mucinous pattern in which more than half of the tumor is composed of cells with intracytoplasmic mucin (47,48). Most of these tumors have a well-differentiated glandular architecture; their behavior is similar to that of common endometrioid carcinomas, and the prognosis is good. It is important to recognize mucinous carcinoma of the endometrium as an entity and to differentiate it from endocervical adenocarcinoma. Features that favor a primary endometrial carcinoma are the merging of the tumor with areas of normal endometrial tissue, presence of foamy endometrial stromal cells, presence of squamous metaplasia, or presence of areas of typical endometrioid carcinoma. Positive perinuclear immunohistochemical staining with vimentin suggests an endometrial origin ( 49). Papillary Serous Carcinoma About 3% to 4% of endometrial carcinomas resemble serous carcinoma of the ovary and fallopian tube (50,51,52 and 53). Most often, these tumors are composed of fibrovascular stalks lined by highly atypical cells with tufted stratification ( Fig. 30.4). Psammoma bodies are frequently observed.

Figure 30.4 Papillary serous carcinoma of endometrium. Branching papillae are supported by delicate fibrovascular cores and lined with columnar cells with moderate nuclear atypism, multiple nucleoli, and mitotic figures. (Reproduced or modified from Berek JS, Hacker NF. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

Uterine papillary serous carcinomas (UPSCs) are all considered high-grade lesions. They are commonly admixed with other histologic patterns, but mixed tumors behave as aggressively as pure serous carcinomas. Serous carcinomas are often associated with lymph–vascular space and deep myometrial invasion. Even when

these tumors appear to be confined to the endometrium or endometrial polyps without myometrial or vascular invasion, they behave more aggressively than endometrioid carcinomas and have a propensity for intraabdominal spread, simulating the behavior of ovarian carcinoma. Of patients with clinical stage I disease, more than half are found to have deep myometrial invasion, three fourths manifest lymph–vascular space invasion (LVSI), and about half have extrauterine disease detected at surgery. The first description of UPSC, in 1982, noted that this entity usually occurred in elderly, hypoestrogenic women who presented with advanced-stage disease and accounted for up to half of deaths from endometrial carcinoma ( 50). Since then, several reports have documented the aggressive nature and poor prognosis of UPSC. Even when the disease was confined to an endometrioid polyp without other evidence of spread, recurrence developed in more than half of patients ( 51,52). More recently, in a report on 50 surgically staged patients with UPSC, extrauterine disease was found in 72% ( 53). Presence of lymph node metastases, positive peritoneal cytology, and intraperitoneal tumor did not correlate with increasing myometrial invasion ( 53). Clear Cell Carcinoma Clear cell carcinoma accounts for less than 5% of all endometrial carcinomas (45,54). Clear cell carcinoma usually has a mixed histologic pattern, including papillary, tubulocystic, glandular, and solid types. The cells have highly atypical nuclei and abundant clear or eosinophilic cytoplasm. Often, the cells have a hobnail configuration arranged in papillae with hyalinized stalks (Fig. 30.5). Clear cell carcinoma characteristically occurs in older women and is a very aggressive type of endometrial cancer; the prognosis is similar to or worse than that of papillary serous carcinoma. Overall survival rates of 33% to 64% have been reported. Myometrial invasion and LVSI are important prognostic indicators.

Figure 30.5 Clear cell adenocarcinoma of the endometrium. Back-to-back glands lined by polygonal to columnar cells with distinct cell membrane, abundant granular to clear cytoplasm, and variably sized nuclei (including binucleated and multinucleated forms) with prominent nucleoli (magnification × 400).

Squamous Carcinoma Squamous carcinoma of the endometrium is rare. Some tumors are pure, but most have a few glands. To establish primary origin within the endometrium, there must be no connection with or spread from cervical squamous epithelium. Squamous carcinoma often is associated with cervical stenosis, chronic inflammation, and pyometra at the time of diagnosis. This tumor has a poor prognosis, with an estimated 36% survival rate in patients with clinical stage I disease ( 55). Simultaneous Tumors of the Endometrium and Ovary Synchronous endometrial and ovarian cancers are the most frequent simultaneously occurring genital malignancies, with a reported incidence of 1.4% to 3.8% (56,57,58,59 and 60). Most commonly, both the ovarian and endometrial tumor are well-differentiated endometrioid adenocarcinomas of low stage, resulting in an excellent prognosis. Patients often are premenopausal and present with abnormal uterine bleeding. The ovarian cancer usually is discovered as an incidental finding and is diagnosed at an earlier stage because of the symptomatic endometrial tumor, leading to a more favorable outcome. As many as 29% of patients with endometrioid ovarian adenocarcinomas have associated endometrial cancer. If more poorly differentiated, nonendometrioid histologic subtypes are present or if the uterine and ovarian tumors are histologically dissimilar, the prognosis is less favorable. Immunohistochemical studies, flow cytometry, and assessment of molecular DNA patterns to detect loss of heterozygosity may be helpful in distinguishing between metastatic and independent tumors, but the differential diagnosis can usually be determined by conventional clinical and pathologic criteria.

Pretreatment Evaluation After establishing the diagnosis of endometrial carcinoma, the next step is to evaluate the patient thoroughly in order to determine the best and safest approach to management of the disease. A complete history and physical examination is of utmost importance. Patients with endometrial carcinoma are often elderly and obese and have a variety of medical problems, such as diabetes mellitus and hypertension, that affect surgical management. Any abnormal symptoms, such as bladder or intestinal complaints, should be evaluated. On physical examination, attention should be directed to enlarged or suspicious-feeling lymph nodes, abdominal masses, and possible areas of cancer spread within the pelvis. Evidence of distant metastasis or locally advanced disease in the pelvis, such as gross cervical involvement or parametrial spread, may alter the treatment approach. Stool should be tested for occult blood. A chest x-ray should be performed to exclude pulmonary metastasis and to evaluate the cardiorespiratory status of the patient. Other routine preoperative studies should include electrocardiography, complete blood and platelet counts, serum chemistries (including renal and liver function tests), blood type and screen, and urinalysis. Other preoperative or staging studies are neither required nor necessary for most patients with endometrial cancer. Studies such as cystoscopy, colonoscopy, intravenous pyelography, barium enema, and CT scanning of the abdomen and pelvis are not indicated unless dictated by patient symptoms, physical findings, or other laboratory tests (61). Ultrasonography and magnetic resonance imaging (MRI) can be used to assess myometrial invasion preoperatively with a fairly high degree of accuracy ( 62). This information may be of use in planning the surgical procedure with regard to whether lymph node sampling should be undertaken. Serum CA125, an antigenic determinant that is elevated in 80% of patients with advanced epithelial ovarian cancers, also is elevated in most patients with advanced or metastatic endometrial cancer (63). In one study, 23 of 81 patients with apparently localized disease preoperatively had elevated CA125 levels ( 64). At surgery, 20 (87%) of these 23 patients with an elevated CA125 were found to have extrauterine disease, whereas only 1 of 58 patients with a normal CA125 had disease spread outside the uterus ( 64). Preoperative measurement of serum CA125 may, therefore, help determine the extent of surgical staging and, if elevated, may be useful as a tumor marker in assessing response to subsequent therapy ( 65).

Clinical Staging Clinical staging, according to the 1971 FIGO system (Table 30.6), should be performed in patients who are deemed not to be surgical candidates, because of their poor medical condition or the spread of their disease (66). With improvements in preoperative and postoperative care, anesthesia administration, and surgical techniques, almost all patients are medically suitable for operative therapy. One study reported an operability rate of 87% in a series of 595 consecutive patients with clinical early-stage endometrial cancer ( 67). A small percentage of patients will not be candidates for surgical staging because of gross cervical involvement, parametrial spread, invasion of the bladder or rectum, or distant metastasis.

Table 30.6. FIGO Clinical Staging of Endometrial Carcinoma (1971)

Surgical Staging Most patients with endometrial cancer should undergo surgical staging based on the 1988 FIGO system (68,69 and 70) (Table 30.7). At a minimum, the surgical procedure should include sampling of peritoneal fluid for cytologic evaluation, exploration of the abdomen and pelvis with biopsy or excision of any extrauterine lesions suggestive of metastatic cancer, extrafascial hysterectomy, and bilateral salpingo-oophorectomy. The uterine specimen should be opened and tumor size (71), depth of myometrial involvement (72,73 and 74), and cervical extension assessed. Any suspicious pelvic and paraaortic lymph nodes should be removed for pathologic examination.

Table 30.7. FIGO Surgical Staging for Endometrial Carcinoma (1988)

Additionally, clinically negative retroperitoneal lymph nodes should be sampled in all patients with one or more of the risk factors noted in Table 30.8. Tumor histology and depth of myometrial invasion appear to be the two most important factors in determining the risk for lymph node metastasis (69,70). The overall incidence of lymph node metastasis in clinical stage I endometrial cancer is about 3% in grade 1, 9% in grade 2, and 18% in grade 3 tumors ( Table 30.9). Less than 5% of patients with no myometrial invasion or with superficial (50%) myometrial invasion ( Table 30.10). Pelvic lymph node metastases are present in less than 5% of grade 1 and 2 tumors with superficial myometrial invasion, in about 15% of grade 1 and 2 tumors with deep myometrial invasion or grade 3 tumors with superficial invasion, and in more than 40% of grade 3 tumors with deep myometrial invasion (Fig. 30.6). About one half to two thirds of patients with positive pelvic lymph nodes also have paraaortic lymph node metastases, but the aortic nodes are seldom involved in the absence of pelvic nodal disease. Cervical involvement is associated with about a 15% risk for pelvic or paraaortic node metastasis (70). The incidence of lymph node metastasis also correlates with tumor size (2 cm, 15%; entire cavity, 35%) ( 71). Extrauterine spread of disease increases the risk for pelvic and paraaortic nodal metastasis. Adnexal metastasis increases the risk for pelvic and paraaortic nodal metastasis to 32% and 20%, respectively. Of patients with positive peritoneal cytology, 25% have positive pelvic nodes, and 19% have positive paraaortic nodes ( 70).

Table 30.8. Indications for Selective Pelvic and Paraaortic Lymph Node Dissection in Endometrial Cancer

Table 30.9. Relationship of Grade to Lymph Node Mestastasis in Clinical Stage I Endometrial Carcinoma

Table 30.10. Relationship of Myometrial Invasion to Lymph Node Metastasis in Clinical Stage I Endometrial Carcinoma

Figure 30.6 The risk for pelvic lymph node metastasis with grade and depth of myometrial penetration in clinical stage I endometrial cancer. Adjuvant pelvic irradiation is recommended for the high-risk group but not for the low-risk group. (From DiSaia PJ, Creasman WT. Management of endometrial adenocarcinoma, stage I with surgical staging followed by tailored adjuvant radiation therapy. Clin Obstet Gynecol 1986;13:751, with permission.)

At a minimum, high common iliac and paraaortic lymph node dissections should be performed in the presence of adnexal or cervical involvement, a large tumor (>2 cm), deep (>50%) myometrial invasion, or a moderate to poorly differentiated endometrioid, papillary serous, or clear cell tumor. Pelvic lymph node biopsy may not be as important in patients with these risk factors because most of these patients are treated postoperatively with whole pelvis irradiation. Because fewer than 10% of patients with lymphatic metastasis have grossly enlarged nodes, palpation is not an acceptable alternative to biopsy. Conversely, because almost all patients with lymph node metastases have one or more of the aforementioned risk factors, lymph node biopsies are not required in patients at very low risk for lymphatic metastasis [i.e., patients with small (3–5 mm Invasion Lesions with invasion of 3 to 5 mm have a 3.8% incidence of pelvic node metastases (47,48 and 49); thus, pelvic node dissection is necessary for these lesions. The primary tumor may be treated with a modified radical hysterectomy (type II). Surgical Treatment of Stage Ib to IIa Stage Ib and IIa Invasive Cancer Stage Ib lesions are subdivided into stage Ib1, which denotes lesions that are 4 cm or smaller in maximum diameter, and stage Ib2, which denotes lesions that are larger than 4 cm. Stage IIa is direct extension to the proximal vagina. Surgical therapy of stage Ib and IIa carcinoma of the cervix involves radical hysterectomy, pelvic lymphadenectomy, and paraaortic lymph node evaluation. A comparison of radical hysterectomy with radiation has resulted in similar survival rates for the two treatment modalities. A randomized study comparing patients treated by either radical hysterectomy or radiation therapy showed similar survival rates for both groups ( 50). Similar outcomes also were reported when patients were treated with radiation therapy or radical surgery ( 51). However, patients treated with type III radical hysterectomy who subsequently received postoperative radiation had a higher rate of intestinal and urinary orbidity. Therefore, many advocate using radiation and avoiding surgery in these patients because many will require adjuvant postoperative radiation. The results from the GOG showing that patients with stage Ib (>4 cm) and IIa disease treated with concurrent chemoradiation had improved survival are presented below. Thus many would advocate that the treatment of choice in patients with stage Ib and IIa disease who have a primary lesion that is larger than 5 cm should be treated with chemoradiation. Prognostic Variables for Early-stage Cervical Cancer The survival of patients with early-stage cervical cancer after radical hysterectomy and pelvic lymphadenectomy depends on several factors (42,51,52,53,54,55,56,57,58,59,60,61,62,63,64 and 65): 1. 2. 3. 4. 5.

Status of the lymph nodes Size of the tumor Involvement of parametrial tissue Depth of invasion Presence or absence of lymph–vascular space invasion

Lymph Nodes The most dependent variable associated with survival is the status of the lymph nodes. Patients with negative nodes have an 85% to 90% 5-year survival rate (64,66), whereas the survival rate for those with positive nodes ranges from 20% to 74%, depending on the number of nodes involved and the location and size of the metastases (60,61 and 62,66,67,68 and 69). Data on lymph node status can be summarized as follows: 1. When the common iliac lymph nodes are positive, the 5-year survival rate is about 25%, compared with about 65% when only the pelvic lymph nodes are involved (70,71 and 72). 2. Bilateral positive pelvic lymph nodes portend a less favorable prognosis (22% to 40% survival rate) than unilateral positive pelvic nodes (59% to 70%) ( 70,71). 3. The presence of more than three positive pelvic lymph nodes is accompanied by a 68% recurrence rate, compared with 30% to 50% when three or fewer lymph nodes are positive ( 60,67). 4. Patients in whom tumor emboli are the only findings in the positive pelvic lymph node have an 82.5% 5-year survival rate, whereas the survival rate with microscopic invasion of the lymph nodes is 62.1% and with macroscopic disease is 54% ( 51). Lesion Size Lesion size is an independent predictor of survival. Patients with lesions smaller than 2 cm have a survival rate of about 90%, and patients with lesions larger than 2 cm have a 60% survival rate ( 54). When the primary tumor is larger than 4 cm, the survival rate drops to 40% ( 52,63). An analysis of a GOG prospective study of 645 patients showed a 94.6% 3-year disease-free survival rate for patients with occult lesions, 85.5% for those with tumors smaller than 3 cm, and 68.4% for patients with tumors larger than 3 cm (64). Depth of Invasion Patients in whom depth of invasion is less than 1 cm have a 5-year survival rate of about 90%, but the survival rate falls to 63% to 78% if the depth of invasion is more than 1 cm (42,64,68). Patients with spread to the parametrium have a 5-year survival rate of 69%, compared with 95% when the parametrium is negative. When the parametrium is involved and pelvic lymph nodes are also positive, the 5-year survival rate falls to 39% to 42% ( 55,65). Lymph–Vascular Space Involvement The significance of the finding of lymph–vascular space involvement is somewhat controversial. Several reports have shown a 50% to 70% 5-year survival rate when lymph–vascular space invasion is present and a 90% 5-year survival rate in its absence ( 42,54,58,72,73,74,75 and 76). Others have found no significant difference in survival if the study is controlled for other risk factors ( 63,64,77,78 and 79). Lymph–vascular space involvement may be a predictor of lymph node metastasis and not an independent predictor of survival. Postoperative Radiation In an effort to improve survival rates, postoperative radiotherapy has been recommended for patients with high-risk factors such as metastasis to pelvic lymph nodes (42,52,66,72), invasion of paracervical tissue ( 55,56), deep cervical invasion (80), or positive surgical margins ( 67,81). Although most authors agree that postoperative radiotherapy is necessary in the presence of positive surgical margins, the use of radiation in patients with other high-risk factors is controversial. Increasing evidence supports the use of adjuvant radiation, however. Particularly controversial but best studied is the use of radiation in the presence of positive pelvic lymph nodes. The rationale for treatment is the knowledge that radiotherapy can sterilize cancer in pelvic lymph nodes and that pelvic node dissection does not remove all of the nodal and lymphatic tissue. The hesitancy to recommend postoperative radiotherapy relates to the significant rate of postradiotherapy bowel and urinary tract complications (82). Most of the data currently available are retrospective. However, the GOG has recently completed a randomized study comparing radiation with no further treatment for patients at high risk for recurrence with negative pelvic nodes ( 83). Based on retrospective studies, it appears that postoperative radiation therapy for positive pelvic nodes can decrease pelvic recurrence but does not improve 5-year actuarial survival rates. One multiinstitutional study showed no difference in survival in patients with three or fewer positive pelvic nodes (59% versus 60%) ( 68). However, there seemed to be a benefit when radiotherapy was given to those with more than three positive nodes. In a study of 60 pairs of irradiated and nonirradiated women matched for age, lesion size, and number and location of positive nodes after radical hysterectomy ( 84), no significant difference was found in projected 5-year survival rates (72% for surgery alone, 64% for surgery plus radiation). The proportion of recurrences confined to the pelvis was 67% in patients treated with surgery only and 27% in patients treated with postoperative radiation ( p = 0.03). In a Cox regression analysis of 320 women who underwent radical hysterectomy, 72 of whom received postoperative radiation ( 61), there was a significant decrease in pelvic recurrence but no survival benefit. A multiinstitutional retrospective study was performed in 185 women with positive pelvic nodes after radical hysterectomy, 103 of whom received postoperative radiotherapy ( 63). Multivariate analysis disclosed that radiotherapy was not an independent predictor of survival, whereas age, lesion diameter, and number of positive nodes were found to influence survival. These authors concluded that additional treatment is needed to improve survival rates. Because survival is limited by distant site recurrence, the addition of chemotherapy to postoperative radiotherapy has been proposed. A 75% disease-free survival rate was reported at 3 years in 40 high-risk patients given cisplatin, vinblastine, and bleomycin after radical hysterectomy, and a 46% disease-free survival rate was found in 79 comparable patients who refused treatment (85). Only 4 (11.8%) of 34 patients with positive pelvic nodes had recurrences, whereas disease recurred in 8 (33%) of 24 untreated patients with positive nodes. An 82% rate of disease-free survival was reported at 2 years among 32 patients who were treated with postoperative radiation therapy plus cisplatin and bleomycin ( 86). The location of lymph node metastases is apparently relevant to postirradiation recurrence rates. When common iliac lymph nodes are involved, the survival rate drops to 20% (73). As the number of positive pelvic nodes increases, the percentage of positive common iliac and low paraaortic nodes increases ( 73) (i.e., 0.6% when pelvic lymph nodes are negative, 6.3% with one positive pelvic node, 21.4% with two or three positive nodes, and 73.3% with four or more positive nodes). This information has been used to recommend extended-field radiotherapy to patients with positive pelvic lymph nodes in an attempt to treat undetected extrapelvic nodal disease (73). A 3-year disease-free survival rate of 85% occurred in patients with positive pelvic nodes and a survival rate of 51% in patients with positive common

iliac nodes; these rates are better than the survival rates of 50% and 23%, respectively, for historical control groups receiving radiotherapy to the pelvis alone. A randomized controlled trial initiated by the GOG has recently reported results of a study on patients with cervical cancer treated by radical hysterectomy and found to have at least two of the following risk factors: capillary lymphatic space invasion, more than one third stromal invasion, and larger tumor ( 84). A total of 277 patients were entered into the study, with 140 randomized to no further therapy and 137 patients randomized to adjuvant pelvic radiotherapy. The results showed that patients with these risk factors who were treated with postoperative radiation therapy had a statistically significant (47%) decrease in recurrent disease. The study results have not had adequate follow-up to show a statistically significant decrease in mortality. The data, however, do demonstrate improved survival rates. The morbidity with the combination of therapy was acceptable, with a low rate of enteric and urinary complications. A second GOG study reporting on patients with high-risk cervical cancer randomized patients to concurrent chemoradiation therapy or radiation therapy alone ( 87). The results of this study are presented in the section discussing chemoradiation. Chemotherapy The use of chemotherapy in the treatment of cervical carcinoma has been limited in part by the success of treating this disease with surgery or radiation therapy. However, neoadjuvant chemotherapy has been used to shrink the tumor before radical hysterectomy or radiotherapy. No randomized study on the effectiveness of this technique has been reported. However, the information available from current studies suggests that, compared with historical controls, neoadjuvant therapy can achieve a 22% to 44% complete response rate, decrease the number of positive pelvic lymph nodes, and improve the 2- and 3-year disease-free survival rates, particularly in patients with stage I or II disease. In a study in which cisplatin, vinblastine, and bleomycin were used before radical hysterectomy in 54 patients with stage I or IIa tumors larger than 4 cm, a complete response rate of 44% and a partial response rate of 50% based on evaluation of the radical hysterectomy specimen were found (88). Tumors recurred in only three patients, giving a 94% disease-free survival with a minimum of 2 years follow-up. Of the 11 patients with positive nodes, 3 had recurrences, and all had three or more positive nodes. A comparison with historical controls for a tumor of this size revealed a 40% disease-free survival rate. In treating 75 patients with stage I, II, or III disease whose tumors were larger than 4 cm, cisplatin, bleomycin, and methotrexate were administered before surgery or radiation therapy ( 89). Three-year disease-free survival rates of 100%, 81%, and 66% were achieved for stages I, II, and III, respectively. Initial large tumor size and parametrial infiltration significantly correlated with a lower response to neoadjuvant therapy. Recurrence was significantly correlated with FIGO stage, parametrial infiltration, and residual cervical tumor. Of the 12 recurrences, 9 involved the pelvis, indicating that additional local treatment is needed for this high-risk group. In treating 151 patients who had stage IIb and III tumors, cisplatin, vinblastine, and bleomycin were administered before surgery plus radiation (62.5%) or radiation alone (37.7%) (90). These investigators reported a 2-year disease-free survival rate in stages II and III of 79% and 50%, respectively, compared with survival rates of 47% and 26% in historical controls treated with radiation alone. For the 25 patients (22%) who experienced a complete response to the chemotherapy, there was a 96% disease-free survival rate and a 0% incidence of lymph node metastasis. To determine the efficacy of neoadjuvant chemotherapy, randomized trials have been initiated by the GOG and other centers. Radiation Radiotherapy can be used to treat all stages of cervical squamous cell cancer, with cure rates of about 70% for stage I, 60% for stage II, 45% for stage III, and 18% for stage IV (2). A comparison of surgery and radiation for treatment of low-stage disease is shown in Table 31.5. The radiation treatment plan generally consists of a combination of external teletherapy to treat the regional nodes and to shrink the primary tumor and intracavitary brachytherapy to boost the central tumor. Intracavitary therapy alone may be used in patients with early disease when the incidence of lymph node metastasis is negligible.

Table 31.5. Comparison of Surgery versus Radiation for Stage Ib/IIa Cancer of the Cervix

The treatment sequence depends on tumor volume. Stage Ib lesions smaller then 2 cm may be treated first with an intracavitary source to treat the primary lesion, followed by external therapy to treat the pelvic nodes. Larger lesions require external radiotherapy first to shrink the tumor and to reduce the anatomic distortion caused by the cancer. This enables the therapist to achieve better intracavitary dosimetry. The usual doses delivered are 7,000 to 8,000 cGy to point A and 6,000 cGy to point B, limiting the bladder and rectal dosage to less than 6,000 cGy. To achieve this level, it is necessary to have adequate packing of the bladder and bowel away from the intracavitary sources. Localization films and careful calculation of dosimetry are mandatory to optimize the dose of radiation and to reduce the incidence of bowel and bladder complications. Local control depends on adequate dose to the tumor from the intracavitary source. Clinical staging fails to predict the extension of disease to the paraaortic nodes in 7% of patients with stage Ib, 18% with stage IIb, and 28% with stage III disease (91). Such patients will have “geographic” treatment failures if standard pelvic radiotherapy ports are used. Thus, treatment plans for these patients are individualized based on CT scans and biopsy of the paraaortic lymph nodes for consideration of extended-field radiotherapy. The routine use of extended-field radiation without documentation of distant metastasis to the paraaortic nodes has been evaluated and is typically not practiced because of the increased enteric morbidity associated with this radiation. Surgical “Staging” before Radiation Surgical staging procedures designed to discover the presence of positive nodes have been devised. Transperitoneal exploration was first used, but it was associated with a 16% to 33% mortality rate from radiotherapy-induced bowel complications and a 5-year survival rate of only 9% to 12% ( 92,93). The radiotherapy dose to the paraaortic chain was 5,500 to 6,000 cGy, which is now known to be excessive. Postsurgical adhesions entrap the intestine in the radiotherapy field; therefore, the bowel receives the full dose of radiation. In the absence of postsurgical adhesions, the small bowel would move in and out of the radiotherapy field and receive a lesser dose. To avoid these postsurgical adhesions, extraperitoneal dissection of the paraaortic nodes is now recommended, and the radiation dose should be reduced to 5,000 cGy or less ( 94,95). When such an approach is used, postradiotherapy bowel complications occur in fewer than 5% of patients ( 96,97), and the 5-year survival rate is 15% to 26% in patients with positive paraaortic nodes ( 16,97). Survival appears to be related to the amount of disease in the paraaortic nodes and to the size of the primary tumor. In patients whose metastases to the paraaortic lymph nodes are microscopic and whose central tumor has not extended to the pelvic sidewall, the 5-year survival rate improves to 20% to 50% ( 98,99). Surgical staging techniques have improved to include laparascopic assessment of the paraaortic and pelvic lymph nodes. Studies have demonstrated benefit from surgical staging with improved survival and changes in treatment plans of 40% of patients (95,96). Supraclavicular Lymph Node Biopsy Although not standard practice, the performance of a supraclavicular lymph node biopsy has been advocated in patients with positive paraaortic lymph nodes before the initiation of extended-field irradiation as well as in patients with a central recurrence before exploration for possible exenteration. The incidence of metastatic disease in the supraclavicular lymph nodes in patients with positive paraaortic lymph nodes is 5% to 30% ( 100). FNA cytologic assessment can obviate the need for an excisional biopsy and thus should be performed if any enlarged nodes are present. If the scalene lymph nodes are found to be positive, the disease is incurable,

and treatment is palliative. Complications during Brachytherapy Perforation of the uterus may occur at the time of insertion of the uterine tandem. This is a problem particularly for elderly patients and those who have had a previous diagnostic conization procedure. When perforation is recognized, the tandem should be removed, and the patient should be observed for bleeding or signs of peritonitis. Survival may be decreased in patients who have had uterine perforation ( 101), possibly because these patients have more extensive uterine disease, which predisposes them to perforation. Fever may occur after insertion of the uterine tandem and ovoids. Fever most often results from infection of the necrotic tumor and occurs 2 to 6 hours after insertion of the intracavitary system. If uterine perforation has been excluded by ultrasonography, intravenous broad-spectrum antibiotic coverage, usually with a cephalosporin, should be administered. If the fever does not decrease promptly or if the temperature is higher than 38.5°C, an aminoglycoside and a Bacteroides species–specific antibiotic should administered. If fever persists or if the patient shows signs of septic shock or peritonitis, the intracavitary system must be removed. Antibiotics are continued until the patient has recovered, and the intracavitary application is delayed for 1 to 2 weeks. Acute Morbidity The acute effects of radiotherapy occur after 2,000 to 3,000 cGy and are caused by ionizing radiation on the epithelium of the intestine and bladder. Symptoms include diarrhea, abdominal cramps, nausea, frequent urination, and occasionally bleeding from the bladder or bowel mucosa. The bowel symptoms can be treated with a low-gluten, low-lactose, and low-protein diet. Antidiarrheal and antispasmodic agents also may help. The bladder symptoms may be treated with antispasmodic medication. Severe symptoms may require a week of rest from radiotherapy. Chronic Morbidity The chronic effects of radiotherapy result from the induction of vasculitis and fibrosis, and they are more serious than the acute effects. These complications occur several months to several years after radiotherapy has been completed. The bowel and bladder fistula rate after pelvic radiation therapy for cervical cancer is 1.4% to 5.3% (35,37). Other serious toxicity (e.g., bowel bleeding, stricture, stenosis, or obstruction) occurs in 6.4% to 8.1% of patients ( 35,37). Proctosigmoiditis Bleeding from proctosigmoiditis should be treated with a low-residue diet, antidiarrheal medications, and steroid enemas. In extreme cases, a colostomy may be required to rest the bowel completely, and occasionally resection of the rectosigmoid must be performed. Rectovaginal Fistula Rectovaginal fistulas or rectal strictures occur in fewer than 2% of patients. The successful closure of fistulas with bulbocavernosus flaps has been reported (102), as has a technique of sigmoid colon transposition to repair rectosigmoid fistulas or rectal strictures ( 103). Occasionally, resection with anastomosis is feasible. Diversion resulting in colostomy may be the optimal therapy in patients who have poor vascular supply to the pelvis and a history of anastomotic leak or breakdown from prior repairs. Small Bowel Complications Patients with previous abdominal surgery are more likely to have pelvic adhesions and thus sustain more radiotherapy complications in the small bowel. The terminal ileum may sustain chronic damage because of its relatively fixed position at the cecum. The patient typically has a long history of crampy abdominal pain, intestinal rushes, and distention characteristic of partial small bowel obstruction. Often, low-grade fever and anemia accompany the symptoms. Patients who have no evidence of disease should be treated aggressively with total parenteral nutrition, nasogastric suction, and early operation after the anemia has resolved and good nutritional status has been attained. The type of procedure performed depends on individual circumstances ( 104). Small bowel fistulas that occur after radiotherapy rarely close spontaneously while total parenteral nutrition is maintained. Recurrent cancer should be excluded; then aggressive fluid replacement, nasogastric suction, and wound care should be instituted. Fistulography and a barium enema should be performed to exclude a combined large and small bowel fistula. The fistula-containing loop of bowel may be either resected or isolated and left in situ. In the latter case, the fistula will act as its own mucous fistula. Urinary Tract Chronic urinary tract complications occur in 1% to 5% of patients and depend on the dose of radiation to the base of the bladder. Vesicovaginal fistulas are the most common complication and usually require supravesicular urinary diversion. Occasionally, a small fistula can be repaired with either a bulbocavernosus flap or an omental pedicle. Ureteral strictures are usually a sign of recurrent cancer, and an FNA cytologic sample should be obtained at the site of the obstruction under CT scan control. If the findings are negative, the patient should undergo exploratory surgery to determine the status of the disease. If radiation fibrosis is the cause, ureterolysis may be possible, or indwelling ureteral stents may be passed through the open urinary bladder. Treatment of Stage IIb to IVb Traditional therapy for patients with stage IIb or greater cervical cancer was radiation therapy. In certain clinical situations, such as with patients who have stage IVa disease and present with vesicovaginal or rectovaginal fistula, urinary or rectal diversion should be performed, followed by radiation therapy. Patients with stage IVb cervical carcinoma are considered candidates for palliative radiation therapy because cure is not attainable for these patients. Control of symptoms with the least morbidity is of concern in this patient population. Primary pelvic radiotherapy fails to control the disease in 30% to 82% of patients with cervical carcinoma ( 2). About two thirds of these failures occur in the pelvis (105). A variety of agents have been used in an attempt to increase the effectiveness of radiation therapy in patients with large primary tumors. Hydroxyurea has produced some improvement in response rate and survival rates when compared with radiation therapy alone in a controlled series of patients ( 106,107). The use 5-fluorouracil (5-FU) and mitomycin C has also been reported to improve response rates for advanced cervical cancer ( 108). Cisplatin has been shown to have cytotoxic activity against cervical carcinoma ( 109) and recently has been demonstrated to be a radiation sensitizer ( 110). It has produced some improvement in response and survival rates when used with radiation therapy for cervical cancer as compared with radiation therapy alone ( 110,111). The results of GOG studies presented later in this chapter demonstrate that combination chemoradiation is superior to radiation therapy. Concurrent Chemoradiation Radiation therapy has failed to achieve control of cancer in 20% to 65% of patients with advanced cervical cancer. Chemotherapy, despite its lack of success in treating patients with cervical cancer, has been studied as neoadjuvant treatment in combination with surgery. Concomitant chemotherapy with radiation has been studied extensively by GOG, and results of five randomized studies have been reported. The concept of chemoradiation encompasses the benefits of regional therapy with radiation and the use of chemotherapy to sensitize cells to radiation therapy, thus improving locoregional control. These new results have changed the way cervical cancer is treated in many medical centers. An intergroup trial involving the GOG, the Southwestern Oncology Group, and the Radiation Therapy Oncology Group evaluated postoperative chemoradiation therapy in patients with stage Ia2, Ib, or IIa cervical cancer who were found to have positive pelvic lymph nodes, positive parametrial extension, or positive vaginal margins at the completion of radical hysterectomy ( 86). A total of 243 patients were assessed in this trial, with 127 receiving chemoradiation ( cisplatin, 5-FU, radiation therapy) and 116 receiving radiation. The results of this trial showed a statistically significant improvement in progression-free survival and overall survival at 43 months for the patients receiving concurrent chemoradiation. The 4-year survival rates for the patients receiving chemoradiation and radiation alone were 81% and 71%, respectively. The toxicity in the two groups was acceptable, with a higher rate of hematologic toxicity in the concurrent chemoradiation arm. This study showed that in patients with these high-risk factors after radical hysterectomy for stage Ia2, Ib, and IIa disease, chemoradiation is the postoperative treatment of choice. Concurrent chemoradiation was evaluated in patients with advanced cervical carcinoma. The GOG protocol 85 was a prospective study that enrolled patients with stage IIb to IVa cervical cancer and compared concurrent chemoradiation ( 112). There were 177 patients treated with cisplatin, 5-FU, and radiation. These patients were compared with the 191 patients treated with hydroxyurea and radiation. The median follow-up of patients who were alive at the time of the analysis was 8.7 years. Patients who received concurrent chemoradiation and were treated with cisplatin and 5-FU had a statistically significant improvement in progression-free interval and overall survival ( 112). The hematologic toxicity between the two groups was similar. This study showed that cisplatin-based concurrent chemoradiation was a superior treatment when compared with hydroxyurea and concurrent radiation. The GOG protocol 120 was initiated to evaluate patients with negative paraaortic nodes and cervical carcinoma stage IIb to IVa and concurrent chemoradiation. The treatment arms in this study consisted of radiation plus weekly cisplatin; or cisplatin, 5-FU, and hydroxyurea; or hydroxyurea. There were 176 patients in the weekly cisplatin arm; 173 patients in the cisplatin, 5-FU, and hydroxyurea arm; and 177 patients in the hydroxyurea arm (113). The two treatment arms with cisplatin-based chemotherapy and radiation showed an improvement in progression-free interval and overall survival at a median follow-up of 35 months. The relative risks for progression of disease or death were 0.55 and 0.57, respectively, for patients treated with cisplatin-based chemotherapy and radiation, compared with the patients treated with hydroxyurea and radiation (114). This study confirmed the findings of GOG 85 and again suggested that cisplatin-based concurrent

chemoradiation is the treatment of choice for patients with advanced-stage cervical cancer. A third GOG trial evaluated patients with stage Ib to IVa cervical cancer. Of the patients enrolled in this study, 70% had stage Ib or IIa disease ( 115). A total of 403 patients were enrolled and evaluated. The 5-year survival rates were 73% in patients treated with chemoradiation and 58% in patients treated with radiation therapy alone. The cumulative rates of disease-free survival at 5 years were 67% in patients treated with concurrent chemoradiation and 40% in patients treated with radiation therapy alone. Survival and progression-free intervals for patients receiving concurrent chemoradiation were significantly improved ( 115). The results of this study suggested that chemoradiation is the treatment for stage IIb to IVa disease and that those patients with stage Ib2 and IIa disease also may benefit from chemoradiation. The role of extended-field radiation was evaluated in this trial, but its role in therapy for patients with no evidence of paraaortic metastasis still needs to be defined. A GOG study of chemoradiation comparing concurrent cisplatin and radiation with radiation alone in patients with bulky Ib cervical cancer also included adjuvant hysterectomy after completion of the radiation (115). There were 183 patients assigned to the concurrent chemotherapy and radiation arm, and 186 patients treated with radiation alone. The median duration of follow-up was 36 months, with disease recurrence detected in 37% of the patients treated with radiation alone, compared with 21% who were treated with concurrent chemoradiation (114). The 3-year survival rates were 83% in the group who received concurrent chemoradiation and 74% in the group that received radiation alone ( 114). The study also included adjuvant hysterectomy after completion of radiation treatment. However, with the results of GOG 71 not showing an improvement in survival by using adjuvant hysterectomy, the authors concluded that adjuvant hysterectomy would not be part of their recommendations. This study supported the results of previous studies and showed that patients with bulky stage Ib and IIa cervical cancer had survival rates superior to those in patients treated with concurrent chemoradiation. These two studies suggest that patients with bulky stage Ib and IIa disease should have primary treatment consisting of chemoradiation, with the chemotherapy agent being weekly cisplatin. Patient Evaluation and Follow-up after Therapy Patients who receive radiotherapy should be closely monitored to assess their response. Tumors may be expected to regress for up to 3 months after radiotherapy. During the pelvic examination, progressive shrinkage of the cervix and possible stenosis of the cervical os and surrounding upper vagina should be noted. During rectovaginal examination, careful palpation of the uterosacral and cardinal ligaments for nodularity is most important. FNA cytologic assessment of suspicious areas should be performed to allow early diagnosis of persistent disease. In addition to the pelvic organs, the supraclavicular and inguinal lymph nodes should be carefully examined, and cervical or vaginal cytologic assessment should be performed every 3 months for 2 years and then every 6 months for the next 3 years. Endocervical curettage may be performed in patients with large central tumors. An x-ray film of the chest may be obtained yearly in patients who have advanced disease. Metastasis to the lung has been reported in 1.5% of cases; solitary nodules are present in 25% of cases. Resection of a solitary nodule in the absence of any other persistent disease may yield some long-term survivors ( 116). Although intravenous pyelography (IVP) is not a part of routine postradiotherapy surveillance, it should be performed if a pelvic mass is detected or if urinary symptoms warrant it. The finding of ureteral obstruction after radiotherapy in the absence of a palpable mass may indicate unresectable pelvic sidewall disease, but this finding should be confirmed, usually by FNA cytologic assessment ( 117). Patients who have had radical hysterectomy and who are at high risk for recurrence may benefit from early recognition of recurrence because they might be saved with radiation therapy. In these patients, a routine IVP 6 to 12 months after surgery may be beneficial. After radical hysterectomy, about 80% of recurrences are detected within 2 years (118). The larger the primary lesion, the shorter the median time to recurrence ( 119).

Special Considerations The incidence of adenocarcinoma of the cervix appears to be increasing relative to that of squamous cancers. Older reports indicated that 5% of all cervical cancers were adenocarcinomas (120), whereas newer reports show a proportion as high as 18.5% to 27% ( 121,122). The FIGO annual report indicates a poorer prognosis for adenocarcinoma than for squamous cell carcinoma in every stage. A Cox proportional hazard analysis of 203 women with adenocarcinoma and 756 women with squamous carcinoma supports these findings (122). This study showed 5-year survival rates of 90% versus 60%, 62% versus 47%, and 36% versus 8% for stages I, II, and III, respectively. Although some have attributed these rates to a relative resistance to radiation, they are more likely a reflection of the tendency of adenocarcinomas to grow endophytically and to be undetected until a large volume of tumor is present. The clinical features of stage I adenocarcinomas have been well studied ( 121,123,124 and 125). These studies have identified size of tumor, depth of invasion, grade of tumor, and age of the patient as significant correlates of lymph node metastasis and survival. When matched with squamous carcinomas for lesion size, age, and depth of invasion, the incidence of lymph node metastases and the survival rate appear to be the same ( 123,124). Patients with stage I adenocarcinomas can be selected for treatment according to the same criteria as for those with squamous cancers ( 124). The choice of treatment for bulky stage I and II tumors is controversial. Radiation alone has been advocated by some ( 126), but others support radiation plus extrafascial hysterectomy (127,128). In 1975, Rutledge and associates (127) reported an 85.2% 5-year survival rate for all patients with stage I disease treated with radiation alone and an 83.8% survival rate for those who had radiation plus surgery. The central persistent disease rate was 8.3%, compared with 4% for those who had radiation plus surgery. In stage II disease, the 5-year survival rate was 41.9% for radiation alone and 53.7% for radiation plus surgery. A subsequent report revealed no significant difference in survival among patients treated with radiation alone or radiation plus extrafascial hysterectomy ( 129). Patients with adenosquamous carcinoma of the cervix have been reported to have a poorer prognosis than those with pure adenocarcinoma or squamous carcinoma (130). Whether this is true when corrected for size of lesion is controversial ( 123,124). The association of adenocarcinoma with squamous intraepithelial neoplasia is well documented ( 131). A squamous intraepithelial lesion may be observed colposcopically and treated with outpatient therapy, and the coexistent adenocarcinoma in the canal may be overlooked. Performing endocervical curettage at colposcopy will help prevent such an occurrence. Cervical Cancer during Pregnancy A review of the literature concluded that the incidence of invasive cervical cancer associated with pregnancy was one in 2,200 ( 132). A Pap test should be performed on all pregnant patients at the initial prenatal visit, and any grossly suspicious lesions should be excised for biopsy. Diagnosis is often delayed during pregnancy because bleeding is attributed to pregnancy-related complications. If the results of the Pap tests are positive for malignant cells and invasive cancer cannot be diagnosed using colposcopy and biopsy, a diagnostic conization procedure may be necessary. Because conization subjects the mother and fetus to complications, it should be performed only in the second trimester and only in patients with colposcopy findings consistent with cancer and biopsy-proven microinvasive cervical cancer or strong cytologic evidence of invasive cancer. Inadequate colposcopic examination may be encountered during pregnancy in patients who have had prior ablative therapy. Close follow-up throughout pregnancy may allow the cervix to evert and develop an ectropion, allowing satisfactory colposcopy in the second or third trimester. Conization in the first trimester of pregnancy is associated with an abortion rate of up to 33% ( 132,133). Patients with an obvious cervical carcinoma may undergo cervical biopsy and clinical staging similar to that of nonpregnant patients. After conization, there appears to be no harm in delaying definitive treatment until fetal maturity is achieved in patients with stage Ia cervical cancer ( 132,134,135). Patients with less than 3 mm of invasion and no lymphatic or vascular space involvement may be followed to term and delivered vaginally. A vaginal hysterectomy may be performed 6 weeks postpartum if further childbearing is not desired. Patients with 3 to 5 mm of invasion and those with lymph–vascular space invasion may also be followed to term ( 132,135). They may be delivered by cesarean birth, followed immediately by modified radical hysterectomy and pelvic lymph node dissection. Patients with more than 5 mm invasion should be treated as having frankly invasive carcinoma of the cervix. Treatment depends on the stage of gestation and the wishes of the patient. Modern neonatal care affords a 75% survival rate for infants delivered at 28 weeks of gestation and 90% for those delivered at 32 weeks of gestation. Fetal pulmonary maturity can be determined by amniocentesis, and prompt treatment can be instituted when pulmonary maturity is documented. Although timing is controversial, it is probably unwise to delay therapy for longer than 4 weeks (134,135). The recommended treatment is classic cesarean delivery followed by radical hysterectomy with pelvic lymph node dissection. There should be a thorough discussion of the risks and options with both parents before any treatment is undertaken.

Patients with cervical cancer in stages II to IV should be treated with radiotherapy. If the fetus is viable, it is delivered by classic cesarean birth, and therapy is begun postoperatively. If the pregnancy is in the first trimester, external radiation therapy can be started with the expectation that spontaneous abortion will occur before the delivery of 4,000 cGy. In the second trimester, a delay of therapy may be entertained to improve the chances of fetal survival. If the patient wishes to delay therapy, it is important to ensure fetal pulmonary maturity before delivery is undertaken. The clinical stage is the most important prognostic factor for cervical cancer during pregnancy. Overall survival is slightly better for patients with cervical cancer in pregnancy because an increased proportion of these patients have stage I disease. For patients with advanced disease, there is evidence that pregnancy impairs the prognosis (132,135). The diagnosis of cancer in the postpartum period is associated with a more advanced clinical stage and a corresponding decrease in survival. Cancer of the Cervical Stump Cancer of the cervical stump is less common today than it was several decades ago when supracervical hysterectomy was popular. Early-stage disease is treated surgically, with very little change in technique from that used when the uterus is intact ( 136). Advanced-stage disease may present a therapeutic problem for the radiotherapist if the length of the cervical canal is less than 2 cm. This length is necessary to allow satisfactory placement of the uterine tandem. If the uterine tandem cannot be placed, radiation therapy can be completed with vaginal ovoids or with an external treatment plan in which lateral ports are used to augment the standard anterior and posterior ports. Such a technique will reduce the dosage to the bowel and bladder and thus reduce the incidence of complications. Pelvic Mass The origin of a pelvic mass must be clarified before treatment is initiated. An IVP can exclude a pelvic kidney, and a barium enema helps to identify diverticular disease or carcinoma of the colon. An abdominal x-ray film may show calcifications typically associated with benign ovarian teratomas or uterine leiomyomas. Pelvic ultrasonography differentiates between solid and cystic masses and indicates uterine or adnexal origin. Solid masses of uterine origin are most often leiomyomas and generally do not need further investigation. Pyometra and Hematometra An enlarged fluid-filled uterine cavity may be a pyometra or a hematometra. The hematometra can be drained by dilation of the cervical canal and will not interfere with treatment. The pyometra also should be drained, and the patient should be given antibiotics to cover Bacteroides species, anaerobic Staphylococcus and Streptococcus species, and aerobic coliform bacterial infection. Placement of a large mushroom catheter through the cervix has been advocated, but the catheter itself may become obstructed, leading to further occlusion of the drainage. Repeated dilation of the cervix with aspiration of pus every 2 to 3 days is more effective. If the disease is stage I, a radical hysterectomy and pelvic node dissection may be performed. However, a pyometra is usually found in patients with advanced disease, and thus radiotherapy is required. External-beam therapy can begin when the pyometra has healed. Patients often have a significant amount of pus in the uterus or a tuboovarian abscess without signs of infection; therefore, a normal temperature and a normal white blood cell count do not necessarily exclude infection. Repeat physical examination or pelvic ultrasonography is necessary to ensure adequate drainage. Cervical Carcinoma after Extrafascial Hysterectomy When invasive cervical cancer is found after simple hysterectomy, it may be treated with radiotherapy or reoperation involving a pelvic node dissection and radical excision of parametrial tissue, cardinal ligaments, and the vaginal stump ( 137). Reoperation Reoperation is indicated particularly for a young patient who has a small lesion and in whom preservation of ovarian function is desirable. It is not indicated for patients who have positive margins or obvious residual disease ( 137). Survival rates after radical reoperation are similar to those after radical hysterectomy for stage I disease. Radiation Therapy Survival after radiotherapy depends on the volume of disease, the status of the surgical margins, and the length of delay from surgery to radiotherapy. Patients with microscopic disease have a 95% to 100% 5-year survival rate; the 5-year survival rate is 82% to 84% in those with macroscopic disease and free margins, 38% to 87% in those with microscopically positive margins, and 20% to 47% in those with obvious residual cancer ( 138,139 and 140). A delay in treatment of more than 6 months is associated with a 20% survival rate ( 140). Stage IVa Although primary exenteration may be considered for patients with direct extension to the rectum or bladder, it is rarely performed. For patients with extension to the bladder, the survival rate with radiation therapy is as high as 30%, with a urinary fistula rate of only 3.8% ( 141). The presence of tumor in the bladder may prohibit cure with radiation therapy alone; thus, consideration must be given to removal of the bladder on completion of external-beam radiation treatment. This is particularly true if the disease persists at that time and the geometry is not conducive to implant therapy. Rectal extension is less commonly observed but may require diversion of the fecal stream before therapy to avoid septic episodes from fecal contamination. Acute Hemorrhage Occasionally, a large lesion can produce life-threatening hemorrhage. A biopsy of the lesion should be performed to verify neoplasia, and a vaginal pack soaked in Monsel's solution (ferric subsulfate) should be packed tightly against the cervix. After proper staging, external radiation therapy can be started with the expectation that control of bleeding may require 8 to 10 daily treatments at 180 to 200 cGy/d. Broad-spectrum antibiotics should be used to reduce the incidence of infection. If the patient becomes febrile, the pack should be removed. Rapid replacement of the pack may be necessary, and a fresh pack should be immediately available. This approach to management of hemorrhage in patients previously untreated is preferable to exploration and vascular ligation. Occasionally, vascular embolization under fluoroscopic control may be required in severe cases, and this procedure may obviate a laparotomy. However, vascular occlusion ultimately may lead to decreased blood flow and oxygenation of the tumor; because the effect of radiotherapy is dependent on tissue oxygen content, the efficacy of the radiotherapy may be compromised. Ureteral Obstruction Treatment of bilateral ureteral obstruction and uremia in previously untreated patients should be determined on an individual basis. Transvesical or percutaneous ureteral catheters should be placed in patients with no evidence of distant disease, and radiotherapy with curative intent should be instituted. Patients with metastatic disease beyond curative treatment fields should be presented with the options of ureteral stenting, palliative radiotherapy, and chemotherapy for the metastatic disease. A median survival rate of 17 months for these patients may be achieved with aggressive management ( 142). Barrel-shaped Cervix The expansion of the upper endocervix and lower uterine segment by tumor has been referred to as a barrel-shaped cervix. Patients with tumors larger than 6 cm in diameter have a 17.5% central failure rate when treated with radiotherapy alone because the tumor at the periphery of the lower uterine segment is too far from the standard intracavitary source to receive an adequate tumoricidal dose ( 143). Attempts have been made to overcome this problem radiotherapeutically by means of interstitial implants into the tumor with a perineal template, but high central failure rates have also been reported with this technique ( 144). Most oncologists prefer a combination of radiotherapy and surgery for treatment of patients with a barrel-shaped cervix. The usual approach is to perform an extrafascial hysterectomy 6 weeks after the completion of radiation therapy in an effort to resect a small, centrally persistent tumor. The dose of external radiotherapy is reduced to 4,000 cGy, and a single intracavitary treatment is given, which is followed by an extrafascial hysterectomy ( 145,146). This approach appears to result in a lower rate of central failure (2%), although it is not clear that the overall survival rate is improved. There is disagreement concerning the need for extrafascial

hysterectomy, and the GOG is undertaking a randomized study to compare adjuvant hysterectomy with radiotherapy alone in patients who have no evidence of occult metastases in the paraaortic nodes. The narrow upper vagina of older patients may preclude the use of an intracavitary source of radiation. Such patients must receive their entire course of therapy from external sources, leading to a higher central failure rate and more significant bowel and bladder morbidity. If stage I disease is present in such a patient, a radical hysterectomy with pelvic node dissection is preferable if the patient's medical condition allows such an approach. Small Cell Carcinoma Local therapy alone gives almost no chance of cure of small cell carcinoma. Regimens of combination chemotherapy have improved the median survival rates in small cell bronchogenic carcinoma, and these regimens are now being used for treatment of small cell (neuroendocrine type) carcinoma of the cervix. Combination chemotherapy may consist of either vincristine, doxorubicin, and cyclophosphamide) (VAC) or VP-16 (etoposide) and cisplatin (EP) (147). Patients must be monitored carefully because they are at high risk for developing recurrent metastatic disease ( 148).

Recurrent Cervical Cancer Treatment of recurrent cervical cancer depends on the mode of primary therapy and the site of recurrence. Patients who have been treated initially with surgery should be considered for radiation therapy, and those who have had radiation therapy should be considered for surgical treatment. Chemotherapy is palliative only and is reserved for patients who are not considered curable by the other two modalities. Radiotherapy for recurrence after surgery consists primarily of external treatment. Vaginal ovoids also may be placed in patients with isolated vaginal cuff recurrences. Patients with a regional recurrence may require interstitial implantation with a Syed type of template in addition to external therapy. A 25% survival rate can be expected in patients treated with radiation for a postsurgical recurrence ( 118). Radiation Retreatment Retreatment of recurrent pelvic disease by means of radiotherapy with curative intent is confined to patients who had suboptimal or incomplete primary therapy. This may allow the radiotherapist to deliver curative doses to the tumor. The proximity of the bladder and rectum to the cancer and their relative sensitivity to radiation injury are the major deterrents to retreatment with radiation. The insertion of multiple interstitial radiation sources into the locally recurrent cancer through a perineal template may help overcome these dosimetric considerations ( 137,149). However, the fistula rates are high, and the consequences must be considered seriously before interstitial therapy is initiated. In general, for patients considered curable with interstitial implant therapy, pelvic exenteration is a better treatment choice. Radiotherapy can be palliative with localized metastatic lesions. Painful bony metastases, central nervous system lesions, and severe urologic or vena caval obstructions are specific indications. Surgical Therapy Surgical therapy for postirradiation recurrence is limited to patients with central pelvic disease. A few carefully selected patients with small-volume disease limited to the cervix may be treated with an extrafascial or radical hysterectomy. However, the difficulty of assessing tumor volume and the 30% to 50% rate of serious urinary complications in these previously irradiated patients have led most gynecologic oncologists to recommend pelvic exenteration as the patient's last chance for cure (150,151). Exenteration The operation can be an anterior exenteration (removal of the bladder, vagina, cervix, and uterus), a posterior exenteration (removal of the rectum, vagina, cervix, and uterus), or a total exenteration (removal of both bladder and rectum with the vagina, cervix, and uterus). A total exenteration that includes a large perineal phase includes the entire rectum and leaves the patient with a permanent colostomy as well as a urinary conduit. In selected patients, a total exenteration may take place above the levator muscle (supralevator), leaving a rectal stump that may be anastomosed to the sigmoid, thus avoiding a permanent colostomy. Preoperative Evaluation and Patient Selection The search for metastatic disease is imperative. Physical examination includes careful palpation of the peripheral lymph nodes with FNA cytologic sampling of any nodes that appear suspicious. A random biopsy of nonsuspicious supraclavicular lymph nodes has been advocated but is not routinely practiced ( 100,152). A CT scan of the lung can detect disease missed on routine x-ray examination of the chest. Abdominal and pelvic CT scans are helpful in the detection of liver metastases and enlarged paraaortic nodes. CT-directed FNA cytologic study of any abnormality should be undertaken. If a positive cytologic diagnosis is obtained, it will obviate the need for exploratory laparotomy. Extension of the tumor to the pelvic sidewall is a contraindication to exenteration; however, this may be difficult for even the most experienced examiner to determine because of radiation fibrosis. If any question of resectability arises, exploratory laparotomy and parametrial biopsies, the patient's last hope for cure, should be offered (153,154,155 and 156). The clinical triad of unilateral leg edema, sciatic pain, and ureteral obstruction is nearly always pathognomonic of unresectable disease on the pelvic sidewall. Preoperatively, the patient should be prepared for a major operation. Total parenteral nutrition may be necessary to place the patient in an anabolic state for optimal healing. A bowel preparation, preoperative antibiotics, and prophylaxis for deep venous thrombosis with low-dose heparin or pneumatic calf compression should be used ( 157). Surgical mortality increases with age, and the operation should rarely be considered in a patient who is older than 70 years of age. Other medical illnesses should be taken into account; when life expectancy is limited, exenterative surgery is unwise. Anterior Exenteration Candidates for anterior exenteration are those in whom the disease is limited to the cervix and anterior portion of the upper vagina. Proctoscopic examination should be performed because a positive finding would mandate a total exenteration. However, a negative proctoscopic examination finding does not exclude disease in the rectal muscularis, and findings at laparotomy still must be considered. Generally, the presence of disease in the posterior vaginal mucosa directly over the rectum mandates removal of the underlying rectum. Posterior Exenteration A posterior exenteration is rarely performed for recurrent cervical cancer. It is indicated, however, for the patient with an isolated posterior vaginal recurrence in which dissection of the ureters through the cardinal ligaments will not be necessary. Total Exenteration Total exenteration with a large perineal phase is indicated when the disease extends down to the lower part of the vagina. Because distal vaginal lymphatics may empty into the inguinal node region, these nodes should be carefully evaluated preoperatively. A supralevator total exenteration with low rectal anastomosis is indicated in the patient whose disease is confined to the upper vagina and cervix ( 158,159). Frozen-section margins of the rectal edge should be obtained because occult metastases to the muscularis may occur. The development of techniques to establish continent urinary diversion has helped improve a woman's physical appearance after exenteration ( 160,161 and 162). When both a rectal anastomosis and a continent diversion are performed, the patient has no permanent external appliance, and the associated psychological trauma is avoided. Every effort should be made to create a neovagina simultaneously with the exenteration ( 163). This procedure also helps in the reconstruction of the pelvic floor after extirpation of the pelvic viscera. Whether or not a neovagina is constructed, it is desirable to mobilize the omentum on the left gastroepiploic artery and use it to create a new pelvic floor. Surgical mortality has steadily decreased to an acceptable level of less than 10%. The most common causes of postoperative death are sepsis, pulmonary thromboembolism, and hemorrhage. Fistulas of the gastrointestinal and genitourinary tract are serious surgical complications, with a 30% to 40% mortality rate despite attempts at surgical repair. The risk for such fistulas has been decreased by the use of nonirradiated segments of bowel for formation of the urinary conduit (157). The 5-year survival rate is 33% to 60% for patients undergoing anterior exenteration and 20% to 46% for those undergoing total exenteration (154,153,154,155,156,157,158,159,160,161,162 and 163). Survival rates are poorer for patients with recurrent disease larger than 3 cm, invasion into the bladder, positive pelvic lymph nodes, and recurrence diagnosed within 1 year after radiotherapy ( 156). The 5-year survival rate of patients with positive pelvic lymph nodes is less than 5%. Thus, the performance of an extensive lymphadenectomy in the irradiated field is not warranted, but discontinuation of the procedure is advisable if any

nodes are positive for metastatic cancer. Patients who have any disease in the peritoneal cavity have no chance of survival. Chemotherapy for Recurrent Cervical Cancer Recurrent cervical cancer is not considered curable with chemotherapy. The delivery of chemotherapy to recurrent tumor in a prior radiated field may be compromised because of altered blood supply caused by radiation. Topotecan has been reported to have a response rate of 17%, with a median duration of 14 months ( 164). Many other agents have shown activity against cervical cancer and may used in attempt to help control symptoms of the cancer. A number of clinical trials with various drugs have shown response rates of up to 45% (165). Complete responses are unusual and are generally limited to patients with chest metastases, in whom the dose of drug delivered to the disease is stronger than that delivered to the fibrotic postirradiation pelvis ( 166). In a review of the literature on the role of chemotherapy in cervical cancer, the author concludes that present data do not support the claim that toxic combination chemotherapy regimens are superior to cisplatin alone in terms of survival benefit, although further studies are required to determine whether combination chemotherapy may offer a benefit for certain subgroups of patients ( 16,17). The response rates for single-agent chemotherapy in cervical cancer are about 10% to 25%; cisplatin and carboplatin are among the most active agents. The response rate for cisplatin combination therapies is about 20% to 40% ( 167). The GOG currently has completed two trials (GOG 149 and 169) evaluating recurrent cervical carcinoma. GOG 169 is comparing cisplatin to cisplatin with paclitaxel. Results of these studies may alter first-line therapy for recurrent cervical carcinoma.

Vaginal Carcinoma Primary vaginal cancer is a relatively uncommon tumor, representing only 1% to 2% of malignant neoplasms of the female genital tract ( 168,169). The incidence of invasive vaginal cancer is 0.42 per 100,000 women and has remained relatively unchanged since the 1980s ( 170). Primary vaginal cancer should be differentiated from cancers metastatic to the vagina. Metastatic cancers constitute the majority of vaginal cancers (80%% to 90%) ( 171).

Staging The FIGO staging of vaginal cancer requires that a tumor that has extended to the vagina from the cervix be regarded as a cancer of the cervix, whereas a tumor that involves both the vulva and the vagina should be classified as a cancer of the vulva. The FIGO staging for vaginal carcinoma is shown in Table 31.6. Staging is done by clinical examination and, if indicated, cystoscopy, proctoscopy, chest x-rays, and skeletal x-ray. Information derived from lymphangiography, CT, and MRI cannot be used to change the FIGO stage, but it can be used for planning treatment. Unfortunately, 75% of patients present with stage II to IV disease, indicating delay in diagnosis and complicating the treatment and subsequent cure rates ( 172,173 and 174).

Table 31.6. FIGO Staging of Vaginal Cancer

Surgical staging and resection of enlarged lymph nodes may be indicated in selected patients. FIGO staging does not include a category for microinvasive disease. Because vaginal cancer is rare and treatment is generally by radiotherapy, there is very little information concerning the spread of disease in relation to depth of invasion, lymph–vascular space invasion, and size of the lesion.

Etiology The cause of squamous cell carcinoma of the vagina is unknown. The association of cervical cancer with HPV suggests that vaginal cancer may have a similar association (175). In addition, up to 30% of women with vaginal cancer have a history of cervical cancer treated at least 5 years earlier ( 176,177 and 178). Similar to cervical cancer, there appears to be a premalignant phase called vaginal intraepithelial neoplasia (VAIN) (see Chapter 16). The exact incidence of progression to invasive vaginal cancer from VAIN is not known; however, there are documented cases of invasive disease occurring despite adequate treatment of VAIN ( 179,180). By convention, any new vaginal carcinoma developing at least 5 years after the cervical cancer should be considered a new primary lesion. There are three possible mechanisms for the occurrence of vaginal cancer after cervical neoplasia: 1. Residual disease in the vaginal epithelium after treatment of the cervical neoplasia 2. New primary disease arising in a patient with increased susceptibility to lower genital tract carcinogenesis; the role of HPV in this setting is suspected. 3. Increased susceptibility of carcinogenesis caused by radiation therapy

Screening Routine screening of all patients for vaginal cancer is inappropriate. For women who have had a cervical or vulvar neoplasm, the Pap test is an important part of routine follow-up with each physician visit. This increased risk for vaginal cancer continues for the lifetime of the patient. It is recommended that Pap test surveillance for vaginal cancer be performed yearly after the patient has completed surveillance for cancer of the cervix or vulva. For women who have had a hysterectomy for benign disease, Pap testing every 3 to 5 years has been standard practice in the United States. When adjusted for age and prior cervical disease, the incidence of vaginal cancer is not increased in women who have had hysterectomy for benign disease ( 181).

Symptoms Painless vaginal bleeding and discharge are the most common symptoms of vaginal cancer. With more advanced tumors, urinary retention, bladder spasm, hematuria, and frequency of urination may occur. Tumors developing on the posterior vaginal wall may produce rectal symptoms, such as tenesmus, constipation, or blood in the stool.

Diagnosis The diagnostic workup includes a complete history and physical examination, careful speculum examination and palpation of the vagina, and bimanual pelvic and rectal examinations. It is important to rotate the speculum to obtain a careful view of the entire vagina because posterior wall lesions frequently occur and may be

overlooked. In early squamous cell lesions, the diagnosis is suggested by an abnormal Pap test result; however, this is not true for clear cell adenocarcinomas, which are characterized by submucosal growth. In these cases, the diagnosis is confirmed by a targeted biopsy using the same instruments as those used for cervical biopsies. The most common site of vaginal cancer is in the upper one third of the vagina on the posterior wall. The developing tumor may be missed during initial inspection because the speculum blades may have obscured it ( 182). Colposcopy is valuable in evaluating patients with abnormal Pap test results, unexplained vaginal bleeding, or ulcerated erythematous patches in the upper vagina. A colposcopically targeted biopsy may not allow a definitive diagnosis, and a partial vaginectomy to determine invasion may be necessary. Occult invasive carcinoma may be detected by such an excision, particularly in patients who had previous hysterectomies, in whom the vaginal vault closure may bury some of the vaginal epithelium that is at risk for cancer ( 183).

Pathology Cancer of the vagina spreads most often by direct extension into the pelvic soft tissues and adjacent organs. Metastases to the pelvic and, subsequently, the paraaortic lymph nodes may occur in advanced disease. Lesions in the lower one third of the vagina may spread directly to the inguinal femoral lymph nodes as well as the pelvic nodes (184). Hematogenous dissemination to the lungs, liver, or bone may occur as a late phenomenon. Squamous cell carcinomas are the most common form of vaginal cancer, occurring in 80% to 90% of vaginal cancers. These tumors most commonly occur in the upper, posterior wall of the vagina. The mean age of patients with squamous cell cancer is 60 years ( 185,186). Malignant melanoma is the second most common cancer of the vagina, accounting for 2.8% to 5% of all vaginal neoplasms ( 187,188 and 189). Other histologic subtypes include adenocarcinoma and sarcoma. Primary adenocarcinoma of the vagina is rare, constituting 9% of primary tumors of the vagina. However, the most common adenocarcinoma of the vagina is metastatic. Metastatic adenocarcinoma of the vagina may originate from the colon, endometrium, ovary, or rarely, pancreas and stomach. In general, they affect a younger population of women, regardless of whether they were exposed to diethylstilbestrol (DES) in utero (190). Adenocarcinomas may arise in wolffian rest elements, periurethral glands, and foci of endometriosis ( 191). In women exposed to DES in utero, adenocarcinoma may develop in vaginal adenosis. DES was used in the United States from 1940 until 1971 to maintain high-risk pregnancies in women with a history of spontaneous abortions. In 1970, Herbst and Scully reported on seven young women with clear cell adenocarcinoma of the vagina ( Fig. 31.11). Later, an association between this cancer and maternal ingestion of DES during pregnancy was identified ( 192). Subsequently, more than 500 cases of clear cell cancer of the vagina and cervix have been reported to the Registry for Research on Hormonal Transplacental Carcinogenesis.

Figure 31.11 Vaginal clear cell carcinoma. Note the formation of tubules with hobnail cells lining the lumen. These cells are characterized by nuclear protrusion into the apical cytoplasm. (From Berek JS, Hacker F. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

The estimated risk for developing clear cell adenocarcinoma from an exposed offspring is 1 in 1,000 or less. The mean age of diagnosis is 19 years ( 193). Clear cell adenocarcinoma in women with a history of in utero exposure to DES typically presents in the exocervix or upper third of the vagina. These tumors vary greatly in size, and are most frequently exophytic and superficially invasive. Stage is the most important prognostic factor. Other statistically significant factors include a tubulocystic growth pattern, size less than 3 cm 2, and less than 3 mm stromal invasion. Because the use of DES in pregnant women was discontinued in 1971, most of these tumors probably have been discovered. It is uncertain, however, what will happen to this cohort of women as they move into their fifth, sixth, and seventh decades of life. Continued surveillance of these women is indicated. Ninety-seven percent of cases of vaginal clear cell adenocarcinoma are associated with adenosis. Adenosis is characterized by the presence of persistent müllerian-type glandular epithelium. Although adenosis is the most common histologic abnormality in women exposed to DES in utero, adenosis can also be found in women without a history of exposure. Adenosis typically appears as red, grapelike clusters in the vagina. Malignant melanoma of the vagina is rare and extremely lethal. The average age of these patients is 58 years, and malignant melanoma occurs most often in white women (194). Most lesions are deeply invasive, corresponding to a level IV when compared with the staging for vulvar melanomas. The most common location of these tumors is in the lower third of the vagina ( 195). Melanomas have a wide variety of size, color, and growth patterns ( 193,196). Radical excision (vaginectomy, hysterectomy, and pelvic lymphadenectomy) has been the mainstay of treatment. The goal of treatment is to avoid local (vaginal) recurrence, which is the most common site of recurrence (194,195). The need to dissect regional lymph nodes is uncertain. Because the disease is deeply invasive, hematogenous spread is the most common lethal recurrence. This finding is consistent with more conservative local excision because there is no difference in overall survival of patients with local as opposed to radical excision (194). The survival rate is about 10% at 5 years. The most common benign and malignant mesenchymal tumors of the vagina in adult women are smooth muscle tumors (197). Vaginal sarcomas are usually fibrosarcomas or leiomyosarcomas and are extremely rare. Radical local excision, followed by adjuvant chemotherapy or radiation therapy, is the indicated treatment. The most common malignant mesenchymal tumor of the vagina in children and infants is botryoid rhabdomyosarcoma ( Fig. 31.12). Botryoid sarcoma is usually found in the vagina during infancy and early childhood, in the cervix during the reproductive years, and in the corpus uteri during postmenopausal years. Preoperative chemotherapy with vincristine, actinomycin D, and cyclophosphamide, followed by conservative surgery or radiation, has led to improved survival as well as organ preservation.

Figure 31.12 Embryonal rhabdomyosarcoma of the vagina (botryoid sarcoma). This lesion consists of primitive mesenchymal cells and rhabdomyoblasts, which have abundant eosinophilic cytoplasm. With further differentiation, cross striations may become evident. (From Berek JS, Hacker F. Practical gynecologic oncology.

2nd ed. Baltimore: Williams & Wilkins, 1994, with permission.)

Treatment Treatment selection is based on the clinical examination, CT scan results, chest x-ray results, age, and condition of the patient. Most tumors are treated by radiation therapy. Surgery is limited to highly selective cases. Women with stage I disease involving the upper posterior vagina may be treated by radical vaginectomy and pelvic lymphadenectomy. If the uterus is in situ, it is removed as a radical hysterectomy specimen. When margins are clear and lymph nodes are negative, no additional therapy is necessary. Patients with stage IV disease with either rectovaginal or vesicovaginal fistula may be candidates for primary pelvic exenteration with pelvic and paraaortic node dissection ( 193). Low rectal anastomosis, continent urinary diversion, and vaginal reconstruction are indicated and are more successful in these nonirradiated patients than in patients who received prior radiation therapy ( 163). Women with central pelvic recurrence after radiation therapy are candidates for pelvic exenteration similar to that for cervical cancer. Surgical staging with resection of enlarged lymph nodes may improve the control of pelvic disease by radiotherapy techniques. Surgical exploration or laparoscopy at the time of insertion of Syed interstitial implants defines more precisely the placement of the needles and ensures that needles do not pass into adherent loops of bowel. Radiation therapy is the treatment of choice for all patients except those described previously. Small superficial lesions may be treated with intracavitary radiation alone (193). Larger, thicker lesions should be treated first with external teletherapy to decrease tumor volume and to treat the regional pelvic nodes, followed by intracavitary and interstitial therapy to deliver a high dose to the primary tumor ( 186,194). If the uterus is intact and the lesion involves the upper vagina, an intrauterine tandem and ovoids can be used. If the uterus has been previously removed, a vaginal cylinder may be used for superficial irradiation. If the lesion is more than 0.5 cm thick, interstitial radiation techniques can improve the dose distribution to the primary tumor. Extended-field radiation may be used for vaginal cancer in a manner similar to its use for cervical carcinoma. There is no experience reported with this technique in the treatment of vaginal cancer. Likewise, there is no reported experience with combination chemoradiation treatment. However, concurrent use of 5-FU and cisplatin has been highly successful in anal and cervical cancer and should be considered.

Sequelae The proximity of the rectum, bladder, and urethra leads to a major complication rate of 10% to 15% for both surgery and radiation treatment. For large tumors, the risk for bladder or bowel fistula is significant. Radiation cystitis and proctitis are common, as are rectal strictures or ulcerations. Radiation necrosis of the vagina occasionally occurs, requiring débridement and often leading to fistula formation. Vaginal fibrosis, stenosis, and stricture are common after radiation therapy. Use of vaginal dilators and resumption of regular sexual relations should be encouraged, along with the use of topical estrogen to maintain adequate vaginal function.

Survival The overall 5-year survival rate for patients with vaginal cancer is 42% ( Table 31.7). Even for patients with stage I disease, the 5-year survival rate is less than 70%, which is 15% lower than that for comparable stages of cervical or vulvar cancer ( 195,196,197,198 and 199). Most recurrences are in the pelvis, either from enlarged regional nodes or from large central tumors to which it is difficult to deliver an adequate dose of radiation. Radiation techniques, such as interstitial implants with Syed applicator and combination chemoradiation, may improve these results. Careful evaluation of patients who receive radiation therapy to detect central recurrence may allow some patients to be salvaged by pelvic exenteration. Because of the rarity of vaginal cancer, these patients should be treated in a center that is familiar with the complexity of treatment and modalities of therapy.

Table 31.7. Primary Vaginal Carcinoma: 5-year Survival

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Reddy S, Lee MS, Graham JE, et al. Radiation therapy in primary carcinoma of the vagina. Gynecol Oncol 1987;26:19–24. Kucera H, Langer M, Smekal G, et al. Radiotherapy of primary carcinoma of the vagina: management and results of different therapy schemes. Gynecol Oncol 1985;21:87–93. Houghton CRS, Iversen T. Squamous cell carcinoma of the vagina: a clinical study of the location of the tumor. Gynecol Oncol 1982;13:365–372. Eddy GL, Marks RD, Miller MC III, et al. Primary invasive vaginal carcinoma. Am J Obstet Gynecol 1991;165:292–296. Pride GL, Schultz AE, Chuprevich TW, et al. Primary invasive squamous carcinoma of the vagina. Obstet Gynecol 1979;53:218–225. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 32. Ovarian Cancer Novak’s Gynecology

Chapter 32

Ovarian Cancer Jonathan S. Berek

Epithelial Ovarian Cancer Pathology Clinical Features Etiology Prevention Screening Genetic Risk for Epithelial Ovarian Cancer Symptoms Signs Diagnosis Patterns of Spread Prognostic Factors Initial Surgery for Ovarian Cancer Treatment with Chemotherapy Treatment Assessment Tumor Markers Radiologic Assessment Second-look Operations Second-line Therapy Intestinal Obstruction Survival Nonepithelial Ovarian Cancers Germ Cell Malignancies Classification Epidemiology Clinical Features Dysgerminoma Immature Teratomas Endodermal Sinus Tumors Embryonal Carcinoma Choriocarcinoma of the Ovary Polyembryoma Mixed Germ Cell Tumors Sex Cord–stromal Tumors Granulosa-stromal Cell Tumors Sertoli-Leydig Tumors Uncommon Ovarian Cancers Lipoid Cell Tumors Sarcomas Small Cell Carcinomas Metastatic Tumors Gynecologic Nongynecologic Krukenberg Tumor Other Gastrointestinal Tumors Melanoma Carcinoid Tumors Lymphoma and Leukemia Fallopian Tube Cancer Clinical Features Staging Treatment Prognosis Tubal Sarcomas References

Of all the gynecologic cancers, ovarian malignancies represent the greatest clinical challenge. Epithelial cancers are the most common ovarian malignancies, and because they are usually asymptomatic until they have metastasized, patients have advanced disease at diagnosis in more than two-thirds of the cases. Ovarian cancer represents a major surgical challenge, requires intensive and often complex therapies, and is extremely demanding of the patient's psychological and physical energy. It has the highest fatality-to-case ratio of all the gynecologic malignancies. There are more than 23,300 new cases annually in the United States, and 13,900 women can be expected to succumb to their illness ( 1). A woman's risk at birth of having ovarian cancer sometime in her life is nearly 1.5%, and that of dying from ovarian cancer almost 1% (2).

Epithelial Ovarian Cancer Approximately 90% of ovarian cancers are derived from tissues that come from the coelomic epithelium or mesothelium ( 2). The cells are a product of the primitive mesoderm, which can undergo metaplasia. A classification of the histologic types of epithelial tumors of the ovary is presented in Table 32.1. Neoplastic transformation can occur when the cells are genetically predisposed to oncogenesis or exposed to an oncogenic agent or both ( 3).

Table 32.1. Epithelial Ovarian Tumors

Pathology Invasive Cancer Seventy-five percent of epithelial cancers are of the serous histologic type. Less common types are mucinous (20%), endometrioid (2%), clear cell, Brenner, and undifferentiated carcinomas; each of the last three types represents less than 1% of epithelial lesions ( 2). Each tumor type has a histologic pattern that reproduces the mucosal features of a section of the lower genital tract ( 3). For example, the serous or papillary pattern has an appearance similar to that of the glandular epithelial lining and fallopian tube. Mucinous tumors contain cells that resemble the endocervical glands, and the endometrioid tumors resemble the endometrium. Borderline Tumors An important group of tumors to distinguish is the tumor of low malignant potential, also called the borderline tumor. Borderline tumors are lesions that tend to remain confined to the ovary for long periods, occur predominantly in premenopausal women, and are associated with a very good prognosis ( 2,3,4,5,6,7 and 8). They are encountered most frequently in women between the ages of 30 and 50 years, whereas invasive carcinomas occur more often in women between the ages of 50 and 70 years (2). Although uncommon, metastatic implants may occur with borderline tumors. Such implants have been divided into noninvasive and invasive forms. The latter group has a higher likelihood of developing into progressive, proliferative disease in the peritoneal cavity, which can lead to intestinal obstruction and death ( 2,6). The criteria for the diagnosis of borderline tumors ( Fig. 32.1) are as follows (7):

Figure 32.1 Borderline malignant serous tumor of the ovary. Complex papillary fronds are lined with pseudostratified columnar cells. The epithelium and the stroma are clearly separated by a basement membrane, indicating no stromal invasion. (From Berek JS, Hacker NF. Practical gynecologic oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994:138, with permission.)

1. Epithelial proliferation with papillary formation and pseudostratification 2. Nuclear atypia and increased mitotic activity 3. Absence of true stromal invasion (i.e., without tissue destruction). It should be emphasized that about 20% to 25% of borderline malignant tumors spread beyond the ovary. The diagnosis of borderline malignant versus malignant ovarian tumor must be based on the histologic features of the primary tumor ( 7). Classification of Epithelial Ovarian Tumors Serous Tumors Serous tumors develop by invagination of the surface ovarian epithelium and are so classified because they secrete serous fluid (as do tubal secretory cells). Psammoma bodies, more correctly foci of foreign material, frequently are associated with these invaginations and may be a response to irritative agents that produce adhesion formation and the entrapment of the surface epithelium. In the wall of the mesothelial invaginations, papillary ingrowths are common, representing the early stages of development of a papillary serous cystadenoma. There are many variations in the proliferation of these mesothelial inclusions. Several foci may be lined with flattened inactive epithelium; in adjacent cavities, papillary excrescences are present, often resulting from local irritants ( 2). Borderline Serous Tumors Approximately 10% of all ovarian serous tumors fall into the category of a tumor of low malignant potential or borderline tumor, and 50% occur before the age of 40 years. As many as 10% of women with ovarian serous borderline tumors have extraovarian implants, and some will eventually die of the disease (9). Although multiple foci of disease have been documented in the abdominal cavity with secondary deposits in the pelvis, omentum, and adjacent tissues, including lymph nodes, metastases outside the abdominal cavity are rare. Death can occur as the result of intestinal obstruction ( 10,11 and 12). The implants are divided histologically into invasive and noninvasive groups ( 6,10). In the noninvasive group, papillary proliferations of atypical cells involve the peritoneal surface and form smooth invaginations ( 6). The invasive implants resemble well-differentiated serous carcinoma and are characterized by atypical cells forming irregular glands with sharp borders. Bell and associates ( 6) have reported that only three of 50 women with noninvasive implants died, whereas four of six women with invasive implants died. In the series of McCaughey, two of 13 patients with noninvasive implants and all five patients with invasive implants died ( 9). Others have noted no differences in prognosis ( 10,11). Rare examples of borderline malignant serous tumors with foci of microinvasion have been reported by Bell and Scully ( 12). Most patients are young, International Federation of Gynecology and Obstetrics (FIGO) stage I, and sometimes pregnant. Only one of 30 such patients died of disease, and she had stage III disease ( 12). Malignant Serous Carcinomas In the malignant tumors, stromal invasion is present ( 2). The grade of tumor should be identified. In well-differentiated serous adenocarcinomas, papillary and glandular structures predominate ( Fig. 32.2); poorly differentiated neoplasms are characterized by solid sheets of cells, nuclear pleomorphism, and high mitotic activity; and moderately differentiated carcinomas are intermediate between these two lesions. Laminated, calcified psammoma

bodies are found in 80% of serous carcinomas.

Figure 32.2 Well-differentiated serous papillary adenocarcinoma of the ovary. Clusters and papillae of malignant cells are in direct contact with fibrous stroma indicative of stromal invasion. (From Berek JS, Hacker NF. Practical gynecologic oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994:140, with permission.)

Mucinous Tumors These cystic tumors have loculi lined with mucin-secreting epithelium. They represent about 8% to 10% of epithelial ovarian tumors. They may reach enormous size, filling the entire abdominal cavity ( 2). Borderline Mucinous Tumors The mucinous tumor of low malignant potential is often a diagnosis difficult to make. Although it is common to find a rather uniform pattern from section to section in the borderline malignant serous lesions, this is not true in the mucinous tumors. Frequently, well-differentiated mucinous epithelium may be seen immediately adjacent to a poorly differentiated focus. Therefore, it is important to take multiple sections from many areas in the mucinous tumor to identify the most malignant alteration. Malignant Mucinous Carcinomas Bilateral tumors occur in 8% to 10% of cases. The mucinous lesions are intraovarian in 95% to 98% of cases ( Fig. 32.3). Because most ovarian mucinous carcinomas contain intestinal type cells, they cannot be distinguished from metastatic carcinoma of the gastrointestinal tract on the basis of histology alone. Primary ovarian neoplasms rarely metastasize to the mucosa of the bowel, although they commonly involve the serosa, whereas gastrointestinal lesions frequently involve the ovary by direct extension of vascular lymphatic spread.

Figure 32.3 Mucinous adenocarcinoma of the ovary. Irregular glandular spaces are lined with a layer of tall columnar cells with abundant mucinous cytoplasm, resembling endocervical cells. The nuclei are mildly atypical. (From Berek JS, Hacker NF. Practical gynecologic oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994:142, with permission.)

Pseudomyxoma Peritonei In pseudomyxoma peritonei, the neoplastic epithelium secretes large amounts of gelatinous mucinous material. It is most commonly secondary to a well-differentiated appendiceal carcinoma, an ovarian mucinous carcinoma or, less commonly, a mucocele of the appendix. Endometrioid Tumors Endometrioid lesions constitute 6% to 8% of epithelial tumors. Endometrioid neoplasia includes all the benign demonstrations of endometriosis. In 1925, Sampson (13) suggested that certain cases of adenocarcinoma of the ovary probably arose in areas of endometriosis. The adenocarcinomas are similar to those seen in the uterine cavity. The malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be demonstrated ( Fig. 32.4).

Figure 32.4 Endometrioid cancer arising in adjacent endometriosis. (From Berek JS, Hacker NF. Practical gynecologic oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994:143, with permission.)

Borderline Endometrioid Tumors The endometrioid tumor of low malignant potential has a wide morphologic spectrum. Tumors may resemble an endometrial polyp or complex endometrial hyperplasia with crowding of glands. When there are back-to-back glands with no intervening stroma, the tumor is classified as a well-differentiated endometrioid carcinoma. Some borderline malignant tumors have a prominent fibromatous component. In such cases, the word adenofibroma is used. Malignant Endometrioid Carcinomas Endometrioid tumors are characterized by an adenomatous pattern with all the potential variations of epithelia found in the uterus. Multifocal Disease The endometrial or endometrioid tumors afford the greatest opportunity to evaluate multifocal disease. Endometrioid tumors of the ovary are often associated with similar lesions in the endometrium. Identification of multifocal disease is important, because patients with disease metastatic from the uterus

to the ovaries have a 30% to 40% 5-year survival, whereas those with synchronous multifocal disease have a 75% to 80% 5-year survival ( 14). When the histologic appearance of endometrial and ovarian tumors is different, the two tumors most likely represent two separate primary lesions. When they appear similar, the endometrial tumor can be considered a separate primary tumor if it is well differentiated and only superficially invasive. Clear Cell Carcinomas Several basic histologic patterns are present in the clear cell adenocarcinoma (i.e., tubulocystic, papillary, and solid). The tumors are made up of clear cells and hobnail cells that project their nuclei to the apical cytoplasm. The tall clear cells have abundant clear or vacuolated cytoplasm, hyperchromatic irregular nuclei, and nucleoli of various sizes ( Fig. 32.5). Focal areas of endometriosis and endometrioid carcinoma sometimes occur. The clear cell carcinoma seen in the ovary is histologically identical to that seen in the uterus or vagina of the young patient who has been exposed to diethylstilbestrol (DES) in utero.

Figure 32.5 Clear cell mesonephroid carcinoma of the ovary. Note the solid variant of clear cell carcinoma with sheets of cells that have clear cytoplasm (“hobnail” cells). (From Berek JS, Hacker NF. Practical gynecologic oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994:144, with permission.)

Brenner Tumors Borderline Brenner Tumors Borderline, or proliferating, Brenner tumors have been described. In such cases, the epithelium does not invade the stroma. Some investigators subclassify those tumors that resemble low-grade papillary transitional cell carcinoma of the urinary bladder as proliferating tumors and those with a higher grade of transitional cell carcinoma in situ as borderline malignant Brenner tumors ( 15). Complete surgical removal usually results in cure. Malignant Brenner Tumors These are rare and are defined as benign Brenner tumors coexisting with invasive transitional cells or another type of carcinoma. The tumor infiltrates the tissue with associated destruction. Transitional Cell Tumors The designation transitional cell tumor refers to a primary ovarian carcinoma resembling transitional cell carcinoma of the urinary bladder without a recognizable Brenner tumor. An important finding is that those ovarian carcinomas that contain more than 50% of transitional cell carcinoma are more sensitive to chemotherapy and have a more favorable prognosis than other poorly differentiated ovarian carcinomas of comparable stage ( 16,17). Transitional cell tumors differ from malignant Brenner tumors in that they are more frequently diagnosed in an advanced stage and, therefore, are associated with a poorer survival rate ( 18). Small cell carcinoma occurs mainly in young women, who may have symptoms of hypercalcemia. Immunohistochemical stains are helpful to differentiate this tumor from a lymphoma, leukemia, or sarcoma. Peritoneal Carcinomas Primary peritoneal tumors are histologically indistinguishable from primary ovarian serous tumors. In the case of borderline serous peritoneal tumors and serous peritoneal carcinomas, the ovaries are normal or minimally involved, and the tumors affect predominantly the uterosacral ligaments, pelvic peritoneum, or omentum. The overall prognosis for borderline serous peritoneal tumors is excellent and comparable to that of ovarian borderline serous tumors ( 21,22 and 23). In the review of 38 cases of peritoneal borderline serous tumors from the literature, 32 women had no persistent disease, four were well after resection of recurrence, one developed an invasive serous carcinoma, and one died from the effects of the tumor ( 21). Peritoneal serous carcinomas have the appearance of a moderately to poorly differentiated serous ovarian carcinoma. Primary peritoneal endometrioid carcinoma is less common. More than 80% of epithelial ovarian cancers are found in postmenopausal women ( Fig. 32.6). These cancers are relatively uncommon in women under age 45.

Figure 32.6 Ovarian cancer incidence: distribution by age. (From J Natl Cancer Inst 1995;87:1280, with permission.)

Mesotheliomas Peritoneal malignant mesotheliomas fall into the following four categories ( 19): (a) fibrosarcomatous, (b) tubulopapillary (papillary-alveolar), (c) carcinomatous, and (d) mixed. These lesions appear as multiple intraperitoneal masses and can develop after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Malignant mesotheliomas should be distinguished from ovarian tumor implants and primary peritoneal müllerian neoplasms. The primary malignant transformation of the peritoneum has been called primary peritoneal carcinoma or primary peritoneal papillary serous carcinoma. Peritoneal carcinoma simulates ovarian cancer clinically. In patients for whom exploratory surgery is performed, there may be microscopic or small macroscopic cancer on the surface of the ovary and extensive disease in the upper abdomen, particularly in the omentum. This phenomenon can thus produce a condition in which so-called ovarian cancer can arise in a patient whose ovaries were surgically removed many years earlier ( 20).

Clinical Features

The peak incidence of invasive epithelial ovarian cancer is at 56 to 60 years of age ( 2,3,24). The age-specific incidence of ovarian epithelial cancer rises precipitously from 20 to 80 years of age and subsequently declines ( 24). Fewer than 1% of epithelial ovarian cancers occur before the age of 21 years, two-thirds of ovarian malignancies in such patients being germ cell tumors ( 2,24,25). About 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only about 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant ( 2,3). The average age of patients with borderline tumors is approximately 46 years ( 2,3,5). Eighty to ninety percent of ovarian cancers, including borderline forms, occur after the age of 40 years, whereas 30% to 40% of malignancies occur after the age of 65 years. The chance that a primary epithelial tumor will be of borderline or invasive malignancy in a patient younger than 40 years is approximately 1 in 10, but after that age it rises to one in three ( 2,3). Fewer than 1% of epithelial ovarian cancers occur before the age of 20 years, with two thirds of ovarian malignancies in such patients being germ cell tumors. Approximately 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only approximately 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant ( 2).

Etiology Ovarian cancer has been associated with low parity and infertility ( 26). Although there have been a variety of epidemiologic variables correlated with ovarian cancer, such as talc use, galactose consumption, and tubal ligation (see Chapter 4), none has been so strongly correlated as prior reproductive history and duration of the reproductive career ( 26,27). Early menarche and late menopause increase the risk of ovarian cancer ( 27). These factors and the relationship of parity and infertility to the risk of ovarian cancer have led to the hypothesis that suppression of ovulation may be an important factor. Theoretically, the surface epithelium undergoes repetitive disruption and repair. It is thought that this process might lead to a higher probability of spontaneous mutations that can unmask germline mutations or otherwise lead to the oncogenic phenotype (see Chapter 6).

Prevention Because parity is inversely related to the risk of ovarian cancer, having at least one child is protective of the disease, with a risk reduction of 0.3 to 0.4. Oral contraceptive use reduces the risk of epithelial ovarian cancer ( 26). Women who use oral contraceptives for 5 or more years reduce their relative risk to 0.5 (i.e., there is a 50% reduction in the likelihood of development of ovarian cancer). Women who have had two children and have used oral contraceptives for 5 or more years have a relative risk of ovarian cancer as low as 0.3, or a 70% reduction ( 28). Therefore, the oral contraceptive pill is the only documented method of chemoprevention for ovarian cancer, and it should be recommended to women for this purpose. When counseling patients regarding birth control options, this important benefit of oral contraceptive use should be emphasized. This is also important for women with a strong family history of ovarian cancer (see discussion below). Fenretinide (4-hydroxyretinoic acid), a vitamin A derivative, has been given to women with unilateral breast cancer in an effort to reduce the risk of contralateral breast cancer. In a prospective, randomized, placebo-controlled trial conducted in Italy ( 29), women with unilateral breast cancer were given for 6 months either fenretinide orally or a placebo. In the treatment group, no ovarian cancers developed, whereas there were six cases of ovarian cancer in the control group. A larger trial is planned in the United States in an attempt to verify these data. The performance of a prophylactic oophorectomy reduces, but does not eliminate, the risk of ovarian cancer ( 20,21). Because the entire peritoneum is at risk, peritoneal carcinomas can occur even after prophylactic oophorectomy. Because the ovaries provide protection from cardiovascular and orthopedic diseases, prophylactic oophorectomy should not be routinely performed in premenopausal women at low risk for ovarian cancer.

Screening The value of tumor markers and ultrasonography to screen for epithelial ovarian cancer has not been clearly established by prospective studies. Screening results with transabdominal ultrasonography have been encouraging ( 30,31 and 32), but specificity has been limited. However, advances in transvaginal ultrasonography have been shown to have a very high (>95%) sensitivity for the detection of early-stage ovarian cancer, although this test alone might require as many as 10 to 15 laparotomy procedures be performed for each case of ovarian cancer detected ( 30,31). Routine annual pelvic examinations have had disappointing results in the early detection of ovarian cancer ( 33). Transvaginal color-flow Doppler to assess the vascularity of the ovarian vessels has been shown to be a useful adjunct to ultrasonography ( 34,35), but it has not been shown to be useful in screening. CA125 has been shown to contribute to the early diagnosis of epithelial ovarian cancer ( 36,37,38,39,40,41 and 42). Regarding the sensitivity of the test, CA125 can detect 50% of patients with stage I disease and 60% of patients if those with stage II disease are included ( 36). Data suggest that the specificity of CA125 is improved when the test is combined with transvaginal ultrasonography ( 43) or when the CA125 levels are followed over time (42,43). These data have encouraged the development of prospective screening studies in Sweden and the United Kingdom ( 38,39). In these studies, patients with elevated CA125 levels (>30 U/ml) have undergone abdominal ultrasonography and 14 ovarian cancers have been discovered among 27,000 women screened. About four laparotomies were performed for each case of cancer detected. A randomized trial of nearly 22,000 women aged 45 years or older was performed in the United Kingdom ( 43). The patients were assigned to either a control group of routine pelvic examination (n = 10,977) or to a screening group (n = 10,958). The screening consisted of three annual screens that involved measurement of serum CA125, pelvic ultrasonography if the CA125 was 30 U/ml or higher, and referral for gynecologic examination if the ovarian volume was 8.8 ml or greater on the ultrasonography. Of the 468 women in the screened group with an elevated CA125, 29 were referred for surgery, 6 cancers were discovered, and 23 had false-positive screening results, yielding a positive predictive value of 20.7%. During a 7-year follow-up period, cancer developed in 10 additional women in the screened group, as it did in 20 women in the control group. Although the median survival of women in whom cancer developed in the screened group was 72.9 months, compared with 41.8 months in the control group ( p = 0.0112), the number of deaths did not differ significantly between the control and screened groups [18/10,977 versus 9/10,958; relative risk 2.0 (0.78 to 5.13)]. Therefore, these data show that a multimodal approach to ovarian cancer screening is feasible, but a larger trial is necessary to determine whether this approach affects mortality. Such a three-arm randomized trial is ongoing in the United Kingdom, and the anticipated accrual is approximately 50,000 women per study arm and 100,000 women in the control arm. Given the false-positive results for both CA125 and transvaginal ultrasonography, particularly in premenopausal women, these tests are not cost effective and should not be used routinely to screen for ovarian cancer. In the future, new markers or technologies may improve the specificity of ovarian cancer screening, but proof of this will require a large, prospective study ( 40,41). Screening in women who have a familial risk may have a better yield, but additional study is necessary (44,45).

Genetic Risk for Epithelial Ovarian Cancer The lifetime risk of ovarian carcinoma for women in the United States is about 1.4% ( 1,2 and 3). The risk of ovarian cancer is higher than that in the general population in women with certain family histories ( 46,47,48,49,50,51,52,53,54 and 55). Most epithelial ovarian cancer is sporadic, with familial or hereditary patterns accounting for 5% to 10% of all malignancies (47). Hereditary Ovarian Cancer BRCA1 and BRCA2 Most hereditary ovarian cancer is associated with mutations in the BRCA1 gene, located on chromosome 17 (46). A small proportion of inherited disease has been traced to another gene, BRCA2, located on chromosome 13 (48). Discovered through linkage analyses, these two genes are associated with the genetic predisposition to both ovarian and breast cancer. There may be other, yet undiscovered genes that predispose to ovarian and breast cancer ( 55). In the past, it had been thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer and hereditary breast-ovarian cancer syndrome. However, it is now believed that these groups essentially represent a continuum of mutations with different degrees of penetrance

within a given family ( 50,55). In addition, there is a higher-than-expected risk of ovarian and endometrial cancer in the Lynch II syndrome, known also as the hereditary nonpolyposis colorectal cancer syndrome (HNPCC syndrome) (56). The mutations are inherited in an autosomal dominant fashion, and therefore a full pedigree analysis (i.e., both maternal and paternal sides of the family) must be carefully evaluated (50). There are numerous distinct mutations that have been identified on each of these genes, and the mutations have different degrees of penetrance that may account for the preponderance of either breast cancer, ovarian cancer, or both, in any given family. Based on analysis of women who have a mutation in the BRCA1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44%, and the risk has been calculated to be as high as 27% for those women with a BRCA2 mutation (47,48,54). The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%. Hereditary ovarian cancers in general occur in women approximately 10 years younger than those with nonhereditary tumors (47). Because the median age of epithelial ovarian cancer is in the mid- to late 50s, a woman with a first- or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene. Breast and ovarian cancer may exist in a family in which there is a combination of epithelial ovarian and breast cancers, affecting a mixture of first- and second-degree relatives. Women with this syndrome tend to have these tumors at a young age, and the breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance ( 43,46). Founder Effect There is a higher carrier rate of BRCA1 and BRCA2 mutations in women of Ashkenazi Jewish descent and in Icelandic women (52,53,55). There have been three specific mutations carried by the Ashkenazi population, 185delAG and 5382insC on BRCA1, and 6174delT on BRCA2. The total carrier rate for a patient of Ashkenazi Jewish descent to have at least one of these three mutations is 1 in 40, or 2.5%, and thus there is a substantial risk in this population. The increased risk is a result of the founder effect, in which a higher rate of mutations occurs in a defined geographic area. Pedigree Analysis The risk of ovarian cancer depends on the number of first- or second-degree relatives (or both) with a history of epithelial ovarian carcinoma or breast cancer (or both), and on the number of malignancies that occur at an earlier age. The degree of risk is difficult to determine precisely unless a full pedigree analysis is performed. 1. In families with two first-degree relatives (i.e., mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative has an affected gene could be as high as 35% to 40% ( 48). 2. In families with a single first-degree relative and a single second-degree relative (i.e., grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman has an affected gene also may be increased. The risk may be 2- to 10-fold higher than in those without a familial history of the disease (48). 3. In families with a single postmenopausal first-degree relative with epithelial ovarian carcinoma, a woman may not have an increased risk of having an affected gene because the case is most likely to be sporadic. However, if the ovarian cancer occurs in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken. 4. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer ( 47). Lynch II Syndrome This syndrome, which includes multiple adenocarcinomas, involves a combination of familial colon cancer (known as the Lynch I syndrome), a high rate of ovarian, endometrial, and breast cancers, and other malignancies of the gastrointestinal and genitourinary systems ( 56). The mutations that have been associated with this syndrome are MSH2, MLH1, PMS1, and PMS2. The risk that a woman who is a member of one of these families will develop epithelial ovarian cancer depends on the frequency of this disease in first- and second-degree relatives, although these women appear to have at least 3 times the relative risk of the general population. A full pedigree analysis of such families should be performed by a geneticist to determine the risk more accurately. Management of Women at High Risk for Ovarian Cancer The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members' ovarian cancer. The value of testing for BRCA1 and BRCA2 has yet to be clearly established, although some guidelines for testing now exist (50,55,57). The importance of genetic counseling cannot be overemphasized because the decision is complex. The American Society of Clinical Oncology has offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, and a clear understanding in a genetic screening clinic of how to counsel and manage these patients. Concerns remain over how the information should be used, the impact on insurability, how the results will be interpreted, and how the information will be used within a specific family (e.g., to counsel children). Although there are some conflicting data, the behavior of breast cancers arising in women with germline mutations in BRCA1 or BRCA2 is comparable to that of sporadic tumors (49). Women with breast cancer who carry these mutations, however, are at a greatly increased risk of ovarian cancer as well as a second breast cancer. Although recommended by the National Institutes of Health Consensus Conference on Ovarian Cancer (58), the value of screening with transvaginal ultrasonography, CA125 levels, or other procedures has not been clearly established in women at high risk. Bourne and co-workers (45) have shown that, using this approach, tumors can be detected approximately 10 times more often than in the general population, and thus they recommend screening in high-risk women. Data derived from a multicenter consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk for development of ovarian cancer in women who have a mutation in either BRCA1 or BRCA2 (59). The risk reduction is significant: in women who have taken oral contraceptives for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease. Prophylactic Oophorectomy The value of prophylactic oophorectomy in these patients is controversial (60,61). Although the risk of ovarian cancer is significantly diminished, there remains the small risk of peritoneal carcinoma, a tumor for which women who have mutations in BRCA1 and BRCA2 may have a higher predisposition. Women at high risk for ovarian cancer who undergo prophylactic oophorectomy have a risk of harboring occult neoplasia. In one series of 42 such operations, four patients (9.5%) had a malignancy, one of which was noted at surgery and three that were microscopic; all were smaller than 5 mm ( 61). Recommendations Current recommendations for management of women at high risk for ovarian cancer are summarized as follows (57,58): 1. Women who appear to be at high risk for ovarian or breast cancer should undergo genetic counseling and, if the risk appears to be substantial, may be offered genetic testing for BRCA1 and BRCA2. 2. Women who wish to preserve their reproductive capacity can undergo screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not clearly established.

3. Oral contraceptives should be recommended to young women before they embark on an attempt to have a family. 4. Women who do not wish to maintain their fertility or who have completed their families may undergo prophylactic bilateral salpingo-oophorectomy. The risk should be clearly documented, preferably established by BRCA1 and BRCA2 testing, before oophorectomy is performed. These women should be counseled that this operation does not offer absolute protection, because peritoneal carcinomas occasionally can occur after bilateral oophorectomy ( 20,21). 5. In women who also have a strong family history of breast cancer, annual mammographic screening should be performed beginning at age 30 years. 6. Women with a documented HNPCC syndrome should undergo periodic screening mammography, colonoscopy, and endometrial biopsy ( 56).

Symptoms Most women with epithelial ovarian cancer have no symptoms for long periods of time. When symptoms do develop, they are often vague and nonspecific (3). In early-stage disease, the patient may experience irregular menses if she is premenopausal. If a pelvic mass is compressing the bladder or rectum, she may report urinary frequency or constipation ( 62,63). Occasionally, she may perceive lower abdominal distention, pressure, or pain, such as dyspareunia. Acute symptoms, such as pain secondary to rupture or torsion, are unusual. In advanced-stage disease, patients most often have symptoms related to the presence of ascites, omental metastases, or bowel metastases. The symptoms include abdominal distention, bloating, constipation, nausea, anorexia, or early satiety. Premenopausal women may complain of irregular or heavy menses, whereas vaginal bleeding may occur in postmenopausal women (64).

Signs The most important sign of epithelial ovarian cancer is the presence of a pelvic mass on physical examination. A solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy. If, in addition, an upper abdominal mass or ascites is present, the diagnosis of ovarian cancer is almost certain. Because the patient usually complains of abdominal symptoms, she may not have a pelvic examination, and a tumor may be missed. In patients who are at least 1 year past menopause, the ovaries should have become atrophic and not palpable. It has been proposed that any palpable pelvic mass in these patients should be considered potentially malignant, a situation that has been referred to as the postmenopausal palpable ovary syndrome ( 65). This concept has been challenged, because subsequent authors have reported that only about 3% of palpable masses measuring 95 U/ml), there is a 96% positive predictive value for malignancy. For premenopausal patients, however, the specificity of the test is low because the CA125 level tends to be elevated in common benign conditions. For the premenopausal patient, a period of observation is reasonable provided the adnexal mass does not have characteristics that suggest malignancy (i.e., it is mobile, mostly cystic, unilateral, and of regular contour). Generally, an interval of no more than 2 months is allowed, during which hormonal suppression with the oral contraceptive may be used. If the lesion is not neoplastic it should regress, as measured by pelvic examination and pelvic ultrasonography. If the mass does not regress or if it increases in size, it must be presumed to be neoplastic and must be removed surgically. The size of the lesion is important. If a cystic mass is >8 cm in diameter, the probability is high that the lesion is neoplastic, unless the patient has been taking clomiphene citrate or other agents to induce ovulation ( 30,31,32 and 33). Patients whose lesions are suggestive of malignancy (i.e., predominantly solid, relatively fixed, or irregularly shaped) should undergo laparotomy, as should postmenopausal patients with adnexal masses. The diagnosis of an ovarian cancer requires an exploratory laparotomy. Before the planned exploration, the patient should undergo routine hematologic and biochemical assessments. A preoperative evaluation in a patient undergoing laparotomy should include a radiograph of the chest and an assessment of the urinary tract with intravenous pyelography. Abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) are of no value for a patient with a definite pelvic mass. A CT or MRI should be performed for patients with ascites and no pelvic mass to look for liver or pancreatic tumors. The findings only rarely preclude laparotomy (67). If the hepatic enzyme values are normal, the likelihood of liver disease is low. Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites. The preoperative evaluation should exclude other primary cancers metastatic to the ovary. A barium enema or colonoscopy is indicated in some patients over 45 years of age to exclude a primary colonic lesion with ovarian metastasis. This study should be performed for any patient who has evidence of occult blood in the stool or of intestinal obstruction. An upper gastrointestinal radiographic series or gastroscopy is indicated if symptoms indicate gastric involvement ( 3,68). Bilateral mammography is indicated if there is any breast mass, because occasionally breast cancer metastatic to the ovaries can simulate primary ovarian cancer. Cervical cytologic study should be performed, although its value for the detection of ovarian cancer is very limited. Patients who have irregular menses or postmenopausal vaginal bleeding should have endometrial biopsy and endocervical curettage to exclude the presence of uterine or endocervical cancer metastatic to the ovary.

Patterns of Spread Ovarian epithelial cancers spread primarily by exfoliation of cells into the peritoneal cavity, by lymphatic dissemination, and by hematogenous spread. Transcoelomic The most common and earliest mode of dissemination of ovarian epithelial cancer is by exfoliation of cells that implant along the surfaces of the peritoneal cavity. The cells tend to follow the circulatory path of the peritoneal fluid. The fluid tends to move with the forces of respiration from the pelvis, up the paracolic gutters, especially on the right, along the intestinal mesenteries, to the right hemidiaphragm. Therefore, metastases are typically seen on the posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal surfaces of the intestines and their mesenteries, and the omentum. The disease seldom invades the intestinal lumen but progressively agglutinates loops of bowel, leading to a functional intestinal obstruction. This condition is known as carcinomatous ileus (3). Lymphatic Lymphatic dissemination to the pelvic and paraaortic lymph nodes is common, particularly in advanced-stage disease ( 69,70 and 71). Spread through the lymphatic channels of the diaphragm and through the retroperitoneal lymph nodes can lead to dissemination above the diaphragm, especially to the supraclavicular lymph nodes (69). Burghardt and others (71) reported that 78% of patients with stage III disease have metastases to the pelvic lymph nodes. In another series ( 70), the rate of paraaortic lymph nodes positive for metastasis was 18% in stage I, 20% in stage II, 42% in stage III, and 67% in stage IV. Hematogenous Hematogenous dissemination at the time of diagnosis is uncommon. Spread to vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to 3% of patients. Most patients with disease above the diaphragm when diagnosed have a right pleural effusion ( 3). Systemic metastases are seen more frequently in patients who have survived for some years. Dauplat and others ( 72) reported that distant metastasis consistent with stage IV disease ultimately occurred in 38% of the patients whose disease was originally intraperitoneal.

Prognostic Factors

The outcome of treatment can be evaluated in the context of prognostic factors, which can be grouped into pathologic, biologic, and clinical factors ( 73). Pathologic Factors The morphology and histologic pattern, including the architecture and grade of the lesion, are important prognostic variables ( 3). Histologic type has not generally been believed to be of prognostic significance, but several papers recently have contained suggestions that clear cell carcinomas are associated with a prognosis worse than that of other histologic types (73,74). Histologic grade, as determined either by the pattern of differentiation or by the extent of cellular anaplasia and the proportion of undifferentiated cells, seems to be of prognostic significance ( 75,76,77 and 78). However, studies of the reproducibility of grading ovarian cancers have shown a high degree of intraobserver and interobserver variation ( 79,80). Because there is significant heterogeneity of tumors and observational bias, the value of histologic grade as an independent prognostic factor has not been clearly established. Baak and colleagues ( 81) have presented a standard grading system based on morphometric analysis, and the system seems to correlate with prognosis, especially in its ability to distinguish low-grade or borderline patterns from other tumors. Biologic Factors Several biologic factors have been correlated with prognosis in epithelial ovarian cancer. Using flow cytometry, Friedlander and co-workers ( 82) showed that ovarian cancers were commonly aneuploid. Furthermore, they and others showed that there was a high correlation between FIGO stage and ploidy; low-stage cancers tend to be diploid and high-stage tumors tend to be aneuploid ( 82,83,84,85 and 86). Patients with diploid tumors have a significantly longer median survival than those with aneuploid tumors: 5 years versus 1 year, respectively ( 82). Multivariate analyses have demonstrated that ploidy is an independent prognostic variable and one of the most significant predictors of survival ( 82). Flow cytometric analysis also provides data on the cell cycle, and the proliferation fraction (S phase) determined by this technique has correlated with prognosis in some studies ( 82,83,84,85 and 86). More than 60 protooncogenes have been identified, and studies have focused on the amplification or expression of these genetic loci and their relationship to the development and progression of ovarian cancer ( 87,88). For example, Slamon and others (89) reported that 30% of epithelial ovarian tumors expressed HER-2/ neu oncogene and that this group had a poorer prognosis, especially patients with more than five copies of the gene. Berchuck and associates ( 90) reported a similar incidence (32%) of HER-2/neu expression. In their series, patients whose tumors expressed the gene had a poorer median survival (15.7 months versus 32.8 months). Others have not substantiated this finding ( 92,93,94 and 95), and a review of the literature by Leary and others ( 92) revealed an overall incidence of HER-2/neu expression of only 11%. Thus, the prognostic value of HER-2/ neu expression in ovarian cancer is unclear and further study is required. The most commonly expressed tumor suppressor gene in ovarian cancer is p53 (97,98 and 99). Indeed, as many as one-half of all epithelial ovarian cancers have evidence of mutated p53 in the tumor. The in vitro clonogenic assay has been studied in relation to ovarian cancer. A significant inverse correlation has been reported between clonogenic growth in vitro and survival (100,101 and 102). Multivariate analysis has found that clonogenic growth in a semisolid culture medium is a significant independent prognostic variable (102), but further study will be needed to evaluate the clinical usefulness of this essay. Clinical Factors In addition to stage, the extent of residual disease after primary surgery, the volume of ascites, patient age, and performance status are all independent prognostic variables (103,104,105,106,107,108,109,110 and 111). Among patients with stage I disease, Dembo and co-workers ( 108) showed, in a multivariate analysis, that tumor grade and dense adherence to the pelvic peritoneum had a significant adverse impact on prognosis, whereas intraoperative tumor spillage or rupture did not. Sjövall and others ( 109) confirmed that eries ovarian cancers that undergo intraoperative rupture or spillage do not worsen prognosis, whereas tumors found to have already ruptured preoperatively do have a poorer prognosis. A multivariate analysis of these and several other studies was performed by Vergote (111), who found that eries for early-stage disease, poor prognostic variables were tumor grade, capsular penetration, surface excrescences, and malignant ascites, but not iatrogenic rupture.

Initial Surgery for Ovarian Cancer Staging Ovarian epithelial malignancies are staged according to the FIGO system listed in Table 32.2 (24). The FIGO staging is based on findings at surgical exploration. A preoperative evaluation should exclude the presence of extraperitoneal metastases.

Table 32.2. FIGO Staging for Primary Carcinoma of the Ovary

The importance of thorough surgical staging cannot be overemphasized, because subsequent treatment will be determined by the stage of disease. For patients in whom exploratory laparotomy does not reveal any macroscopic evidence of disease on inspection and palpation of the entire intraabdominal space, a careful search for microscopic spread must be undertaken. In earlier series in which patients did not undergo careful surgical staging, the overall 5-year survival for patients with apparent stage I epithelial ovarian cancer was only about 60% ( 112). Since then, survival rates of 90% to 100% have been reported for patients who were properly staged and were found to have stage Ia or Ib disease ( 113,114). Technique for Surgical Staging For patients whose preoperative evaluation suggests a probable malignancy, a midline or paramedian abdominal incision is recommended to allow adequate access to the upper abdomen (3). When a malignancy is unexpectedly discovered in a patient who has a lower transverse incision, the rectus muscles can be either divided or detached from the symphysis pubis to allow better access to the upper abdomen. If this is not sufficient, the incision can be extended on one side to create a “J” incision ( 3). The ovarian tumor should be removed intact, if possible, and a frozen histologic section should be obtained. If ovarian malignancy is present and the tumor is apparently confined to the ovaries or the pelvis, thorough surgical staging should be performed. Staging involves the following steps ( 3): 1. Any free fluid, especially in the pelvic cul-de-sac, should be submitted for cytologic evaluation. 2. If no free fluid is present, peritoneal washings should be performed by instilling and recovering 50 to 100 ml of saline from the pelvic cul-de-sac, each

3.

4.

5. 6.

7.

paracolic gutter, and beneath each hemidiaphragm. Obtaining the specimens from under the diaphragms can be facilitated with the use of a rubber catheter attached to the end of a bulb syringe. A systematic exploration of all the intraabdominal surfaces and viscera is performed, proceeding in a clockwise fashion from the cecum cephalad along the paracolic gutter and the ascending colon to the right kidney, the liver and gallbladder, the right hemidiaphragm, the entrance to the lesser sac at the paraaortic area, across the transverse colon to the left hemidiaphragm, down the left gutter and the descending colon to the rectosigmoid colon. The small intestine and its mesentery from the Treitz ligament to the cecum should be inspected. Any suspicious areas or adhesions on the peritoneal surfaces should be sampled for biopsy. If there is no evidence of disease, multiple intraperitoneal biopsies should be performed. Tissue from the peritoneum of the pelvic cul-de-sac, both paracolic gutters, the peritoneum over the bladder, and the intestinal mesenteries should be taken for biopsy. The diaphragm should be sampled either by biopsy or by scraping with a tongue depressor and obtaining a sample for cytologic assessment. Biopsies of any irregularities on the surface of the diaphragm can be facilitated by use of the laparoscope and the associated biopsy instrument. The omentum should be resected from the transverse colon, a procedure called an infracolic omentectomy. The procedure is initiated on the underside of the greater omentum, where the peritoneum is incised just a few millimeters away from the transverse colon. The branches of the gastroepiploic vessels are clamped, ligated, and divided, along with all the small branching vessels that feed the infracolic omentum. If the gastrocolic ligament is palpably normal, it does not need to be resected. The retroperitoneal spaces should be explored to evaluate the pelvic and paraaortic lymph nodes. The retroperitoneal dissection is performed by incision of the peritoneum over the psoas muscles. This may be performed on the ipsilateral side only for unilateral tumors. Any enlarged lymph nodes should be resected and submitted for frozen section. If no metastases are present, a formal pelvic lymphadenectomy should be performed.

Results Metastases in apparent stage I and II epithelial ovarian cancer occur in as many as 3 in 10 patients whose tumors appear to be confined to the pelvis but who have occult metastatic disease in the upper abdomen or the retroperitoneal lymph nodes (70,113,114,115,116,117,118,119,120,121,122 and 123). In a review of the literature ( 112), occult metastases were found in biopsies of the diaphragm in 7.3% of such patients, biopsies of the omentum in 8.6%, the pelvic lymph nodes in 5.9%, the aortic lymph nodes in 18.1%, and in 26.4% of peritoneal washings. The importance of careful initial surgical staging is emphasized by the findings of a cooperative national study ( 113) in which 100 patients with apparent stage I and II disease who were referred for subsequent therapy underwent additional surgical staging. In this series, 28% of the patients initially believed to have stage I disease were “upstaged” and 43% of those believed to have stage II disease had more advanced lesions. A total of 31% of the patients were upstaged as a result of additional surgery, and 77% were reclassified as having stage III disease. Histologic grade was a significant predictor of occult metastasis. Sixteen percent of the patients with grade 1 lesions were upstaged, compared with 34% with grade 2 disease and 46% with grade 3 disease. Stage I The primary surgical treatment for stage I epithelial ovarian cancer is surgical, and patients should undergo total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging ( 112,113). In certain circumstances, a unilateral oophorectomy may be performed. Based on the findings at surgery and the pathologic evaluation, patients with stage I ovarian cancer can be grouped into low-risk and high-risk categories ( Table 32.3).

Table 32.3. Prognostic Variables in Early-stage Epithelial Ovarian Cancer

Borderline Tumors The principal treatment of borderline ovarian tumors is surgical resection of the primary tumor. There is no evidence that either subsequent chemotherapy or radiation therapy improves survival. After a frozen section has determined that the histology is borderline, premenopausal patients who desire preservation of ovarian function may undergo a conservative operation, a unilateral oophorectomy ( 3,123,124). In a study of patients who underwent unilateral ovarian cystectomy only for apparent stage I borderline serous tumors, Lim-Tan and associates ( 124) found that this conservative operation was also safe; only 8% of the patients had recurrences 2 to 18 years later, all with curable disease confined to the ovaries. Recurrence was associated with positive margins of the removed ovarian cyst ( 124). Thus, hormonal function and fertility can be maintained ( 3,123,124). For patients in whom an oophorectomy or cystectomy has been performed and a borderline tumor is later documented in the permanent pathology, no additional immediate surgery is necessary. Stage I Low-grade, Low-risk For patients who have undergone a thorough staging laparotomy and for whom there is no evidence of spread beyond the ovary, abdominal hysterectomy and bilateral salpingo-oophorectomy are appropriate therapy. The uterus and the contralateral ovary can be preserved in women with stage Ia, grade 1 to 2 disease who desire to preserve fertility. The conditions of the women should be monitored carefully with routine periodic pelvic examinations and determinations of serum CA125 levels. Generally, the other ovary and the uterus are removed at the completion of childbearing. Guthrie and others ( 122) studied the outcome of 656 patients with early-stage epithelial ovarian cancer. No untreated patients who had stage Ia, grade 1 cancer died of their disease; thus, adjuvant radiation and chemotherapy are unnecessary. Furthermore, the Gynecologic Oncology Group (GOG) carried out a prospective, randomized trial of observation versus melphalan for patients with stage Ia and Ib, grade 1 disease ( 74). Five-year survival for each group was 94% and 96%, respectively, confirming that no further treatment is needed for such patients. Stage I High-grade, High-risk For patients whose disease is more poorly differentiated or in whom there are malignant cells either in ascitic fluid or in peritoneal washings, complete surgical staging must be performed (3). The surgery should include the performance of a hysterectomy and bilateral salpingo-oophorectomy in addition to the staging laparotomy ( 3). Additional therapy is indicated, and although the optimal therapy for these patients is not known, most patients are treated with chemotherapy, as outlined below. Cytoreductive Surgery for Advanced-stage Disease Patients with advanced-stage epithelial ovarian cancer documented at initial exploratory laparotomy should undergo cytoreductive surgery to remove as much of the tumor and its metastases as possible (125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144 and 145) (Fig 32.7). The operation to remove the primary tumor as well as the associated metastatic disease is referred to as debulking surgery. The operation typically includes the performance of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, along with a complete omentectomy and resection of any metastatic lesions from the peritoneal surfaces or from the intestines. The pelvic tumor often directly involves the rectosigmoid colon, the terminal ileum, and the cecum ( Fig. 32.8). In a minority of patients,

most or all of the disease is confined to the pelvic viscera and the omentum, so that removal of these organs will result in extirpation of all gross tumor, a situation that is associated with a reasonable chance of prolonged progression-free survival.

Figure 32.7 Treatment scheme for patients with advanced-stage ovarian cancer. (*under selected circumstances or clinical trials). (From Berek JS, Hacker NF. Practical gynecologic oncology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:474, with permission.)

Figure 32.8 Extensive ovarian carcinoma involving the bladder, rectosigmoid, and ileocecal area. (From Heintz APM, Berek JS. Cytoreductive surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian malignancies. Edinburgh: Churchill Livingstone, 1987:134, with permission.)

The removal of bulky tumor masses may reduce the volume of ascites present. Often, ascites will completely disappear after removal of the primary tumor and a large omental “cake.” Also, removal of the omental cake often alleviates the nausea and early satiety that many patients experience. Removal of intestinal metastases may restore adequate intestinal function and lead to an improvement in the overall nutritional status of the patient, thereby facilitating the patient's ability to tolerate subsequent chemotherapy. A large, bulky tumor may contain areas that are poorly vascularized, and such areas will be exposed to suboptimal concentrations of chemotherapeutic agents. Similarly, these areas are poorly oxygenated, so that radiation therapy, which requires adequate oxygenation to achieve maximal cell kill, will be less effective. Thus, surgical removal of these bulky tumors may eliminate areas that are most likely to be relatively resistant to treatment. In addition, larger tumor masses tend to be composed of a higher proportion of cells that are either nondividing or in the “resting” phase (i.e., G 0 cells, which are essentially resistant to the therapy). A low growth fraction is characteristic of bulky tumor masses, and cytoreductive surgery can result in smaller residual masses with a relatively higher growth fraction. Goals of Cytoreductive Surgery The principal goal of cytoreductive surgery is removal of all of the primary cancer and, if possible, all metastatic disease. If resection of all metastases is not feasible, the goal is to reduce the tumor burden by resection of all individual tumors to an optimal status. Griffiths ( 125) initially proposed that all metastatic nodules should be reduced to 35 U/ml), disease was always detectable in patients at the second-look procedure. The predictive value of a negative test was only 56%; if the level was 5 cm, (b) infiltrating margins, (c) 5 or more mitotic figures per 10 high-power fields, (d) moderate-to-severe cytological atypia ( 162). The absence of one, or even all, of these features does not guarantee against recurrence ( 163). Lymphatic metastases are uncommon, and radical local excision is the usual treatment. Epithelioid sarcomas characteristically develop in the soft tissues of the extremities of young adults but rarely may occur on the vulva. In a description of two cases and review of three other reports, the authors concluded that these tumors may mimic a Bartholin cyst, thus leading to inadequate initial treatment ( 164). They also believed that vulvar epithelioid sarcomas behave more aggressively than their extragenital counterparts, with four of the five patients dying of metastatic disease. They suggested that early recognition and wide excision should improve the prognosis. Rhabdomyosarcomas are the most common soft tissue sarcomas in childhood, and 20% involve the pelvis or genitourinary tract ( 165). Dramatic gains have been made in the treatment of these tumors during the past 20 years. Previously, radical pelvic surgery was the standard approach, but results were poor. More recently, a multimodal approach has evolved, and survival rates have improved significantly, with a corresponding decrease in morbidity. In a report of the experience of the Intergroup Rhabdomyosarcoma Study I and II (1972 to 1984) with primary tumors of the female genital tract, nine patients aged 1 to 19 years had primary vulvar tumors, and these tumors were often regarded as a form of Bartholin gland infection before biopsy ( 166). They were all managed with chemotherapy (vincristine, or actinomycin D and cyclophosphamide and doxorubicin), with or without radiotherapy. Wide local excision of the tumor, with or without inguinal-femoral lymphadenectomy, was carried out before or after the chemotherapy. Seven of the nine patients were free of disease 4 or more years from diagnosis, one patient was free of disease when lost to follow-up at 5 years, and one patient was alive with disease.

Rare Vulvar Malignancies In addition to the previously mentioned tumors, a number of malignancies more commonly seen in other areas of the body may rarely occur as isolated vulvar tumors. Lymphomas The genital tract may be involved primarily by malignant lymphomas but, more commonly, involvement is a manifestation of systemic disease. In the lower genital tract, the cervix is most often involved, followed by the vulva and the vagina ( 147). Most patients are in their third to sixth decade of life, and about three-fourths of the cases involve diffuse large cell or histiocytic non-Hodgkin's lymphomas. The remainder are nodular or Burkitt's lymphomas ( 134). Treatment is by surgical excision followed by chemotherapy and radiation or both, and the overall 5-year survival rate is about 70% ( 167). Endodermal Sinus Tumor There have been four case reports of endodermal sinus tumor of the vulva, and three of the four patients died of distant metastases ( 147,168). All patients were in their third decade of life, but none was treated with modern chemotherapy. Merkel Cell Carcinoma Merkel cell carcinomas are primary small cell carcinomas of the skin, which resemble oat cell carcinomas of the lung. They metastasize widely and have a very poor prognosis (169,170). They should be locally excised and treated with cisplatin-based chemotherapy. Dermatofibrosarcoma Protuberans This rare, low-grade cutaneous malignancy occasionally involves the vulva. It has a marked tendency for local recurrence but a low risk of systemic spread ( 171). Radical local excision should be sufficient treatment.

Metastatic Tumors of the Vulva Eight percent of vulvar tumors are metastatic (147). The most common primary site is the cervix, followed by the endometrium, kidney, and urethra. Most patients in whom vulvar metastases develop have advanced primary tumors when diagnosed, and in about one-fourth of the patients the primary lesion and the vulvar metastasis are diagnosed simultaneously (172).

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Chapter 34. Gestational Trophoblastic Disease Novak’s Gynecology

Chapter 34

Gestational Trophoblastic Disease Ross S. Berkowitz Donald P. Goldstein

Hydatidiform Mole Epidemiology Complete Versus Partial Hydatidiform Mole Clinical Features Natural History Diagnosis Treatment Follow-up Persistent Gestational Trophoblastic Tumor Nonmetastatic Disease Metastatic Disease Staging Prognostic Scoring System Diagnostic Evaluation Management of Persistent GTT Chemotherapy Single-agent Treatment Combination Chemotherapy References

Gestational trophoblastic disease (GTD) is among the rare human tumors that can be cured even in the presence of widespread dissemination ( 1,2). This classification includes a spectrum of interrelated tumors, including complete and partial hydatidiform mole, placental-site trophoblastic tumor, and choriocarcinoma, which have varying propensities for local invasion and metastasis. Although persistent gestational trophoblastic tumors (GTTs) most commonly follow a molar pregnancy, they may ensue after any gestational event, including therapeutic or spontaneous abortion, ectopic pregnancy, or term pregnancy. Advances in the understanding of the pathogenesis, natural history, and treatment of GTD and the current approach to management are reviewed.

Hydatidiform Mole Epidemiology Estimates of the incidence of GTD vary dramatically in different regions of the world. For example, the incidence of molar pregnancy in Japan (2 per 1,000 pregnancies) has been reported to be about threefold higher than the incidence in Europe or North America (about 0.6 to 1.1 per 1,000 pregnancies) ( 3). The variation in the incidence rates of molar pregnancy may in part result from differences between reporting population-based versus hospital-based data. The incidences of both complete and partial mole have been investigated in Ireland by reviewing all products of conception from first- and second-trimester abortions ( 4). Based on a complete pathologic review, the incidence of complete and partial mole was found to be 1 per 1,945 and 1 per 695 pregnancies, respectively. Case-control studies have been undertaken to identify risk factors for both complete and partial molar pregnancy. The high incidence of molar pregnancy in some populations has been attributed to nutritional and socioeconomic factors. Case-control studies from Italy and the United States have shown that low dietary intake of carotene may be associated with an increased risk of complete molar pregnancy (5,6). Areas with a high incidence of molar pregnancy also have a high frequency of vitamin A deficiency. Dietary factors, therefore, may partly explain regional variations in the incidence of complete mole. Maternal age older than 35 years has consistently been shown to be a risk factor for complete mole. Ova from older women may be more susceptible to abnormal fertilization. In one study, the risk for complete mole was increased 2.0-fold for women older than 35 years and 7.5-fold for women older than 40 years ( 7). Limited information is available concerning risk factors for partial molar pregnancy. However, the epidemiologic characteristics of complete and partial mole may differ. There is no association between maternal age and the risk for partial mole ( 7). The risk for partial mole has been reported to be associated with the use of oral contraceptives and a history of irregular menstruation, but not with dietary factors ( 8).

Complete Versus Partial Hydatidiform Mole Hydatidiform moles may be categorized as either complete or partial moles on the basis of gross morphology, histopathology, and karyotype (Table 34.1).

Table 34.1. Features of Complete and Partial Hydatidiform Moles

Complete Hydatidiform Mole

Pathology Complete moles lack identifiable embryonic or fetal tissues, and the chorionic villi exhibit generalized hydatidiform swelling and diffuse trophoblastic hyperplasia (Fig. 34.1).

Figure 34.1 Photomicrograph of complete mole demonstrating diffusely hydropic chorionic villi and diffuse trophoblastic hyperplasia.

Chromosomes Cytogenetic studies have demonstrated that complete hydatidiform moles usually have a 46,XX karyotype, and the molar chromosomes are entirely of paternal origin (Fig. 34.2) (9). It appears that complete moles usually arise from an ovum that has been fertilized by a haploid sperm, which then duplicates its own chromosomes. The ovum nucleus may be either absent or inactivated (10). Although most complete moles have a 46,XX chromosomal pattern, about 10% have a 46,XY karyotype (11). Chromosomes in a 46,XY complete mole also appear to be entirely of paternal origin, although mitochondrial DNA is of maternal origin (12).

Figure 34.2 The karyotype of complete hydatidiform mole.

Partial Hydatidiform Mole Pathology Partial hydatidiform moles are characterized by the following pathologic features ( 13) (Fig. 34.3):

Figure 34.3 Photomicrograph of partial mole showing varying-sized chorionic villi with focal trophoblastic hyperplasia, stromal trophoblastic inclusions, and villous scalloping. (From Berkowitz RS, Goldstein OP. Gestational trophoblastic diseases. In: Ryan KJ, Berkowitz R, Barbieri R, eds. shape Kistner's gynecology principles and practice, 5th ed. Chicago: Year Book Medical Publishers, 1990:433, with permission.)

1. 2. 3. 4.

Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia Marked villous scalloping Prominent stromal trophoblastic inclusions Identifiable embryonic or fetal tissues.

Chromosomes Partial moles generally have a triploid karyotype (69 chromosomes); the extra haploid set of chromosomes usually is derived from the father (Fig. 34.4) (14). One study reported that 93% of partial moles were triploid ( 14), whereas another found 90% to be triploid (15). When a fetus is present in conjunction with a partial mole, it generally exhibits the stigmata of triploidy, including growth restriction and multiple congenital malformations such as syndactyly and hydrocephaly (Fig. 34.5).

Figure 34.4 The karyotype of partial hydatidiform mole.

Figure 34.5 Photomicrograph of a fetal hand demonstrating syndactyly. The fetus had a triploid karyotype and the chorionic tissues were a partial mole.

Clinical Features Increasingly, patients with complete molar pregnancy are being diagnosed earlier in pregnancy and are being treated before they develop the classic clinical signs and symptoms. This may be due to changes in clinical practice, such as the frequent use of vaginal probe ultrasonography in early pregnancy in women with vaginal staining and even asymptomatic women. Following is a description of the classic and current clinical features of complete molar pregnancy based on the authors' experience (16). Complete Hydatidiform Mole Vaginal Bleeding Vaginal bleeding is the most common symptom causing patients to seek treatment for complete molar pregnancy. Previously, it was reported to occur in 97% of cases, whereas currently it is reported to occur in 84% of patients ( 17). Molar tissues may separate from the decidua and disrupt maternal vessels, and large volumes of retained blood may distend the endometrial cavity. Because vaginal bleeding may be considerable and prolonged, one-half of these patients had anemia (hemoglobin 100,000 mIU/ml 2. Excessive uterine enlargement 3. Theca lutein cysts 6 cm in diameter. Patients with any one of these signs were considered at high risk. After molar evacuation, local uterine invasion occurred in 31% and metastases developed in 8.8% of the 352 high-risk patients. For the 506 low-risk patients, local invasion was found in only 3.4%, and metastases developed in 0.6%. Older patients are also at increased risk of developing postmolar GTT. One study reported that persistent tumor developed after a complete molar pregnancy in 37% of women older than 40 years (23), whereas in another study this finding occurred in 56% of women older than 50 years ( 23,24). Partial Hydatidiform Mole Persistent tumor, usually nonmetastatic, develops in approximately 4% of patients with a partial mole, and chemotherapy is required to achieve remission (25). Patients who develop persistent disease have no distinguishing clinical or pathologic characteristics (26). Additionally, it has been reported that 11 (85%) of 13 patients with partial moles who developed persistent tumor had a triploid karyotype ( 27).

Diagnosis Ultrasonography is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles produce a characteristic vesicular ultrasonographic pattern. Ultrasonography also may contribute to the diagnosis of partial molar pregnancy by demonstrating focal cystic spaces in the placental tissues and an increase in the transverse diameter of the gestational sac (28). When both of these criteria are present, the positive predictive value for partial mole is 90%.

Treatment After molar pregnancy is diagnosed, the patient should be evaluated carefully for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient's condition has been stabilized, a decision must be made concerning the most appropriate method of evacuation. Hysterectomy If the patient desires surgical sterilization, a hysterectomy may be performed with the mole in situ. The ovaries may be preserved at the time of surgery, even though prominent theca lutein cysts are present. Large ovarian cysts may be decompressed by aspiration. Hysterectomy does not prevent metastasis; therefore, patients still require follow-up with assessment of hCG levels. Suction Curettage Suction curettage is the preferred method of evacuation, regardless of uterine size, for patients who desire to preserve fertility. It involves the following steps: 1. Oxytocin infusion—This procedure is begun in the operating room before the induction of anesthesia. 2. Cervical dilation—As the cervix is being dilated, the surgeon frequently encounters increased uterine bleeding. Retained blood in the endometrial cavity may be expelled during cervical dilation. However, active uterine bleeding should not deter the prompt completion of cervical dilation. 3. Suction curettage—Within a few minutes of commencing suction curettage, the uterus may decrease dramatically in size, and the bleeding is generally well controlled. The use of a 12-mm cannula is strongly advised to facilitate evacuation. If the uterus is larger than 14 weeks of gestation, one hand should be placed on top of the fundus, and the uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation. 4. Sharp curettage—When suction evacuation is believed to be complete, gentle sharp curettage is performed to remove any residual molar tissue. Because trophoblast cells express RhD factor, patients who are Rh negative should receive Rh immune globulin at the time of evacuation. Prophylactic Chemotherapy The use of prophylactic chemotherapy at the time of molar evacuation is controversial ( 29). The debate concerns the wisdom of exposing all patients to potentially toxic treatment when only about 20% are at risk of developing persistent tumor. In a study of 247 patients with complete molar pregnancy who received prophylactically a single course of actinomycin D at the time of evacuation, local uterine invasion subsequently developed in only 10 patients (4%), and no patients experienced metastasis ( 29). Furthermore, all 10 patients with local invasion achieved remission after only one additional course of chemotherapy. Prophylactic chemotherapy, therefore, not only prevented metastasis but also reduced the incidence and morbidity of local uterine invasion. In a prospective randomized study of prophylactic chemotherapy in patients with a complete mole, a significant decrease in persistent tumor was detected in patients with high-risk mole who received prophylactic chemotherapy (47% versus 14%) ( 30). Prophylaxis may be particularly useful in the management of high-risk complete molar pregnancy, especially when hormonal follow-up is unavailable or unreliable.

Follow-up Human Chorionic Gonadotropin After molar evacuation, patients should be monitored with weekly determinations of b-subunit hCG levels until these levels are normal for 3 consecutive weeks, followed by monthly determinations until the levels are normal for 6 consecutive months. The average time to achieve the first normal hCG level after evacuation is about 9 weeks (31). At the completion of follow-up, pregnancy may be undertaken. Contraception Patients are encouraged to use effective contraception during the entire interval of hCG follow-up. Because of the potential risk of uterine perforation, intrauterine devices should not be inserted until the patient achieves a normal hCG level. If the patient does not desire surgical sterilization, the choice is to use either oral contraceptives or barrier methods. The incidence of postmolar persistent tumor has been reported to be increased among patients who used oral contraceptives before gonadotropin remission ( 32).

However, more recent data indicate that oral contraceptives do not increase the risk of postmolar trophoblastic disease ( 33,34). It appears that oral contraceptives may be used safely after molar evacuation during the entire interval of hormonal follow-up.

Persistent Gestational Trophoblastic Tumor Nonmetastatic Disease Locally invasive GTT develops in about 15% of patients after molar evacuation and infrequently after other gestations (1). These patients usually are seen clinically with the following symptoms: 1. 2. 3. 4.

Irregular vaginal bleeding Theca lutein cysts Uterine subinvolution or asymmetric enlargement Persistently elevated serum hCG levels.

The trophoblastic tumor may perforate through the myometrium, causing intraperitoneal bleeding, or erode into uterine vessels, causing vaginal hemorrhage. Bulky, necrotic tumor may involve the uterine wall and serve as a nidus for infection. Patients with uterine sepsis may have a purulent vaginal discharge and acute pelvic pain. After molar evacuation, persistent GTT may exhibit the histologic features of either hydatidiform mole or choriocarcinoma. After a nonmolar pregnancy, however, persistent GTT always has the histologic pattern of choriocarcinoma. Histologically, choriocarcinoma is characterized by sheets of anaplastic syncytiotrophoblast and cytotrophoblast without chorionic villi. Placental-site Trophoblastic Tumor Placental-site trophoblastic tumor is an uncommon but important variant of choriocarcinoma that consists predominantly of intermediate trophoblast ( 35). Relative to their mass, these tumors produce small amounts of hCG and human placental lactogen (hPL), and they tend to remain confined to the uterus, metastasizing late in their course. In contrast to other trophoblastic tumors, placental-site tumors are relatively insensitive to chemotherapy.

Metastatic Disease Metastatic GTT occurs in about 4% of patients after evacuation of a complete mole, but it is seen more often when GTT develops after nonmolar pregnancies (1). Metastasis is usually associated with choriocarcinoma, which has a tendency toward early vascular invasion with widespread dissemination. Because trophoblastic tumors often are perfused by fragile vessels, they are frequently hemorrhagic. Symptoms of metastases may result from spontaneous bleeding at metastatic foci. The most common sites of metastases are lung (80%), vagina (30%), pelvis (20%), liver (10%), and brain (10%). Pulmonary At the time of diagnosis, lung involvement is visible on chest radiographs of 80% of patients with metastatic GTT. Patients with pulmonary metastasis may have chest pain, cough, hemoptysis, dyspnea, or an asymptomatic lesion on chest radiograph. Respiratory symptoms may be acute or chronic, persisting over many months. GTT may produce four principal pulmonary radiographic patterns: 1. 2. 3. 4.

An alveolar or “snowstorm” pattern Discrete rounded densities Pleural effusion An embolic pattern caused by pulmonary arterial occlusion.

Because respiratory symptoms and radiographic findings may be dramatic, the patient may be thought to have a primary pulmonary disease. Some patients with extensive pulmonary involvement have minimal, if any, gynecologic symptoms because the reproductive organs may be free of trophoblastic tumor. Unfortunately, the diagnosis of GTT may be confirmed only after thoracotomy has been performed, particularly in patients with a nonmolar antecedent pregnancy. Pulmonary hypertension may develop in patients with GTT secondary to pulmonary arterial occlusion by trophoblastic emboli. The development of early respiratory failure requiring intubation is associated with a dismal clinical outcome ( 36,37). Vaginal Vaginal metastases occurs in 30% of the patients with metastatic tumor. These lesions are usually highly vascular and may bleed vigorously if a sample is taken for biopsy. Metastases to the vagina may occur in the fornices or suburethrally and may produce irregular bleeding or a purulent discharge. Hepatic Liver metastases occur in 10% of patients with disseminated trophoblastic tumor. Hepatic involvement is encountered almost exclusively in patients with protracted delays in diagnosis and extensive tumor burdens. Epigastric or right upper quadrant pain may develop if metastases stretch the hepatic capsule. Hepatic lesions may be hemorrhagic, causing hepatic rupture and exsanguinating intraperitoneal bleeding. Central Nervous System Metastatic trophoblastic disease involves the brain in 10% of patients. Cerebral involvement is generally seen in patients with advanced disease; virtually all patients with brain metastasis have concurrent pulmonary or vaginal involvement or both. Because cerebral lesions may hemorrhage spontaneously, patients may develop acute focal neurologic deficits.

Staging P> An anatomic staging system for GTT has been adopted by the International Federation of Gynecology and Obstetrics (FIGO) (Table 34.2). It is hoped that this staging system will encourage the objective comparison of data among various centers.

Table 34.2. Staging of Gestational Trophoblastic Tumors

Stage I: Patients have persistently elevated hCG levels and tumor confined to the uterine corpus. Stage II: Patients have metastases to the vagina and pelvis or both. Stage III: Patients have pulmonary metastases with or without uterine, vaginal, or pelvic involvement. The diagnosis is based on a rising hCG level in the presence of pulmonary lesions on chest radiograph. Stage IV: Patients have advanced disease and involvement of the brain, liver, kidneys, or gastrointestinal tract. These patients are in the highest risk category, because they are most likely to be resistant to chemotherapy. The histologic pattern of choriocarcinoma is usually present, and disease commonly follows a nonmolar pregnancy.

Prognostic Scoring System In addition to anatomic staging, it is important to consider other variables to predict the likelihood of drug resistance and to assist in selecting appropriate chemotherapy (38). A prognostic scoring system proposed by the World Health Organization reliably predicts the potential for resistance to chemotherapy (Table 34.3).

Table 34.3. Scoring System Based on Prognostic Factors

When the prognostic score is higher than 7, the patient is categorized as high risk and requires intensive combination chemotherapy to achieve remission. Patients with stage I disease usually have a low-risk score, and those with stage IV disease have a high-risk score. The distinction between low and high risk applies mainly to patients with Stage II or III disease.

Diagnostic Evaluation Optimal management of persistent GTT requires a thorough assessment of the extent of the disease prior to the initiation of treatment. All patients with persistent GTT should undergo a careful pretreatment evaluation, including the following: 1. 2. 3. 4.

Complete history and physical examination Measurement of the serum hCG value Hepatic, thyroid, and renal function tests Determination of baseline peripheral white blood cell and platelet counts.

The metastatic workup should include the following: 1. Chest radiograph or computed tomography (CT) scan 2. Ultrasonography or CT scan of the abdomen and pelvis 3. CT or magnetic resonance imaging (MRI) scan of the head. When the pelvic examination and chest radiographic findings are negative, metastatic involvement of other sites is uncommon. Liver ultrasonography and CT scanning will document most hepatic metastases in patients with abnormal liver function tests. CT or MRI scan of the head has facilitated the early diagnosis of asymptomatic cerebral lesions ( 39). Chest CT scans may demonstrate micrometastases not visible on a chest radiograph. In patients with choriocarcinoma or metastatic disease, hCG levels may be measured in the cerebrospinal fluid (CSF) to exclude cerebral involvement if the results of CT scanning of the brain are normal. The ratio of plasma-to-CSF hCG tends to be lower than 60 in the presence of cerebral metastases ( 40). However, a single plasma-to-CSF hCG ratio may be misleading, because rapid changes in plasma hCG levels may not be reflected promptly in the CSF ( 41). Pelvic ultrasonography appears to be useful in detecting extensive trophoblastic uterine involvement and may also aid in identifying sites of resistant uterine tumor (42). Because ultrasonography can accurately and noninvasively detect extensive uterine tumor, it may help identify patients who would benefit from hysterectomy.

Management of Persistent GTT A protocol for the management of GTT is presented in Table 34.4.

Table 34.4. Protocol for Treatment of GTT

Stage I In patients with stage I disease, the selection of treatment is based primarily on whether the patient desires to retain fertility. Hysterectomy plus Chemotherapy If the patient does not wish to preserve fertility, hysterectomy with adjuvant single-agent chemotherapy may be performed as primary treatment. Adjuvant chemotherapy is administered for three reasons: 1. To reduce the likelihood of disseminating viable tumor cells at surgery 2. To maintain a cytotoxic level of chemotherapy in the bloodstream and tissues in case viable tumor cells are disseminated at surgery 3. To treat any occult metastases that may already be present at the time of surgery. Chemotherapy can be administered safely at the time of hysterectomy without increasing the risk of bleeding or sepsis. In a series of 30 patients treated with primary hysterectomy and a single course of adjuvant chemotherapy, all have achieved complete remission with no additional therapy. Hysterectomy is also performed in all patients with stage I placental-site trophoblastic tumor. Because placental-site tumors are resistant to chemotherapy, hysterectomy for presumed nonmetastatic disease is the only curative treatment. To date, only a small number of patients with metastatic placental-site tumor have been reported to be in sustained remission as a result of chemotherapy ( 43). Chemotherapy Alone Single-agent chemotherapy is the preferred treatment in patients with stage I disease who desire to retain fertility. When primary single-agent chemotherapy was administered to 468 patients with stage I GTT, 431 patients (92.1%) attained complete remission. The remaining 37 resistant patients subsequently achieved remission after combination chemotherapy or surgical intervention. When patients are resistant to single-agent chemotherapy and desire to preserve fertility, combination chemotherapy should be administered. If the patient is resistant to both single-agent and combination chemotherapy and wants to retain fertility, local uterine resection may be considered. When local resection is planned, a preoperative ultrasonography, MRI, or arteriography may help to define the site of the resistant tumor. Stages II and III Low-risk patients are treated with primary single-agent chemotherapy, and high-risk patients are treated with primary intensive combination chemotherapy. Vaginal and Pelvic Metastasis In one series, 27 treated patients with stage II disease achieved remission. Single-agent chemotherapy induced complete remission in 16 (84.2%) of 19 low-risk patients. In contrast, only two of eight high-risk patients achieved remission with single-agent treatment; the others required combination chemotherapy. Vaginal metastases may bleed profusely because they are highly vascular and friable. When bleeding is substantial, it may be controlled by packing the vagina or by wide local excision. Infrequently, arteriographic embolization of the hypogastric arteries may be required to control hemorrhage from vaginal metastases. Pulmonary Metastasis Of 143 patients treated with stage III disease, 142 (99%) attained complete remission. Gonadotropin remission was induced with single-agent chemotherapy in 80 of 97 (82.5%) patients with low-risk disease. All patients who were resistant to single-agent treatment subsequently achieved remission with combination chemotherapy. Thoracotomy Thoracotomy has a limited role in the management of stage III disease. If a patient has a persistent viable pulmonary metastasis despite intensive chemotherapy, however, thoracotomy may be attempted to excise the resistant focus. A thorough metastatic workup should be performed before surgery to exclude other sites of persistent disease. Evidence of fibrotic pulmonary nodules may persist indefinitely on chest radiographs, even after complete gonadotropin remission has been attained. In patients undergoing thoracotomy for resistant disease, chemotherapy should be administered postoperatively to treat potential occult sites of micrometastasis. Hysterectomy Hysterectomy may be required in patients with metastatic disease to control uterine hemorrhage or sepsis. Furthermore, in patients with extensive uterine tumor, hysterectomy may substantially reduce the trophoblastic tumor burden and thereby limit the need for multiple courses of chemotherapy. Follow-up All patients with stage I through stage III disease should receive follow-up with: 1. Weekly measurement of hCG levels until they are normal for 3 consecutive weeks 2. Monthly measurement of hCG values until levels are normal for 12 consecutive months 3. Effective contraception during the entire interval of hormonal follow-up. Patients with stage IV disease are at greatest risk of developing rapidly progressive and unresponsive tumors despite intensive multimodal therapy. They should preferably be referred to centers with special expertise in the management of trophoblastic disease. Stage IV All patients with stage IV disease should be treated with primary intensive combination chemotherapy and the selective use of radiation therapy and surgery. Before 1975, only 6 of 20 patients (30%) treated with stage IV disease attained complete remission, whereas after that time, 14 of 18 patients (77.8%) achieved remission.

This improvement in survival has resulted from the use of primary combination chemotherapy in conjunction with radiation and surgical treatment. Hepatic Metastasis The management of hepatic metastasis is particularly difficult. If a patient is resistant to systemic chemotherapy, hepatic arterial infusion of chemotherapy may induce complete remission in selected cases. Hepatic resection may also be required to control acute bleeding or to excise a focus of resistant tumor. New techniques of arterial embolization may reduce the need for surgical intervention. Cerebral Metastasis If cerebral metastases are diagnosed, whole-brain irradiation (3,000 cGy in 10 fractions) can be instituted promptly. The risk of spontaneous cerebral hemorrhage may be lessened by the concurrent use of combination chemotherapy and brain irradiation, because irradiation may be both hemostatic and tumoricidal. However, excellent remission rates (86%) have been reported in patients with cranial metastases treated with intensive intravenous combination chemotherapy and intrathecal methotrexate (MTX) (44). Craniotomy Craniotomy may be required to provide acute decompression or to control bleeding. It should be performed to manage life-threatening complications in the hope that the patient ultimately will be cured with chemotherapy. In one study ( 45), the use of craniotomy to control bleeding in six patients resulted in complete remission in three patients. Infrequently, cerebral metastases that are resistant to chemotherapy may be amenable to local resection. Fortunately, patients with cerebral metastases who achieve sustained remission generally have no residual neurologic deficits. Follow-up Patients with stage IV disease should receive follow-up with: 1. Weekly determination of hCG levels until they are normal for 3 consecutive weeks 2. Monthly determination of hCG levels until they are normal for 24 consecutive months. These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence. An algorithm for the management of persistent GTT is presented in Fig. 34.6.

Figure 34.6 Algorithm for the management of persistent gestational trophoblastic tumor. (From Berkowitz RS, Goldstein DP. Gestational trophoblastic neoplasia. In: Berek JS, Hacker NF, eds. shape Practical gynecologic oncology, 3rd ed. Philadelphia: Lippincot Williams & Wilkins, 2000;632, with permission.)

Chemotherapy Single-agent Treatment Single-agent chemotherapy with either actinomycin D (Act-D) or MTX has achieved comparable and excellent remission rates in both nonmetastatic and low-risk metastatic GTT (46). Several protocols using these agents are available. Act-D can be given every other week as a 5-day regimen or in a pulsatile fashion; similarly, MTX can be given either in a 5-day regimen or pulsatile weekly. No study has compared all of these protocols with regard to success. An optimal regimen should maximize the response rate while minimizing morbidity and cost. The administration of methotrexate with folinic acid (MTX-FA) in GTT to limit systemic toxicity was first reported in 1964 ( 47). Subsequently, it has been confirmed that MTX-FA is both effective and safe in the management of GTT (48). MTX-FA has been the preferred single agent in the treatment of GTT. An evaluation of 185 patients treated in this manner revealed that complete remission was achieved in 162 patients (87.6%); of these patients, 132 (81.5%) required only one course of MTX-FA to attain remission (48). MTX-FA induced remission in 147 of 163 patients (90.2%) with stage I GTT and in 15 of 22 patients (68.2%) with low-risk stages II and III GTT. Resistance to therapy was more common in patients with choriocarcinoma, metastasis, and pretreatment serum hCG levels higher than 50,000 mIU/ml. After treatment with MTX-FA, thrombocytopenia, granulocytopenia, and hepatotoxicity developed in only 3 (1.6%), 11 (5.9%), and 26 (14.1%) patients, respectively. Thus, MTX-FA achieved an excellent therapeutic outcome with minimal toxicity and attained this goal with limited exposure to chemotherapy. Technique of Single-agent Treatment The serum hCG level is measured weekly after each course of chemotherapy, and the hCG regression curve serves as the primary basis for determining the need for additional treatment. After the first treatment: 1. Further chemotherapy is withheld as long as the hCG level is falling progressively. 2. Additional single-agent chemotherapy is not administered at any predetermined or fixed interval. A second course of chemotherapy is administered under the following conditions: 1. If the hCG level plateaus for more than 3 consecutive weeks or begins to rise again 2. If the hCG level does not decline by 1 log within 18 days after completion of the first treatment. If the patient's response to the first treatment was adequate and a second course of MTX-FA is required the dosage of MTX is unaltered. An adequate response is defined as a fall in the hCG level by 1 log after a course of chemotherapy. If the response to the first treatment is inadequate, the dosage of MTX is increased from 1.0 mg/kg per day to 1.5 mg/kg per day for each of the 4 treatment days. If the response to two consecutive courses of MTX-FA is inadequate, the patient is considered to be resistant to MTX, and Act-D is promptly substituted. If the hCG levels do not decline by 1 log after treatment with Act-D, the patient also is considered resistant to Act-D as a single agent. She must then be treated intensively with

combination chemotherapy to achieve remission.

Combination Chemotherapy Triple Therapy Triple therapy with MTX, Act-D, and cyclophosphamide is inadequate as an initial treatment in patients with metastasis and a high-risk prognostic score. Collectively, data from various centers indicate that triple therapy induced remission in only 21 (49%) of 43 patients with metastasis and a high-risk score (score >7) ( 49,50 and 51). Etoposide has been reported to induce complete remission in 56 (95%) of 60 patients with nonmetastatic and low-risk metastatic GTT ( 52). A new combination regimen described in 1984 included etoposide, MTX, Act-D, cyclophosphamide, and vincristine (EMA-CO) and had an 83% remission in patients with metastasis and a high-risk score (53). Another study (54) confirmed that primary EMA-CO induced complete remission in 76% of the patients with metastatic GTT and a high-risk score (54). Still another study reported that EMA-CO induced complete sustained remission in 61 (94%) of 65 patients with high-risk (score >5) GTT ( 55). Furthermore, remission occurred with EMA-CO in 13 (86%) of 15 patients with brain metastasis ( 44). The EMA-CO regimen is generally well tolerated, and treatment seldom has to be suspended because of toxicity. The EMA-CO regimen is the preferred primary treatment in patients with metastasis and a high-risk prognostic score. However, the optimal combination drug protocol for management of GTT has not yet been clearly defined. If patients experience resistance to EMA-CO, they may then be treated successfully by substituting etoposide and cisplatin on day 8 (EMA-EP). EMA-EP has induced remission alone or with surgery in 16 (76%) of 21 patients who were resistant to EMA-CO (56). The optimal combination drug protocol will most likely include etoposide, MTX, and Act-D and perhaps other agents administered in the most dose-intensive manner. Duration of Therapy Patients who require combination chemotherapy must be treated intensively to attain remission. Combination chemotherapy should be given as often as toxicity permits until the patient achieves three consecutive normal hCG levels. After normal hCG levels are attained, at least two additional courses of chemotherapy are administered to reduce the risk of relapse. Subsequent Pregnancies Pregnancies After Hydatidiform Mole Patients with hydatidiform moles can anticipate normal reproduction in the future (57). From 1965 until 1999, patients who were treated for complete mole had 1,239 subsequent pregnancies that resulted in 850 term live births (68.6%), 93 premature deliveries (7.5%), 11 ectopic pregnancies (0.9%), 7 stillbirths (0.5%), and 17 repeat molar pregnancies (1.4%). First- and second-trimester spontaneous abortions occurred in 205 (16.5%) and 18 (1.5%) pregnancies, respectively. Major and minor congenital malformations were detected in 38 infants (4.0%), and primary cesarean delivery was performed in 56 of 345 (16.2%) term or preterm births from 1979 to 1999. Although data regarding pregnancies after partial mole are limited (205 subsequent pregnancies), the information is reassuring ( 57). Patients with both complete and partial mole should be reassured that they are at no increased risk of complications in later gestations. When a patient has had a molar pregnancy, she is at an increased risk of having a molar gestation in subsequent conceptions (58). After one molar pregnancy, the risk of having molar disease in a future gestation is about 1%. Of 29 patients with at least two documented molar pregnancies, every possible combination of repeat molar pregnancy was observed. After two molar gestations, these 29 patients had 34 later conceptions resulting in 19 (55.9%) term deliveries, 7 (20.6%) moles (6 complete, 1 partial), 3 spontaneous abortions, 3 therapeutic abortions, 1 intrauterine fetal death, and 1 ectopic pregnancy. In six patients, the medical records indicated that the patient had a different partner at the time of different molar pregnancies ( 59). Therefore, for any subsequent pregnancy, it seems prudent to undertake the following approach: 1. Perform pelvic ultrasonographic examination during the first trimester to confirm normal gestational development. 2. Obtain a thorough histologic review of the placenta or products of conception. 3. Obtain an hCG measurement 6 weeks after completion of the pregnancy to exclude occult trophoblastic neoplasia. Pregnancies After Persistent GTT Patients with GTT who are treated successfully with chemotherapy can expect normal reproduction in the future. Patients who were treated with chemotherapy at the authors' institution from 1965 to 1999 had 522 subsequent pregnancies that resulted in 358 term live births (68.6%), 30 preterm deliveries (5.8%), 6 ectopic pregnancies (1.1%), 8 stillbirths (1.5%), and 6 repeat molar pregnancies (1.1%) ( 57). First- and second-trimester spontaneous abortions occurred in 81 (15.5%) and 7 (1.4%) pregnancies, respectively. Major and minor congenital malformations were detected in 10 infants (2.5%). Primary cesarean delivery was performed in 57 (19.4%) of 294 subsequent term and preterm births from 1979 to 1999. It is particularly reassuring that the frequency of congenital anomalies is not increased, although chemotherapeutic agents are known to have teratogenic and mutagenic potential.

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31. Genest DR, LaBorde O, Berkowitz RS, et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991;78: 402–409. 32. Stone M, Dent J, Kardana A, et al. Relationship of oral contraception to development of trophoblastic tumour after evacuation of a hydatidiform mole. Br J Obstet Gynaecol 1976;83:913–916. 33. Berkowitz RS, Goldstein DP, Marean AR, et al. Oral contraceptives and postmolar trophoblastic disease. Obstet Gynecol 1981;58:474–477. 34. Curry SL, Schlaerth JB, Kohorn EI, et al. Hormonal contraception and trophoblastic sequelae after hydatidiform mole (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1989;160:805–809. 35. Finkler NJ, Berkowitz RS, Driscoll SG, et al. Clinical experience with placental site trophoblastic tumors at the New England Trophoblastic Disease Center. Obstet Gynecol 1988;71:854–857. 36. Kelly MP, Rustin GJ, Ivory C, et al. Respiratory failure due to choriocarcinoma: a study of 103 dyspneic patients. Gynecol Oncol 1990;38:149–154. 37. Bakri YN, Berkowitz RS, Khan J, et al. Pulmonary metastases of gestational trophoblastic tumor—risk factors for early respiratory failure. J Reprod Med 1994;39:175–178. 38. Goldstein DP, Vzanten-Przybysz I, Bernstein MR, et al. Revised FIGO staging system for gestational trophoblastic tumors: recommendations regarding therapy. J Reprod Med 1998;43:37–43. 39. Athanassiou A, Begent RHJ, Newlands ES, et al. Central nervous system metastases of choriocarcinoma: 23 years' experience at Charing Cross Hospital. Cancer 1983;52:1728–1735. 40. Bagshawe KD, Harland S. Immunodiagnosis and monitoring of gonadotropin-producing metastases in the central nervous system. Cancer 1976;38:112–118. 41. Bakri Y, Al-Hawashim N, Berkowitz RS. Cerebrospinal fluid/serum b-subunit human gonadotropin ratio in patients with brain metastases of gestational trophoblastic tumor. J Reprod Med 2000;45:94–96. 42. Berkowitz RS, Birnholz J, Goldstein DP, et al. Pelvic ultrasonography and the management of gestational trophoblastic disease. Gynecol Oncol 1983;15:403–412. 43. Newland ES, Bower M, Fisher RA, et al. Management of placental site trophoblastic tumors. J Reprod Med 1998;43:53–59. 44. Rustin GJ, Newlands ES, Begent RHJ, et al. Weekly alternating etoposide, methotrexate, actinomycin D/ vincristine and cyclophosphamide chemotherapy for the treatment of CNS metastases of choriocarcinoma. J Clin Oncol 1989;7:900–903. 45. Weed JC Jr, Hammond CB. Cerebral metastatic choriocarcinoma: intensive therapy and prognosis. Obstet Gynecol 1980;55:89–94. 46. Homesley HD. Single-agent therapy for nonmetastatic and low-risk gestational trophoblastic disease. J Reprod Med 1998;43:69–74. 47. Bagshawe KD, Wilde CE. Infusion therapy for pelvic trophoblastic tumors. J Obstet Gynaecol Br Commonw 1964;71:565–570. 48. Berkowitz RS, Goldstein DP, Bernstein MR. Ten years' experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986;23:111–118. 49. Curry SL, Blessing JA, DiSaia PJ, et al. A prospective randomized comparison of methotrexate, dactinomycin and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine in “poor prognosis” metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 1989;73:357–362. 50. Gordon AN, Gershenson DM, Copeland LJ, et al. High-risk metastatic gestational trophoblastic disease: further stratification into clinical entities. Gynecol Oncol 1989;34:54–56. 51. DuBeshter B, Berkowitz RS, Goldstein DP, et al. Metastatic gestational trophoblastic disease: experience at the New England Trophoblastic Disease Center, 1965–1985. Obstet Gynecol 1987;69:390–395. 52. Wong LC, Choo YC, Ma HK. 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Tuncer ZS, Bernstein MR, Wang J, et al. Repetitive hydatidiform mole with different male partners. Gynecol Oncol 1999;75:224–226. Books@Ovid Copyright © 2002 by Lippincott Williams & Wilkins Jonathan S. Berek Novak’s Gynecology

Chapter 35. Breast Cancer Novak’s Gynecology

Chapter 35

Breast Cancer Dean T. Nora Armando E. Giuliano

Predisposing Factors Family History Diet, Obesity, and Alcohol Reproductive and Hormonal Factors History of Cancer Diagnosis Biopsy Techniques Pathology and Natural History Growth Patterns Staging Preoperative Evaluation Treatment Mastectomy Modified Radical Mastectomy Total Mastectomy Adjuvant Radiation Therapy Conservative Therapy with or without Radiation Therapy Adjuvant Systemic Therapy Hormonal Therapies General Recommendations Prognosis Special Breast Cancers Paget's Disease Inflammatory Carcinoma In Situ Carcinomas Breast Cancer in Pregnancy References

Breast cancer accounts for approximately one-third of all cancers in women and is second only to lung cancer as the leading cause of cancer deaths in women. Breast cancer, however, has the highest incidence rate of all cancers. According to estimates from the American Cancer Society, in the United States during 2002 there will be 203,500 new cases of breast cancer and 39,600 deaths from this disease in women ( 1). During the past 50 years, the incidence of breast cancer in this country has increased significantly; nearly one in every eight women in the United States will develop breast cancer. Fortunately, the mortality rate actually declined between 1993 and 1997, implying an increased success in earlier diagnosis and treatment.

Predisposing Factors Less than 1% of all breast cancers occur in women less than 25 years of age. After 30 years of age, however, there is a sharp increase in the incidence of breast cancer. Except for a short plateau between the ages of 45 and 50 years, the incidence increases steadily with age ( 2).

Family History Only 20% of women who develop breast cancer have a family history of the disease. Any family history of breast cancer increases the overall relative risk (3). However, the risk is not increased significantly in women whose mothers or sisters had breast cancer after menopause, whereas women whose mothers or sisters had bilateral breast cancer premenopausally have at least a 40% to 50% lifetime risk. If the patient's mother or sister had unilateral breast cancer premenopausally, her lifetime risk of developing breast cancer is approximately 30%. The increased incidence in this group is probably due to inherited oncogenes. Approximately 5% to 10% of all breast cancers have an inherited basis. All inherited genes are autosomal dominant but have variable penetrance. Males can carry the gene 50% of the time. Carriers of these germline mutations have up to a 4%-per-year risk of developing breast cancer and a lifetime risk of up to 85% ( 4). The most common gene mutations are the BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q12–13) gene deletions. These mutations are rare in the general public (0.1%) but are more commonly identified in Jews of Ashkenazi descent (1% to 2%) ( 5). Testing should be performed only if there is a high likelihood that results will be positive, can be interpreted accurately, and will be used to influence decisions regarding medical management of the patient and family.

Diet, Obesity, and Alcohol Marked geographic differences in the incidence of breast cancer may be related to diet, in particular with regard to variations in fat intake ( 6). It is not clear, however, that a high-fat diet is a specific risk factor, because most studies have not clearly separated obesity from other known risk factors ( 7). Alcohol consumption may increase the risk of breast cancer, but again this relationship is not clear ( 8).

Reproductive and Hormonal Factors The risk of breast cancer increases with the length of a woman's reproductive phase ( 9). Thus, the median age at menarche is lower for women who develop breast cancer, and either natural or artificial early menopause protects against the development of breast cancer ( 10). Artificial menopause as a result of oophorectomy lowers the risk of breast cancer farther than does early natural menopause. There is no clear association between the risk of breast cancer and menstrual irregularity and duration of menses. There is some evidence that these reproductive factors, although decreasing the risk of developing breast cancer, may adversely affect a patient's prognosis (11). Lactation does not affect the incidence of breast cancer, but women who have never been pregnant have a higher risk of breast cancer than those who are multiparous. Also, women who bear their first child later in life have a higher incidence of breast cancer than do younger primigravida females ( 12). A well-controlled study from the Centers for Disease Control and Prevention showed that oral contraceptive use does not increase the risk of breast cancer, regardless of duration of use, family history, or coexistence of benign breast disease ( 13). However, a recent pooled analysis from 54 epidemiologic studies showed

current users of oral contraceptives had a small, but real, increased risk when compared with nonusers. Ten years after discontinuation, the risk of past users declined to that of the normal population ( 14). Although short-term estrogen treatment for menopausal symptoms probably does not increase the risk of breast cancer, prolonged use (longer than 10 years) or higher dosages of estrogen may increase the risk. Current data suggest that postmenopausal estrogen administration is a risk factor ( 15). The current consensus is that, postmenopausally, estrogen should be given in a relatively low dose either cyclically or in combination with progestins when the uterus is present. Although estrogens may slightly increase the incidence of breast cancer, this risk should be weighed against the possible benefits in preventing osteoporosis and heart disease.

History of Cancer Women with a history of breast cancer have an approximately 50% risk of developing microscopic breast cancer and about a 20% risk of developing clinically apparent cancer in the contralateral breast, which occurs at a rate of 1% to 2% per year (16). Lobular carcinoma has a higher incidence of bilaterality than does ductal carcinoma. A history of endometrial carcinoma, ovarian carcinoma, or colon cancer has also been associated with an increased risk of breast cancer.

Diagnosis Breast cancer most commonly arises in the upper outer quadrant, where there is more breast tissue. Breast masses are most often discovered by the patient and less frequently by the physician during routine breast examination. The increasing use of screening mammography has expanded the ability to detect nonpalpable abnormalities. Rarely metastatic breast cancer may be found as an axillary mass without obvious malignancy. Mammography and physical examination, the standard screening modalities, are complementary. In the past, most cases of breast cancer were discovered as a palpable mass. However, 10% to 50% of cancers detected mammographically are not palpable. Conversely, physical examination detects 10% to 20% of cancers not seen on mammography (17). The purpose of screening is to detect cancers when they are small (