Evaluation and Management of Women With Endometriosis

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1 CLINICAL GYNECOLOGIC SERIES: AN EXPERT S VIEW We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners. Evaluation and Management of Women With Endometriosis Craig A. Winkel, MD, MBA Endometriosis is a condition that often leads to a variety of symptoms that range from pain complaints to infertility. Endometriosis is also found in women who are asymptomatic. The diagnosis of endometriosis can be made clinically with reliability similar to that of one made surgically. Medical treatment options are effective, as are surgical treatment options. Complications associated with surgery, however, push the balance in favor of medical therapy whenever possible. Based on the body of evidence available at present, women with endometriosis-related complaints should be treated with a first-line medical therapy. If that fails, a second-line medical therapy is warranted under most conditions. Laparoscopic surgery should be reserved for patients in whom second-line medical therapy has failed or is contraindicated by desire to conceive immediately or as soon as possible. (Obstet Gynecol 2003;102: by The American College of Obstetricians and Gynecologists.) From the Department of Obstetrics and Gynecology, Georgetown University, Washington, DC. We thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD. Endometriosis as a disease is both puzzling and frustrating: puzzling in the sense that little is known about its true prevalence, distribution in the population, or predisposing factors; frustrating for women because there is no definitive cure and considerable confusion exists regarding optimal methods of therapy; and frustrating for physicians because it is associated with symptoms of pain and altered fertility that do not necessarily correlate with extent of disease. Endometriosis is a common disease, with a prevalence among women of reproductive age that approaches 45% if laparoscopic visualization of lesions regardless of symptoms is the parameter assessed. 1,2 Because of its high prevalence and associated symptoms of pelvic pain and infertility, endometriosis is a major public health problem recognized as the third leading cause for gynecologic hospitalization and a leading cause of hysterectomy. 3 Costs of inpatient treatments alone for women with endometriosis were estimated in 1992 at $579 million. 4 Our lack of understanding of the pathophysiology of the disease and how it may cause pain confounds attempts to select optimal clinical management. Largely found in the dependent areas of the abdominopelvic cavity, endometriosis is defined classically as the presence of endometrial-like tissue (glands and stroma) outside the uterine cavity and musculature. We still do not know why women develop endometriosis. Whether it develops through coelomic metaplasia, through lymphatic or hematological spread, or by implantation of cells carried in retrograde menstrual flow remains unproven. Even more confusing is the fact that most women with endometriotic implants are completely asymptomatic. 2 Common complaints associated with endometriosis are pelvic pain and infertility. It has been estimated that 15% of the population of women between the ages of 18 and 50 years suffer from chronic pelvic pain. 5 The annual direct medical cost of chronic pelvic pain is estimated conservatively at $2.8 billion, with an additional $600 million in indirect costs. Up to 97% of women with chronic pelvic pain have endometriosis, 6 but we cannot identify before surgical intervention those who have endometriosis but no pain. The incidence of infertility directly attributable to endometriosis is difficult to assess. A large percentage of women with unexplained infertility are subjected to laparoscopy in an attempt to identify an etiology for infertility. Endometriosis may be coincident with infertility rather than causally related, given reports of endometri- VOL. 102, NO. 2, AUGUST /03/$ by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi: /s (03)

2 osis in almost 45% of women undergoing laparoscopy for tubal sterilization. 4 Nonetheless, it is estimated that between 30% and 50% of women with endometriosis have some degree of infertility. Severe disease may distort pelvic anatomy and result in impaired egg release, distortion of the fallopian tubes, and inhibited ovum pickup. The cause of infertility in less severe cases is much more controversial, and the search continues for plausible and provable mechanisms to explain the infertility associated with endometriosis. As a result, data supportive of altered immunological function, altered endometrial function, and chronic inflammatory states as causes of infertility in women with endometriosis are replete in the literature. Retrograde menstruation, which occurs in 90% of women, is believed to be important in seeding the peritoneal cavity with endometrial cells. Stimulated angiogenesis is likely a factor in the development of lesions from those cells because lesions are frequently found surrounded by areas of increased vascularity 7 and peritoneal fluid from women with endometriosis is higher in angiogenic activity than that of women without the disease Moreover, it has been demonstrated that estrogen enhances the production of vascular endothelial growth factor, a potent angiogenic factor, by endometriotic implants. 11 It is believed that the recruitment of resident pelvic cells initiates an intraperitoneal cascade of cytokines that mediate the pain and infertility that accompany endometriosis. 12 Endometrial cells enhance the production of haptoglobin and, perhaps, other factors by the peritoneum that in turn activate the endometrial cells to produce a number of inflammatory mediators (such as interleukin 6) and result in an inflammatory response. 13 Normal mechanisms for the clearance of ectopic endometrial cells are inhibited early in the development of the disease by the local production of macrophage migratory inhibitory factor. 14 At the same time, an increase in activated macrophages and peritoneal elevations in a host of cytokines and growth factors modulate the growth and inflammatory behavior of the endometrial implants and contribute to a cascade of events that contribute to endometriotic proliferation and invasion, recruitment of capillaries, and further chemoattraction of leukocytes to the foci of inflammation. 15 Genetic factors have been implicated in the etiology of endometriosis since concordance for endometriosis in 14 of 16 monozygotic twins has been reported. 16 An association with a specific human leukocyte antigen haplotype has not been demonstrated. Alterations in expression of the major histocompatibility complex, however, have been reported among women with endometriosis. 17 Given its significance as a public health problem, the Table 1. Common Laparoscopic Appearances of Endometriotic Lesions Clear lesions Red polypoid lesions Red flame lesions Powder-burn lesions Blue black lesions Brown lesions Yellow lesions White lesions Peritoneal windows considerable resource utilization required for the management of patients with this disease, and the continued lack of agreement regarding the optimal approach for management of women with this disease, it is the intent of the following discussion to focus on the clinical aspects of endometriosis. Based on the medical evidence currently available, a practical guide for the clinician is presented. The purpose is to develop a cogent approach to a clinical problem of considerable magnitude in the practice of gynecology today. DIAGNOSTIC APPROACH Endometriosis was first noted by von Rokitansky in 1860 and termed adenomyoma. It was Sampson s classic publication in 1920 that described the variable appearance of endometriotic implants 18 discovered at the time of exploratory laparotomy. Thereafter, histological confirmation of endometrial glands and stroma in extrauterine sites was considered the gold standard for the diagnosis of endometriosis. The advent of laparoscopy began a transition in the parameters required for a diagnosis of endometriosis. At laparotomy, most gynecologists feel comfortable excising large endometriotic lesions. At laparoscopy, however, many are reluctant to excise endometriotic implants because of concern for potential serious surgical complications. 19 With laparoscopic techniques to diagnose endometriosis and the disinclination to excise lesions, most physicians accept visualization of apparent lesions as sufficient to make the diagnosis. The protean appearances of endometriotic lesions (Table 1) have been described, 20 and the frequency of diagnosis of endometriosis at laparoscopy has increased dramatically. The question remains whether the incidence of endometriosis really has increased or whether the frequency of recognition based on visualization has increased. To rely on laparoscopic visualization of lesions to make a diagnosis may lead to inaccurate conclusions. Laparoscopic visualization of peritoneal lesions has a low 398 Winkel Endometriosis OBSTETRICS & GYNECOLOGY

3 positive predictive value for histological confirmation of endometriosis in women with chronic pelvic pain when all suspected lesions are excised and evaluated histologically. The positive predictive value of visual findings consistent with endometriosis versus histological confirmation of endometriosis ranges from 14% to 65% depending on the anatomic site (ie, ovarian fossae, anterior cul-de-sac, etc) and from 0% to 76% depending on lesion type (red vesicles, pigmented lesions, peritoneal windows, etc). 21 For sites such as the posterior cul-de-sac, the positive predictive value is relatively high, whereas for unusual sites such as the psoas muscle, the positive predictive value is very low. The overall positive predictive value for laparoscopic visualization is 43 45%. 21,22 With inaccuracy of visualization of lesions follows potential inaccuracy in assignation of stage of endometriosis at the time of laparoscopy. The American Fertility Society system for staging endometriosis was revised in This system relies on visualization of the peritoneal surfaces and identification of endometriosis visually to assign a score on which assignation of stage is based. No requirement for histological confirmation is included. With a low positive predictive value for visualization, the accuracy of American Fertility Society staging at the time of laparoscopic evaluation must be questioned. 21 A variety of pathologic lesions are confused visually with endometriosis implants. Endosalpingiosis, mesothelial hyperplasia, hemosiderin deposition (rather than hemosiderin-laden macrophages), hemangiomas, adrenal rests, residual carbon from previous ablation procedures, reactions to oil-based radiographic dyes, inflammatory changes, and splenosis all may be mistaken for endometriosis. Microscopic endometriosis may be present in visually normal peritoneum. 4 Although the true incidence of microscopic disease varies among reports and the clinical relevance of microscopic disease remains to be defined, the fact remains that not seeing endometriotic lesions does not mean that endometriosis is not present. Based on these data, the value of laparoscopic examination without biopsy of lesions must be questioned. Because laparoscopy may be misleading, the question arises as to whether the diagnosis of endometriosis can be made clinically. If the accuracy of clinical diagnosis of endometriosis approximates that of laparoscopy, the case can be made for avoiding laparoscopy altogether. In a study designed to assess the accuracy of clinical diagnosis of endometriosis, the investigators reported laparoscopic confirmation of the presence of endometriosis in 78 87% of patients evaluated. 6 There are a number of criticisms of this study: The number of subjects was small, the duration of treatment was short, and the potential for selection biases exists. Nonetheless, clinical diagnosis of endometriosis alone when based on a structured evaluation with appropriate history-taking, physical examination, appropriate imaging, and other testing appears about as accurate as laparoscopy. Endometriosis should be suspected when symptoms of pelvic pain, dysmenorrhea, dyspareunia, or infertility are present. Signs of endometriosis may include greater than normal tenderness during bimanual pelvic examination, nodularity (especially along the uterosacral ligaments or in the posterior cul-de-sac), uterine retroversion and decreased uterine mobility, pain during attempted movement of the uterus, and adnexal mass or tenderness. No single constellation of findings is pathognomonic of endometriosis. Most women with endometriosis will have completely normal pelvic examinations. 23 No laboratory findings are particularly helpful in making or confirming a diagnosis of endometriosis. An association between endometriosis and elevated serum CA 125 levels has been reported, and the CA 125 level may be of value in the woman with severe endometriosis (usually involving an ovarian endometrioma), but assessment of CA 125 is of limited value in detecting women with minimal or mild disease. 24 Among women with endometriosis, a normal CA 125 level neither confirms the absence of endometriosis 25 nor predicts recurrence. Therefore, the use of CA 125 levels to make or confirm the diagnosis of endometriosis is not warranted. Imaging studies, such as ultrasonography, magnetic resonance imaging, and computed tomography, are useful only in the presence of a pelvic or an adnexal mass. Ovarian endometriomas are typically cystic structures that contain low-level, homogeneous internal echoes consistent with old blood. 26 Sonography alone has greater predictive accuracy than sonography combined with assessment of serum CA Magnetic resonance imaging may have some value for the detection of deeply infiltrating endometriosis of the posterior cul-de-sac and uterosacral ligaments but lacks sensitivity in detection of rectal involvement. 28 With respect to women who present with infertility, diagnostic tests to confirm or disprove endometriosis are not helpful. For women with normal findings on pelvic examination, a history negative for other signs of endometriosis, and patent fallopian tubes, it is unclear that endometriosis is a cause of infertility. Laparoscopic staging of endometriosis by the modified American Fertility Society staging system correlates poorly with symptoms of pain and dyspareunia and is not predictive of fertility after treatment despite adjustments to the point scores and cut points for disease staging. 29 For the infertile woman, laparoscopic evaluation to detect anatomic dis- VOL. 102, NO. 2, AUGUST 2003 Winkel Endometriosis 399

4 tortions that might account for infertility remains a standard approach. THERAPEUTIC APPROACH Endometriosis has a high likelihood of recurrence. Also, it is unclear whether it is a progressive disease. Most treatments focus on management of symptoms believed to be secondary endometriosis. No treatment has been shown to prevent recurrence. Recurrence rates vary considerably following different treatment modalities because investigators fail to agree on specific definitions of recurrence and persistence. It has been argued that the only definitive cure for the woman with endometriosis is total hysterectomy and bilateral salpingo-oophorectomy, and yet the rates of recurrence after curative surgery are as great as 5 10%. 30 Medical and surgical therapies that do not involve hysterectomy and castration have been reported, with various rates of success and various rates of symptom recurrence. The fact that no one single therapeutic approach has emerged as the most effective reinforces the magnitude of our lack of understanding of this disease. We do not know how signs and symptoms relate to the presence of implants. There is a real need for multicenter randomized controlled trials (RCTs) to answer the question about how best to manage women with endometriosis. Before beginning such trials, we need to agree on end points of therapy. Visualization of endometriotic lesions as a starting point may be erroneous, so histological confirmation of endometriosis must be required. Likewise, using improvement in pain as a measure of success is encumbered with potential error. Some investigators have used pain scores to quantitate the improvement after therapy. Pain scores are not quantities, they are ranks. Although a score of 6 represents more pain than a score of 3, it does not necessarily mean twice as much pain. Similarly, a woman who experiences a decrease in score from 6 to 3 and a woman who decreases from 3 to 0 can both be said to have improved but cannot be said to have had the same degree of improvement. Medical Treatment Options Most medical treatments for women with endometriosis are based on the consensus that endometriosis is a hormonally responsive disease. Two physiologic conditions, pregnancy and menopause, are often associated with resolution of signs and symptoms of endometriosis. Pharmacological analogues of these conditions are pseudopregnancy, recapitulated through administration of progestins or oral contraceptives (OCs), and pseudomenopause (suppression of endogenous estrogen biosynthesis) produced by androgens and gonadotropinreleasing hormone (GnRH) analogues. Oral contraceptives are believed by many gynecologists to be the drug of choice in managing women with endometriosis. There are few comparative trials of OCs for the management of symptoms associated with endometriosis. Oral contraceptives are comparably effective to medroxyprogesterone acetate or GnRH analogues for women who complain of dysmenorrhea. 31 With respect to pelvic pain or dyspareunia, the data are less clear because there are no RCTs involving continuous use of OCs and no study with follow-up of more than 6 months. Whether continuous OCs are more effective than cyclic OCs has not been evaluated in controlled, comparative studies. It would make sense, however, if endometriosis-related pain is linked causally to estrogen and progesterone withdrawal, to use OCs in a continuous manner to induce amenorrhea. Based on a favorable side-effect profile, as well as the high level of comfort expressed by most women and physicians, continuous (noncyclic) OCs should be the first line of therapy for the medical treatment of women with endometriosis who do not wish to conceive at the time. The symptoms associated with endometriosis usually regress during pregnancy partly because of the action of progesterone. Long-term exposure of endometriotic lesions to progestins results in decidualization and atrophy. Progestins also downregulate the pituitary gland, leading to decreased ovarian biosynthesis and secretion of estrogen. The most common progestational agent used in the United States is medroxyprogesterone acetate. Twenty to 30 milligrams per day orally is the usual dosage, but investigators have reported use of doses as high as 50 mg per day. 31 In one RCT a daily dose of medroxyprogesterone acetate of 50 mg was no more effective than a placebo after 12 weeks of therapy. 32 A significant number of the women in this and other studies of medroxyprogesterone acetate relate complaints of abnormal uterine bleeding, nausea, breast tenderness, fluid retention, and depression associated with the use of medroxyprogesterone acetate. 33 Depot medroxyprogesterone acetate is a contraceptive formulation that has been recommended for women with endometriosis and pain-related symptoms. When compared with treatment with the impeded androgen danazol, depot medroxyprogesterone acetate was found to be equally effective. 34 A difficulty with depot medroxyprogesterone acetate is the high incidence of side effects such as bloating, weight gain, and depression that are experienced by 15 65% of patients treated. 31 Danazol, an impeded androgen derived from ethisterone, suppresses pituitary secretion of gonadotropins and inhibits ovulation. Danazol has been shown to re- 400 Winkel Endometriosis OBSTETRICS & GYNECOLOGY

5 Table 2. Add-Back Regimens Tested for Use With Gonadotropin-Releasing Hormone Agonists CEE, mg, MPA, 2.5 mg Daily CEE, mg, NE, 5 mg Daily NE, 5 mg Daily MPA, 20 mg Daily NE, 5 mg, etidronate Daily CEE conjugated equine estrogens; MPA medroxyprogesterone acetate; NE norethindrone acetate. lieve pain and result in clinical improvement in 55 93% of women treated for 6 months. 35 Associated with its use, however, is a high incidence of side effects. Weight gain, edema, decrease in breast size, acne, hirsutism, increased oiliness of the skin, and deepening of the voice, to name a few, are experienced in 85% of women. Gonadotropin-releasing hormone analogues, administered to induce a hypoestrogenic state, have become a standard means of therapy for women with pain associated with endometriosis. An % rate of improvement can be expected with GnRH analogue therapy. 31 Comparative trials of various GnRH analogues and danazol have also been reported. 31 In nearly all comparisons, danazol and GnRH analogues have similar effectiveness for improving pain during treatment and for maintenance of symptom relief (for at least 6 12 months) after the cessation of treatment. 31 Although depot medroxyprogesterone acetate, danazol, and GnRH analogues appear to be similarly effective, their side effect profiles are quite disparate. For side effects experienced with both depot medroxyprogesterone acetate and danazol, discontinuation is most effective, even though diuretics and antidepressants have been tried. Most side effects with GnRH analogues, on the other hand, result from hypoestrogenism (viz, vasomotor instability, vaginal dryness, irritability, arthralgia, and myalgia) and can be managed by adding back small quantities of exogenous estrogen, progestogen, or a combination of both. 36 In general, add-back regimens that involve mg of conjugated estrogens or the equivalent have been shown to be similarly effective as progestin alone in reducing side effects, while limiting bone mineral loss 36 (Table 2). In fact, in most cases there is no reason not to use add-back therapy whenever a GnRH analogue is prescribed for the management of pain. The add-back regimen to be used depends on preference of physician and patient because no one regimen has been shown to be better than another (Table 2). Importantly, there is no compromise in the effectiveness of the GnRH analogue therapy with regard to pain improvement when add-back regimens are employed. I prefer a combination of estrogen and progestin in a continuous fashion and at doses consistent with those commonly employed for the management of menopausal symptoms. With this regimen, GnRH analogues and add-back therapy can be prescribed as an effective regimen for 12 months or more. There are no data available concerning the limit for the use of GnRH analogues. If therapy is continued for longer than 12 months, it is probably a good idea to obtain bone mineral density studies at least every 24 months. Oral contraceptives should not be used because the dose of estrogen is likely to negate the effect of the GnRH agonist. Medical therapy with either GnRH analogues or danazol does not improve fecundity. 37 Therapy with GnRH analogues, danazol, or medroxyprogesterone acetate (oral or depot) decreases the chance of conception for the duration of therapy. Surgical Treatment Options There are no prospective, randomized trials that compare medical treatments with surgical treatments. There are also no comparative data on the best surgical approach. It is not clear whether lesions should be ablated (vaporized, cauterized, or desiccated) or excised. It is unclear whether adjunctive surgical procedures, such as presacral neurectomy or uterosacral nerve ablation transection, improve the outcomes of surgical therapy in terms of pain relief. It is unclear whether surgical therapy is effective for improving fertility. The decision of the clinician to undertake surgery, to choose one form of treatment over another, and to combine surgery with adjunctive procedures appears to be based more on personal opinion than evidence derived from prospective RCTs. Surgical therapy is warranted as the first line of treatment for women with pain symptoms who desire to become pregnant as soon as possible. Medical therapies, as discussed above, do not improve fertility and by their nature prevent conception. Surgical therapy has been categorized as either conservative or radical. Radical surgery commonly implies total hysterectomy and bilateral oophorectomy. This surgical approach is often referred to as definitive therapy despite the fact that endometriosis may recur in 5 10% of women who have undergone hysterectomy. 38,39 Conservative surgery is accomplished primarily via the laparoscopic approach. A number of retrospective cohort studies have compared laparotomy and laparoscopic surgical approaches for the management of endometriosis. From the results of these studies, it can be concluded that laparotomy and laparoscopic surgical approaches have similar outcomes and are similarly effective, even though the lengths of hospitalization and recovery times are shorter with the laparoscopic approach. 31,40,41 VOL. 102, NO. 2, AUGUST 2003 Winkel Endometriosis 401

6 Assessment of the outcomes that can be anticipated after the various laparoscopic techniques is confounded by a number of factors. First, visualization of endometriotic lesions at the time of laparoscopy does not necessarily correlate with histological confirmation of endometriosis. 21,22 Second, there is little correlation between findings at laparoscopy and the severity of symptoms. 42 Third, differences in technique (viz, ablation versus excision) have not been studied in any well-designed, prospective, comparative fashion. Infiltrating lesions of endometriosis are most likely associated with pain symptoms, whereas superficial lesions are less likely to be associated with pain and may be found incidentally in asymptomatic women. 43 Because infiltrating lesions may extend deep (up to 20 mm) into the subperitoneum, it might be expected that techniques aimed at excision would be more likely successful in eradicating the disease. Unfortunately, even when surgeons with a great deal of expertise in laparoscopic surgery employ aggressive excisional techniques, at least 10% of lesions are incompletely removed. 19 Although there are a number of retrospective analyses of surgical therapy for endometriosis, the results are often misquoted and the quality of the evidence often misunderstood. Consider Redwine s report. 44 The objective of this longitudinal, uncontrolled study was to define the efficacy of surgical excision of endometriosis by determining the rates of recurrence at the time of reoperation. For the 359 women in the study, recurrence at the fifth year was only 19%. This study is often quoted as the basis for choosing excisional therapy as the optimal surgical approach. The author, however, reported recurrence on the basis of visualization of lesions and provided no information on the number of women with recurrent pain symptoms. There is only one prospective, blinded RCT of surgical treatment. In 1994, Sutton et al reported the results of a study of women with minimal, mild, and moderate endometriosis (on the basis of visualization of endometriosis implants) who were randomly assigned to undergo either ablation of lesions plus uterosacral nerve ablation or sham surgery. 45 A blinded coinvestigator followed up with the patients over a 6-month period. Three months after laparoscopy, 56% of the surgically treated women continued to experience pain relief, whereas 48% of the sham operation women also experienced pain relief. Thus, for at least 3 months there is a persistent placebo effect of surgery. After 6 months, whereas 62.5% of the surgically treated women experienced pain relief, 22% of the sham operation women experienced pain relief. 45 Several points can be made regarding this study. First, there is a significant placebo effect of laparoscopy. That effect persists to some degree for more than 6 months. These results call into question the other surgical studies that have been reported because none of them included a placebo-treated group for comparison. Second, even in the best of hands and when studied in a controlled and prospective manner, laparoscopic surgery in which lesions are ablated results in a nearly 40% failure rate 6 months after surgery. Unfortunately, uterosacral nerve ablation was performed in conjunction with ablation of the endometriosis implants. We cannot be certain, therefore, that the outcomes observed were the direct result of destruction of the endometriosis. Another prospective RCT addressed indirectly the outcomes that may be anticipated with surgical therapy for women with pelvic pain and endometriosis. Women assigned at the time of laparoscopic ablation of endometriosis received postoperative GnRH analogues or placebos. The median time to initiation of additional medical treatment for pain symptoms in women treated with placebos after surgery was 11.9 months. At the end of the 2-year follow-up period, only 43% required no pain medications. 46 Seventy percent of the GnRH analogue treated women required no pain medication during the same follow-up period. From these two independent RCTs, it appears that pain recurrence after surgical therapy occurs in 40 60% of women within 1 to 2 years of surgery. Postoperative treatment with a GnRH analogue, however, prolongs pain relief when ablation is the technique employed. Surgery is the therapy usually considered for women actively seeking conception. Endometriosis may result in anatomic distortion sufficient to result in infertility, and surgical correction may improve fecundity. The question is whether or not destruction of endometriotic lesions in women without anatomic distortion will improve fecundity. Two prospective RCTs 47,48 reported conflicting results. One study of 341 women with minimal or mild endometriosis reported fecundity rates of 4.7 per 100 person-months in surgically treated women versus 2.4 in controls. 47 The Gruppo Italiano per lo Studio dell Endometriosi conducted a near identical study in 111 women. 48 The fecundity rates were 29% in the untreated group and 24% in the treated group and did not statistically differ. At present, the value of surgery for ablation of lesions remains unknown. If lesions are observed at the time of laparoscopy, however, it appears that destruction does not reduce and may improve fecundity. Adjunctive surgical procedures. Two adjunctive surgical procedures have been the subject of dispute in the management of women with endometriosis-related pelvic pain. Uterosacral nerve ablation and presacral neurectomy are procedures that many believe play a role 402 Winkel Endometriosis OBSTETRICS & GYNECOLOGY

7 in improving the effectiveness of surgical treatment of women with pain. Laparoscopic uterosacral nerve ablation is a procedure based on the premise that destruction of the efferent nerve fibers in the uterosacral ligaments will diminish pain arising from the uterus. Uterosacral nerve ablation has been shown to be effective for the management of primary dysmenorrhea but no more effective for secondary dysmenorrhea in women with endometriosis than conservative surgery alone. Therefore, there appears to be minimal efficacy for laparoscopic uterosacral nerve ablation in the management of most women with endometriosis. 49 Presacral neurectomy is designed to interrupt efferent sympathetic pathways from the uterus. There are potential side effects with presacral neurectomy. Increased incidences of constipation, urinary urgency, and painless first stage of labor have been reported after presacral neurectomy. 49 Presacral neurectomy combined with surgical treatment for endometriosis is no more effective than surgical treatment of endometriosis alone, although data suggest that midline, dysmenorrheic pain may be relieved. 49 Based on these reports, I believe that presacral neurectomy should not be undertaken routinely. Ovarian endometriomas. Ovarian endometriosis may present as an adnexal mass. Although the clinician may suspect an endometrioma, the finding of a mass on pelvic examination of a woman in her 40s presents the physician with a diagnostic dilemma. Sonographic evaluation may support a diagnosis of endometriosis but cannot rule out a malignancy. 26 Medical therapy has proven ineffective in reducing the size of ovarian endometriomas. Surgery is the appropriate approach to evaluate and treat women suspected of having ovarian endometriomas. A variety of techniques for surgical management of ovarian endometriomas have been reported. There is, however, no prospective comparative study upon which to base a recommendation regarding the optimal approach. Smaller cysts may be excised, but most should be drained and tissue samples obtained for histological evaluation. If endometriotic lesions are visualized elsewhere in the pelvis and the cyst is 10 cm or less, the likelihood that the mass is an endometrioma is high. There is limited and somewhat contradictory information regarding the effect of endometriosis, in general, and an ovarian endometrioma, specifically, on fertility. 50 Among women with ovarian endometriomas treated via in vitro fertilization (IVF) there is some reduction in numbers of eggs retrieved, and increased incidence of early pregnancy loss is associated with larger cysts. 51 Small endometriomas appear not to adversely affect the results that can be expected with assisted reproductive techniques. 52 The issue of endometriosis and its effect on IVF success remains somewhat controversial, but most reports suggest that the presence of lesions per se has little or no effect on success with IVF. 50 Based on current data regarding the surgical approach for the management of women with endometriosis, the following statements can be made: First, surgical treatment is associated with significant rates of failure (40 60%) with respect to pain recurrence within 1 to 2 years. Second, the value of surgical therapy for women with minimal or mild disease who have reduced fertility has yet to be established. Third, postoperative medical therapy appears to extend the pain-free interval after ablative surgical treatment. Fourth, adjunctive surgical procedures add little to the success of surgical treatments and cannot be recommended routinely. Fifth, ovarian endometriomas should be managed surgically. Given that surgical therapy and medical therapies have similar effectiveness with respect to pain relief, I believe a strong case can be made for choosing medical therapy as the initial treatment approach provided other disease processes such as gastrointestinal and urinary tract and pain processing disorders such as fibromyalgia have been eliminated 29 (Figure 1). If first-line therapy with continuous OCs and nonsteroidal anti-inflammatory drugs fail to improve symptoms within a reasonable time (3 months), a second-line therapy with GnRH analogues and add-back should be tried, for a time. If second-line therapy fails, the clinician should reconsider other causes of pain. It is appropriate to perform laparoscopy if GnRH analogue therapy has failed because pelvic adhesions may be a cause of pain. Importantly, this plan for the management of pain and endometriosis has been ratified by a consensus panel made up of practicing gynecologists from throughout the United States. 53 Many physicians argue that laparoscopy should be performed to rule out ovarian cancer as a cause of pain. It would be unlikely that a diagnosis of ovarian cancer would be made, however, given normal pelvic examination and normal imaging studies. COMPLICATIONS Serious events with the use of OCs have been described but are unusual among women who do not smoke. The cardiovascular death rate in nonsmokers under the age of 35 is less than 0.1 per 100,000 users, versus rates of 3 per 100,000 for nonsmokers ages and 19.4 per 100,000 users ages who are smokers. 21 Estimates of serious health risks of OC use are reduced when the dose of ethinyl estradiol in the OC is 50 g or less. Oral contraceptives, therefore, appear to be a safe, first line of medical therapy. VOL. 102, NO. 2, AUGUST 2003 Winkel Endometriosis 403

8 Figure 1. Recommended strategy for the management of women with endometriosis and pain symptoms. NSAIDs nonsteroidal antiinflammatory drugs; GnRHa gonadotropin-releasing hormone analogues. Winkel. Endometriosis. Obstet Gynecol Published results of treatments with danazol or GnRH analogues demonstrate no serious side effects from either medication. There are no reports specific to depot medroxyprogesterone acetate. To evaluate the possibility of serious side effects with danazol or GnRH analogues, the US Food and Drug Administration Adverse Event Reporting System for November 1997 through March 2000 was consulted recently and revealed no differences in adverse event reports for either drug. 21 No serious side effects from either medication were reported, although the appearance of depression in women on either therapy might be considered potentially serious. Adverse events experienced by women on GnRH analogues included cognitive dysfunction, bone pain, and joint pain. Similar events were reported for women on danazol. The incidences of adverse events were 3% and 4% for danazol and GnRH analogues, respectively. Surgical treatment of women with endometriosis is associated with risks of surgical complications. One highly experienced laparoscopist has reported surgical complications associated with excisional techniques that vary between 6% (bowel injury) and 0.5% (ureteral injury). 19 In a survey of nearly 2000 gynecologic surgeons who considered themselves experienced surgeons, 5% admitted major vascular injuries, 3.8% ureteral injuries, and 17.5% bowel injuries during laparoscopic procedures. 54 The total number of procedures performed by this group is not known, so the rate of each type of complication cannot be stated. Clearly the incidence of complications with laparoscopic surgery is higher than commonly stated. When discussing risks of surgery with a woman with endometriosis in whom one is contemplating surgery, the associated risks need to be discussed in detail. Most clinicians do not keep accurate statistics regarding the rates of complications associated with their own surgical procedures. In lieu of personal statistics, which are always preferable, the patient should be counseled regarding risks of vascular, gastrointestinal, and urinary tract injury and the real possibility of the need for exploratory laparotomy suggested by the data reviewed by Feste and Winkel. 54 It might be expected that excisional techniques are more likely associated with certain types of complications than ablative techniques. The literature does not support a benefit of one surgical technique over another. Because postoperative medical therapy appears to extend the pain-free interval after ablative surgery, the use of postoperative medical therapy may allow surgeons to use a less invasive surgical technique. If ablative surgery is undertaken, adjunctive postoperative medical therapy should be recommended if immediate attempts at conception are not contemplated. Likewise, despite the absence of scientific data, postoperative therapy should be considered after excisional therapy. CONCLUSION The answers to many important questions regarding evaluation and management of women with endometriosis remain unknown. From the information currently available, however, I believe we can answer some commonly posed ones (Table 3). The evidence available at present regarding the diagnosis and management of endometriosis among women with symptoms of pelvic pain, dysmenorrhea, dyspareunia, and infertility needs to be expanded to address many important issues that 404 Winkel Endometriosis OBSTETRICS & GYNECOLOGY

9 Table 3. Common Questions in Management of Women With Endometriosis Clinical question Pertinent evidence Clinical recommendation How accurate is laparoscopic visualization of endometriosis? The PPV for visualization is 43 45%. 21,22 Laparoscopy is much less than perfect as a diagnostic tool. How accurate is clinical diagnosis of endometriosis? Endometriosis has been confirmed in 78 87% of women in whom a clinical A clinical diagnosis of endometriosis does not need to be confirmed by laparoscopy What is the role for OCs in the management of endometriosis? What are the appropriate secondline medical therapies for endometriosis? Which surgical technique is best for management of endometriosis? What outcome can be expected with surgical or medical treatments? Does treatment for endometriosis improve fertility if there are no anatomic abnormalities? Can endometriosis be present in postmenopausal women? diagnosis was made. 6 In RCTs, OCs have been shown as effective for specific management of dysmenorrhea as MPA and GnRHa. 31 Danazol, depot MPA, and GnRHa appear equally effective for the management of pain due to endometriosis. 31 There are no prospective trials of excision versus ablation techniques. The pain recurrence rate within 1 y after surgical destruction is nearly 40%. 45 Two years after GnRHa, the recurrence rate is 30 40%. 30,31 One RCT 47 found improved fecundity with lesion destruction and one 48 did not. Women without ovarian function can develop recurrences of endometriosis if given exogenous estrogen. 30,31 if response to medication is as expected. OCs are an appropriate first-line medical therapy for women with endometriosisrelated dysmenorrhea. Continuous rather than cyclic use is preferred. Although all three drugs are similar in effectiveness, they vary significantly in side effects. Those associated with GnRHa can be managed effectively with add-back treatments. Because deep lesions cause pain, excision would be expected to be most effective. But ablation followed by GnRHa may be as effective and less risky. Although no RCT comparing surgical and medical treatment has been reported, results from individual RCTs are similar. If medical therapy fails, surgery can be accomplished. With normal tubal studies, laparoscopy to destroy lesions and improve fertility is controversial, but if lesions are found incidentally at laparoscopy in an infertile woman, destruction should be performed. A diagnosis of endometriosis should be considered in the postmenopausal woman on estrogen who complains of pain. This is especially so if she has a history of endometriosis. PPV positive predictive value; OC oral contraceptive; RCT randomized controlled trial; MPA medroxyprogesterone acetate; GnRHa gonadotropin-releasing hormone analogues. are still debated. Recommendations made today may well change in the future, just as we have witnessed an evolution in our thinking about this topic over time. A good history and physical examination, in conjunction with appropriate laboratory and imaging studies, are predictive of laparoscopic findings of endometriosis. Thus, it is likely that laparoscopy and its attendant complications can be avoided in the majority of women. There is a serious need for prospective, randomized, comparative trials of medical versus surgical therapy to define the optimal approach. Given the limitations that persist, it appears that the outcomes in terms of pain relief are similar when comparing surgical and medical treatment approaches. Because most surgeons tend to employ ablative techniques, the accuracy of laparoscopic visualization of endometriosis may be low, and excisional techniques likely are associated with a greater incidence of complications, use of a GnRH analogue or other adjunctive medical treatments postoperatively appears to be warranted to extend the pain-free interval. If medical treatment is selected, OCs should be the initial therapeutic choice. If OCs fail, the choice of second-line medical therapy should be made on the basis of optimizing management of side effects because medroxyprogesterone acetate, danazol, and GnRH analogues appear equally effective for the management of pain symptoms. Only with GnRH analogues can side effects be managed effectively while therapy is continued. When a GnRH analogue is prescribed, add-back therapy should be considered from the outset because it effectively ameliorates side effects without compromising effectiveness. Surgical approaches do retain a place in the treatment armamentarium. The management of women who seek conception and who experience pain symptoms should be surgical because medical treatments postpone concep- VOL. 102, NO. 2, AUGUST 2003 Winkel Endometriosis 405

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12 53. Gambone JC, Mittman B, Munro M, Scialli A, Winkel CA. Consensus statement for the management of chronic pelvic pain and endometriosis: Proceedings of an expert-panel consensus process. Fertil Steril 2002;78: Feste JR, Winkel CA. Is the standard of care what we think it is? J Soc Laparoendosc Surg 1999;3: Address reprint requests to: Craig A. Winkel, MD, MBA, Department of Obstetrics and Gynecology, Georgetown University, 3800 Reservoir Road NW, #3PHC, Washington, DC 20007; [email protected]. Received May 2, Received in revised form December 18, Accepted December 26, Winkel Endometriosis OBSTETRICS & GYNECOLOGY