Endometriosis - Chapter 13 PDF

CHAPTER 13 Endometriosis Arne Vanhie, Thomas M. D’Hooghe Epidemiology Prevalence Risk and Protective Factors Endometriosis and Cancer Etiology Genetic Factors Germline Variants Somatic Alterations Immunologic Factors and Inflammation Environmental Factors and Dioxin Human Da...

CHAPTER 13 Endometriosis Arne Vanhie, Thomas M. D’Hooghe Epidemiology Prevalence Risk and Protective Factors Endometriosis and Cancer Etiology Genetic Factors Germline Variants Somatic Alterations Immunologic Factors and Inflammation Environmental Factors and Dioxin Human Data Nonhuman Primates Rodents Stem Cells Future Research Diagnosis Clinical Presentation Pain Infertility Endocrinologic Abnormalities 665  Extrapelvic Endometriosis Clinical Examination Imaging Ultrasound Other Imaging Techniques Assessment of Intestinal and Urologic Involvement Blood and Other Tests CA125 Laparoscopy General Considerations Laparoscopic Technique Laparoscopic Findings Histologic Confirmation Laparoscopic Classification Spontaneous Evolution Management Primary Prevention Principles of Treatment Treatment of Endometriosis-Associated Pain Surgical Treatment Medical Treatment of Endometriosis-Associated Pain Primary Dysmenorrhea Treatment of Endometriosis-Associated Pain Oral Contraceptives Progestins Progesterone Antagonists and Selective Progesterone Receptor Modulators Danazol Aromatase Inhibitors Selective Estrogen Receptor Modulators GnRH Antagonists Nonhormonal Medical Therapy Treatment of Endometriosis-Associated Infertility Surgical Treatment Preoperative and Postoperative Medical Treatment Hormonal Treatment Medically Assisted Reproduction Management of Adolescents Management of Postmenopausal Women Management of Recurrent Endometriosis Recurrence After Medical Treatment Recurrence After Conservative Surgery Recurrence After Hysterectomy Risk Factors for Recurrence Prevention of Recurrence 666  Medical Treatment of Recurrence Surgical Treatment of Recurrence Coping With Disease KEY POINTS 1 Endometriosis is diagnosed by visualization of lesions during laparoscopy, ideally with histologic confirmation; positive histology confirms the diagnosis, but negative histology does not exclude it. 2 Endometriosis can be associated with infertility, pelvic pain, that is, dysmenorrhea, dyspareunia and nonmenstrual pain, and reduced quality of life. 3 Severe or deep endometriosis should be managed in a facility with the necessary expertise to provide treatment in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy. 4 The American Society for Reproductive Medicine (ASRM) staging system for endometriosis is subjective and correlates poorly with pelvic pain and infertility. 5 The Endometriosis Fertility Index (EFI) predicts non-in vitro fertilization (IVF) pregnancy rates after surgical treatment of endometriosis. 6 Suppression of ovarian function reduces pain associated with endometriosis. Different classes of hormonal drugs—combination oral contraceptives, progestins, gonadotropin-releasing hormone (GnRH) agonists—are equally effective in reducing pain but have differing side effects and costs. 7 Ablation or resection of endometriotic lesions plus adhesiolysis in minimal to mild endometriosis is more effective than diagnostic laparoscopy alone in improving fertility. 8 Suppression of ovarian function is not effective in improving subsequent fertility in patients with endometriosis. Endometriosis is defined as the presence of endometrial-like tissue (glands and/or stroma) outside the uterus. The most frequent sites of implantation are the pelvic viscera and the peritoneum but, although rare, it can also be found in the pericardium, pleura, lung, and even the brain. Endometriosis varies in appearance from a few minimal lesions on otherwise intact pelvic organs, to deep infiltrating nodules and massive ovarian endometriotic cysts with extensive adhesions involving bowel, bladder, and ureter resulting in significant distortion of the pelvic anatomy. It is estimated to occur in 10% of reproductive- age women and is associated with pelvic pain and infertility. Considerable progress in understanding the pathogenesis, spontaneous evolution, diagnosis, and treatment of endometriosis has occurred. The European Society for Human 667 Reproduction and Embryology (ESHRE) guidelines for the clinical management of endometriosis are published and regularly updated to present emerging clinical evidence (1). EPIDEMIOLOGY Prevalence Endometriosis is found predominantly in women of reproductive age but is reported in adolescents and in postmenopausal women receiving hormonal replacement therapy (2). It is found in women of all ethnic and social groups. Estimates of the frequency of endometriosis vary widely, but the prevalence of the condition is assumed to be around 10% women of reproductive age (3,4). Although no consistent information is available on the incidence of the disease, temporal trends suggest an increase among women of reproductive age (4). The World Endometriosis Research Foundation (WERF) EndoCost study calculated the costs of women with histologically proven endometriosis treated in referral centers (5). The study showed that the costs to women with endometriosis are substantial, resulting in an economic burden similar to the estimated annual health care costs for diabetes mellitus, Crohn disease, and rheumatoid arthritis (5). In women with pelvic pain or infertility, a high prevalence of endometriosis (from a low of 20% to a high of 90%) is reported (6,7). In women with unexplained infertility (regular menstrual cycle, normal pelvic imaging, normospermic partner) with or without pain, the prevalence of endometriosis is reported to be as high as 50% (8). In asymptomatic women undergoing tubal ligation (women of proven fertility), the prevalence of endometriosis ranges from 3% to 43% (9–14). This variation in the reported prevalence may be explained by several factors. First, it may vary with the diagnostic method used: laparoscopy, the operation of choice for diagnosis, is a better method than laparotomy for diagnosing minimal to mild endometriosis. Second, minimal or mild endometriosis may be more thoroughly evaluated in asymptomatic patients than in asymptomatic patients during tubal sterilization. Third, the interest and experience of the surgeon has relevance because there is a wide variation in the appearance of subtle endometriosis implants, cysts, and adhesions. Most studies that evaluate the prevalence of endometriosis in women of reproductive age lack histologic confirmation (9–11,15–20). Risk and Protective Factors The following are possible risk factors for endometriosis: infertility, red hair, early age at menarche, shorter menstrual cycle length, hypermenorrhea, nulliparity, müllerian anomalies, low birth weight (less than 7 pounds), being 668 one of multiple fetal gestation, diethylstilbestrol (DES) exposure, endometriosis in first-degree relative, tall height, dioxin or polychlorinated biphenyls (PCB) exposure, a diet high in fat and red meat, and prior surgeries or medical therapy for endometriosis (21,22). Prior use of contraception or intrauterine device (IUD), or smoking is not associated with increased risk of endometriosis (23,24). Protective factors against the development of endometriosis include multiparity, lactation, tobacco exposure in utero, increased body mass index, increased waist-to-hip ratios, and diet high in vegetables and fruits (21,25). Some evidence suggests that women with a “pinpoint cervix” have an increased risk for endometriosis, but more studies are needed to confirm this observation (26). Endometriosis and Cancer Several publications link endometriosis with an increased risk for certain gynecologic and nongynecologic cancers (27,28). These associations are controversial and no good data exist to inform clinicians regarding the best management of patients who might be at risk of developing such cancers (1). Endometriosis should not be considered a medical condition associated with a clinically relevant risk of any specific cancer (29). Data from large cohort and case-control studies indicate an increased risk of ovarian cancers in women with endometriosis. The observed effect sizes are modest, varying between 1.3 and 1.9 (30). Evidence from clinical series consistently demonstrates that the association is confined to the endometrioid and clear-cell histologic types of ovarian cancer (31). A causal relationship between endometriosis and these specific histotypes of ovarian cancer should be recognized, but the low magnitude of the risk observed is consistent with the view that ectopic endometrium undergoes malignant transformation with a frequency similar to its eutopic counterpart (32). Evidence for an association with melanoma and non-Hodgkin lymphoma has been reported but needs to be verified, whereas an increased risk for other gynecologic cancer types is not supported (31). ETIOLOGY Although signs and symptoms of endometriosis have been described since the 1800s, its widespread occurrence was acknowledged only during the 20th century. Endometriosis is an estrogen-dependent disease. Three theories were proposed to explain the pathogenesis of endometriosis: 1. Ectopic transplantation of endometrial tissue 2. Coelomic metaplasia 669 3. The induction theory No single theory can account for the location of endometriosis in all cases. Transplantation Theory The transplantation theory, originally proposed by Sampson in the mid- 1920s, is based on the assumption that endometriosis is caused by the seeding and implantation of endometrial cells by transtubal regurgitation during menstruation (33). Substantial clinical and experimental data support this hypothesis (6,34). Retrograde menstruation occurs in 70% to 90% of women, and it may be more common in women with endometriosis than in those without the disease (9,35). The presence of endometrial cells in the peritoneal fluid, indicating retrograde menstruation, is reported in 59% to 79% of women during menses or in the early follicular phase, and these cells can be cultured in vitro (36,37). The presence of endometrial cells in the dialysate of women undergoing peritoneal dialysis during menses supports the theory of retrograde menstruation (38). Endometriosis is most often found in dependent portions of the pelvis—the ovaries, the anterior and posterior cul-de-sac, the uterosacral ligaments, the posterior uterus, and the posterior broad ligaments (39). The menstrual reflux theory combined with the clockwise peritoneal fluid current explains why endometriosis is predominantly located on the left side of the pelvis (refluxed endometrial cells implant more easily in the rectosigmoidal area) and why diaphragmatic endometriosis is found more frequently on the right side (refluxed endometrial cells implant there by the falciform ligament) (40,41). Endometrium obtained during menses can grow when injected beneath abdominal skin or into the pelvic cavity of animals (42,43). Endometriosis was found in 50% of Rhesus monkeys after surgical transposition of the cervix to allow intra-abdominal menstruation (44). Increased retrograde menstruation by obstruction of the outflow of menstrual fluid from the uterus is associated with a higher incidence of endometriosis in women and in baboons (45–47). Women with shorter intervals between menstruation and longer duration of menses are more likely to have retrograde menstruation and are at higher risk for endometriosis (48). Menstruation is associated with intraperitoneal inflammation in women and baboons, but a limited quantity of endometrial cells can be identified in peritoneal fluid during menstruation in women, possibly because endometrial–peritoneal attachment is reported to occur within 24 hours (49–51). Ovarian endometriosis may be caused by either retrograde menstruation or by lymphatic flow from the uterus to the ovary; metaplasia and bleeding from a corpus luteum may be a critical event in the development of some endometriomas (52–54). 670  Deep endometriosis, with a depth of at least 5 mm beneath the peritoneum, can present as nodules in the cul-de-sac, rectosigmoid, and bladder area and occurs with other forms of peritoneal or ovarian endometriosis (55). According to anatomic, surgical, and pathologic findings, deep endometriotic lesions originate intraperitoneally rather than extraperitoneally. The lateral asymmetry in the occurrence of ureteral endometriosis is compatible with the menstrual reflux theory and with the anatomic differences of the left and right hemipelvis (40). Adolescents and young women can have peritoneal disease (56). This observation, together with evidence from the development and spontaneous evolution of endometriosis in baboons, supports the notion that endometriosis starts as peritoneal disease and that the three different phenotypes and locations of endometriosis (peritoneal, ovarian, and deep) represent a homogeneous disease continuum with a single origin (i.e., regurgitated endometrium), rather than three different disease entities (40,57,58). Extrapelvic endometriosis, although rare (1% to 2%), may result from vascular or lymphatic dissemination of endometrial cells to many gynecologic (vulva, vagina, cervix) and nongynecologic sites. The latter include bowel (appendix, colon, small intestine, hernia sacs), lungs and pleural cavity, skin (cesarean section, episiotomy or other surgical scars, inguinal region, extremities, umbilicus), lymph glands, nerves, and brain (59). Coelomic Metaplasia The transformation (metaplasia) of coelomic epithelium into endometrial tissue is a proposed mechanism for the origin of endometriosis. One study evaluating structural and cell surface antigen expression in the rete ovarii and epoophoron reported little commonality between endometriosis and ovarian surface epithelium, suggesting that serosal metaplasia is unlikely in the ovary (60). The results of another study involving the genetic induction of endometriosis in mice suggest that ovarian endometriotic lesions may arise directly from the ovarian surface epithelium through a metaplastic differentiation process induced by activation of an oncogenic K-ras allele (53). Induction Theory The induction theory is an extension of the coelomic metaplasia theory. It proposes that an endogenous (undefined) biochemical factor can induce undifferentiated peritoneal cells to develop into endometrial tissue. This theory is supported by experiments in rabbits but is not substantiated in women or nonhuman primates (61,62). Genetic Factors 671 Endometriosis is a complex disorder caused by a combination of multiple genetic and environmental factors. These genetic factors need to be divided into germline and somatic genetic variants. The former is inherited and results in a higher chance of developing endometriosis, the latter are somatic alterations that possibly play a role in the pathophysiology of endometriosis. Germline Variants Inherited genetic variants associated with endometriosis confer a genetic susceptibility to develop the disease but represent only approximately 50% of the risk associated with the disease (63). The heritable component of endometriosis is demonstrated by familial clustering in humans and in Rhesus monkeys, a founder effect detected in the Icelandic population, higher concordance in monozygotic versus dizygotic twins, a similar age at onset of symptoms in affected nontwin sisters, an increased prevalence of endometriosis among first-degree relatives and a 15% prevalence of magnetic resonance imaging (MRI) findings suggestive of endometriosis in the first-degree relatives of women with ASRM stage III or IV disease (64). The induction of human-like endometriosis in mice by genetic activation of an oncogenic K-ras allele lends further support to the genetic basis of this disorder (53). The risk of endometriosis is seven times greater if a first-degree relative is affected by endometriosis (65). Because no specific mendelian inheritance pattern is identified, multifactorial inheritance is postulated. Family linkage studies and genome-wide association studies (GWAS) have provided insights on the genetic variants contributing to the hereditary risk of endometriosis. Family linkage studies identify genetic variants that lead to clustering of endometriosis in certain families, but these variants are often rare in the general population. GWAS studies uncover common genetic variants in the general population related to an increased risk of endometriosis (63). A meta-analysis of 11 GWAS identified 19 independent single nucleotide polymorphisms associated with endometriosis (66). However, all these polymorphisms combined explain only approximately 5% of variance in endometriosis. These genetic variants are located in or near a wide variety of genes with functions in diverse pathways: sex steroid hormone signaling (FSHB, ESR1), inflammation (NFE2L3), oncogenesis (ID4), uterine development (HOXA10, HOXA11), WNT signaling (WNT4, MIR148), estrogen responsive genes (GREB1, KDR) and genes involved in the actin cytoskeleton or cellular adhesion (FN1, VEZT, ANRIL). Large genome-wide linkage studies, including more than 1,300 families with multiple women affected by endometriosis, have identified three linkage regions of endometriosis: on chromosome 10q26, chromosome 20p13, and chromosome 7p13-15 (63,67,68). The genes in these 672 linkage regions have roles in estrogen metabolism (CYP2C19 in the 10q26 region) and in endometrial or uterine development (INHBA, SFRP4 and HOXA10 in the 7p13-15 region). Functional studies of the genes in these endometriosis risk loci are needed to elucidate their precise role and determine the effects of the variants in underlying pathways. These targeted functional gene studies have the potential to provide us with important new insights on the pathogenesis of endometriosis. Somatic Alterations Aneuploidy Epithelial cells of endometriotic cysts are monoclonal on the basis of phosphoglycerate kinase gene methylation, and normal endometrial glands are monoclonal (69,70). In a comparison of endometriotic tissue with eutopic endometrium, flow cytometric DNA analysis failed to show aneuploidy (71). Studies using comparative genomic hybridization, or multicolor in situ hybridization, showed aneuploidy for chromosomes 11, 16, and 17, increased heterogeneity of chromosome 17 aneuploidy, and losses of 1p and 22q (50%), 5p (33%), 6q (27%), 70 (22%), 9q (22%), and 16 (22%) of 18 selected endometriotic tissues (72–74). In another study, trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium (75). The proportions of aneusomic cells were significantly higher in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (p 4 cm in diameter) and in deep endometriosis, histology is recommended to exclude rare instances of malignancy (1). 689 690 FIGURE 13-2 Typical and subtle endometriotic lesions on peritoneum. A: Typical black- puckered lesions with hypervascularization and orange polypoid vesicles. B: Red polypoid lesions with hypervascularization. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) 691 692 693 694 FIGURE 13-3 Ovarian endometriosis. A: Superficial ovarian endometriosis. B: Superficial ovarian endometriosis and endometrioma—laparoscopic image prior to adhesiolysis. C: Laparoscopic image of uterus and right ovary with dark endometrioma. D: Ovarian endometriotic cystectomy. E: Ovarian endometriotic cystectomy. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) 695 696 697 FIGURE 13-4 Laparoscopic excision of deep endometriosis from the cul-de-sac. A: Extensive endometriosis with deep nodule at the right uterosacral ligament, masked by adhesions. B: Deep nodule still present in dense adhesion between rectum and uterosacral ligaments. C: Cul-de-sac after resection of deep nodule with CO2 laser. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) 698 699 FIGURE 13-5 Revised American Society for Reproductive Medicine Classification. (From the American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis. Am Soc Reprod Med 1997;5:817– 821.) 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 approach resulted in a low diagnostic accuracy of laparoscopic inspection with a positive predictive value of only 45%, explained by a specificity of only 77% (225). Microscopically, endometriotic implants consist of endometrial glands and/or stroma, with or without hemosiderin-laden macrophages (Fig. 13-6). It is suggested that using these stringent and unvalidated histologic criteria may result in significant underdiagnosis of endometriosis (6). 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 (226). The presence of stromal endometriosis, which contains endometrial stroma with hemosiderin-laden macrophages or hemorrhage, was reported in women and in baboons and may represent a very early event in the pathogenesis of endometriosis (148,220,221). Isolated endometrial stromal cell nodules, immunohistochemically positive for vimentin and estrogen receptor, can be found in the absence of endometrial glands along blood or lymphatic vessels (227). 700 FIGURE 13-6 Histologic appearance of endometriosis: endometrial glandular epithelium, surrounded by stroma in typical lesion and clear vesicle. Different types of lesions may have different degrees of proliferative or secretory glandular activity (226). Vascularization, mitotic activity, and the three- dimensional structure of endometriosis lesions are key factors (171,228,229). Deep endometriosis is described as a specific type of pelvic endometriosis characterized by proliferative strands of glands and stroma in dense fibrous and smooth muscle tissue (20). Smooth muscles are frequent components of endometriotic lesions on the peritoneum, ovary, rectovaginal septum, and uterosacral ligaments (174). Microscopic endometriosis is defined as the presence of endometrial glands and stroma in macroscopically normal pelvic peritoneum. It is important in the histogenesis of endometriosis and its recurrence after treatment (230,231). The clinical relevance of microscopic endometriosis is controversial because it is not 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 (231). 701 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 were demonstrated by light microscopy in areas that showed no obvious evidence of disease (232). In serial sections of laparoscopic biopsies of normal peritoneum, 10% to 15% of women had microscopic endometriosis, and endometriosis was found in 6% of those without macroscopic disease (219,233,234). Other studies were unable to detect microscopic endometriosis in 2-mm biopsy specimens of visually normal peritoneum (235–238). Examination of larger samples (5 to 15 mm) of visually normal peritoneum revealed microscopic endometriosis in only 1 of 55 patients studied (239). 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 (96). Macroscopically appearing normal peritoneum rarely contains microscopic endometriosis (239). Laparoscopic Classification Endometriosis is a complex disease and at present there is no perfect staging system available. The most widely used staging system is the revised American Society for Reproductive Medicine classification (rASRM). The Endometriosis Fertility Index (EFI) has been shown to predict non-IVF pregnancy rates for patients following surgical staging and treatment of endometriosis (177,240). To supplement the rASRM classification with regard to the description of deep endometriosis, the ENZIAN score was introduced (241–243). Although the ENZIAN score appears to be a good complement to the rASRM score for morphologic description of deep endometriosis and planning of surgery, it is not widely used. Recently the World Endometriosis Society (WES) published a consensus statement in which they recommend that all women undergoing surgery should have the rASRM classification completed, women with deep endometriosis should additionally have ENZIAN completed, and women for whom future fertility is a concern should additionally have the EFI completed (244). American Society for Reproductive Medicine Staging The revised ASRM staging system, 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 (179,201). In this 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), 702 according to color photographs provided by ASRM. This system reflects the extent of endometriotic disease but has considerable intraobserver and interobserver variability (245,246). The ASRM classification for endometriosis is subjective and correlates poorly with pain and fertility outcomes (175). Despite these important shortcomings the WES recommends its use because of two important reasons: it is the most widely used staging system in clinical practice and endometriosis research, and it is the rASRM system (partially) incorporated in the EFI and ENZIAN. Endometriosis Fertility Index The EFI staging system predicts non-IVF pregnancy rates after surgical staging and treatment of endometriosis (Fig. 13-7) (177). The EFI is based on historical and surgical factors. The historical factors are age, years of infertility, and prior pregnancies. The surgical factors consist of the total ASRM score, the ASRM endometriosis score, and the least function score, which describes functionality of the fallopian tubes, fimbriae, and ovaries. The EFI was designed specifically for infertility patients who have had surgical staging and treatment of their disease. It is not intended to predict any aspect of endometriosis associated pain. It is required that the male and female gametes are sufficiently functional to enable attempts at non-IVF conception. Severe uterine abnormality that is clinically significant is not included in the EFI. However, when this condition is found it does need to be taken into account in predicting pregnancy rates. ENZIAN Classification The ENZIAN staging system supplements the rASRM staging with a precise description of the location and extent of deep endometriosis lesions and the involvement of retroperitoneal structures or other organs. The anatomic location of the deep endometriotic lesions is described in three compartments: A = rectovaginal septum and vagina; B = sacrouterine ligament to pelvic wall; and C = rectum and sigmoid colon. The depth of invasion is rated for all compartments (grade 1 = invasion 3 cm). Deep endometriotic lesions outside the pelvis and invasion of organs is registered separately: FA = adenomyosis; FB = bladder; FU = intrinsic involvement of the ureter; FI = intestinal disease cranial to the rectosigmoid junction; and FO = other locations, such as abdominal wall endometriosis. The ENZIAN classification seems to be useful in planning endometriosis surgery, but more research is needed on the correlation with pain or infertility and clinical relevant outcomes. 703 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 (247,248). In another study, endometriosis progressed in 64%, improved in 27%, and remained unchanged in 9% of patients over 12 months (249). 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 with spontaneous endometriosis over 24 months demonstrated disease progression in all baboons and in 6 of 7 women (250–252). Several studies 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 (253). This finding was 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 (7). Remodeling of endometriotic lesions (transition between typical and subtle subtypes) is reported to occur in women and in baboons, indicating that endometriosis is a dynamic condition (254,255). Several studies in women, cynomolgus monkeys, and rodents showed that endometriosis is ameliorated after pregnancy (255–258). The characteristics of endometriosis are variable during pregnancy, and lesions tend to enlarge during the first trimester but regress thereafter (259). Studies in baboons revealed no change in the number or surface area of endometriosis lesions during the first two trimesters of pregnancy (260). These results do not exclude a beneficial effect that may occur during the third trimester or in the immediate postpartum period. Establishment of a “pseudopregnant state” with exogenously administered estrogen and progestins is based on the belief that symptomatic improvement may result from decidualization of endometrial implants during pregnancy (261). This hypothesis is not substantiated, and it is possible that amenorrhea can explain the beneficial effect of pregnancy and lactation on endometriosis-associated pain symptoms. MANAGEMENT Primary Prevention No strategies to prevent endometriosis are uniformly successful. A reduced incidence of endometriosis was reported in women who engaged in aerobic activity from an early age, but the possible protective effect of exercise was not investigated thoroughly (48). There is insufficient evidence that OC use offers 704 protection against the development of endometriosis. One report showed an increased risk for endometriosis in a select population of women taking OCs, possibly explained by the observation that dysmenorrhea as a reason to initiate estroprogestins is significantly more common in women with endometriosis than in women without the disease (262,263). OCs inhibit ovulation, substantially reduce the volume of menstrual flow, and may interfere with implantation of refluxed endometrial cells, but the hypothesis of recommending OCs for primary prevention of endometriosis is not sufficiently substantiated (264). Although the risk of endometriosis appears reduced during OC use, it is possible that this effect results from postponement of surgical evaluation caused by temporary suppression of pain symptoms (265). Confounding by selection and indication biases may explain the trend toward an increase in risk of endometriosis observed after discontinuation, but further clarification is needed (265). 705 FIGURE 13-7 Endometriosis Fertility Index. (From Adamson D, Pasta D. Endometriosis 706 fertility index: The new, validated endometriosis staging system. Fertil Steril 2010;94:1609–1615.) Principles of Treatment Treatment of endometriosis must be individualized, taking into consideration the clinical problem in its entirety, including the impact of the disease and the effect of its treatment on quality of life. Evidence-based recommendations that are continuously updated can be found in the ESHRE guidelines for the clinical management of endometriosis (1). In most women with endometriosis, preservation of reproductive function is desirable (1). Many women with endometriosis have pain and infertility at the same time or may desire children after sufficient pain relief, which complicates the choice of treatment. Endometriosis surgery should be considered as reproductive surgery, defined by the World Health Organization (WHO) as “all surgical procedures carried out to diagnose, conserve, correct and/or improve reproductive function” (266). The least invasive and least expensive approach that is effective with the least long-term risks should be chosen (1). Symptomatic endometriosis patients can be treated with analgesics, hormones, surgery, assisted reproduction, or a combination of these modalities (1). Regardless of the clinical profile (infertility, 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 it is not possible to predict in which patients it will progress (249). Elimination of the endometriotic implants by surgical or medical treatment often provides only temporary relief. In addition to eliminating the endometriotic lesions, the goal should be to treat the sequelae (pain and infertility) often associated with this disease and to prevent recurrence of endometriosis (1). Endometriosis is a chronic disease and the recurrence rate is high after both hormonal and surgical treatment (1). Treatment of extragenital endometriosis will depend on the site. If complete excision is possible, this is the treatment of choice; when this is not possible, long-term medical treatment is necessary using the same principles of medical treatment for pelvic endometriosis (1). It is important to involve the patient in all decisions, to be flexible in considering diagnostic and therapeutic approaches, and to maintain a good relationship. It may be appropriate to seek advice from more experienced colleagues or to refer the patient to a center with the necessary expertise to offer treatments in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy (1,267). Because the management of severe or deep endometriosis is complex, referral is strongly recommended when disease of such 707 severity is suspected or diagnosed (1). Treatment of Endometriosis-Associated Pain Pain may persist despite seemingly adequate medical or surgical treatment of the disease. A multidisciplinary approach involving a pain clinic and counseling should be considered early in the treatment plan. The least invasive and least expensive approach that is effective should be used (1). Surgical Treatment Depending on the severity of disease, diagnosis and removal of endometriosis should be performed simultaneously at the time of surgery, provided that preoperative consent was obtained (1,268–271). The goal of surgery is to excise all visible endometriotic lesions and associated adhesions—peritoneal lesions, ovarian cysts, deep rectovaginal endometriosis—and to restore normal anatomy (1). Laparoscopy is preferred over laparotomy because the two techniques are equally effective and laparoscopy is associated with quicker recovery, better cosmesis, less postoperative pain, decreased costs, lower morbidity, and fewer postoperative adhesions (1). Laparotomy is only indicated in the rare cases of advanced-stage disease where laparoscopy is impossible. Conservative Surgery Peritoneal Endometriosis Endometriosis lesions can be removed during laparoscopy by surgical excision with scissors, bipolar coagulation, or laser methods (CO2 laser, potassium-titanyl-phosphate laser, or argon laser). Some surgeons claim that the CO2 laser is superior because it causes only minimal thermal damage, but no evidence is available to show the superiority of one technique over another. Surgical ablation of peritoneal endometriosis is considered equally effective as surgical excision. However, surgical excision of lesions could be preferred because it allows histologic analysis and confirmation of endometriosis. Ovarian Endometriosis Superficial ovarian lesions can be vaporized. The surgical management of pain associated with ovarian endometriotic cysts is controversial. The most common procedures for the treatment of ovarian endometriomas are either excision of the cyst wall or drainage and ablation of the cyst wall. During excision, the ovarian endometrioma is aspirated, followed by incision and removal of the cyst wall from the ovarian cortex with maximal preservation of 708 normal ovarian tissue. During drainage and ablation, the ovarian endometrioma is aspirated and irrigated. Its wall can be inspected with ovarian cystoscopy for intracystic lesions, and it is vaporized to destroy the mucosal lining of the cyst. According to a systematic review, there is good evidence that excisional surgery for endometriomas with a diameter of 3 cm provides a more favorable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile or had subsequent spontaneous pregnancy (272). Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhea (odds ratio [OR] 0.15; 95% CI, 0.06– 0.38), dyspareunia (OR 0.08; 95% CI, 0.01–0.51), and nonmenstrual pelvic pain (OR 0.10; 95% CI, 0.02–0.56), a reduced rate of recurrence of the endometrioma (OR 0.41; 95% CI, 0.18–0.93), and with a reduced requirement for further surgery (OR 0.21; 95% CI, 0.05–0.79) than surgery to ablate the endometrioma. For those women subsequently attempting to conceive, it was associated with an increased spontaneous pregnancy rate in women who had documented prior infertility (OR 5.21; 95% CI, 2.04–13.29). Based on this evidence, the ESHRE guideline recommends cystectomy over drainage and coagulation because a cystectomy reduces endometriosis- associated pain and has a lower recurrence rate. In case of very large endometriomas where excision is technically difficult without removing a large part of the ovary, a three-step procedure (marsupialization and rinsing followed by hormonal treatment with GnRH analogs and cyst wall electrocoagulation or laser vaporization 3 months later) can be considered (1,273). It is possible that the surgical techniques used to treat ovarian endometriotic cysts may influence postoperative adhesion formation and/or ovarian function. In a randomized study comparing surgical methods to achieve ovarian hemostasis after laparoscopic endometriotic ovarian cystectomy, closure of the ovary with an intraovarian suture resulted in a lower rate and extension of postsurgical ovarian adhesions at 60 to 90 days follow-up when compared to only bipolar coagulation on the internal ovarian surface (274). Deep Endometriosis Deep endometriosis is usually multifocal and complete surgical excision must be performed in a one-step surgical procedure in order to avoid more than one surgery, provided the patient is fully informed (1,173,269). Because management of deep endometriosis is complex, referral to a center with sufficient expertise to offer all available treatments in a multidisciplinary approach is strongly recommended (1). Surgical management is only for symptomatic deep endometriosis. Asymptomatic patients must not undergo surgery, except for cases 709 with complete obstruction of a ureter resulting in asymptomatic loss of renal function. Progression of the disease and appearance of specific symptoms rarely occurred in patients with asymptomatic rectovaginal endometriosis (270). When surgical treatment is decided, the treatment must be radical with excision of all lesions (1). It is difficult to perform randomized studies to detect the best surgical technique to treat deep endometriosis because these severe cases are all managed individually and not all surgeons are familiar with all treatment options (1). Complete excision while preserving the uterus and ovarian tissue might include the resection of the uterosacral ligaments, the resection of the upper part of the posterior vaginal wall, and urologic and bowel operations. The patients’ surgical agreement must be obtained preoperatively to perform this difficult and high-risk procedure, especially in cases of expected or possible bowel or urologic surgery. Preoperative imaging is necessary to assess bowel and urologic impact of deep endometriosis. As endometriosis sometimes involves nongynecologic organs (i.e., the bowel, the urinary tract, or pelvic bones), other surgical specialists should be consulted as appropriate. These severe cases should be handled in centers with special expertise. Preoperative intestinal preparation may be recommended. Placement of ureteric catheters may facilitate the excision of periureteral endometriosis to facilitate ureterolysis and end-to-end ureteral reanastomosis that may be needed in cases of infiltrative periureteral endometriosis. The pattern of pain in endometriosis is complicated and pain does not always respond to treatment, so consultation with pain specialists may be useful. In patients with severe endometriosis, it is common clinical practice that surgical treatment be preceded by a 3-month course of medical treatment (194). It is believed that this facilitates surgery by reducing inflammation and vascularization of lesions. The role of preoperative hormonal treatment was evaluated in a Cochrane review that concluded that there was no evidence of a benefit of preoperative medical therapy on the outcome of surgery. Therefore, although common clinical practice, the ESHRE guideline does not recommend preoperative hormonal therapy. Surgical treatment of bladder endometriosis is usually in the form of excision of the lesion and primary closure of the bladder wall. Removal of full-thickness bladder detrusor endometriosis entails excision of the bladder dome or posterior wall, generally well above the trigone. Transurethral resection is contraindicated. Ureteral lesions may be excised after stenting the ureter. In the presence of intrinsic lesions or significant obstruction, segmental excision with end-to-end anastomosis or reimplantation with antireflux vesicoureteral plasty may be necessary (275). Surgical excision of deep rectovaginal and rectosigmoidal endometriosis is 710 difficult and can be associated with major complications such as bowel perforations with resulting peritonitis (276). It is debated whether this type of endometriosis is best treated by shaving, conservative excision, or resection reanastomosis, by laparoscopy and laparotomy, or laparoscopically assisted vaginal technique (277). Appendicular endometriosis is usually treated by appendectomy. In a randomized study comparing colorectal resection for endometriosis by laparoscopy or laparotomy, clinical outcome was similar with respect to dyschezia, bowel pain and cramping, and dysmenorrhea and dyspareunia, but laparoscopy was associated with less blood loss, fewer complications, and a higher pregnancy rate than laparotomy (278). There are very few methodologically valid studies evaluating clinical outcome after surgery for deep endometriosis with colorectal extension, as demonstrated in a systematic review (279). In a review on the clinical outcome of surgical treatment of deep endometriosis with colorectal involvement, most of the 49 reviewed studies included complications (94%) and pain (67%); few studies reported recurrence (41%), fertility (37%), and quality of life (10%); only 29% reported (loss of) follow-up. Of 3,894 patients, 71% underwent bowel resection and anastomosis, 10% had full-thickness excision, and 17% were treated with superficial surgery. Comparison of clinical outcome between different surgical techniques was not possible. Postoperative complications were present in 0% to 3% of the patients. Although pain improvement was reported in most studies, pain evaluation was patient based in less than 50% (visual analog scale [VAS] in only 18%). Although quality of life was improved in most studies, prospective data were available for only 149 patients. Pregnancy rates were 23% to 57% with a cumulative pregnancy rate of 58% to 70% within 4 years. The overall endometriosis recurrence rate in studies (longer than 2 years follow-up) was 5% to 25%, with most of the studies reporting 10%. Because high quality prospective studies reporting standardized and well- defined clinical outcomes after surgical treatment of deep endometriosis with long-term follow-up are needed, the Consensus On Recording Deep Endometriosis Surgery (CORDES) statement was published in 2016 (280). This consensus statement provides definition and standards for recording deep endometriosis surgery and outcome reporting in clinical trials on the surgical management of deep endometriosis. Adhesiolysis Endometriosis is often associated with pelvic adhesions, which can be very extensive and result in severe distortion of the pelvic anatomy. The removal of endometriosis-related adhesions (adhesiolysis) should be performed carefully and 711 focused at restoration of the normal anatomy. However, adhesions lysed at surgery can form again. Cutting, surgical denudation, ischemia, desiccation, or abrasion can cause peritoneal trauma during surgery and the subsequent healing mechanism in the peritoneal cavity can result in adhesion formation between damaged serosal surfaces. Minimally invasive techniques such as laparoscopy reduce the risk of adhesion formation but do not eliminate it entirely. Several barrier agents have been tested for adhesion prevention during surgery. The ESHRE guideline acknowledges that clinicians can consider the use of oxidized regenerated cellulose and potentially other barrier agents. However, a recent systematic review including 18 randomized controlled trials (RCTs) with a total of 1,262 enrolled women found no effects of any barrier agent used during pelvic surgery on either pain or fertility outcomes (281). Low- quality evidence suggests that oxidized regenerated cellulose, expanded polytetrafluoroethylene and sodium hyaluronate with carboxymethylcellulose may all be more effective than no treatment in reducing the incidence of adhesion formation following pelvic surgery. Based on this systematic review, routine use of barrier agents to prevent postoperative adhesions after pelvic surgery can be considered but cannot be recommended. Interruption of Pelvic Nerve Pathways Surgical interruption of pelvic nerve pathways has been suggested as an additional procedure to conservative surgery for endometriosis. Two techniques have been suggested for endometriosis-associated pain: laparoscopic uterine nerve ablation (LUNA) and presacral neurectomy (PSN). The effectiveness of LUNA and PSN was evaluated in several clinical trials and data of six RCTs were analyzed in a Cochrane review (282). Based on the systematic review it can be concluded that laparoscopic excision or ablation of endometriosis should not be combined with LUNA because this procedure offers no additional benefit. PSN is effective as an additional procedure, but it requires a high degree of surgical skill and is associated with increased adverse effects such as bleeding, constipation, urinary urgency, and less pain during the first stage of labor (1). Outcome of Conservative Surgery 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. It is difficult to evaluate scientifically the objective effect of different surgical approaches because the extirpation and destruction of the pathologic tissue can impact the results as can surgery per se, the doctor–patient relationship, complications, and other factors. There is 712 a significant placebo response to surgical therapy: diagnostic laparoscopy without complete removal of endometriosis may alleviate pain in 50% of patients (283–285). Similar results were reported using oral placebos (286). Although some reports claimed pain relief with laser laparoscopy in 60% to 80% of patients with very low morbidity, none were prospective or controlled or allowed a definitive conclusion regarding treatment efficacy (194,287–290). The longstanding effect of surgery on pain is difficult to evaluate because the follow- up time is too short, usually just a few months. The major shortcoming of surgical treatment in endometriosis-related pain is the lack of prospective randomized studies with sufficient follow-up time to draw clear clinical conclusions. In a systematic review assessing the efficacy of laparoscopic surgery in the treatment of pelvic pain associated with endometriosis and including five randomized controlled studies, meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only at 6 months (OR 5.72; 95% CI, 3.09–10.60; 171 participants, three trials) and 12 months (OR 7.72; 95% CI, 2.97–20.06; 33 participants, one trial) after surgery (291). Few women diagnosed with severe endometriosis were included in the meta-analysis and any conclusions from this meta-analysis regarding treatment of severe endometriosis should be made with caution. It was not possible to draw conclusions from the meta-analysis in which specific laparoscopic surgical intervention was most effective (291). The extent and duration of the therapeutic benefit of surgery for endometriosis-related pain are poorly defined, and the expected benefit is operator dependent (292). In a systematic review based on three randomized controlled studies, the absolute increased benefit from destruction of lesions compared with diagnostic only operation in terms of proportion of women reporting pain relief was between 30% and 40% after short follow-up periods (292). The pain relief tended to decrease with time, and the reoperation rate, based on long-term follow-up studies, was as high as 50% (292). In most case series on excisional surgery for rectovaginal endometriosis, substantial short-term pain relief was experienced by approximately 70% to 80% of the patients who continued the study. At 1-year follow-up, approximately 50% of the women needed analgesics or hormonal treatments (292). Medium-term recurrence of lesions was observed in approximately 20% of the cases, and approximately 25% of the women underwent repetitive surgery (292). It appears that pain recurrence and reoperation rates after conservative surgery for symptomatic endometriosis are high and probably underestimated (292). Prevention of Recurrence After Conservative Surgical Treatment The addition of postoperative hormonal therapy to conservative surgery for 713 endometriosis has been suggested for two main reasons. First, short-term postoperative hormonal therapy (up to 6 months after the operation) could potentially improve the outcomes of the operation through their effect on any residual endometriosis. Secondly, long-term hormonal therapy after surgery could be prescribed for secondary prevention: suppression of ovarian function and menstruation could prevent the development of new lesions. Systemic Medical Therapy In a systematic review published in 2004 to determine the effectiveness of systemic medical therapies used for hormonal suppression before or after surgery for endometriosis, or before and after surgery for the eradication of endometriosis, improvement of symptoms, pregnancy rates, and overall tolerability, by comparing them with no treatment or placebo, 11 trials were included (293). Five trials compared postsurgical medical therapy with surgery alone (without medical therapy) and assessed the outcomes of pain recurrence, disease recurrence, and pregnancy rates (294–297). There was no statistically significant reduction in pain recurrence at 12 months (relative risk [RR] 0.76; 95% CI, 0.52–1.10), but the difference at 24 months approached statistical significance (RR 0.70; 95% CI, 0.47–1.03). There was no statistically significant difference between the use of these medical therapies after surgery compared to surgery alone with regard to disease recurrence (RR 1.02; 95% CI, 0.27–3.84) or pregnancy rates (RR 0.78; 95% CI, 0.50–1.22). Postsurgical medical therapy was compared to surgery plus placebo in three studies (295,298,299). There was no difference between medical therapy and placebo with regard to the measures for pain; multidimensional pain score (WMD −0.40; 95% CI, −2.15–1.35); linear scale score (0.10; 95% CI, −2.24–2.44); or change in pain (−0.40; 95% CI, −1.48–0.68). There was no difference between medical therapy and placebo for pregnancy rates (RR 1.05; 95% CI, 0.44–2.51) or total AFS scores (WMD −2.10; 95% CI, −4.56–0.36). There was no significant difference between preoperative hormonal suppression and postoperative hormonal suppression for the outcome of pain in one trial (300). These results were confirmed in another RCT with 5 years of follow-up, showing that GnRH analog treatment with triptorelin depot 3.75 intramuscular after operative laparoscopy for stages III and IV endometriosis was comparable to placebo injections with respect to time to relapse of endometrioma, pain recurrence, and time to pregnancy (301). There is circumstantial evidence that regular postoperative use of OCs effectively prevents endometrioma recurrence (302). In a prospective controlled cohort study with a median follow-up of 28 months after laparoscopic excision of ovarian endometriomata, the 36-month cumulative proportion of 714 subjects free from endometrioma recurrence was 94% in women who always used cyclic oral contraception compared with 51% in those who never used it (p