Thomas M. D'Hooghe
• Endometriosis is diagnosed by visual inspection of the pelvis during laparoscopy, ideally with histological confirmation; positive histology confirms the diagnosis, but negative histology does not exclude it.
• Endometriosis can be associated with subfertility, pelvic pain, i.e., dysmenorrhea, dyspareunia and nonmenstrual pain, and reduced quality of life.
• Severe or deeply infiltrating endometriosis should be managed in a facility with the necessary expertise to provide treatment in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy.
• Classification systems for endometriosis are subjective and correlate poorly with pain symptoms, but have some value in determining the prognosis and management of infertility.
• Suppression of ovarian function for 6 months reduces pain associated with endometriosis. Hormonal drugs are equally effective in reducing pain but have differing side effects and cost.
• Ablation of endometriotic lesions with laparoscopic uterine nerve ablation (LUNA) in minimal to moderate disease reduces pain associated with endometriosis; however, because LUNA used alone has no effect on dysmenorrhea associated with endometriosis, there is no evidence that LUNA is a necessary component of treatment.
• Ablation of endometriotic lesions plus adhesiolysis in minimal to mild endometriosis is more effective than diagnostic laparoscopy alone in improving fertility.
• Suppression of ovarian function is not effective in improving subsequent fertility in patients with endometriosis.
Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterus. The most frequent sites of implantation are the pelvic viscera and the peritoneum.Endometriosis varies in appearance from a few minimal lesions on otherwise intact pelvic organs, to massive ovarian endometriotic cysts that distort tubo-ovarian anatomy and extensive adhesions involving bowel, bladder, and ureter. 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 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 (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% (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).
In women with pelvic pain or infertility, a high prevalence of endometriosis (from a low of 20% to a high of 90%) is reported (5,6). In women with unexplained subfertility with or without pain (regular cycle, partner with normal sperm), the prevalence of endometriosis is reported to be as high as 50% (7). In asymptomatic women undergoing tubal ligation (women of proven fertility), the prevalence of endometriosis ranges from 3% to 43% (8–13). 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 a symptomatic patient given general anesthesia than in an asymptomatic patient during tubal sterilization. Third, the interest and experience of the surgeon is important 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 (8–10,14–19).
Risk and Protective Factors
The following are identified risk factors for endometriosis: infertility, red hair, early age at menarche, shorter menstrual cycle length, hypermenorrhea, nulliparity, müllerian anomalies, birth weight (less than 7 pounds), 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 (20). Prior use of contraception or intrauterine device (IUD), or smoking is not associated with increased risk of endometriosis (21,22). Protective factors against the development of endometriosis include multiparity, lactation, tobacco exposure in utero, increased body mass index, increased waist-to-hip ratios and exercise, and diet high in vegetables and fruits (20). Some evidence suggests that women with a “pinpoint cervix” have an increased risk for endometriosis, but more studies are needed to confirm this observation (23).
Endometriosis and Cancer
Several publications link endometriosis with an increased risk for certain gynecologic and nongynecologic cancers (24,25). These associations are controversial and no 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 (26). 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 (27). Evidence from clinical series consistently demonstrates that the association is confined to the endometrioid and clear-cell histologic types of ovarian cancer (28). 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 (29). Evidence for an association with melanoma and non-Hodgkin’s lymphoma is increasing but needs to be verified, whereas an increased risk for other gynecologic cancer types is not supported (28).
Etiology
Although signs and symptoms of endometriosis were 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 histogenesis of endometriosis:
1. Ectopic transplantation of endometrial tissue
2. Coelomic metaplasia
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 or implantation of endometrial cells by transtubal regurgitation during menstruation (30). Substantial clinical and experimental data support this hypothesis (5,31). 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 (8,32). 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 (33,34). The presence of endometrial cells in the dialysate of women undergoing peritoneal dialysis during menses supports the theory of retrograde menstruation (35). 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 (36). 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) (37,38).
Endometrium obtained during menses can grow when injected beneath abdominal skin or into the pelvic cavity of animals (39,40). Endometriosis was found in 50% of Rhesus monkeys after surgical transposition of the cervix to allow intra-abdominal menstruation (41). 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 (42–44). 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 (45). Menstruation is associated with intraperitoneal inflammation in both 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 (46–48). 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 (49–51).
Deeply infiltrative 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 (52). 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 (37). Adolescents and young women can have peritoneal disease (53). 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 homogenous disease continuum with a single origin (i.e., regurgitated endometrium), rather than three different disease entities, as advocated by some investigators (37,54,55).
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, rectum, sigmoid colon, small intestine, hernia sacs), lungs and pleural cavity, skin (episiotomy or other surgical scars, inguinal region, extremities, umbilicus), lymph glands, nerves, and brain (56).
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 (57). 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 (50).
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 (58,59).
Genetic Factors
Increasing evidence suggests that endometriosis is partially a genetic disease. Recent findings that support this association include evidence of familial clustering in humans and in Rhesus monkeys, a founder effect detected in the Icelandic population, concordance in monozygotic twins, a similar age at onset of symptoms in affected nontwin sisters, a six- to nine-times increased prevalence of endometriosis among first-degree relatives of women compared with the general population, and a 15% prevalence of magnetic resonance imaging (MRI) findings suggestive of endometriosis in the first-degree relatives of women with stage III or IV disease based on the classification of the American Society of Reproductive Medicine (60). The induction of humanlike endometriosis by genetic activation of an oncogenic K-ras allele lends further support to the genetic basis of this disorder (50).
Population Studies
The risk of endometriosis is seven times greater if a first-degree relative is affected by endometriosis (61). Because no specific Mendelian inheritance pattern is identified, multifactorial inheritance is postulated. A relative risk for endometriosis of 7.2 was found in mothers and sisters, and a 75% (six in eight) incidence was noted in homozygotic twins of patients with endometriosis (62). In another study of twins, 51% of the variance of the latent liability to endometriosis may be attributable to additive genetic influences (63). Other investigators reported that 14 monozygotic twin pairs were concordant for endometriosis, and two pairs were discordant (64). Of these twin pairs, nine had moderate to severe endometriosis. A relationship was shown between endometriosis and systematic lupus erythematosus, dysplastic nevi, and a history of melanoma in women of reproductive age (65,66). Endometriosis is linked to the presence of individual human leukocyte antigens (67–69). Genome-wide association studies show that the risk of endometriosis is associated with a mutation on the short arm of chromosome 7 (7p15.2) in women of European ancestry and that this association is the strongest for moderate to severe disease (70).
Genetic Polymorphisms and Endometriosis
A number of studies investigated genetic polymorphisms as a possible factor contributing to the development of endometriosis. About 50% of the studies in one review demonstrated positive correlations between different polymorphisms and endometriosis (71). This relation was seen most clearly in groups 1 (cytokines and inflammation), 2 (steroid-synthesizing enzymes and detoxifying enzymes and receptors), 4 (estradiol metabolism), 5 (other enzymes and metabolic systems), and 7 (adhesion molecules and matrix enzymes). Group 8 (apoptosis, cell-cycle regulation, and oncogenes) seemed to be negatively correlated with the disease, whereas groups 3 (hormone receptors), 6 (growth factor systems), and especially 9 (human leukocyte antigen system components) showed a relatively strong correlation. As many results were contradictory, the review concluded that genetic polymorphisms might have a limited value in assessing possible development of endometriosis (71). Future studies should include large numbers of women with laparoscopically and histologically confirmed endometriosis and women with a laparoscopically confirmed normal pelvis as controls, taking into account ethnic variability.
Aneuploidy
Epithelial cells of endometriotic cysts are monoclonal on the basis of phosphoglycerate kinase gene methylation, and normal endometrial glands are monoclonal (72,73). In a comparison of endometriotic tissue with eutopic endometrium, flow cytometric DNA analysis failed to show aneuploidy (74). 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 (75–77). In another study, trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium (78). The proportions of aneusomic cells were significantly higher in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (p < 0.001), suggesting a role of the ovarian stromal milieu in the induction of genetic changes, which may lead to invasive cancer in isolated cases (78).
Microsatellite DNA assays reveal an allelic imbalance (loss of heterozygosity) in p16 (Ink4), GALT, p53, and APOA2 loci in patients with endometriosis and in stage II of endometriosis (79). Another report found a loss of heterozygosity in 28% of endometriotic lesions at one or more sites: chromosomes 9p (18%), 11q (18%), and 22q (15%) (73).
Immunologic Factors and Inflammation
Although retrograde menstruation appears to be a common event in women, not all women who have retrograde menstruation develop endometriosis. The immune system may be altered in women with endometriosis, and it is hypothesized that the disease may develop as a result of reduced immunologic clearance of viable endometrial cells from the pelvic cavity (80,81). Endometriosis can be caused by decreased clearance of peritoneal fluid endometrial cells resulting from reduced natural killer (NK) cell activity or decreased macrophage activity (82). Decreased cell-mediated cytotoxicity toward autologous endometrial cells is associated with endometriosis (82–86). These studies used techniques that have considerable variability in target cells and methods (87,88). Whether NK cell activity is lower in patients with endometriosis than in those without endometriosis is controversial. Some reports demonstrate reduced NK activity and others found no increase in NK activity in women with moderate to severe disease (84–86,89–94). There is great variability in NK cell activity among normal individuals that may be related to variables such as smoking, drug use, and exercise (87).
In contrast, endometriosis can be considered a condition of immunologic tolerance, as opposed to ectopic endometrium, which essentially is self-tissue (80). It can be questioned why viable endometrial cells in the peritoneal fluid would be a target for NK cells or macrophages. Autotransplantation of blood vessels, muscles, skin grafts, and other tissues is extremely successful (83–85). There is no in vitro evidence that peritoneal fluid macrophages actually attack and perform phagocytosis of viable peritoneal fluid endometrial cells. High-dose immunosuppression can increase slightly the progression of spontaneous endometriosis in baboons (95). There is no clinical evidence that the prevalence of endometriosis is increased in immunosuppressed patients. The fact that women with kidney transplants, who undergo chronic immunosuppression, are not known to have increased infertility problems can be considered indirect evidence that these patients do not develop extensive endometriosis.
Substantial evidence suggests that endometriosis is associated with a state of subclinical peritoneal inflammation, marked by an increased peritoneal fluid volume, increased peritoneal fluid white blood cell concentration (especially macrophages with increased activation status), and increased inflammatory cytokines, growth factors, and angiogenesis-promoting substances. It is reported in baboons that subclinical peritoneal inflammation occurs during menstruation and after intrapelvic injection of endometrium (93). A higher basal activation status of peritoneal macrophages in women with endometriosis may impair fertility by reducing sperm motility, increasing sperm phagocytosis, or interfering with fertilization, possibly by increased secretion of cytokines such as tumor necrosis factor-α(TNF-α) (96–100). Tumor necrosis factor may facilitate the pelvic implantation of ectopic endometrium (99,100). The adherence of human endometrial stromal cells to mesothelial cells in vitro is increased by the pretreatment of mesothelial cells with physiologic doses of TNF-α (101). Macrophages or other cells may promote the growth of endometrial cells by secretion of growth and angiogenetic factors such as epidermal growth factor (EGF), macrophage-derived growth factor (MDGF), fibronectin, and adhesion molecules such as integrins (101–107). After attachment of endometrial cells to the peritoneum, subsequent invasion and growth appear to be regulated by matrix metalloproteinases (MMP) and their tissue inhibitors (108,109).
There is increasing evidence that local inflammation and secretion of prostaglandins (PG) is related to differences in endometrial aromatase activity between women with and without endometriosis. Expression of aromatase cytochrome P450 protein and mRNA is present in human endometriotic implants but not in normal endometrium, suggesting that ectopic endometrium produces estrogens, which may be involved in the tissue growth interacting with the estrogen receptor (110). Inactivation of 17β-estradiol is impaired in endometriotic tissues because of deficient expression of 17β-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrium in response to progesterone (111). The inappropriate aromatase expression in endometriosis lesions can be stimulated by prostaglandin E2 (PGE2). This reaction leads to local production of E2, which stimulates PGE2 production, resulting in a positive-feedback system between local inflammation and estrogen-driven local growth of ectopic endometrium (112).
The subclinical pelvic inflammatory status associated with endometriosis is reflected in the systemic circulation. Increased concentrations of C-reactive protein, serum amyloid A (SAA), TNF-α, membrane cofactor protein-1, interleukin-6 (IL-6), IL-8, and chemokine (C-C motif) receptor 1 (CCR1) are observed in peripheral blood samples of patients with endometriosis when compared with controls (113). This observation offers a basis for the development of noninvasive diagnostic tests.
Both hypothesis-driven research and system biology approaches using mRNA microarray and proteomic techniques studies show that eutopic endometrium is biologically different in women with endometriosis when compared to controls with respect to proliferation, apoptosis, angiogenesis, and inflammatory pathways (114–117). Several studies show a higher prevalence of nerve fibers and neurotrophic factors in the eutopic endometrium from women with endometriosis when compared to controls (46,118).
Environmental Factors and Dioxin
There is an increasing awareness of potential links between reproductive health, infertility, and environmental pollution. Attention was directed toward the potential role of dioxins in the pathogenesis of endometriosis, but the issue remains controversial. A meta-analysis concluded that there is insufficient evidence in women or in nonhuman primates that endometriosis is caused by dioxin exposure (119).
Human Data
A 1976 explosion of a factory in Seveso, Italy, resulted in the highest recorded levels of dioxin exposure in humans, but data are not published (120). The Seveso Women’s Health Study will correlate prospective individual data on exposure to dioxin with reproductive endpoints such as the incidence of endometriosis, infertility, and decreased sperm quality. One case-control study failed to show an association in the general population between endometriosis and exposure to PCB and chlorinated pesticides during adulthood. No differences in mean plasma concentrations of 14-PCB and 11-chlorinated pesticides were found between women with and those without endometriosis (121). In another study, increased exposure to dioxin-like compounds is associated with (moderate to severe) endometriosis in a case-control study in women (122). Genetic mechanisms may play a role in dioxin exposure and the development of endometriosis. Transcripts of the CYP1A1 gene, a dioxin-induced gene, are significantly higher (nine times higher) in endometriotic tissues than in eutopic endometrium (112). Other investigators report a similar expression of arylhydrocarbon receptor and dioxin-related genes (using semiquantitative reverse transcriptase polymerase chain reaction) in the endometrium from women with or without endometriosis (123). In Japanese women, no association was found between endometriosis prevalence or severity and polymorphisms for arylhydrocarbon receptor repressor, arylhydrocarbon (x2) receptor, and arylhydrocarbon nuclear translocator or CYP1A1 genes (124). Based on these data, there is insufficient evidence supporting the association between endometriosis and dioxin exposure in humans.
Primates
An initial retrospective case-control study reported that the prevalence of endometriosis was not statistically different (p = 0.08) between monkeys chronically exposed to dioxin during 4 years (11 of 14, 79%) and unexposed animals (2 of 6, 33%) after a period of 10 years. A positive correlation was found between the severity of endometriosis and dioxin dose, serum levels of dioxin, and dioxin-like chemicals (125,126). Two prospective studies evaluated the association between dioxin exposure and development of endometriosis in Rhesus monkeys. In one study, monkeys exposed over 12 months to low-dose dioxin (0.71 ng/kg/day) had endometriosis implants with smaller maximal and minimal diameters and similar survival rate when compared with endometriotic lesions in unexposed controls, suggesting no effect of dioxin on endometriosis (127). After 12 months of exposure to high-dose dioxin (17.86 ng/kg/day), larger diameters and a higher survival rate of endometriosis implants were observed in exposed Rhesus monkeys compared with unexposed controls. The second randomized study performed in 80 Rhesus monkeys compared those with no treatment with those treated with 0, 5, 20, 40, and 80 μg of Aroclor (1,254 kg per day) for 6 years. Endometriosis occurred in 37% of controls and in 25% of treated monkeys as determined by laparoscopy and necropsy data (128). No association was observed between endometriosis severity and PCB exposure. These data question the importance of dioxin exposure, except at high doses, in the development of endometriosis in primates.
Rodents
Continuous exposure to 2,3,7,8-tetrachlorodibenzo-P-dioxin inhibited the growth of surgically induced endometriosis in ovariectomized mice treated with high-dose estradiol. No correlation was observed between the dose of dioxin and survival of endometrial implants, adhesions, and serum E2 levels (129). In ovariectomized mice induced with endometriosis, similar stimulating effects of estrone and 4-chlorodiphenyl ether (4-CDE) were observed on survival rates of endometriotic mice, suggesting an estrogen-like effect of 4-CDE (130). Potential mechanisms mediating dioxin action to promote endometriosis in rodents are complex and probably different in rats and mice, and furthermore in women. The mouse appears to be a better model to elucidate these mechanisms, but both models have important limitations (131,132).
Stem Cells
Endometrial stem cells are identified, are bone marrow derived, can differentiate into neurogenic or pancreatic-β cells, may contribute to the development of endometriosis in a murine model, and their potential role in the pathogenesis of endometriosis needs to be investigated (133–136).
Future Research
The study of endometriosis is compounded by the need to determine the presence or absence of pathology. The pathogenesis of endometriosis, the pathophysiology of related infertility, and the spontaneous evolution of endometriosis are being studied. At the time of diagnosis, most patients with endometriosis had the disease for an unknown period, making it difficult to initiate clinical experiments that would determine the etiology or progression of the disease (31). Because endometriosis occurs naturally only in women and nonhuman primates, and invasive experiments cannot be performed easily, it is difficult to undertake properly controlled studies. There is a need for the development of a good animal model with spontaneous endometriosis. The main advantage of the rat and rabbit models used to study endometriosis is their low cost relative to primates, but the disadvantages are numerous (137–140). In both models, the type of lesion appears to be quite different from the variety of pigmented and nonpigmented lesions observed in women (137–139). Primates are phylogenetically close to humans, have a comparable menstrual cycle, are afflicted with spontaneous endometriosis, and when induced with endometriosis, develop macroscopic lesions that are similar to those found in human disease (41,141–145). Spontaneous endometriosis in the baboon is minimal and disseminated, similar to the different stages of endometriosis in women (141,146–148).
Immunomodulatory drugs inhibiting pelvic inflammation associated with endometriosis may offer new approaches to medical treatment and can be studied in these models (149–153). In a consensus workshop following the 10th World Congress on Endometriosis in 2008, it was agreed that multidisciplinary expertise is required to advance our understanding of this disease, and 25 recommendations for research were developed (154).
Diagnosis
Clinical Presentation
Endometriosis should be suspected in women with subfertility, dysmenorrhea, dyspareunia, or chronic pelvic pain, although these symptoms can be associated with other diseases. Endometriosis may be asymptomatic, even in women with more advanced disease, (i.e., ovarian endometriosis or deeply invasive rectovaginal endometriosis).
Risk factors for endometriosis include short cycle length, heavier menstruation, and longer flow duration, probably related to a higher incidence of retrograde menstruation (45,155,156). Patient height and weight are positively and negatively, respectively, associated with the risk of endometriosis (157).
Endometriosis can be associated with significant gastrointestinal symptoms (pain, nausea, vomiting, early satiety, bloating and distention, altered bowel habits). A characteristic motility change (ampulla of Vater–duodenal spasm, a seizure equivalent of the enteric nervous system, along with bacterial overgrowth), is documented in most women with the disease (158). Women of reproductive age with endometriosis are not osteopenic (159).
The average delay between onset of pain symptoms and surgically confirmed endometriosis is quite long: 8 years or longer in the United Kingdom and 9 to 12 years in the United States (160). Similar durations were observed in Scandinavia and in Brazil (161,162). A delay in diagnosis of endometriosis of 6 and 3 years in women with pain and women with infertility, respectively, was reported. Over the past two decades, there was a steady decrease in the delay in diagnosis and a decline in the prevalence of advanced endometriosis at first diagnosis (163). Patient awareness of endometriosis was increased. Many patients' quality of life is affected by pain, emotional impact of subfertility, anger about disease recurrence, and uncertainty about the future regarding repeated surgeries or long-term medical therapy and its side effects (164). Endometriosis should be perceived as a chronic disease, at least in a subset of highly symptomatic women, and quality-of-life issues should be evaluated using reliable and valid questionnaires (165).
Pain
In adult women, dysmenorrhea may be especially suggestive of endometriosis if it begins after years of pain-free menses. Dysmenorrhea often starts before the onset of menstrual bleeding and continues throughout the menstrual period. In adolescents, the pain may be present after menarche without an interval of pain-free menses. Evidence suggests that absenteeism from school and both the incidence and duration of oral contraceptive use for severe primary dysmenorrhea during adolescence is higher in women who later develop deeply infiltrative endometriosis than in women without deeply infiltrative endometriosis (166).
The distribution of pain is variable but most often is bilateral. Local symptoms can arise from rectal, ureteral, and bladder involvement, and lower back pain can occur. Some women with extensive disease have no pain, whereas others with only minimal to mild disease may experience severe pelvic pain. All endometriosis lesion types are associated with pelvic pain, including minimal to mild endometriosis (167). Endometriomas are not associated with dysmenorrheal severity, and dysmenorrhea is less frequent in women with only ovarian endometriomas compared with other locations (168,169). Endometriomas can be considered a marker for greater severity of deeply infiltrative lesions (170). Deeply infiltrative lesions are consistently associated with pelvic pain, gastrointestinal symptoms, and painful defecation (171). The role of adhesions in pain and endometriosis is poorly understood (172).
Many studies failed to detect a correlation between the degree of pelvic pain and the severity of endometriosis (11,169,173). Some studies reported a positive correlation between endometriosis stage and endometriosis-related dysmenorrhea or chronic pelvic pain (174,175). In one study, a significant but weak correlation was observed between endometriosis stage and severity of dysmenorrhea and nonmenstrual pain, whereas a strong association was found between posterior cul-de-sac lesions and dyspareunia (176).
Possible mechanisms causing pain in patients with endometriosis include local peritoneal inflammation, deep infiltration with tissue damage, adhesion formation, fibrotic thickening, and collection of shed menstrual blood in endometriotic implants, resulting in painful traction with the physiologic movement of tissues (177,178). The character of pelvic pain is related to the anatomic location of deeply infiltrating endometriotic lesions (171). Severe pelvic pain and dyspareunia may be associated with deep infiltrating subperitoneal endometriosis (6,177,179). In rectovaginal endometriotic nodules, a close histologic relationship was observed between nerves and endometriotic foci and between nerves and the fibrotic component of the nodule (180). Increasing evidence suggests a close relationship between the density of innervation of endometriotic lesions and pain symptoms (176).
Subfertility
Many arguments support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility (181). The following factors have been reported:
1. Increased prevalence of endometriosis in subfertile women (33%) when compared to women of proven fertility (4%), a reduced monthly fecundity rate (MFR) in baboons with mild to severe (spontaneous or induced) endometriosis when compared to those with minimal endometriosis or a normal pelvis.
2. Trend toward a reduced monthly fecundity rate in infertile women with minimal to mild endometriosis when compared to women with unexplained infertility.
3. Endometriotic ovarian cysts that negatively affect the rate of spontaneous ovulation (182).
4. Dose–effect relationship: a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and cumulative pregnancy rate (181,183).
5. Reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal to mild endometriosis when compared to those with a normal pelvis.
6. Reduced monthly fecundity rate after husband sperm insemination in women with minimal to mild endometriosis when compared to those with a normal pelvis.
7. Reduced implantation rate per embryo after in vitro fertilization (IVF) in women with endometriosis when compared to women with tubal factor infertility (181,184).
8. Increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis.
When endometriosis is moderate or severe, involving the ovaries and causing adhesions that block tubo-ovarian motility and ovum pickup, it is associated with subfertility (182,185). This effect was shown in primates, including cynomolgus monkeys and baboons (144,186). Numerous mechanisms (ovulatory dysfunction, luteal insufficiency, luteinized unruptured follicle syndrome, recurrent abortion, altered immunity, and intraperitoneal inflammation) are proposed as explanations, but an association between fertility and minimal or mild endometriosis remains controversial (187).
Spontaneous Abortion
A possible association between endometriosis and spontaneous abortion was suggested in uncontrolled or retrospective studies. Some controlled studies evaluating the association between endometriosis and spontaneous abortion have important methodologic shortcomings: heterogeneity between cases and controls, analysis of the abortion rate before the diagnosis of endometriosis, and selection bias of study and control groups (80,188,189). Based on controlled prospective studies, there is no evidence that endometriosis is associated with (recurrent) pregnancy loss or that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate (190–192). Some data suggest that miscarriage rates may be increased after treatment with assisted reproductive technology (193).
Endocrinologic Abnormalities
Endometriosis is associated with anovulation, abnormal follicular development with impaired follicle growth, reduced circulating E2 levels during the preovulatory phase, disturbed luteinizing hormone (LH) surge patterns, premenstrual spotting, luteinized unruptured follicle syndrome, and galactorrhea and hyperprolactinemia (194). Increased incidence and recurrence of the luteinized unruptured follicle syndrome is reported in baboons with mild endometriosis, but not in primates with minimal endometriosis or a normal pelvis (195). Luteal insufficiency with reduced circulating E2 and progesterone levels, out-of-phase endometrial biopsies, and aberrant integrin expression was reported in the endometrium of women with endometriosis by some researchers, but these findings were not confirmed by other investigators (194,196,197). No convincing data exist to conclude that the incidence of these endocrine abnormalities is increased in women who have endometriosis.
Extrapelvic Endometriosis
Extrapelvic endometriosis, although often asymptomatic, should be suspected when symptoms of pain or a palpable mass occur outside the pelvis in a cyclic pattern. Endometriosis involving the intestinal tract (especially colon and rectum) is the most common site of extrapelvic disease and may cause abdominal and back pain, abdominal distention, cyclic rectal bleeding, constipation, and obstruction. Ureteral involvement can lead to obstruction and result in cyclic pain, dysuria, and hematuria. Pulmonary endometriosis can manifest as pneumothorax, hemothorax, or hemoptysis during menses. Umbilical endometriosis should be suspected when a patient has a palpable mass and cyclic pain in the umbilical area (56).
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). Appendicular endometriosis is usually treated by appendectomy. Surgical treatment of bladder endometriosis is usually in the form of excision of the lesion and primary closure of the bladder wall. 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 may be necessary. Abdominal wall and perineal endometriosis is usually treated by complete excision of the nodule (1).
Clinical Examination
In many women with endometriosis, no abnormality is detected during the clinical examination. However, the vulva, vagina, and cervix should be inspected for any signs of endometriosis, although the occurrence of endometriosis in these areas is rare (e.g., episiotomy scar). The presence of a narrow pinpoint cervical ostium can be a risk factor for endometriosis (23). Other signs of possible endometriosis include uterosacral or cul-de-sac nodularity, lateral or cervical displacement caused by uterosacral scarring, painful swelling of the rectovaginal septum, and unilateral ovarian cystic enlargement (198). In more advanced disease, the uterus is often in fixed retroversion, and the mobility of the ovaries and fallopian tubes is reduced. Evidence of deeply infiltrative endometriosis (deeper than 5 mm under the peritoneum) in the rectovaginal septum with cul-de-sac obliteration or cystic ovarian endometriosis should be suspected when there is clinical documentation of uterosacral nodularities during menses, especially if CA125 serum levels are higher than 35 IU/mL (199–201). In these cases, black-blue colored lesions can sometimes be observed in the vagina during speculum examination.
The clinical examination may have false-negative results. The diagnosis of endometriosis should be confirmed by visual inspection during laparoscopy and by histological confirmation of endometriosis in biopsied lesions.
Imaging
Ultrasound
Peritoneal endometriosis cannot be reliably visualized by imaging techniques. Compared to laparoscopy, transvaginal ultrasound has no value in diagnosing peritoneal endometriosis, but it is useful in making or excluding the diagnosis of an ovarian endometrioma (1,202). Either transvaginal or transrectal ultrasonography can be used with high sensitivity and specificity for the diagnosis of ovarian endometrioma (202–204). The typical ultrasound features of an endometriotic ovarian cyst in premenopausal women were described as “ground glass echogenicity of the cyst fluid, one to four locules and no solid parts” (205). Transvaginal ultrasound may have a role in the diagnosis of endometriosis nodules with a diameter of 1 cm involving the bladder or rectum, but this is dependent on the interest and experience of the ultrasonographer and the quality and resolution of the ultrasound equipment.
Local guidelines for the management of suspected ovarian malignancy should be followed in cases of ovarian endometrioma (1). Ultrasound scanning with or without serum CA125 testing is usually used to try to identify rare instances of ovarian cancer; however, CA125 levels are frequently elevated in the presence of endometriomas, so this approach is often not useful (1).
Other Imaging
Other imaging techniques, including computed tomography (CT) and MRI, can be used to provide additional and confirmatory information, but they cannot be used for primary diagnosis (1,206). These techniques are more costly than ultrasonography, and their added value is unclear.
Hysterosalpingography is not recommended as a diagnostic test for endometriosis, although the presence of filling defects (presence of hypertrophic or polypoid endometrium) has a significant positive correlation with endometriosis (positive and negative predictive values of 84% and 75%, respectively) (207).
Imaging to Assess Intestinal and Urologic Involvement
If there is clinical evidence of deeply infiltrating endometriosis, ureteral, bladder, and bowel involvement should be assessed. Ureteral involvement may be asymptomatic in up to 50% of patients with deeply infiltrative endometriosis (208). Consideration should be given to performing ultrasound (transrectal, transvaginal or renal), a CT urogram, or an MRI. A barium enema study might be useful, depending on the individual circumstances, to map the extent of disease present, which may be multifocal (1). There is no proof that one technique is superior to another; it is recommended that the technique that is most familiar to the radiologist involved be used.
Blood and Other Tests
There is no specific blood test for the diagnosis of endometriosis. A general endometriosis screening test may be neither appropriate (risk for overdiagnosis) nor feasible. A blood test with a high sensitivity would be useful if that would identify women with symptomatic endometriosis (pelvic pain, infertility) that is not detectable by ultrasound imaging (209). This would include all cases of minimal to mild endometriosis and those cases of moderate to severe endometriosis without detectable ovarian endometriotic cysts or nodules (210). These are patients who could benefit from laparoscopic surgery to reduce endometriosis-associated pain and infertility or to diagnose and treat other pelvic causes of pelvic pain or infertility, like pelvic adhesions. From that perspective, a lower specificity would be acceptable because the main goal of such a test would be to rule in all women with potential endometriosis or other pelvic disease who might benefit from surgery (211).
CA125
Levels of CA125, a glycoprotein from coelomic epithelium and common to most nonmucinous epithelial ovarian carcinomas, are significantly higher in women with moderate or severe endometriosis and normal in women with minimal or mild disease (212,213). It is presumed that endometriosis lesions produce peritoneal irritation and inflammation and this leads to an increased shedding of CA125 (213). During menstruation, an increase in CA125 levels was shown in women with and without endometriosis (214–218). Other studies did not find an increase during menses, or found an increase only with moderate to severe endometriosis (219–222). The levels of CA125 vary widely: in patients without endometriosis (8–22 U/mL in the nonmenstrual phase), in those with minimal to mild endometriosis (14–31 U/mL in the nonmenstrual phase), and in those with moderate to severe disease (13–95 U/mL in the nonmenstrual phase). Compared with laparoscopy, measurement of serum CA125 levels has no value as a diagnostic tool (223).
The specificity of CA125 is reported to be higher than 80% in most studies. This high level of specificity is achieved in selected women with infertility or pain, who are known to be at risk for endometriosis. The low level of sensitivity of CA125 (20% to 50% in most studies) poses limitations for the clinical use of this test for diagnosis of endometriosis. Theoretically, the sensitivity might increase during the menstrual period, when the increase in CA125 level is more pronounced in women who have endometriosis. Studies using cutoff levels of 35 U/mL or 85 U/mL did not find a significant improvement in sensitivity (221,222,224). A sensitivity of 66% was found when the CA125 level was determined during both the follicular phase and the menstrual phase in each patient and when the ratio of menstrual versus follicular values (> 1.5) was used instead of one CA125 level (222). Other studies reported that the value of CA125 in diagnosis of endometriosis is limited but higher for moderate to severe disease, especially if serum CA125 concentrations are measured during the midfollicular phase (223,225).
Serial CA125 determinations may be useful to predict the recurrence of endometriosis after therapy (226,227). CA125 levels decrease after combined medical and surgical therapy or during medical treatment of endometriosis with danazol, gonadotropin-releasing hormone (GnRH) analogues, or gestrinone, but not with medroxyprogesterone acetate (MPA) or placebo (228–230). Levels of CA125 are reported to increase to pretreatment levels as early as 3, 4, or 6 months after the cessation of therapy with danazol, GnRH analogues, or gestrinone (218,229–233). Posttreatment increases in CA125 levels are reported to correlate with endometriosis recurrence (217,227,234). Other studies did not substantiate a correlation between posttreatment CA125 levels and disease recurrence (228,231,235).
Other Tests
It is not possible to diagnose endometriosis in a noninvasive way based on the increased concentration of cytokines and growth factors in peripheral blood or on endometrial biopsy analysis (46,236).
Laparoscopy
General Considerations
Unless disease is visible in the vagina or elsewhere, laparoscopy is the standard technique for visual inspection of the pelvis and establishment of a definitive diagnosis (1). There is insufficient evidence to justify timing the laparoscopy at a specific time in the menstrual cycle, but it should not be performed during or within 3 months of hormonal treatment so as to avoid underdiagnosis (1). Laparoscopic recognition of endometriosis will vary with the experience of the surgeon, especially for subtle bowel, bladder, ureteral, and diaphragmatic lesions (1). A meta-analysis of its value against a histological diagnosis showed (assuming a 10% pretest probability of endometriosis) that a positive laparoscopy increases the likelihood of disease to 32% (95% confidence interval [CI], 21%–46%) and a negative laparoscopy decreases the likelihood to 0.7% (95% CI, 0.1%–5.0%) (1,237). Diagnostic laparoscopy is associated with an approximately 3% risk of minor complications (e.g., nausea, shoulder tip pain) and a risk of major complications (e.g., bowel perforation, vascular damage) of 0.6 to 1.8 per 1,000 cases (1,238,239). Endometriosis can be treated during laparoscopy, thus combining diagnosis and therapy.
Laparoscopic Technique
During diagnostic laparoscopy, the pelvic and abdominal cavity should be systematically investigated for the presence of endometriosis. This examination should include a complete inspection in a clockwise or counterclockwise fashion with a blunt probe, with palpation of lesions to check for nodularity as a sign of deeply infiltrative endometriosis of the bowel, bladder, uterus, tubes, ovaries, cul-de-sac, or broad ligament (Fig. 17.1). The type, location, and extent of all lesions and adhesions should be documented in the operative notes; ideally, the findings should be recorded with photographs or on video such as a DVD (1).
Figure 17.1 Pelvic endometriosis.
Laparoscopic Findings
The laparoscopic findings of endometriosis include peritoneal lesions, ovarian endometriotic cysts, and deeply infiltrative endometriosis invading the peritoneal surface with a depth of at least 5 mm. Most patients with ovarian endometriotic cysts or deeply infiltrative endometriosis also have peritoneal disease.
Peritoneal Endometriosis
Characteristic findings include typical (“powder-burn” or “gunshot”) lesions on the serosal surfaces of the peritoneum. These lesions are black, dark brown, or bluish nodules or small cysts containing old hemorrhage surrounded by a variable degree of fibrosis (Fig. 17.2). Endometriosis can appear as subtle lesions, including red implants (petechial, vesicular, polypoid, hemorrhagic, red flamelike), serous or clear vesicles, white plaques or scarring, yellow-brown discoloration of the peritoneum, and subovarian adhesions (Fig. 17.3) (138,139,141,240,241). Histologic confirmation of the laparoscopic impression is essential for the diagnosis of endometriosis, for subtle lesions, and for the typical lesions reported to be histologically negative in 24% of cases (242,243).
Figure 17.2 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 kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.)
Figure 17.3 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 kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.)
Deeply Infiltrative Endometriosis
Mild forms of deep endometriosis may be detected only by palpation under an endometriotic lesion or by discovery of a palpable mass beneath visually normal peritoneum, most notably in the posterior cul-de-sac (Fig. 17.4) (200). At laparoscopy, deeply infiltrating endometriosis may have the appearance of minimal disease, resulting in an underestimation of disease severity (200). Reduced size of the cul-de-sac in women with deep endometriosis suggests that such lesions develop not in the rectovaginal septum but intraperitoneally and that burial of anterior rectal wall adhesions creates a false bottom, giving an erroneous impression of extraperitoneal origin (244).
Figure 17.4 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 kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.)
Ovarian Endometriosis
The diagnosis of ovarian endometriosis is facilitated by careful inspection of all sides of both ovaries, which may be difficult when adhesions are present in more advanced stages of disease (Fig. 17.5). With superficial ovarian endometriosis, lesions can be both typical and subtle. Larger ovarian endometriotic cysts (i.e., endometriomas) usually are located on the anterior surface of the ovary and are associated with retraction, pigmentation, and adhesions to the posterior peritoneum. These ovarian endometriotic cysts often contain a thick, viscous dark brown fluid (i.e., “chocolate fluid”), composed of hemosiderin derived from previous intraovarian hemorrhage.Because this fluid may be found in other conditions, such as in hemorrhagic corpus luteum cysts or neoplastic cysts, biopsy and preferably removal of the ovarian cyst for histologic confirmation are necessary for the diagnosisin the revised endometriosis classification of the American Society for Reproductive Medicine (ASRM). If that is not possible, the presence of an ovarian endometriotic cyst should be confirmed by the following features: cyst diameter of less than 12 cm, adhesion to pelvic sidewall or broad ligament, endometriosis on surface of ovary, and tarry, thick, chocolate-colored fluid content (245). Ovarian endometriosis appears to be a marker for more extensive pelvic and intestinal disease. Exclusive ovarian disease is found in only 1% of endometriosis patients, with the remaining patients having extensive pelvic or intestinal endometriosis (246).
Figure 17.5 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.)
Histologic Confirmation
Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it (1). Whether histology should be obtained when peritoneal disease alone is present is controversial; visual inspection is usually adequate but histological confirmation of at least one lesion is ideal (1). In cases of ovarian endometrioma (> 4 cm in diameter) and in deeply infiltrating disease, histology is recommended to exclude rare instances of malignancy (1).
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% (247).
Microscopically, endometriotic implants consist of endometrial glands and stroma, with or without hemosiderin-laden macrophages (Fig. 17.6). It is suggested that using these stringent and unvalidated histologic criteria may result in significant underdiagnosis of endometriosis (5). 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 (248). 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 (147,242,243). Isolated endometrial stromal cell nodules and immunohistochemically positive for vimentin and estrogen receptor can be found in the absence of endometrial glands along blood or lymphatic vessels (249).
Figure 17.6 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 (248). Vascularization, mitotic activity, and the three-dimensional structure of endometriosis lesions are key factors (177,250,251). 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 (19). Smooth muscles are frequent components of endometriotic lesions on the peritoneum, ovary, rectovaginal septum, and uterosacral ligaments (252).
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 (253,254). 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 (254). 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 (255). 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 (241,256,257). Other studies were unable to detect microscopic endometriosis in 2-mm biopsy specimens of visually normal peritoneum (258–261). Examination of larger samples (5–15 mm) of visually normal peritoneum revealed microscopic endometriosis in only 1 of 55 patients studied (262). 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 (95). Macroscopically appearing normal peritoneum rarely contains microscopic endometriosis (262).
Laparoscopic Classification
Many classification systems were proposed, but only one was accepted. This system is the revised American Fertility Society (AFS) system, which 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 (185,210). In this ASRM 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), according to color photographs provided by ASRM.
This system reflects the extent of endometriotic disease but has considerable intraobserver and interobserver variability (263,264). Like all classification systems, the ASRM classification for endometriosis is subjective and correlates poorly with pain symptoms, but may be of value in infertility prognosis and management (181). Because this ASRM revised classification of endometriosis is the only internationally accepted system, it is the best available tool to describe objectively the extent of endometriosis and relate it to spontaneous evolution. More outcome-based research is needed to discover whether it is possible to improve the standardization and positive correlation of the ASRM classification of endometriosis with symptoms (pain, infertility) and with therapeutic outcome (pain relief, enhancement of fertility) after medical or surgical treatment. More variables than only the stage of endometriosis may have to be entered in such prediction models. Evidence suggests that endometriosis with an ASRM score of 16 or more, together with other variables like age, duration of infertility, and least functional score for ovaries and fallopian tubes after endometriosis surgery, is predictive of pregnancy (183).
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 (265,266). In another study, endometriosis progressed in 64%, improved in 27%, and remained unchanged in 9% of patients over 12 months (267). 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 (268–270). 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 (271). 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 (6). 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 (272,273). Several studies in women, cynomolgus monkeys, and rodents showed that endometriosis is ameliorated after pregnancy (273–276).
The characteristics of endometriosis are variable during pregnancy, and lesions tend to enlarge during the first trimester but regress thereafter (277). Studies in baboons revealed no change in the number or surface area of endometriosis lesions during the first two trimesters of pregnancy (278). 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 (279). 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
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 (45). There is insufficient evidence that oral contraceptive use offers protection against the development of endometriosis. One report showed an increased risk for endometriosis in a select population of women taking oral contraceptives, 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 (280,281). Oral contraceptives (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 (282). 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 (283). 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 (283).
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 subfertility 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, recently defined by the World Health Organization (WHO) as “all surgical procedures carried out to diagnose, conserve, correct and/or improve reproductive function” (284). 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 (subfertility, pain, asymptomatic findings), treatment of endometriosis may be justified because endometriosis appears to progress in 30% to 60% of patients within a year of diagnosis and it is not possible to predict in which patients it will progress (267). 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 subfertility) 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).
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 (1,285). Because the management of severe or deeply infiltrating endometriosis is complex, referral is strongly recommended when disease of such 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 preoperative consent was obtained (1,286–289). 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). In most women, laparoscopy can be used, and this technique decreases cost, morbidity, and the possibility of recurrence of adhesions postoperatively (1). Laparotomy should be reserved for patients with advanced-stage disease who cannot undergo a laparoscopic procedure and for those in whom fertility conservation is not necessary (1).
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 CO2laser is superior because it causes only minimal thermal damage, but no evidence is available to show the superiority of one technique over another. Comparable cumulative pregnancy rates were reported after treatment of mild endometriosis with laparoscopic excision and electrocoagulation (290). Ablation of endometriotic peritoneal lesions plus laparoscopic uterine nerve ablation (LUNA) in minimal to moderate disease reduces endometriosis-associated pain at 6 months compared to diagnostic laparoscopy; the smallest effect is seen in patients with minimal disease (1,291). There is no evidence that LUNA is a necessary component, and LUNA by itself has no effect on dysmenorrhoea associated with endometriosis (1,292,293). The effectiveness of surgical ablation of peritoneal endometriosis is convincingly shown in two randomized trials where the control group underwent a laparoscopy without surgical ablations of lesions. The treated group had a significant reduction of symptoms that persisted for 12 months and 18 months, respectively (268,294,295). The effectiveness of surgical treatment by laparotomy was not investigated by a randomized trial, although many published observational studies claim a high percentage of success (1).
Adhesiolysis
The removal of endometriosis-related adhesions (adhesiolysis) should be performed carefully. Adhesions lysed at surgery can form again (296). Routine use of pharmacologic or liquid agents to prevent postoperative adhesions after fertility surgery cannot be recommended based on a systematic review, including 16 randomized controlled trials, with the following indications for surgery included myomectomy (five trials), ovarian surgery (five trials), pelvic adhesions (four trials), endometriosis (one trial), and mixed (one trial) (297). No studies reported pregnancy or reduction in pain as outcomes (297). The absorbable adhesion barrier Interceed [MB1]reduced the incidence of adhesion formation following laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates (297). Gore-Tex [MB2]may be superior to Interceed in preventing adhesion formation, but its usefulness is limited by the need for suturing and later removal (297). There was no evidence of effectiveness of Seprafilm and Fibrin [MB3]sheet in preventing adhesion formation (297). In a randomized trial in patients with surgically treated stages I to III endometriosis without endometrioma, postoperative adnexal application of Oxiplex/AP (FzioMed, San Luis Obispo, California) gel treatment was superior to surgery alone (control group) with respect to postoperative adhesion formation (defined as secondary outcome) 6 to 8 weeks later in a subgroup of patients with red lesions (298). This observation needs to be confirmed in other randomized trials with postoperative adhesion formation as primary outcome. In the same study, control patients with at least 50% red lesions had a greater increase in ipsilateral adnexal adhesion scores than patients with mostly black or white and/or clear lesions (298).
Ovarian Endometriosis
Surgical Technique
Superficial ovarian lesions can be vaporized. The surgical management of ovarian endometriotic cysts is controversial. The primary indication for extirpation of an endometrioma is to ensure it is not malignant (1). The laparoscopic approach to the management of endometriomata is favored over a laparotomy approach because it offers the advantage of a shorter hospital stay, faster patient recovery, and decreased hospital costs (299). The most common procedures for the treatment of ovarian endometriomas are either excision of the cyst capsule or drainage and electrocoagulation 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 normal ovarian tissue. During drainage and electrocoagulation, 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. Small ovarian endometriomata (less than 3-cm diameter) can be treated by drainage and electrocoagulation (1). Ovarian endometriomata larger than 3 cm should be removed completely (1,300). In cases 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 analogues and cyst wall electrocoagulation or laser vaporization 3 months later) should be considered (1,301).
Outcome after Cystectomy
Although as little as one-tenth of an ovary may be enough to preserve function and fertility, at least for a while, there is increasing concern that ovarian cystectomy with concomitant removal or destruction of normal ovarian tissue may reduce ovarian follicle reserve and reduce fertility (302). One study reported reduced follicular response in natural and clomiphene citrate–stimulated cycles, but not in gonadotropin-stimulated cycles, in women younger than 35 years of age who underwent cystectomy compared with controls of similar age with normal ovaries (302). 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 (299). This approach should be the favored surgical approach, based on two randomized studies of the laparoscopic management of ovarian endometriomata of greater than 3 cm in size for the primary symptom of pain (303,304). 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 subfertility (OR 5.21; 95% CI, 2.04–13.29).
A randomized study demonstrated an increased ovarian follicular response to gonadotrophin stimulation for women who underwent excisional surgery when compared to ablative surgery(weighted mean difference (WMD) 0.6; 95% CI, 0.04–1.16) (305). There is insufficient evidence to favor excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intrauterine insemination (OR 1.40; 95% CI, 0.47–4.15) or treatment with assisted reproductive technology (299). It is controversial whether there is a potential negative effect of ovarian cystectomy on reproductive function. In a small prospective randomized clinical trial, 10 patients assigned to undergo laparoscopic cystectomy had a lower antral follicle count and a more pronounced reduction in serum anti-müllerian hormone (AMH) levels (from 3.9 to 2.9 ng/mL) 6 months after surgery when compared to the 10 patients treated with a “three-stage procedure” as described above (reduction in AMH levels from 4.5 to 3.99 ng/mL) (306,307). More randomized trials are needed to assess the effect of ovarian cystectomy on ovarian reserve and on reproductive function, especially with respect to conception after treatment with medically assisted reproduction.
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 (308).
Deeply Infiltrating Rectovaginal and Rectosigmoid Endometriosis
Deeply infiltrating 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(1,179,287). Because management of deeply infiltrating 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 deeply infiltrating endometriosis. Asymptomatic patients must not undergo surgery. Progression of the disease and appearance of specific symptoms rarely occurred in patients with asymptomatic rectovaginal endometriosis (288). When surgical treatment is decided, the treatment must be radical with excision of all infiltrating lesions (1). It is difficult to perform randomized studies to detect the best surgical technique to treat deeply infiltrative 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 urological and bowel operations..
Preoperative Preparation
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 urological surgery. Preoperative imaging is necessary to assess bowel and urological impact of deeply infiltrative endometriosis, as described above. CT urogram to exclude ureteral endometriosis and flexible sigmoidoscopy or double-contrast colon radiography to exclude transmural rectosigmoidal endometriosis, supplemented with MRI in selected cases, are preferred (285). 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 causing ureteral obstruction. The pattern of pain in endometriosis is complicated and pain does not always respond to treatment, so consultation with pain specialists may be useful.
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. A radical approach to obstructive uropathy is suggested, with resection of the stenotic ureteral tract and reimplantation with antireflux vesicoureteral plasty (309).
Surgical excision of deep rectovaginal and rectosigmoidal endometriosis is difficult and can be associated with major complications such as bowel perforations with resulting peritonitis (310). 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 (311).
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 (312).
There are very few methodologically valid studies evaluating clinical outcome after deeply infiltrative with colorectal extension, as demonstrated in a systematic review (313). In a review on the clinical outcome of surgical treatment of deeply infiltrating 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%. Owing to highly variable study design and data collection, a Consolidated Standards of Reporting Trials (CONSORT)-inspired checklist was developed for future studies (313). Prospective studies reporting standardized and well-defined clinical outcome after surgical treatment of deeply invasive endometriosis with colorectal involvement with long-term follow-up are needed (313).
Surgical Treatment of Pain
The outcome of surgical therapy in patients with endometriosis and pain is influenced by many psychological factors relating to personality, depression, and marital and sexual problems. It is difficult to evaluate scientifically the objective effect of different surgical approaches because the extirpation and destruction of the pathological tissue can impact the results as can surgery per se, the doctor–patient relationship, complications, and other factors. There is a significant placebo response to surgical therapy: diagnostic laparoscopy without complete removal of endometriosis may alleviate pain in 50% of patients (295,314,315). Similar results were reported using oral placebos (316). Although some reports claimed pain relief with laser laparoscopy in 60% to 80% of patients with very low morbidity, none was prospective or controlled or allowed a definitive conclusion regarding treatment efficacy (200,317–320). 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.
Laparoscopic Uterine Nerve Ablation
In a prospective, controlled, randomized, study, surgical therapy with ablation of endometriotic lesions and LUNA was shown to be superior to expectant management 6 months after treatment of mild and moderate endometriosis (295). In women with mild and moderate disease treated with laser, 74% achieved pain relief. Treatment was least effective in women with minimal disease. There were no reported operative or laser complications (295). One year later, symptom relief was still present in 90% of those who responded initially (268,295). Patients with severe disease were not included because surgery resulted in pain relief in 80% of patients who did not respond to medical therapy (295,319). There is randomized evidence that LUNA is not a necessary part of this treatment because addition of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis stages I to IV did not reduce the medium- or long-term frequency and severity of recurrence of dysmenorrhea (292,293). These data were confirmed in a second randomized trial in women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, where LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation (321).
In a randomized crossover study, laparoscopic excision of endometriosis was found to be more effective than placebo in reducing pain and improving quality of life (294). These results suggest that laparoscopic surgery may be effective for the treatment of pain associated with mild to severe endometriosis. In women with minimal endometriosis, laser treatment may limit progression of disease.
Meta-analysis and Systematic Review
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 which specific laparoscopic surgical intervention is 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 (322). In a systematic review based on three randomized controlled studies, the absolute benefit increase of 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 (322). The pain relief ended to decrease with time, and the reoperation rate, based on long-term follow-up studies, was as high as 50% (322). 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 (322). Medium-term recurrence of lesions was observed in approximately 20% of the cases, and approximately 25% of the women underwent repetitive surgery (322). It appears that pain recurrence and reoperation rates after conservative surgery for symptomatic endometriosis are high and probably underestimated (322).
Preoperative Hormonal Treatment
In patients with severe endometriosis, it is recommended that surgical treatment be preceded by a 3-month course of medical treatment to reduce vascularization and nodular size (200). A randomized controlled study comparing presurgical medical therapy (3 months of GnRH agonists) with surgery alone in women with moderate to severe endometriosis showed a significant improvement in AFS scores in the medical therapy group (WMD −9.60; 95% CI, −11.42–−7.78), without significant difference in ease of surgery between the two groups and without documentation of improved outcomes for the patients (323). Hormonal therapy prior to surgery improves r-AFS scores, but there is insufficient evidence of any effect on outcome measures such as pain relief (1,324).
Oophorectomy and Hysterectomy
Radical procedures such as oophorectomy or total hysterectomy are indicated only in severe situations and can be performed laparoscopically or by laparotomy. Women aged 30 years or younger at the time of hysterectomy for endometriosis-associated pain are more likely than older women to have residual symptoms, to report a sense of loss, and to report more disruption from pain in different aspects of their lives (325). If a hysterectomy is performed, all visible endometriotic tissue should be removed. Although associated with improved pain relief and a reduced chance of future surgery, a bilateral salpingo-oophorectomy in young women should be considered in only the most severe or recurrent cases (326,327). Resection is an effective treatment for rectovaginal endometriosis, in combination with hysterectomy (328).
Hormone Therapy after Bilateral Oophorectomy
When postoperative hormone therapy with estrogen is used after bilateral oophorectomy, there is a negligible risk for renewed growth of residual endometriosis (329). To reduce this risk, hormone therapy should be withheld until 3 months after surgery. The addition of progestins to this regimen protects the endometrium. The decision to start hormone therapy with a combination of estrogen and progestin should be balanced against the increased risk of breast cancer and heart disease associated with hormone therapy. Some cases of adenocarcinoma were reported, presumably arising from endometriosis lesions remaining in women treated with unopposed estrogen (330).
Recurrence after Postoperative Treatment
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 (324). Five trials compared postsurgical medical therapy with surgery alone (without medical therapy) and assessed the outcomes of pain recurrence, disease recurrence, and pregnancy rates (331–334). 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 (332,335,336). 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 presurgery hormonal suppression and postsurgery hormonal suppression for the outcome of pain in one trial (323).
These results were confirmed in another randomized controlled trial with 5 years of follow-up, showing that GnRH analogue 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 (337).
There is circumstantial evidence that regular postoperative use of OCs effectively prevents endometrioma recurrence (338). 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 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 < .001; adjusted incidence rate ratio [IRR[0.10; 95% CI, 0.04–0.24) (338).
Some randomized controlled studies suggest that postoperative hormonal treatment can be useful in delaying the recurrence of endometriosis and/or pelvic pain. One study supported the long-term postoperative use of OCs to reduce the frequency and the severity of recurrent endometriosis-related dysmenorrhea (339). The prevention of endometriosis-related pain recurrence by postoperative long-term (24 months) cyclic and continuous administration of OCs was compared to no treatment in women after surgery for ovarian endometrioma. A significant reduction in recurrence rate and VAS scores for dysmenorrhea was evident in the continuous users versus the other groups at 6 months, and in cyclic users versus nonusers at 18 months postoperatively. No significant differences in recurrence rate and VAS scores for dyspareunia and chronic pelvic pain were demonstrated among the groups. The increase of VAS scores for dysmenorrhea, dyspareunia, and chronic pelvic pain during the postoperative follow-up of 6 to 24 months was significantly higher in nonusers than in the users (339).
In a second study, long-term cyclic and continuous postoperative use of OCs was shown to effectively reduce and delay endometrioma recurrence (340). The crude recurrence rate within 24 months was significantly lower in cyclic (14.7%) and continuous users (8.2%) compared with nonusers (29%). The recurrence-free survival was significantly lower in nonusers compared with cyclic and continuous users. The mean recurrent endometrioma diameter at first observation and the mean diameter increase every 6 months of follow-up were significantly lower in cyclic and continuous users compared with nonusers, whereas no significant differences between cyclic users and continuous users in terms of endometrioma recurrence were demonstrated (340).
In a third study, women who underwent conservative pelvic surgery for symptomatic endometriosis stages III and IV (r-AFS) were treated postoperatively during 6 months with either placebo, GnRH agonist (triptorelin or leuprorelin, 3.75 mg every 28 days), continuous estroprogestin (ethinylestradiol, 0.03 mg plus gestodene, 0.75 mg) or dietary therapy (vitamins, minerals salts, lactic ferments, fish oil) (341). At 12 months after surgery, patients treated with postoperative hormonal suppression therapy showed a lower VAS score for dysmenorrhea than patients in the other groups. Hormonal suppression therapy and dietary supplementation were equally effective in reducing nonmenstrual pelvic pain. Postoperative medical and dietary therapy allowed a better quality of life when compared to placebo treatment(341).
Local Treatment
In a systematic review to determine whether postoperative use of an levonorgestrel intrauterine system in women with endometriosis improves pain symptoms associated with menstruation and reduces recurrence compared with surgery only, placebo, or systemic hormones, one small randomized controlled trial was identified showing a statistically significant reduction in the recurrence of painful periods in the levonorgestrel intrauterine system treated group compared with the control group receiving a GnRH agonist (OR 0.14; 95% CI, 0.02–0.75) (342,343). The proportion of women who were satisfied with their treatment was higher in the levonorgestrel intrauterine system treated group than in the control group, but this difference did not reach statistical difference (OR 3.00; 95% CI, 0.79–11.44) (342,343). In another small randomized trial, postsurgical treatment with either levonorgestrel intrauterine system or depot MPA for 3 years indicated symptom control and recurrence were comparable, but compliance and change in bone mineral density were better in the levonorgestrel intrauterine system treated group than in the depot MPAgroup (344).
Medical Treatment
If the patient desires treatment of pain symptoms that are suggestive of endometriosis in the absence of a definitive diagnosis, empirical treatment is appropriate and includes counseling, analgesia, nutritional therapy, progestins, or combined oral contraceptives. It is unclear whether oral contraceptives should be taken in a conventional, continuous, or tricycle regimen. A GnRH agonist may be taken, but is not recommended, because this class of drug is more expensive and associated with more side effects and concerns about bone density than oral contraceptives (1).
Primary Dysmenorrhea
Analgesics
Women suffering from dysmenorrhea are treated with analgesics; many women treat themselves with over-the-counter oral analgesics. Primary dysmenorrhea is defined as menstrual pain without organic pathology, based on physical examination alone, and it can be argued that some women with so-called primary dysmenorrhea probably have endometriosis (345). In a systematic review it was concluded that nonsteroidal anti-inflammatories (NSAIDs), except niflumic acid, were more effective than placebo for relief of primary dysmenorrhea, but there was insufficient evidence to suggest whether any individual NSAID was more effective than another (345). In another review, selective cyclo-oxygenase-2 inhibitors rofecoxib and valdecoxib were as effective as naproxen and more effective than placebo for the treatment of primary dysmenorrhea (346). Concerns were raised about the safety of these medications, and its manufacturers withdrew rofecoxib from the market.
According to another systematic review based on two relatively small, randomized controlled trials comparing paracetamol and coproxamol with placebo, coproxamol (paracetamol 650 mg and dextropropoxyphene 65 mg) but not paracetamol (500 mg 4 times daily) was more effective than placebo in reducing primary dysmenorrhea (346). This observation may be explained by the suboptimal dosage of paracetamol used. A small randomized trial demonstrated that paracetamol (acetaminophen) 1,000 mg four times daily was superior to placebo for the treatment of primary dysmenorrhea (347).
Oral Contraceptives
There is a paucity of information for the use of modern OCs for primary dysmenorrhea. A Cochrane review suggested that first- and second-generation OCs with 50 μg or more estrogen may be more effective than placebo treatment for dysmenorrhea. It concluded that the studies included for analysis were of poor quality and heterogenous so that no recommendation could be made regarding the efficacy of modern, lower dose OCs (evidence level 1a) (348). A randomized controlled trial comparing a low-dose oral contraceptive containing 20 μg ethinyl estradiol and 100 μg levonorgestrel with placebo showed better pain relief in adolescent girls with dysmenorrhea using the OC than placebo (349).
There is some evidence in general populations that OCs can effectively treat dysmenorrhea (350). OCs have the advantage of long-term safety; hence they can be used indefinitely in low-risk women. In clinical practice, when they are used for menstrual pain, they may be taken tricyclicly or continuously to reduce the number of periods or avoid them altogether (evidence level 4). There is no direct comparison of these options with the conventional approach.
Other Treatments
Several Cochrane reviews and one clinical-evidence review suggest that other treatment modalities that might be helpful in primary dysmenorrhea include supplemental thiamine or vitamin E, high frequency transcutaneous nerve stimulation, topical heat and herbal remedy toki-shakuyaku-san. They suggest that treatment modalities with unknown benefit are vitamin B12, fish oil, magnesium, acupuncture, other herbal remedies and behavioral interventions, and that spinal manipulation is unlikely to be beneficial (348,350–352).
Treatment of Endometriosis-Associated Pain
Nonsteroidal Anti-inflammatory Drugs
Considering that endometriosis is a chronic inflammatory disease, anti-inflammatory drugs would appear to be effective for treatment of endometriosis-related dysmenorrhea. Although NSAIDs are used extensively and are often the first-line therapy for reduction of endometriosis-related pain, the analgesic effect of NSAIDs was not studied extensively. Only one small, double-blind, placebo-controlled, four-period, crossover clinical study was published (353). This study claimed complete or substantial pain relief of endometriosis-related dysmenorrhea in 83% of cases treated with naproxen compared with 41% in cases treated with placebo. A different analysis of the data from the same study by the Cochrane Collaborative Network did not confirm a positive effect of naproxen on pain relief (OR 3.27; 95% CI. 0.61–17.69) in women with endometriosis (354). There was inconclusive evidence to indicate whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12; 95% CI, 0.01–1.29) or to experience side effects (OR 0.46; 95% CI, 0.09–2.47) when compared to placebo (354).
Endometriosis-related pain is nociceptive, but persistent nociceptive input from endometriotic lesions leads to central sensitization manifested by somatic hyperalgesia and increased referred pain (355). The potential effectiveness of NSAIDs in the reduction of endometriosis-related pain may be explained by a local antinociceptive effect and a reduced central sensitization in addition to the anti-inflammatory effect. NSAIDs have significant side effects, including gastric ulceration and possible inhibition of ovulation. Prostaglandins are involved in the follicle rupture mechanism at ovulation, which is why women who wish to become pregnant should not take NSAIDs at the time of ovulation (356).
Hormonal Treatment
Effect of Hormonal Treatment on Pain
Because estrogen is known to stimulate the growth of endometriosis, hormonal therapy is designed to suppress estrogen synthesis, thereby inducing atrophy of ectopic endometrial implants or interrupting the cycle of stimulation and bleeding (1). Implants of endometriosis react to gonadal steroid hormones in a manner similar, but not identical, to normally stimulated ectopic endometrium. Ectopic endometrial tissue displays histologic and biochemical differences from normal ectopic endometrium in characteristics such as glandular activity (proliferation, secretion), enzyme activity (17β-hydroxysteroid dehydrogenase), and steroid (estrogen, progestin, and androgen) hormone receptor levels. Withdrawal of estrogen stimulation causes cellular inactivation and degeneration of endometriotic implants but not their disappearance.
There is strong evidence that suppression of ovarian function for 6 months reduces pain associated with endometriosis. Combined oral contraceptives danazol, gestrinone, medroxyprogesterone acetate, and GnRH agonists are all equally effective but their side effects and cost profiles differ (1). Pain relief may be of short duration, presumably because endometriosis and endometriosis-associated pain recur after the cessation of medical treatment.The use of diethylstilbestrol, methyltestosterone, or other androgens is no longer advocated because they lack efficacy, have significant side effects, and pose risks to the fetus if pregnancy occurs during therapy. A new generation of aromatase inhibitors, estrogen receptor modulators, and progesterone antagonists may offer new hormonal treatment options.
Hormonal Treatment for Pain from Rectovaginal Endometriosis
Surgical treatment may reduce the pain associated with rectovaginal endometriosis, but it is associated with a high risk of morbidity and major complications. The effect of medical treatment in terms of pain relief in women with rectovaginal endometriosis appears to be substantial (357). In a systematic review including 217 cases of medically treated rectovaginal endometriosis, the antalgic effect of the considered medical therapies (vaginal danazol, GnRH agonist, progestin, and estrogen-progestin combinations used transvaginally, transdermally, or orally) for the entire treatment period (from 6 to 12 months) was 60% to 90%, with patients reporting considerable reduction or complete relief from pain symptoms, with the exception of when an aromatase inhibitor was used alone (357).
Oral Contraceptives
Although oral contraceptives are effective in inducing a decidualized endometrium, the estrogenic component in oral contraceptives may stimulate endometrial growth and increase pelvic pain in the first few weeks of treatment. The long-term significance of this effect is undetermined. Oral contraceptives are less costly than other treatments and may be helpful in the short-term management of endometriosis with potential long-term benefits in some women.
The use of cyclic oral contraceptives may provide prophylaxis against the development or recurrence of endometriosis. Estrogens in oral contraceptives may stimulate the proliferation of endometriosis. The reduced menstrual bleeding that often occurs in women taking oral contraceptives may be beneficial to women with prolonged, frequent menstrual bleeding, which is a known risk factor for endometriosis (45).
Further research is warranted to assess the effect of low-dose oral contraceptives in preventing endometriosis and treating associated pain, because the evidence for its efficacy is limited. In a systematic review to assess the effects of OC’s in comparison to other treatments for painful symptoms of endometriosis in women of reproductive age, only one study met the inclusion criteria (all truly randomized controlled trials of the use of OCs in the treatment of women of reproductive age with symptoms ascribed to the diagnosis of endometriosis and made visually at surgical procedure were included) (358,359). In this study, a total of 57 women were allocated to two groups to compare an OC to a GnRH analogue (359). Methods of randomization and allocation concealment were unclear and the analogue group became amenorrheic during the treatment period of 6 months, while women in the OC group reported a decrease in dysmenorrhea (358,359). No evidence of a significant difference between the two groups was observed in terms of dysmenorrhea at 6 months follow-up after stopping treatment (OR 0.48; 95% CI, 0.08–2.90). Some evidence for a decrease in dyspareunia was found at the end of treatment in women in the GnRH analogue group; although no evidence of a significant difference in dyspareunia was observed at the end of the 6 months follow-up (OR 4.87; 95% CI, 0.96–24.65). According to these data, there is no evidence of a difference in outcomes between the OC studied and GnRH analogue in the treatment of endometriosis-associated painful symptoms (358). The lack of studies with larger sample sizes or studies focusing on other comparable treatments is concerning, and further research is needed to evaluate the role of OCs in managing symptoms associated with management of endometriosis (358).
In a recent double-blind, randomized, placebo-controlled trial, patients with suspected or surgically proven endometriosis were randomly assigned to receive either monophasic OC (ethinylestradiol plus norethisterone) or placebo during four cycles (360). Total dysmenorrhea scores assessed by verbal rating scale were significantly decreased at the end of treatment in both groups. From the first cycle through the end of treatment, dysmenorrhea in the OC group was significantly milder than in the placebo group. The volume of ovarian endometrioma was significantly decreased in the OC group but not in the placebo group (360).
Continuous Contraceptives
The treatment of endometriosis with continuous low-dose monophasic oral contraceptives (one pill per day for 6 to 12 months) was originally used to induce pseudopregnancy caused by the resultant amenorrhea and decidualization of endometrial tissue (279). The concept was to induce an adynamic endometrium through elimination of the normal cyclic hormonal changes characteristic of the menstrual cycle (361). This induction of a pseudopregnancy state with combination oral contraceptive pills is effective in reducing dysmenorrhea and pelvic pain. The subsequent amenorrhea induced by oral contraceptives could decrease the risk for disease progression by preventing or reducing (retrograde) menstruation. Pathologically, oral contraceptive use is associated with decidualization of endometrial tissue, necrobiosis, and possibly absorption of the endometrial tissue (362). There is no convincing evidence that medical therapy with oral contraceptives offers definitive therapy. Instead, the endometrial implants survive the induced atrophy and, in most patients, reactivate after termination of treatment.
Any low-dose OC containing 30 to 35 μg of ethinyl estradiol used continuously can be used for the management of endometriosis. The objective of the treatment is the induction of amenorrhea, which should be continued for 6 to 12 months. Continuous or extended cyclic use of oral contraceptives is well tolerated when compared to the cyclic use of OCs for contraceptive purposes (363). In a randomized controlled trial of women with recurrent moderate or severe pelvic pain after unsuccessful conservative surgery for symptomatic rectovaginal endometriosis, continuous treatment with oral ethinyl E2, 0.01 mg plus cyproterone acetate, 3 mg per day, or norethindrone acetate, 2.5 mg per day during 12 months resulted in substantially reduced dysmenorrhea, deep dyspareunia, nonmenstrual pelvic pain, and dyschezia scores without major between-group differences in patient satisfaction rates (62% and 73%, respectively) (364).
In a patient preference cohort study to evaluate the efficacy and tolerability of a contraceptive vaginal ring (supplying 15 μg of ethinyl E and 120 μg per day of etonogestrel) and transdermal patch (delivering 20 μg of ethinyl E and 150 μg per day norelgestromin) in the treatment of women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis and endometriosis-associated pain, patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch (282). Both systems were associated with poor bleeding control when used continuously.
Progestins
Progestins may exert an antiendometriotic effect by causing initial decidualization of endometrial tissue followed by atrophy. They can be considered as the first choice for the treatment of endometriosis because they are as effective as danazol or GnRH analogues and have a lower cost and possibly a lower incidence of side effects than these agents (365).
There is no evidence that any single agent or any particular dose is preferable to another. The effective doses of several progestins are summarized in Table 17.1. In most studies, the effect of treatment was evaluated after 3 to 6 months of therapy. Progestins appear to be an effective therapy for the painful symptoms associated with endometriosis (366).
Table 17.1 Medical Treatment of Endometriosis-Associated Pain: Effective Regimens (Usual Duration: 6 Months)
Medroxyprogesterone Acetate
MPA is the most studied agent. It is effective in relieving pain starting at a dose of 30 mg per day, increasing the dose based on the clinical response and bleeding patterns according to data from nonrandomized trials (367,368). A randomized placebo-controlled study reported a significant reduction in stages and scores of endometriosis in both the placebo group and the group treated with MPA 50 mg per day and placebo at laparoscopy within 3 months after cessation of therapy (369). These findings raise questions about the need for medical therapy with MPA in this dose.
Evidence suggests a possible role for depot MPA in the treatment of endometriosis. In a randomized controlled study, depot MPA (150 mg every 3 months) was more effective in the relief of dysmenorrhea than treatment with a cyclic 21-day oral contraceptive (ethinyl estradiol 20 μg plus desogestrel 0.15 mg) combined with very low-dose danazol (50 mg per day) (370). In another multicenter, randomized, evaluator-blinded, comparator-controlled trial, depot MPA (150 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months were equivalent in reducing endometriosis-associated pain during the study and the 12-month posttreatment follow-up period, with less impact on bone mineral density and fewer hypoestrogenic side effects but more bleeding being observed in the depot MPA treated group (371). Add-back therapy would prevent the negative effects on bone density and hypoestrogenic side effects associated with GnRH-agonist therapy. In a pilot study, pain relief, side effects, and treatment satisfaction were comparable during a 12-month treatment with etonogestrel implantate subcutaneous (68 mg) or depot medroxyprogesterone acetate 150 mg intramuscular depot MPA in 41 patients with dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia associated with histologically proven endometriosis (372). Although depot MPAtreatment is effective for the treatment of pain associated with endometriosis, it is not indicated in infertile women because it induces profound amenorrhea and anovulation, and a varying length of time is required for ovulation to resume after discontinuation of therapy.
Dienogest
In two randomized noninferiority trials, treatment during 6 months with dienogest 2 mg per day orally demonstrated equivalent efficacy to depot leuprolide acetate (3.75 mg, depot intramuscular injection, every 4 weeks) or intranasal buserelin acetate (900 μg per day, intranasally) in relieving the pain associated with endometriosis, offering a different safety and tolerability profile (less bone loss, fewer hot flushes, more irregular genital bleeding) (373,374). Dienogest treatment was not compared to the recommended treatment of GnRH agonist combined with add-back (see discussion above) in these two trials.
Other Progestins
Megestrol Acetate
Megestrol acetate was administered in a dose of 40 mg per day with good results (370). Pain was reduced significantly during luteal phase treatment with 60 mg dydrogesterone, and this improvement was still evident at 12-month follow-up (316). Other treatment strategies included dydrogesterone (20 to 30 mg per day, either continuously or on days 5 to 21) and lynestrenol (10 mg per day).
Side effects of progestins include nausea, weight gain, fluid retention, and breakthrough bleeding caused by hypoestrogenemia. Breakthrough bleeding, although common, is usually corrected by short-term (7-day) administration of estrogen. Depression and other mood disorders are a significant problem in about 1% of women taking these medications.
Intrauterine Progesterone
The levonorgestrel intrauterine system releasing 20 μg per day of levonorgestrel reduces endometriosis-associated pain caused by peritoneal and rectovaginal endometriosis and reduces the risk of recurrence of dysmenorrhea after conservative surgery (375). Levonorgestrel induces endometrial glandular atrophy and decidual transformation of the stroma, reduces endometrial cell proliferation, and increases apoptotic activity (375). A systematic review identified two randomized trials and three prospective observational studies, all involving small numbers and a heterogeneous group of patients (376). The evidence suggests that the levonorgestrel intrauterine system reduces endometriosis associated pain with symptom control maintained over 3 years (377–380). Twelve months of treatment results in a significant reduction in dysmenorrhea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules (377,378). After the first year of use, a 70% to 90% reduction in menstrual blood loss is observed.
Progesterone Antagonists
Progesterone antagonists and progesterone receptor modulators may suppress endometriosis based on their antiproliferative effects on the endometrium, without the risk for hypoestrogenism or bone loss that occurs with GnRH treatment. These products are not available in the United States, and their clinical effectiveness is unproven.
Mifepristone
Mifepristone (RU-486) is a potent antiprogestagen with a direct inhibitory effect on human endometrial cells and, in high doses, an antiglucocorticoid action (381). The recommended dose for endometriosis is 25 to 100 mg per day. In uncontrolled studies, mifepristone, 50 to 100 mg per day, reduced pelvic pain and induced 55% regression of the lesions without significant side effects (382,383). In an uncontrolled pilot study, low-dose mifepristone, 5 mg per day, resulted in pain improvement, without change in endometriosis lesions, suggesting that this dosage was probably too low (384).
Onapristone
The progesterone antagonists onapristone (ZK98299) and ZK136799, used in the treatment of rats with surgically induced endometriosis, resulted in a remission in 40% to 60% of treated animals. In animals with persistent endometriosis, growth inhibition was obtained in 48% and 85% of endometriotic lesions after therapy with onapristone and ZK136799, respectively (385).
Other Progesterone Antagonists
The chemical synthesis and pharmacologic characterization of a highly potent progesterone antagonist, ZK230211, were reported, with little or no other endocrinologic effects. ZK230211 is active on progesterone receptors A and B (386). In primates, this drug blocks ovulation and menstruation at all effective doses, whereas another progesterone antagonist, ZK137316, allowed ovulation but blocked menstruation in a dose-dependent fashion (387). All progesterone antagonist–treated animals maintained normal follicular phase concentration of estradiol and returned to menstrual cyclicity within 15 to 41 days after treatment (387). Both progesterone antagonists block unopposed estrogen action on the endometriosis through their antiproliferative effect.
Gestrinone
Gestrinone is a 19-nortestosterone derivative with androgenic, antiprogestagenic, antiestrogenic, and antigonadotropic properties. It acts centrally and peripherally to increase free testosterone and reduce sex hormone–binding globulin levels (androgenic effect), reduce serum estradiol values to early follicular phase levels (antiestrogenic effect), reduce mean LH levels, and obliterate the LH and follicle-stimulating hormone (FSH) surge (antigonadotropic effect). Gestrinone causes cellular inactivation and degeneration of endometriotic implants but not their disappearance (388). Amenorrhea occurs in 50% to 100% of women and is dose dependent.
Resumption of menses generally occurs 33 days after discontinuing the medication (389,390). An advantage of gestrinone is its long half-life (28 hours) when given orally. The standard dose is 2.5 mg twice a week. Although 1.25 mg twice weekly is effective, a randomized study demonstrated in women with mild to moderate endometriosis that 2.5 mg gestrinone twice weekly for 24 weeks is more effective and has a better effect on bone mass (+7% vs. −7%) when compared with 1.25 mg gestrinone twice weekly for 24 weeks (391). The clinical side effects of gestrinone are dose dependent and similar to but less intense than those caused by danazol (391). They include nausea, muscle cramps, and androgenic effects such as weight gain, acne, seborrhea, and oily hair and skin.
In a multicenter, randomized, double-blind study, gestrinone was as effective as GnRH for the treatment of pelvic pain associated with endometriosis, with fewer side effects and the added advantage of twice-weekly administration (392). Pregnancy is contraindicated while taking gestrinone because of the risk for masculinization of the fetus.
Danazol
Recognized pharmacologic properties of danazol include suppression of GnRH or gonadotropin secretion, direct inhibition of steroidogenesis, increased metabolic clearance of estradiol and progesterone, direct antagonistic and agonistic interaction with endometrial androgen and progesterone receptors, and immunologic attenuation of potentially adverse reproductive effects (98,393). The multiple effects of danazol produce a high-androgen, low-estrogen environment (estrogen levels in the early follicular to postmenopausal range) that does not support the growth of endometriosis, and the amenorrhea that is produced prevents new seeding of implants from the uterus into the peritoneal cavity.
The immunologic effects of danazol were studied in women with endometriosis and adenomyosis and include a decrease in serum immunoglobulins, a decrease in serum C3, a rise in serum C4 levels, decreased serum levels of autoantibodies against various phospholipid antigens, and decreased serum levels of CA125 during treatment (218,230–234,394,395). Danazol inhibits peripheral blood lymphocyte proliferation in cultures activated by T-cell mitogens but does not affect macrophage-dependent T-lymphocyte activation of B lymphocytes (396). Danazol inhibits IL-1 and TNF production by monocytes in a dose-dependent manner and suppresses macrophage- and monocyte-mediated cytotoxicity of susceptible target cells in women with mild endometriosis (397,398). These immunologic findings may be important in the remission of endometriosis with danazol treatment and may offer an explanation of the effect of danazol in the treatment of a number of autoimmune diseases, including hereditary angioedema, autoimmune hemolytic anemia, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura (399–403). Doses of 800 mg per day are used frequently in North America, whereas 600 mg per day is prescribed in Europe and Australia. It appears that the absence of menstruation is a better indicator of response than drug dose. A practical strategy for the use of danazol is to start treatment with 400 mg daily (200 mg twice a day) and increase the dose, if necessary, to achieve amenorrhea and relieve symptoms (393).
In a systematic review to determine the effectiveness of danazol compared to placebo or no treatment in the treatment of the symptoms and signs, other than infertility, of endometriosis in women of reproductive age, five randomized trials were included in which danazol (alone or as adjunctive therapy to surgery) was compared to placebo or no therapy (404). Treatment with danazol (including adjunctive to surgical therapy) was effective in relieving painful symptoms related to endometriosis when compared to placebo (404). Laparoscopic scores improved with danazol treatment (including as adjunctive therapy) when compared with either placebo or no treatment (404). Side effects were more commonly reported in those patients receiving danazol than for placebo (404).
The significant adverse side effects of danazol are related to its androgenic and hypoestrogenic properties. The most common side effects include weight gain, fluid retention, acne, oily skin, hirsutism, hot flashes, atrophic vaginitis, reduced breast size, reduced libido, fatigue, nausea, muscle cramps, and emotional instability. Deepening of the voice is another potential side effect that is nonreversible. Danazol can cause increased cholesterol and low-density lipoprotein levels and decreased high-density lipoproteins levels, but it is unlikely that these short-term effects are clinically important. Danazol is contraindicated in patients with liver disease because it is largely metabolized in the liver and may cause hepatocellular damage. Danazol is contraindicated in patients with hypertension, congestive heart failure, or impaired renal function because it can cause fluid retention. The use of danazol is contraindicated in pregnancy because of its androgenic effects on the fetus.
Because of the many side effects of oral danazol, alternative routes of administration were studied. In an uncontrolled pilot study, local danazol treatment using a vaginal danazol ring (1,500 mg) was effective for pain relief in deeply infiltrative endometriosis. This treatment did not cause the classic danazol side effects or detectable serum danazol levels, and it allowed ovulation and conception to occur (405).
Gonadotropin-Releasing Hormone Agonists
Gonadotropin-releasing hormone agonists bind to pituitary GnRH receptors and stimulate LH and FSH synthesis and release. The agonists have a much longer biologic half-life (3 to 8 hours) than endogenous GnRH (3.5 minutes), resulting in the continuous exposure of GnRH receptors to GnRH-agonist activity. This exposure causes a loss of pituitary receptors and downregulation of GnRH activity, resulting in low FSH and LH levels. Ovarian steroid production is suppressed, providing a medically induced and reversible state of pseudomenopause. A direct effect of GnRH agonists on ectopic endometrium is possible, because expression of the GnRH receptor gene is documented in ectopic endometrium and because direct inhibition of endometriosis cells was shown in vitro (406). In rat models used to study surgical adhesion formation and endometriosis, GnRH-agonist therapy decreased activity of plasminogen activators and matrix MMPs and increased the activity of their inhibitors, suggesting potential GnRH-agonist–regulated mechanisms for reducing adhesion formation (407).
Various GnRH agonists were developed and used in treating endometriosis. These agents include leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, and triptorelin. These drugs are inactive orally and must be administered intramuscularly, subcutaneously, or by intranasal absorption. The best therapeutic effect is often associated with an estradiol dose of 20 to 40 pg/mL (75–150 pmol/L). These so-called depot formulations are attractive because of the reduced frequency of administration and because nasal administration can be complicated by variations in absorption rates and problems with patient compliance (390). The results with GnRH agonists are similar to those with oral contraceptive progestin or gestrinone therapy. Treatment for 3 months with a GnRH agonist is effective in improving pain for 6 months (332).
Although GnRH agonists do not have an adverse effect on serum lipids and lipoproteins levels, their side effects are caused by hypoestrogenism and include hot flashes, vaginal dryness, reduced libido, and osteoporosis (6% to 8% loss in trabecular bone density after 6 months of therapy). Reversibility of bone loss is equivocal and therefore of concern, because treatment periods of longer than 6 months may be required (408,409). The goal is to suppress endometriosis and maintain serum estrogen levels of 30 to 45 pg/mL. More extreme estradiol suppression will induce bone loss (408). The dose of daily GnRH agonist can be regulated by monitoring estradiol levels, by the addition of low-dose progestin or estrogen–progestin in an add-back regimen, or by draw-back therapy.
The goal of add-back therapy is to treat endometriosis and endometriosis-associated pain effectively while preventing vasomotor symptoms and bone loss related to the hypoestrogenic state induced by GnRH analogues.Add-back therapy can be achieved by administering progestins only, including norethisterone, 1.2 mg, and norethindrone acetate, 5 mg, but bone loss is not prevented by medrogestone, 10 mg per day (409–411). Add-back therapy can be achieved by tibolone, 2.5 mg per day, or by an estrogen–progestin combination (i.e., conjugated estrogens, 0.625 mg, combined with medroxyprogesterone acetate, 2.5 mg, or with norethindrone acetate, 5 mg; estradiol, 2 mg, combined with norethisterone acetate, 1 mg) (405,408,410–414). Treatment for up to 2 years with combined estrogen and progestagen add-back appears to be effective and safe in terms of pain relief and bone density protection; progestagen only add-back is not protective (415).
GnRH agonists should not be prescribed to girls who have not yet attained their maximal bone density, as some concern remains about the long-term effects of GnRH analogues on bone loss. In one report, bone mineral density reduction occurred during long-term GnRH-agonist use and was not fully recovered up to 6 years after treatment (416). Use of add-back therapy (2 mg estradiol and 1 mg norethisterone acetate) did not affect this process (416). Draw-back therapy was suggested as an alternative in a study showing that 6 months of intake of 400 μg per day of nafarelin was as effective as a draw-back regimen consisting of 1 month of intake of 400 μg per day of nafarelin followed by 5 months of 200 μg per day of nafarelin, with similar estradiol levels (30 pg/mL) but less loss of bone mineral density (417).
Aromatase Inhibitors
Treatment of rats with induced endometriosis using the nonsteroidal aromatase inhibitor fadrozole hydrochloride or YM511 resulted in a dose-dependent volume reduction of endometriosis transplants (418,419). In one case report, treatment of severe postmenopausal endometriosis with an aromatase inhibitor, anastrozole, 1 mg per day, and elemental calcium, 1.5 g per day for 9 months resulted in hypoestrogenism, pain relief after 2 months, and after 9 months a 10-fold reduction in the 30-mm diameter size of red, polypoid vaginal lesions, along with remodeling to gray tissue (420).
There is concern with the use of aromatase inhibitors such as anastrozole or letrozole in the treatment of menopausal women because these drugs are known to stimulate ovulation and continuous administration can result in the development of functional ovarian cysts. This side effect can be prevented by combining aromatase inhibitors with ovarian suppressing drugs such as OCs or progestins in premenopausal women. A systematic review assessing the effects of aromatase inhibitors in women symptomatic of pain with endometriosis included eight studies including 137 women (421). In case series (seven studies, 40 women), aromatase inhibitors combined with progestins or OCs or GnRH analogues reduced mean pain scores and lesion size and improved quality of life (421). A randomized controlled trial including 97 women demonstrated that aromatase inhibitors in combination with GnRH analogues significantly improved pain (p < 0.0001), compared with GnRH analogues alone, with significant improvement in multidimensional patient scores (p < 0.0001), without significant reduction in spine or hipbone densities (422). Aromatase inhibitors appear to have a promising effect on pain associated with endometriosis, but the strength of this inference is limited because of a dearth of evidence and because aromatase inhibitors need to be combined with other hormonal medication (421).
Selective Estrogen Receptor Modulators
The role of selective estrogen receptor modulators (SERMs) in the treatment of endometriosis is unclear. In animal models, raloxifene therapy resulted in regression of endometriosis. The effect was seen in a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure (423). In a placebo-controlled randomized trial in women with chronic pelvic pain and surgically treated biopsy-proven endometriosis, postoperative treatment with raloxifene during 6 months resulted in a shortened time to return of pain (defined as 2 months of pain equal to or more severe than that at study entry) and to repeat laparoscopy, suggesting that raloxifene is not effective in the treatment of endometriosis-associated pain (424). Biopsy-proven endometriosis was not associated with return of pain, suggesting that other factors were implicated in recurrent pelvic pain after surgery in this study (424).
Nonhormonal Medical Therapy
Recent progress in understanding the pathogenesis of endometriosis led to the expectation that new pharmaceutic agents affecting inflammation and angiogenesis activity may prevent or inhibit the development of endometriosis. Most of these compounds were tested only in rodent models, and more research is needed in the baboon model for endometriosis and in women to ensure their safety and efficacy, as they may interfere with normal physiological processes like ovulation, menstruation, and implantation (54).
Selective Inhibition of Tumor Necrosis Factor-α
In rats with experimental endometriosis, recombinant human TNF-α–binding protein can reduce 64% of the size of endometriosis-like peritoneal lesions (425). Several prospective randomized placebo- and drug-controlled studies in baboons showed that TNF-α antagonists effectively prevent and treat induced endometriosis and endometriosis-related adhesions and are effective in the treatment of spontaneous endometriosis in baboons (54). These results were not confirmed in a small placebo-controlled randomized trial in women with deeply infiltrative endometriosis awaiting surgery, possibly because the endometriosis phenotype in these women (deeply infiltrative and fibrotic disease) was different from the endometriosis phenotype in the baboon studies (inflammatory peritoneal disease with adhesions) (426). TNF-α antagonists are less effective in fibrotic inflammatory bowel disease than in earlier nonfibrotic inflammatory bowel disease.
Pentoxifylline
In a systematic review determining the effectiveness and safety of pentoxifylline, which has anti-inflammatory effects in the management of endometriosis in subfertile, premenopausal women, four trials involving 334 participants were included (427). Pentoxifylline had no significant effect on reduction in pain (one randomized trial, MD −1.60; 95% CI, −3.32–0.12), improvement of fertility (three randomized trials, OR 1.54; 95% CI, 0.89–2.66) or recurrence of endometriosis (one randomized trial, OR 0.88; 95% CI, 0.27–2.84) (427). No trials reported the effects of pentoxifylline on the odds of live birth rate per woman, improvement of endometriosis-related symptoms, or adverse events (427).
Peroxisome Proliferator Activated Receptor-γ Agonists
Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists prevent and treat endometriosis in both rodent and baboon models for endometriosis and show promise for treatment of human endometriosis (152,153,428,429).
Many substances potentially capable of modulating immunologic or inflammatory mechanisms involved in the onset or progression of the disease could be the targets for future research in endometriosis (430,431). Preliminary trials with cyclooxygenase-2 (COX-2) inhibitors, leukotriene receptor antagonists, TNF-α inhibitors, antiangiogenic agents and kinase inhibitors show promising results in vitro in rodent and in nonhuman primate models, but their safety is an important issue regarding human use (432).
Chinese Herbal Medicine
In China, treatment of endometriosis using herbal medicines is routine, and considerable research into the role of herbal medicines in alleviating pain, promoting fertility, and preventing relapse has occurred (433). A systematic review of the effectiveness and safety of herbal medicines in alleviating endometriosis-related pain and infertility, including two Chinese randomized trials involving 158 women, concluded that postsurgical administration of herbal medicines may have comparable benefits to hormonal treatment with gestrinone but with fewer side effects (433). Oral herbal medicines might have a better overall treatment effect than danazol; it could be more effective in relieving dysmenorrhea and shrinking adnexal masses when used in conjunction with an herbal enema (433). More rigorous research is required to accurately assess the potential role of herbal medicines in treating endometriosis (433).
Treatment of Endometriosis-Associated Subfertility
Surgical Treatment
The treatment of endometriosis-related infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms, and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means, and the expected results. If surgery is performed and spontaneous pregnancy does not occur within 2 years of surgery, there is little chance of subsequent natural conception (434).
Surgery for Minimal to Mild Endometriosis
Surgical management of infertile women with minimal to mild endometriosis is controversial. Based on the results of a meta-analysis of two randomized trials, ablation of endometriotic lesions plus adhesiolysis to improve fertility in minimal to mild endometriosis is effective compared to diagnostic laparoscopy alone (191,192,435). One Canadian study reported that laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis (191). They studied 341 infertile women, 20 to 39 years of age, with minimal or mild endometriosis. During diagnostic laparoscopy, the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They found that resection or ablation of minimal and mild endometriosis increased the likelihood of pregnancy in infertile women. They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy. The study participants were recruited among infertile women scheduled for diagnostic laparoscopy with strict eligibility criteria. The women in the study had no previous surgical treatment for endometriosis, no medical treatment for endometriosis in the previous 9 months, and no other medical or surgical treatment for infertility in the previous 3 months. They had no history of pelvic inflammatory disease and no severe pelvic pain precluding expectant management. The diagnosis of endometriosis required the presence of one or more typical bluish or black lesions. The stage of endometriosis was determined according to the revised American Society of Reproductive Medicine classification. Both the monthly fecundity rate and the cumulative pregnancy rate after 36 weeks were significantly higher and twice as high after surgical excision of minimal to mild endometriosis (4.7% and 30.7%, respectively) than after diagnostic laparoscopy (2.4% and 17.7%, respectively). In the treated group, 31% of the patients became pregnant, compared with 18% in the nontreated group (p = 0.006). Limitations of this study include the lack of blinding of the patients, and the fecundity rate after surgery was below that observed in control groups from other studies (1,436).
In a multicenter study in Italy, a similar study design was used to compare the effect of diagnostic laparoscopy with surgical resection and ablation of visible endometriosis (on fertility parameters) in infertile women with minimal to mild endometriosis (192). Eligible patients were less than 36 years old, were trying to conceive, and had a laparoscopically confirmed diagnosis of minimal or mild endometriosis. None of the women had therapy for endometriosis or infertility. Treatment was randomly allocated during laparoscopy. There was a follow-up period of 1 year after the laparoscopy. The results of this study did not show a beneficial effect of surgery regarding fertility. During the follow-up period after laparoscopy, no statistically significant differences in conception and live birth rates were observed in the treated group (24% and 20%, respectively) or in the control group (29% and 22%, respectively). The methodological quality of the Italian study was inferior to the Canadian study, as reviewed before (181,191,192). First, the study was underpowered, including only 91 patients, compared to 341 patients in the Canadian study. Second, it is remarkable and unexplained that the Italian study included after randomization more patients undergoing surgical excision of endometriosis (n = 54) than patients undergoing diagnostic laparoscopy (n = 47). Third, the duration of infertility was considerably longer in the Italian study (4 years) than in the Canadian study (X years[MB4]). Duration of infertility is an important factor influencing both monthly fecundity rate and cumulative pregnancy rates independently from other causes of infertility. The bias introduced by the long duration of infertility in couples participating in the Italian trial may have reduced the possibility to find any significant effect of surgical treatment, especially in view of the lack of proper power calculation in the Italian study. Fourth, the Italian study did not present any data on monthly fecundity rate or cumulative pregnancy rates using life table analysis, but only published the crude live birth rate per patient, not controlled for number of cycles per patient. Fertility outcome should be measured by more controlled variables such as monthly fecundity rate and the cumulative pregnancy rates or time to pregnancy. Fifth, 41 of 91 patients in the Italian study had received GnRH analogue treatment after surgery (18 from the surgical excision group, 23 from the diagnostic laparoscopy group) (192). There was no specification for how long this medical treatment was given and how ovarian function was affected. The lack of this information introduces another bias influencing fertility outcome. Taking into account the relative methodological weaknesses of the Italian study when compared to the Canadian study, extreme caution is needed before combining these two studies in a meta-analysis, especially because the fertility outcome data are reported so differently. It seems preferable to use the data of the better study demonstrating that surgical treatment of minimal to mild endometriosis appears to offer a small, but significant, benefit with regard to fertility outcome (1,181,191,437). The surgical removal of peritoneal endometriosis may be important to prevent progression of endometriosis. Care is needed to prevent adhesion formation that could result as a consequence of overenthusiastic excision of minimal to mild endometriosis.
Surgery for Moderate to Severe Endometriosis
When endometriosis causes mechanical distortion of the pelvis, surgery should be performed to achieve reconstruction of normal pelvic anatomy. No randomized trials or meta-analyses are available to answer the question of whether surgical excision of moderate to severe endometriosis enhances pregnancy rate (1). Most studies present only crude pregnancy rates without detailed information regarding time of follow-up and are therefore not relevant (1).
Based on three studies, there seems to be a negative correlation between the stage of endometriosis and the spontaneous cumulative pregnancy rate after surgical removal of endometriosis, but statistical significance was reached in only one study (438–440).
Other studies reported a significant negative correlation between endometriosis stage and pregnancy rate and decreased pregnancy rates when the revised scores exceeded 15 or 70 (183,438,441). Data from different studies cannot be compared easily because of retrospective design, lack of a control group, significant variability and lack of standardization with respect to inclusion criteria, surgical procedures, extent of surgery, skill of the surgeon, variable duration of follow-up without life table analysis, postoperative hormonal suppression or medically assisted reproduction, and lack of control for other infertility-related factors such as male infertility or ovarian dysfunction. These limitations explain why management differed and was not standardized, and why the cumulative pregnancy rates 9 to 12 months after surgery for moderate to severe endometriosis vary between 24% and 30% (1,442–444).
Surgery for Ovarian Endometriomas in Subfertile Patients
Laparoscopic cystectomy for ovarian endometriomas greater than 4 cm diameter improves fertility compared with drainage and coagulation (300,303).
Perioperative Medical Treatment
Preoperative medical treatment with danazol, GnRH agonists, or progestins may be useful to reduce the extent of endometriosis in patients with advanced disease. Postoperative medical treatment is rarely indicated because it is ineffective based on randomized trials, prevents pregnancy, and because the highest spontaneous pregnancy rates occur during the first 6 to 12 months after conservative surgery (333,335).
Hormonal Treatment
Conception is either impossible or contraindicated during medical treatment of endometriosis. There is no evidence that medical treatment of minimal to mild endometriosis leads to better chances of pregnancy than expectant management (436). The published evidence does not comment on more severe disease (1).
Medically Assisted Reproduction
Medically assisted reproduction—including controlled ovarian hyperstimulation with intrauterine insemination, IVF, and gamete intrafallopian transfer—may be an option for infertility treatment in addition to surgical reconstruction and expectant management (284). Assisted reproductive technology (ART) is the method of choice when distortion of the tubo-ovarian anatomy contraindicates the use of superovulation with intrauterine insemination or gamete intrafallopian transfer (284).
The role of ART in the treatment of endometriosis-associated infertility may be limited in large tertiary care and referral centers for surgical treatment of endometriosis (445). After conservative surgery for endometriosis, 44% conceived in vivo (44%), and 51% of those who failed to conceive in vivo did not undergo ART treatment with the cumulative rate of IVF use at 36 months of infertility at 33%. The live birth/ongoing pregnancy rate per started cycle and per patient was 10% and 20%, respectively (445). For a full discussion on the application of ART infertility, see Chapter 32.
Management of Adolescents
The most common presenting symptom in adolescents with endometriosis is cyclic pain (1). Less commonly acyclic pain, dyspareunia, gastrointestinal symptoms, irregular menses, urinary symptoms, and vaginal discharge are described (1,446–449). Similar presenting symptoms occur in adolescent patients evaluated for pelvic pain with and without endometriosis (449,450). It is hard to predict the presence of endometriosis in adolescents with pelvic pain merely from the presenting symptoms, because similar symptoms occur in patients evaluated laparoscopically for pelvic pain with and without endometriosis (1,449,450). Laparoscopy should be considered for adolescents with chronic pelvic pain who do not respond to medical treatment (NSAIDs, OCs) because endometriosis is very common (up to 70%) under these circumstances (446,449–456). Minimal and mild endometriosis, according to the revised ASRM classification, are the most common stages of the disease in adolescents. Gynecologic surgeons should pay special attention to red, clear, or white lesions, which are more prevalent in adolescents than in adults with endometriosis (1,446–458). Mild disease can be treated by laparoscopic surgical removal of implants at the time of diagnosis, followed by continuous administration of low-dose combination OCs to prevent recurrence. More advanced disease can be treated medically for 6 months, followed by continuous OCs to prevent progression of disease. Surgery is indicated if this hormonal treatment is not effective. GnRH agonists with add-back therapy can only be considered for adolescents older than 17 years of age who have completed pubertal and bone maturation, and then only if symptoms persist during other forms of hormonal suppression (1,459–461).
Menstrual outflow obstructions such as müllerian anomalies may cause early development of endometriosis in adolescents. Regression of the disease was observed when surgical correction of the anomaly was accomplished (462–464).
Evidence suggests that absenteeism from school and the incidence and duration of OC use for severe primary dysmenorrhea during adolescence is higher in women who later develop deeply infiltrative endometriosis than in women without deeply infiltrative endometriosis (166).
Physicians treating adolescents with endometriosis should adopt a multidimensional approach, where surgery, hormonal manipulation, pain medication, mental health support, complementary and alternative therapies, and education in self-management strategies are useful components (1).
Management of Postmenopausal Women
Despite available studies supporting standard hormone therapy for women with endometriosis and postsurgical menopause, there is still concern that estrogens may induce a recurrence of the disease and its symptoms. The evidence in the literature is insufficient to suggest depriving symptomatic patients of this treatment. In a systematic review evaluating pain and disease recurrence in women with endometriosis who used hormone therapy for postsurgical menopause, two randomized trials were included (465). In one trial, recurrence of pain in women with a conserved uterus was not significantly different in 1 of 11 women treated with continuous tibolone (2.5 mg per day), or in 4 of 10 women receiving nonstop transdermal application of 17-β estradiol (0.05 mg per day) combined with cyclic medroxyprogesterone acetate (10 mg per day) for 12 days per month (466). In the second trial, recurrence of pain was not significantly different in any of 57 patients in the no-treatment arm, or in 4 of 115 women receiving sequential administration of estrogens and progesterone with two 22-cm patches applied weekly to produce a controlled release of 0.05 mg per day, combined with oral administration of micronized progesterone administered orally (200 mg per day) for 14 days with a 16-day interval free of treatment (5,329). In this study, the endometriosis recurrence and reoperation rate were comparable in both groups (2 of 115 of the treatment group; 0 of 57of the no-treatment group) (329).
Recurrent Endometriosis After Treatment
Recurrence After Medical Treatment
Because hormonal suppressive treatment does not cure endometriosis (it only suppresses the activity of endometriotic lesions during the treatment), “recurrence,” or rather persistence, of endometriosis can be expected in nearly all patients within 6 months to 2 years after the cessation of medical treatment, and this is positively correlated with the severity of endometriosis.
Recurrence After Conservative Surgery
Endometriosis tends to recur unless definitive surgery is performed. Pain recurs within 5 years in about one in five patients with pelvic pain treated by complete laparoscopic excision of visible endometriotic lesions(467). The endometriosis recurrence rate is about 5% to 20% per year, reaching a cumulative rate of 40% after 5 years. Medical treatment appears to have limited and inconsistent effects when used for only a few months after conservative procedures (468). Data on the benefit of prolonged drug regimens with OCs or progestogen are lacking. The current ASRM classification system has low value to predict pain recurrence and endometriosis relapse after conservative surgical treatment (469).
Recurrence After Hysterectomy
The medium-term outcome of hysterectomy for endometriosis-associated pain is satisfactory; the probability of pain persistence after hysterectomy is 15% and risk of pain worsening is 3% to 5%, with a six times higher risk of further surgery in patients with ovarian preservation as compared to concomitant bilateral ovarian removal (470). At least one ovary should be preserved in young women, especially in those who cannot or will not receive estrogen-progestin therapy (471). The risk of recurrence of endometriosis during hormonal therapy seems marginal if combined preparations or tibolone are used and estrogen-only treatments are avoided (471).
Risk Factors for Recurrence
The rate of recurrence increases with the stage of disease, the duration of follow-up, and the occurrence of previous surgery (14,472–475). The likelihood of recurrence appears to be lower when endometriosis is located only on the right side of the pelvis than when the left side is involved (475). The risk of endometriosis recurrence is significantly correlated to the age of the patient. The younger the patient is at the moment of the diagnosis the higher the risk of recurrence. Higher recurrence rates in younger patients seem to justify a more radical treatment in this group (288). Persistence of dysmenorrheal and nonmenstrual pelvic pain after excision of endometriosis can be related to adenomyosis as defined by a thickened (> 11 mm) uterine junctional zone on MRI (476). More data are needed to define the best therapeutic option in women with recurrent endometriosis, in terms of pain relief, pregnancy rate, and patient compliance (470).
Prevention of Recurrence
After first-line surgery for endometriosis, women should be invited to seek conception as soon as possible. Alternatively, OC use until pregnancy is desired should be considered because several lines of evidence suggest that ovulation inhibition reduces the risk of endometriosis recurrence (477). A recurrent endometrioma developed in 26 of 250 regular users (10%; 95% CI, 7%–15%) compared with 46 of 115 never users (40%; 95% CI, 31%–50%), with a common odds ratio of 0.16 (95% CI, 0.04–0.65) (477).
Medical Treatment of Recurrence
In a randomized prospective clinical study, continuous treatment for 6 months with desogestrel (75 μg per day) (n = 20) versus a combined oral contraceptive (ethinyl estradiol 20 μg plus desogestrel 150 μg) resulted in a significant and comparable improvement of both pelvic pain and dysmenorrhea with breakthrough bleeding in 20% of the desogestrel-treated patients, and a significant body weight increase in 15% of the OC-treated women (478).
Surgical Treatment of Recurrence
The optimal surgical solution in women with recurrent symptoms after previous conservative procedures for endometriosis should be based on the desire for conception and on psychological characteristics (479). Studies on surgical management of recurrent rectovaginal endometriosis are warranted because of the peculiar technical difficulties and the high risk of complications associated with this challenging disease (479).
Conservative Surgery
According to review papers, the long-term probability of pain recurrence after repeat conservative surgery for recurrent endometriosis varies from 20% to 40%, and a further surgical procedure will occur in 15% to 20% of the cases (470,479). These figures are probably an underestimate related to drawbacks in study design, exclusions of dropouts, and publication bias and should be considered with caution (479). No studies evaluated the association of presacral neurectomy to the surgical treatment of recurrent endometriosis among patients with recurrent disease (470). The spontaneous conception rate among women undergoing repetitive surgery for recurrent endometriosis associated with infertility is 20% (12- and 24-month cumulative pregnancy rates of 14% and 26%), whereas the overall crude pregnancy rate after a primary surgical procedure is 40% (12- and 24-month cumulative pregnancy rates of 32% and 38%) (470,479). Among infertile patients treated with repetitive surgery for recurrent endometriosis the spontaneous pregnancy rate was 19% (12- and 24-month cumulative pregnancy rates), whereas it was 34% for those untreated (12- and 24-month cumulative pregnancy rates of 25% and 30%). The probability of conception after IVF is not significantly lower after repetitive surgery (20%) when compared to primary surgery (30%) (hazard ratio [HR] 1.51; 95% CI, 0.58–3.91%) (479).
Hysterectomy
The outcome of hysterectomy for endometriosis-associated pain at medium-term follow-up seems satisfactory. About 15% of patients had persistent symptoms and 3% to 5% experienced worsening of pain (479).
Coping with Disease
Coping with endometriosis as a chronic disease is an important component of management. According to guidelines for the management of endometriosis, evidence from two systematic reviews suggests that high frequency transcutaneous electrical nerve stimulation (TENS), acupuncture, vitamin B1, and magnesium may help to relieve dysmenorrhea (1,348,351). Whether such treatments are effective in endometriosis-associated dysmenorrhea is unknown. Many women with endometriosis report that nutritional and complementary therapies such as reflexology, traditional Chinese medicine, herbal treatments, and homeopathy improve pain symptoms. Although there is no evidence from randomized controlled trials to support the effectiveness of these treatments in endometriosis, they should not be ruled out if the woman feels they work in conjunction with more traditional therapies or that they could be beneficial to her overall pain management and quality of life. Patient self-help groups can provide invaluable counseling, support, and advice. ESHRE provides a comprehensive international list of self-help groups on their web site (1).
References
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