Version May 2024
INTRODUCTION — Similar to eutopic endometrial tissue, endometriosis lesions contain endometrial glands and stroma but occur outside the uterine cavity. The lesions are typically located in the pelvis but can occur at multiple sites including the bowel, diaphragm, and pleural cavity. While endometriosis is a common and nonmalignant process, ectopic endometrium-like tissue and resultant inflammation can cause dysmenorrhea, dyspareunia, chronic pain, and infertility. Symptoms can range from minimal to severely debilitating. Endometriosis is an estrogen-dependent, benign, inflammatory disease that affects females during their premenarcheal, reproductive, and postmenopausal hormonal stages.
This topic will review the clinical presentation and diagnosis of endometriosis. Information on the treatment of endometriosis is presented separately.
●(See "Endometriosis: Treatment of pelvic pain".)
●(See "Endometriosis: Surgical management of pelvic pain".)
●(See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
HISTOLOGY AND LESION PHENOTYPES
Histology — Similar to eutopic endometrial tissue, endometriosis lesions contain endometrial glands and stroma (picture 1) [1]. Unlike eutopic endometrium, endometriosis implants exist outside of the uterine endometrium and myometrium and often contain fibrous tissue, blood, and cysts. Breakdown of red blood cells by inflammatory cells results in formation of pigmented histiocytes and hemosiderin-laden macrophages; the older the lesion, the more likely it is to be pigmented [2].
Lesion phenotypes — Endometriosis lesions in the pelvis can be categorized as superficial peritoneal, ovarian, and deep [1,3,4].
●Superficial peritoneal – While superficial peritoneal lesions classically contain endometrial glands and stroma, diagnostic challenges arise when there are alterations or absence of glandular or stromal components [5]. The glandular component can be absent, sparse, or transformed by hormonal and metaplastic changes or cellular atypia. The stromal component can be obscured by infiltrates of foamy and pigmented histiocytes, fibrosis, or other processes. Inflammatory and reactive changes within or adjacent to foci of endometriosis can also confuse the histologic findings. Histologic diagnosis can also be hindered by a small biopsy sample.
●Ovarian endometrioma – An ovarian endometrioma occurs when endometrium-like tissue forms an ovarian cyst [1]; ectopic endometrial tissue within the ovary bleeds and results in a hematoma surrounded by duplicated ovarian parenchyma [6]. Both ovaries are involved in one-third of cases.
•Typical findings – In contrast with most hemorrhagic physiologic ovarian cysts, endometriomas typically have fibrotic walls and surface adhesions; are filled with syrup-like chocolate-colored material; are surrounded by duplicated ovarian parenchyma [3]; and are lined by endometrial epithelium, stroma, and glands [7].
•Cellular transformation – Epithelial abnormalities, such as complex hyperplasia or atypia, can develop in the cyst lining; the clinical significance of these changes has not been determined [8-12]. The endometrial epithelium and stroma lining the endometrioma can be lost over time and replaced by granulation tissue and dense fibrous tissue, which makes histological diagnosis difficult. In these cases, the contents of the cyst (semifluid chocolate-colored material versus watery fluid), presence of adhesions and hemosiderin-filled macrophages (indicative of chronic bleeding), and histologically proven endometriosis at other sites in the pelvis aid the diagnosis.
Management of ovarian endometriomas is presented separately. (See "Endometriosis: Management of ovarian endometriomas".)
●Deep endometriosis – Deep endometriosis (DE) is endometrium-like tissue in the abdomen that extends under the peritoneum [1]. Some definitions include depth more than 5 mm deep to the peritoneum [13]. DE is generally found in the retrovaginal septum (also referred to as the rectocervical septum), rectum, rectosigmoid colon, bladder, ureter, and other pelvic fibromuscular structures such as the uterine ligaments and vagina [14].
•(See "Endometriosis: Clinical manifestations and diagnosis of rectovaginal or bowel disease".)
•(See "Endometriosis of the bladder and ureter".)
ANATOMY AND STAGING
●Common pelvic sites – In general, the most common sites of endometriosis, in decreasing order of frequency, are [15,16]:
•Ovary and ovarian fossa – 67 and 32 percent [17]
•Anterior and posterior cul-de-sac
•Posterior broad ligaments
•Uterosacral ligaments – 46 percent [17]
•Pouch of Douglas – 30 percent [17]
•Bladder – 21 percent [17]
•Uterus
•Fallopian tubes
•Sigmoid colon
•Appendix
•Round ligaments
•Other - vagina, cervix, rectovaginal (or retrovaginal) septum, cecum, ileum, inguinal canals, perineal scars, ureters, and umbilicus [18-20]
●Extra-pelvic sites – Occasionally, an endometrioma arises in the anterior abdominal wall, usually in the vicinity of a surgical incision [21-23], or umbilicus, although these lesions can occur in individuals with no history of surgery or history of endometriosis. Rarely, endometriosis has been reported in the breast, pancreas, liver, gallbladder, kidney, urethra, extremities, vertebrae, bone, peripheral nerves, spleen, diaphragm, central nervous system, hymen [24], and lung [25]. (See "Thoracic endometriosis: Pathogenesis, epidemiology, and pathology".)
●Surgical staging – Endometriosis is surgically staged according to the revised American Society for Reproductive Medicine scoring system (form 1 and figure 1) [26], but other staging systems exist [27-29]. (See "Endometriosis: Clinical features, evaluation, and diagnosis", section on 'Surgical staging of disease'.)
PATHOGENESIS — While many theories have been proposed to explain the etiology, no single theory explains all cases and all the theories help to explain some aspects of the disease. It is likely that the cause of endometriosis is multifactorial, with contributions from several of the proposed mechanisms.
●Pathogenesis and genetics – Endometriosis results when ectopic endometrial cells implant, grow, and elicit an inflammatory response [30]. The pathogenesis of endometriosis appears to be multifactorial, including transportation from the uterus to the peritoneal cavity of ectopic endometrial tissue, altered immunity, imbalanced cell proliferation and apoptosis, aberrant endocrine signaling, and genetic factors. Genetic studies, including genome-wide association studies and exome sequencing, have identified genomic regions and abnormalities in cancer driver genes (PIK3CA, KRAS, ARID1A) associated with endometriosis [31-33]. The presence of cancer driver mutations in nonmalignant cells may partly explain the aggressive nature of deeply invasive lesions compared with superficial peritoneal lesions.
●Theories of endometriosis development – There are multiple proposed theories to explain the development of endometriosis; these may work in concert to create the clinical disease.
•Retrograde menstruation – In the most common theory of ectopic endometrial cells (Sampson's theory of retrograde menstruation), endometrial cells flow backwards through the fallopian tubes and into the peritoneal cavity during menses [34]. Evidence supporting retrograde menstruation comes from the observation that the incidence of endometriosis is increased in girls with genital tract obstructions that prevent drainage of menses through the vagina and therefore increase tubal reflux [35,36]. However, while up to 90 percent of females have retrograde menstruation [37], most do not develop endometriosis, which suggests that additional factors are involved [3].
•Alternate mechanisms – Other potential sources of ectopic endometrial cells include mesothelium, stem cells, müllerian rests [38], bone marrow stem cells [38,39], and embryonic vestiges [40] as well as lymphatic or vascular dissemination [41,42] and coelomic metaplasia [43,44]. The cellular immunity theory suggests that a deficiency or aberration in cellular immunity allows ectopic endometrial tissue to proliferate [45-47].
•Premenarcheal endometriosis – The existence of endometriosis in girls prior to menstruation, and thus not yet exposed to retrograde menstruation, challenges the retrograde menstruation hypothesis regarding the etiology of endometriosis. Possible explanations for premenarcheal endometriosis include the existence of müllerian embryonic rests [48], that these lesions are preexisting antecedents to the classic form of endometriosis [49], and that the lesions are the result of neonatal uterine bleeding, including retrograde bleeding, caused by maternal hormone exposure [50-53].
●Mechanism of pain – Once endometriosis is established, the process appears to cause symptoms through inflammatory changes. Endometriosis-related pelvic pain is associated with increased production of inflammatory and pain mediators as well as neurologic dysfunction related to the implants [54-58]. An increase of nerve fibers [54,59] and imbalance of sympathetic and sensory nerve fibers [60,61] have been demonstrated in individuals with endometriosis-related pain. Proposed mechanisms for pain symptoms include estrogen acting as a neuromodulator that selectively repulses the sympathetic axons while preserving sensory innervation [62], inflammation stimulating peripheral nerve sensitization [63], and chronic pain inducing changes in the central nervous system [64].
●Mechanism of subfertility – The mechanism for subfertility appears to involve anatomic distortion from pelvic adhesions and endometriomas and/or production of substances (eg, prostanoids, cytokines, growth factors) that are "hostile" to normal ovarian function/ovulation, sperm mobility, fertilization, and implantation. (See "Endometriosis: Treatment of infertility in females", section on 'Pathogenesis of infertility from endometriosis'.)
EPIDEMIOLOGY
Prevalence — Globally, it is estimated that approximately 10 percent of reproductive-age females have endometriosis [65-67]. Determining the prevalence of endometriosis in a general population is challenging because some individuals are asymptomatic, those with symptoms can have varied and nonspecific presentations, and definitive diagnosis typically requires surgery [68].
Reported prevalence ranges for different populations include [36,65-79]:
●Asymptomatic individuals – 1 to 7 percent
●Individuals undergoing hysterectomy for benign indications – 15 percent
●Adolescents with genital tract anomalies – 40 percent
●Females presenting with infertility – up to 50 percent
●Adolescent and adult females presenting for evaluation of chronic pelvic pain – up to 70 percent
Risk factors
●Increase risk – Established factors associated with an increased risk of endometriosis include family history [31,80], nulliparity [73,81,82], prolonged exposure to endogenous estrogen (eg, early menarche [before age 11 to 13 years] [30,83,84] or late menopause [30]), shorter menstrual cycles (defined as ≤27 days) [73], heavy menstrual bleeding [73], obstruction of menstrual outflow (eg, cervical stenosis, müllerian anomalies [30,85]), exposure to diethylstilbestrol in utero [86,87], taller height [81,88], and lower body mass index [73,81].
●Reduce risk – Factors associated with a decreased risk of endometriosis include multiple births [89,90], extended intervals of lactation [89,91], and late menarche (after age 14 years) [83].
CLINICAL IMPACT
Fertility — The impact of endometriosis on fertility is presented elsewhere. (See "Endometriosis: Treatment of infertility in females".)
Pregnancy
Course during pregnancy — During pregnancy, endometriosis lesions may undergo decidualization or regression, and the endometriosis-associated pain symptoms often disappear or improve [92]. However, decidualization of lesions does not make them biologically inactive and complications have been reported. As these events are rare overall, no additional monitoring or interventions are recommended for pregnant individuals with a history of endometriosis.
●Reported complications of endometriosis – Case reports have described complications caused by endometriosis in pregnant individuals, including intestinal perforation [93], hemoperitoneum [94-97], uroperitoneum [98,99], acute appendicitis [100,101], and ruptured or infected ovarian endometrioma [102].
●Possible mechanisms – Possible mechanisms of endometriosis-induced complications during pregnancy include traction by the growing uterus on adhesions, increased friability of inflamed tissues, and alteration of vessel walls by decidualized lesions (either intrusion or retraction) [102].
Obstetric outcomes — The body of evidence suggests endometriosis negatively impacts some pregnancy outcomes, particularly increasing the risk of preterm birth, although not all studies support this association [103-112]. Other reported outcomes include placenta previa, hemorrhage, and low birth weight [104,112,113]. The mechanism behind these associations is not known, and additional surveillance for pregnant individuals with known endometriosis is not advised [102].
Supporting data include:
●Birth outcomes – A meta-analysis of 33 studies that included over 3 million pregnancies reported that, among those who conceived spontaneously, endometriosis was associated with placenta previa, cesarean delivery, preterm birth, and low birth weight [112].In two large retrospective population-based studies (including over 82,000 and 91,000 total births, respectively), individuals with endometriosis had an increased risk of preterm birth, preeclampsia, and cesarean birth when compared with individuals without endometriosis [103,110].
●Severe maternal morbidity – A retrospective cohort study including over 2.4 million deliveries in Quebec, Canada reported increased risk of severe maternal morbidity with any prior endometriosis (risk ratio [RR] 1.43, 95% CI 1.36-1.51) and active endometriosis (RR 1.93, 95% CI 1.76-2.11) compared with no endometriosis exposure [114].
Large studies support the findings of prior smaller studies that noted an increased risk of preterm birth [105-108] and pregnancy loss [107,115-117] in individuals with endometriosis. In contrast, older, smaller studies reported decreased or no change in risk of hypertensive disorders of pregnancy in patients with endometriosis [118,119]. These studies should be interpreted with caution because the presence of endometriosis and/or prior treatments was not known at the time of conception.
Postmenopause — Endometriosis may remain an active disease after menopause. Approximately 2 percent of all patients with an initial surgical diagnosis of endometriosis are postmenopausal based on data from older studies [120-122]. Severely symptomatic endometriosis is not common in postmenopause.
●Potential etiologies and mechanisms – It is not known if postmenopausal endometriosis results from lesions established during the reproductive years or if postmenopausal endometriosis arises de novo. Symptomatic postmenopausal endometriosis occurs in those both on and off hormone therapy [123]. In a study of 72 women with symptomatic postmenopausal endometriosis, only two were using hormone therapy at the time of surgery [124].
Possible mechanisms of postmenopausal estrogen production include extra-ovarian estrogen production (eg, skin, fat tissue) and or lesion-specific production [125,126].
●Treatment options – Treatment of symptomatic postmenopausal endometriosis must balance the potential risk of underlying malignancy as a cause of symptoms with the limited hormonal treatment options for this age group. (See "Endometriosis: Treatment of pelvic pain", section on 'Surgical treatment options'.)
•Surgery – One society advises surgery as the first-line approach [123]. At least one case of postmenopausal endometriosis that required pelvic exenteration for treatment has been reported [127]. (See "Endometriosis: Treatment of pelvic pain", section on 'Surgical treatment options'.)
•Medical therapy – Medical treatment options include nonsteroidal anti-inflammatory drugs, progestins, and aromatase inhibitors (AIs). The limited available data suggest that AI treatment can reduce symptoms but its use may be limited by side effects [128,129]. (See "Endometriosis: Treatment of pelvic pain", section on 'Medical treatment options'.)
Ovarian cancer risk
●Summary – There appears to be an increased risk of ovarian cancer, particularly endometrioid and clear cell types, in individuals with ovarian endometriosis but not for patients with peritoneal or deeply infiltrating endometriosis [130]. It is unclear if the increased risk of ovarian cancer applies to superficial ovarian endometriosis lesions, endometriomas, or both. Some ovarian endometriosis lesions harbor genetic changes (mutations in ARID1A, PTEN, HNF1B and k-ras) that also may be found in ovarian cancer lesions. Future molecular analysis of surgical ovarian endometriosis specimens may help to identify patients at highest risk of developing ovarian cancer. While the relative risk of ovarian cancer may be increased, the absolute risk of developing ovarian cancer from ovarian endometriosis remains low, with approximately two additional cases per 10,000 women-years of follow-up for individuals with ovarian endometriosis compared with those without endometriosis [130].
●Risk of transformation to cancer – The risk of malignant transformation of endometriosis has been estimated at 1 percent for premenopausal females [131] and 1 to 2.5 percent for postmenopausal females [132,133]. In a study of individuals with postmenopausal endometriosis, 35 percent (20 of 57) had different grades of metaplasia, hyperplasia, atypia, and endometrioid carcinoma arising in ovarian endometriosis [124].
Endometriosis appears to be associated with some epithelial ovarian cancers (EOCs) [134]; whether those with endometriosis are at risk for other types of cancers is unclear, but the overall risk appears to be low [135-137]. In a meta-analysis of 13 case-control studies including nearly 8000 women with EOC, those with a self-reported history of endometriosis had three times the risk of clear cell EOC and double the risk of endometrioid and low-grade serous EOC but no change in risk of high-grade serous or mucinous EOC [138]. A subsequent population-based study of nearly 50,000 Finnish women with endometriosis again reported an overall increased risk of ovarian cancer (endometrioid, clear cell, and serous types) in individuals with ovarian endometriomas (ie, ovarian endometriosis; overall standardized incidence ratio [sIR] 2.56, 95% CI 1.98-3.27), but not for those with peritoneal or deep infiltrating endometriosis [130]. The excess risk of ovarian cancer for patients with ovarian endometriosis resulted in two additional cases per 1000 women followed for 10 years. In this study, there was no statistically significant association with isolated peritoneal endometriosis and ovarian cancer.
●Increased risk of ovarian cancer – Supporting evidence comes from a Finnish database study including 49,933 women with a surgical diagnosis of endometriosis identified between 1987 and 2012 that included 838,685 women-years of follow-up [130].
•Impact of any endometriosis – A surgical diagnosis of endometriosis was associated with a significantly increased risk of developing ovarian cancer (all types) compared with self-reported women without endometriosis (sIR 1.76, 95% CI 1.47-2.08) [130]. The greatest increases in risk were seen with endometrioid ovarian cancer (sIR 3.12, 95% CI 2.15-4.38) and clear cell ovarian cancer (sIR 5.17, 95% CI 3.20-7.89).
•Impact of ovarian endometriosis – Ovarian endometriosis was associated with an increased risk of ovarian cancer (standardized incidence ratio [sIR] 2.56, 95% CI 1.98-3.27), with a higher risk reported for clear cell (sIR 10.1, 95% CI 5.5-16.9) and endometrioid (sIR 4.72, 95% CI 2.75-7.56) ovarian cancers [130].
•Lack of risk with isolated peritoneal endometriosis – Isolated peritoneal endometriosis was associated with a slightly increased risk of ovarian cancer that did not reach statistical significance (sIR 1.32, 95% CI 0.99-1.72) [130].
•No impact on uterine cancer – Surgically documented endometriosis was not associated with development of corpus uteri cancer (sIR 1.04, 95% CI 0.80-1.32) [130].
●Prognosis if ovarian cancer develops – Endometriosis-associated EOC appears to develop in younger women and has a better prognosis than most cases of EOC [139,140]. In one retrospective series of 84 women with clear cell EOC, those with carcinoma arising in endometriosis lesions were younger (49 versus 59 years old) and had a better medial overall survival (196 versus 34 months) than patients without endometriosis [141]. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Prognosis'.)
●Proposed mechanisms of malignant transformation – Activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A have been suggested as mechanisms for the transformation of endometriosis, particularly ovarian endometriomas, to malignancy [134]. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Histopathology and pathogenesis'.)
●Ovarian cancer surveillance not advised – While there appears to be an association between endometriosis and EOCs, endometriosis is not considered a premalignant lesion and surveillance for ovarian cancer is not recommended. There are no high-quality data indicating that prophylactic removal of endometriosis lesions reduces the risk of EOC. However, use of oral contraceptive pills decreases the risk of ovarian cancer in all users.
•(See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)
•(See "Screening for ovarian cancer".)
Cardiovascular disease — A possible association between atherosclerosis and endometriosis is supported by studies reporting a proatherogenic profile [142,143] and increased subclinical atherosclerosis [144] in patients with endometriosis. Studies of individuals with endometriosis reported increased risk of cardiovascular disease, including risk of myocardial infarction, composite cardiovascular disease, ischemic stroke, and all-cause mortality [145-147].
In the prospective Nurses' Health Study (NHS) II, among 116,430 women enrolled in 1989, 5296 reported laparoscopically confirmed endometriosis. In follow-up through 2009, there were 1438 incident cases of coronary heart disease (CHD). The risk of combined CHD endpoints was increased in those with endometriosis (risk ratio 1.62, 95% CI 1.39-1.89). Among the study participants with endometriosis, compared with not having a hysterectomy, having had a hysterectomy/oophorectomy was associated with an increased risk of CHD (1.51, 95% CI 1.34-1.71). A related study for NHS II also reported increased risk of stroke (multivariable-adjusted hazard ratio 1.34, 95% CI 1.10-1.62), of which nearly 40 percent was attributed to the impact of prior hysterectomy/oophorectomy [148]. More data are needed on the risk of CHD in those with endometriosis and potential benefits of CHD screening for these individuals.
Depression and anxiety — Similar to other chronic pelvic pain disorders, endometriosis has been associated with increased risks of depression and anxiety [149,150]. While the prevailing thought has been that the symptoms of pain and infertility negatively impact mental health [151], a genome-wide association study (GWAS) raised the possibility of a common genetic pathway [152]. A subsequent GWAS including over 8200 patients with endometriosis identified one gene locus, DGKB4212666606, with evidence of pleiotropy between endometriosis and depression [153]. Pleiotropy occurs when a genetic variant impacts multiple traits or has multiple biologic effects. (See "Mendelian randomization" and "Mendelian randomization", section on 'Pleiotropy'.)
RESOURCES FOR PATIENTS AND CLINICIANS
●www.endometriosis.org – A nonprofit website dedicated to information about endometriosis and treatment.
●European Society of Human Reproduction and Embryology Guideline: Endometriosis – Includes patient information in multiple languages as well as management guidelines for clinicians.
●American College of Obstetricians and Gynecologists – Frequently asked questions about endometriosis.
●Center for Young Women's Health – An informational site sponsored by Boston Children's Hospital.
●American Society for Reproductive Medicine – Provides free materials on reproductive health issues for patients.
●The Endometriosis Association – An independent, nonprofit, self-help organization of individuals with endometriosis, clinicians, and others interested in the disease.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Endometriosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Endometriosis (The Basics)")
●Beyond the Basics topic (see "Patient education: Endometriosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Histology and lesion phenotypes – Endometriosis lesions contain endometrial glands and stroma (picture 1). Unlike eutopic endometrium, endometriosis implants exist outside of the uterine endometrium and myometrium and often involve fibrous tissue, blood, and cysts. Pelvic endometriosis lesions can be categorized as superficial peritoneal, ovarian, and deep. The gross appearance and size of the implants vary. (See 'Histology and lesion phenotypes' above.)
●Anatomy and staging – Common pelvic sites of endometriosis include the ovary and ovarian fossa, uterosacral ligaments, pouch of Douglas, and bladder. Endometriosis is staged at the time of surgery; the revised American Society for Reproductive Medicine scoring system is commonly used (form 1 and figure 1). (See 'Anatomy and staging' above.)
●Pathogenesis – The pathogenesis of endometriosis has not been definitively established and appears to be multifactorial, including ectopic endometrial tissue, altered immunity, imbalanced cell proliferation and apoptosis, aberrant endocrine signaling, and genetic factors. (See 'Pathogenesis' above.)
●Epidemiology – Globally, it is estimated that approximately 10 percent of reproductive-age females have endometriosis; prevalence varies by clinical population. Determining the prevalence of endometriosis is challenging because some individuals are asymptomatic, those with symptoms can have varied and nonspecific presentations, and definitive diagnosis typically requires surgery. (See 'Epidemiology' above.)
●Impact of endometriosis other clinical conditions – Endometriosis has been associated with an increased risk of poor pregnancy outcomes, epithelial ovarian cancer (EOC), and atherosclerosis. More data are needed before changes in screening or patient care are made. (See 'Clinical impact' above.)
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