Endometriosis

Endometriosis is a chronic, inflammatory gynecological disease in which tissue resembling the lining of the uterus grows outside the uterine cavity, most often on the pelvic peritoneum, the ovaries, and the surfaces of nearby organs. The lesions respond to the hormonal cycle, bleed and scar over time, and produce a range of symptoms, including painful menstruation, painful intercourse, bowel and bladder pain, and infertility. It is a common condition in people of reproductive age, and it is studied within medicine, epidemiology, and public health because of its prevalence, its long diagnostic delays, and its effect on quality of life. Its causes are not fully understood, and there is no cure, so the disease is managed through symptom control, hormonal suppression, surgery, and fertility support.

This entry covers the clinical picture and the classification of lesions, followed by the main hypotheses about origin and the roles of hormones, inflammation, the immune system, and genetics. It then describes the mechanisms of pain, current diagnostic practice (including recent changes in guidance), medical and surgical treatment, and the effects on fertility. The final sections address comorbidities, the social and economic burden, the history of research, and the questions that remain open.

Clinical Features and Symptoms

Endometriosis is characterized by endometrial-like glands and supporting tissue, or stroma, outside the uterus. The 2021 international terminology developed by four specialist societies defines it more precisely as endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually accompanied by inflammation. This distinguishes the lesions from normal uterine lining and recognizes inflammation as part of the disease rather than merely a secondary consequence. Although usually managed within gynecology, endometriosis is a chronic inflammatory condition whose clinical manifestations include bowel and urinary symptoms as well as reproductive symptoms. Local inflammatory reactions can produce fibrosis and adhesions, while the clinical presentation ranges from disabling pain to no apparent symptoms. (academic.oup.com)

The principal pain presentations are dysmenorrhea, deep dyspareunia, dyschezia, dysuria, and chronic pelvic pain. Dysmenorrhea is pain associated with menstruation; NICE distinguishes clinically concerning period-related pain by its interference with daily activities and quality of life. Deep dyspareunia describes pain felt internally during or after penetrative intercourse, rather than pain confined to the vaginal entrance. Dyschezia means painful defecation, and dysuria means painful urination. Pelvic pain may follow the menstrual cycle or occur independently of it, including between periods. The European Society of Human Reproduction and Embryology’s 2022 guideline explicitly includes both cyclical and non-cyclical presentations: absence of a consistent menstrual pattern therefore does not exclude endometriosis. (nice.org.uk)

Associated symptoms include abdominal bloating, nausea, fatigue, and heavy menstrual bleeding, although none is specific to endometriosis. Gastrointestinal symptoms may include constipation or diarrhea alongside painful bowel movements; urinary presentations may include cyclical pain or blood in the urine. Pain may also be experienced in the lower back or thighs. A recurring combination—for example, disabling menstrual pain together with deep pain during intercourse and painful defecation around menstruation—is more suggestive than any single symptom in isolation. Nevertheless, the 2022 ESHRE guideline describes the evidence for predicting endometriosis from symptoms alone as weak and incomplete. Symptoms identify a possible clinical presentation, not a definitive anatomical diagnosis. (who.int)

Symptom severity does not reliably track the anatomical extent of disease. A person with relatively limited lesions may experience severe pain, whereas extensive disease may produce few symptoms or none. Consequently, pain intensity cannot serve as a substitute for anatomical staging, and the absence of pain does not establish the absence of endometriosis. Some cases become apparent during investigation of fertility problems rather than through a pain complaint. This variability also means that “mild” anatomical disease and mild clinical illness are not interchangeable descriptions; the functional effects of symptoms require separate assessment from lesion extent. (nice.org.uk)

Infertility is another common presentation, sometimes accompanied by pain and sometimes without prominent painful symptoms. WHO’s 2025 fact sheet reports that approximately 25–50% of women with infertility have endometriosis; this figure concerns an infertility population and does not mean that the same proportion of all people with endometriosis cannot conceive. Pelvic pain and bowel or bladder complaints also overlap with other conditions. Irritable bowel syndrome can cause abdominal pain, bloating, constipation, and diarrhea, while painful bladder syndrome can cause bladder-region pain and urinary urgency or frequency. Such overlap limits the specificity of individual symptoms and makes the overall pattern—including menstrual timing, sexual pain, bowel or urinary pain, and fertility history—clinically important. (who.int)

Lesion Types, Location, and Staging

Three principal lesion types are distinguished: superficial peritoneal endometriosis, ovarian endometriomas, and deep endometriosis; these may coexist in the same person. Superficial lesions involve the peritoneal surface, including the lining of the pelvic sidewalls and the pouch of Douglas behind the uterus. An ovarian endometrioma is a cyst containing endometriotic tissue and blood products; its thick, dark-brown contents account for the name “chocolate cyst.” Deep endometriosis extends beneath the peritoneal surface and commonly forms nodules involving the uterosacral ligaments, vagina, bowel, bladder, or ureters. Older definitions used penetration greater than 5 mm as the boundary for deep disease. The 2021 international terminology instead defines deep disease by subperitoneal extension, noting that depth cannot always be measured accurately. (pmc.ncbi.nlm.nih.gov)

Lesions do not have a uniform appearance. Superficial implants may be clear vesicles, red petechial or flame-like lesions, or black, blue, and brown spots resembling powder burns. Dark pigmentation commonly reflects old hemorrhage, whereas white plaques, puckering, and scarred areas may indicate prominent fibrosis. Color alone does not establish the histological identity of a lesion: a study of 133 women examined lesion color, size, depth, and location against microscopic findings rather than treating visual appearance as definitive. Fibrosis and adhesions can tether an ovary to the pelvic sidewall, bind the ovaries and bowel together, or obliterate the pouch of Douglas, substantially altering pelvic anatomy. Endometriomas may be densely adherent to their surroundings rather than existing as isolated cysts. (guidelines.endometriosis.org)

Disease also occurs outside the pelvis. Recognized sites include the abdominal wall, umbilicus, and surgical scars, particularly scars following cesarean delivery. Thoracic disease can involve the diaphragm, pleura, lung parenchyma, or airways. Its anatomical manifestations may accompany menstrual-cycle-related shoulder pain, cough, or pneumothorax, although symptoms and lesion distribution vary. Extrapelvic location is therefore a separate descriptive feature, not simply another step on a pelvic severity scale. (pmc.ncbi.nlm.nih.gov)

The revised American Fertility Society classification of 1985 developed into the revised American Society for Reproductive Medicine classification, or rASRM; the revision entitled “1996” was published in May 1997. This surgical scoring system assigns points for the size and depth of peritoneal and ovarian lesions, ovarian and tubal adhesions, and obliteration of the pouch of Douglas. Totals define stage I, minimal disease, at 1–5 points; stage II, mild, at 6–15; stage III, moderate, at 16–40; and stage IV, severe, above 40. These labels describe scored anatomical findings rather than symptom severity. The system also incompletely represents deep disease: in a 2022 study of 735 women with deep endometriosis, bladder lesions occurred even among patients classified as rASRM stage I. (eege.gr)

The #Enzian classification, published in expanded form by Jörg Keckstein and colleagues in 2021, provides a compartment-based anatomical description usable with ultrasonography, magnetic resonance imaging, and surgical findings. It records peritoneal disease as P, ovarian disease as O, and tubo-ovarian adhesions and function as T. Deep compartments include A for the vagina and rectovaginal region, B for the uterosacral ligaments and parametria, and C for the rectum; additional codes identify bladder, ureteral, and other intestinal involvement. Unlike a single rASRM total, this notation preserves the location of disease. Neither anatomical system reliably predicts an individual’s pain or fertility outcome. The separate Endometriosis Fertility Index incorporates reproductive history and postoperative assessment of tubal and ovarian function for fertility prediction, rather than relying on lesion extent alone. (pubmed.ncbi.nlm.nih.gov)

Adenomyosis and Related Conditions

Adenomyosis is the presence of endometrial-type glands and stroma within the myometrium, the muscular wall of the uterus. Its defining location differs from that of endometriosis, which involves endometrial-like tissue outside the uterus. Although historically called “internal endometriosis,” adenomyosis is not classified as an endometriosis subtype in the 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline. Adenomyotic changes may be focal or diffuse; surrounding muscular hypertrophy can produce a thickened, globular uterus. Thus, the uterine-wall abnormality is distinct from an ovarian endometrioma or an extrauterine deep lesion, even when these occur together. (eshre.eu)

Heavy menstrual bleeding and painful menstruation are prominent manifestations, accompanied in some patients by chronic pelvic pain, painful intercourse, or reduced fertility. The 2023 Asian Society of Endometriosis and Adenomyosis guideline reports dysmenorrhea in 50–93% and heavy menstrual bleeding in 27–65% of affected patients across the studies it cites; approximately one-third are asymptomatic. These ranges reflect differences between clinical populations rather than a uniform symptom profile. Uterine enlargement and bleeding distinguish an important component of the clinical presentation from extrauterine endometriosis, although symptoms alone cannot separate the conditions. Proposed contributors to bleeding include increased vascularity, altered uterine contractility, and changes in local estrogen and prostaglandin activity; enlargement is not simply the result of accumulated menstrual blood. (pmc.ncbi.nlm.nih.gov)

Co-occurrence is common in clinical cohorts but is not obligatory. A 2025 study analysing ultrasound features reported concurrent endometriosis in 27% of patients diagnosed with adenomyosis. This is a cohort-specific proportion, not a population prevalence estimate. Shared pain and reproductive symptoms complicate attribution when both conditions are present. Research is further complicated by inconsistent adenomyosis diagnostic thresholds: studies using imaging, uterine histology, or selected surgical populations do not necessarily identify comparable groups. The Asian guideline specifically identifies coexisting endometriosis as a confounder when assessing the fertility effects of adenomyosis surgery, because reproductive outcomes cannot readily be attributed to treatment of the uterine disease alone. (pmc.ncbi.nlm.nih.gov)

Transvaginal ultrasonography and magnetic resonance imaging permit assessment of the uterine wall without requiring hysterectomy for histological confirmation. In 2022, Marlies Harmsen and colleagues revised the Morphological Uterus Sonographic Assessment (MUSA) definitions, separating direct signs—myometrial cysts, hyperechogenic islands, and echogenic subendometrial lines or buds—from indirect signs such as a globular uterus, asymmetric wall thickening, and an irregular junctional zone. Direct signs represent the ectopic tissue, whereas indirect signs reflect secondary muscular changes or imaging effects; indirect signs alone leave diagnostic uncertainty. Uterine fibroids are an important differential diagnosis and may coexist. Doppler imaging can help distinguish vessels traversing adenomyotic tissue from the more peripheral vascular pattern of a fibroid. (pmc.ncbi.nlm.nih.gov)

Guidelines differ in scope: ESHRE’s 2022 endometriosis guideline excludes adenomyosis, whereas the German–Austrian–Swiss 2025 guideline on endometriosis includes a dedicated adenomyosis section. The 2023 Asian guideline, led by Tasuku Harada, explicitly incorporates concomitant endometriosis and fibroids into treatment planning. This distinction matters because controlling extrauterine lesions does not address all uterine bleeding or wall abnormalities. Conversely, hysterectomy removes the adenomyotic uterus but does not itself remove extrauterine implants. The German–Austrian–Swiss guideline therefore discusses assessment for deep disease and the opportunity for simultaneous removal of peritoneal lesions when hysterectomy is undertaken for adenomyosis. (eshre.eu)

Epidemiology and Risk Factors

The World Health Organization estimates that endometriosis affects approximately 10% of reproductive-age women worldwide, equivalent to 190 million people. This prevalence estimate is not a count of confirmed diagnoses: historically, identifying disease usually required surgery, making representative population surveys difficult. Surgical series disproportionately include patients investigated for pain, infertility, or pelvic masses, while administrative records omit undiagnosed disease. The 2011 Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) study illustrates this dependence on sampling and ascertainment: endometriosis was visualized in 41% of its 495 surgical participants, whereas magnetic resonance imaging identified disease in 11% of a separate, geographically matched population cohort of 131 women. Neither proportion is directly transferable to the global population. (who.int)

A first-degree family history—an affected mother, sister, or daughter—is an established risk marker. A population-based sibling study published in 2021 found an incidence rate ratio of 2.75 (95% confidence interval, 2.25–3.36) for women with an affected sibling compared with those without one; the corresponding estimate for affected twins was 6.98 (4.19–11.62). Familial clustering supports a contribution from genetic susceptibility, although family-history associations alone cannot separate inherited effects from shared exposures or patterns of diagnosis. These relative estimates describe differences between groups, not the probability that an individual relative will develop disease. (nichd.nih.gov)

Earlier menarche and shorter menstrual cycles are associated with higher rates of diagnosis. In a 2004 prospective analysis of the Nurses’ Health Study II, involving 1,721 laparoscopically confirmed cases among participants without previous infertility, menarche before age 10 was associated with a rate ratio of 1.3 compared with menarche at age 12; cycles shorter than 26 days were associated with a rate ratio of 1.3 compared with cycles lasting 26–31 days. More frequent menstruation and greater cumulative menstrual exposure provide a plausible connection with the retrograde-menstruation hypothesis, without establishing causation. Nulliparity, meaning no previous birth, is also associated with higher risk. Its interpretation is complicated by reverse causation: endometriosis can impair fertility, while pregnancy and lactation interrupt menstrual cycling. (pubmed.ncbi.nlm.nih.gov)

Lifestyle associations are less straightforward. A 2013 Nurses’ Health Study II analysis, with 5,504 incident cases, found inverse associations between endometriosis and both body mass index at age 18 and current body mass index; associations were stronger among participants with infertility. These observations do not establish that greater body weight prevents disease. Alcohol findings vary: a 2022 meta-analysis reported an odds ratio of 1.22 (1.03–1.45) for moderate consumption compared with none, but no statistically significant association for heavy consumption, providing no consistent dose–response pattern. An ENDO analysis found no association with alcohol consumption or smoking. Similarly, a 2014 meta-analysis of 38 studies found no significant association for current smoking, with a relative risk of 0.92 (0.82–1.04). Differences in exposure measurement, control selection, and diagnostic pathways complicate comparisons. (pubmed.ncbi.nlm.nih.gov)

Reported rates also vary with age, ethnicity, and region, but diagnosis is not equivalent to biological onset or underlying prevalence. England’s Office for National Statistics, linking the 2011 Census with hospital records through 2021, estimated that approximately 2% of reproductive-age women in its linked population had a recorded diagnosis, with an average diagnostic age of 35 years. Women born outside the United Kingdom and those whose main language was not English had lower adjusted odds of diagnosis. A 2019 meta-analysis likewise found lower diagnostic odds among Black women and higher odds among Asian women compared with White women, but substantial between-study heterogeneity. Such differences cannot independently establish biological differences in susceptibility: access to specialists, referral practices, surgical availability, and case definitions shape recorded rates across populations and health systems. (ons.gov.uk)

Theories of Origin

Retrograde menstruation is the leading explanation for the origin of pelvic endometriosis. John A. Sampson developed the implantation hypothesis in the early twentieth century and presented it systematically in 1927: menstrual fluid carrying viable endometrial fragments passes backward through the fallopian tubes into the peritoneal cavity, where cells attach to surfaces and establish ectopic tissue. Experimental support includes a 1995 baboon study in which intrapelvic injection of menstrual endometrium produced peritoneal lesions. Such experiments demonstrate that displaced uterine tissue can generate lesions, but do not establish that every naturally occurring lesion develops by this route. (ndlsearch.ndl.go.jp)

The principal limitation is that menstrual reflux also occurs commonly without endometriosis. In a 1984 laparoscopic study, J. Halme and colleagues found blood in peritoneal fluid around menstruation in 90% of women with patent fallopian tubes, compared with 15% of those with occluded tubes; the finding occurred in participants both with and without endometriosis. Blood in the pelvis indicates reflux, not necessarily the presence of viable, implantation-capable endometrial cells. Consequently, the frequently cited 90% figure describes an observation in a selected surgical population, rather than proving that all menstruating individuals regularly reflux comparable quantities of tissue. Reflux alone cannot explain why lesions establish in only some individuals. (pubmed.ncbi.nlm.nih.gov)

The coelomic metaplasia hypothesis proposes a local origin: cells lining the peritoneum or ovarian surface change their differentiation program and acquire endometrial-like characteristics, rather than arriving as displaced uterine tissue. Laboratory evidence supports the possibility of such transformation. In 1999, Hideyuki Ohtake and colleagues cultured human ovarian surface epithelial cells with endometrial stromal cells in three-dimensional collagen gels. In the presence of estradiol, the epithelial cells formed gland-like structures with features resembling endometrial epithelium. This provides experimental support for cellular plasticity under specific conditions, but does not establish how frequently spontaneous metaplasia initiates human lesions. Ultrastructural observations of human peritoneal lesions have likewise suggested a contribution from adjacent mesothelial cells to gland formation, without definitively tracing their ancestry. (pubmed.ncbi.nlm.nih.gov)

The embryonic-remnant hypothesis instead places the initial displacement during fetal development. Primitive tissue associated with the Müllerian ducts—the developmental precursors of much of the female reproductive tract—could remain outside its normal location and later develop into endometrial-like lesions. In 2009, Pietro G. Signorile and colleagues examined pelvic organs from 36 female fetuses and reported misplaced endometrial-like structures in four. Locations included the rectovaginal septum, tissue near the pouch of Douglas, and the rectal muscular wall. These observations support the possibility of developmental misplacement before menstruation begins; they do not demonstrate that the structures would have persisted or become symptomatic endometriosis after birth. (pubmed.ncbi.nlm.nih.gov)

Stem cells and progenitor cells provide another potential source of ectopic tissue, including cells transported through blood or lymphatic vessels. A 2007 study by Hongling Du and Hugh S. Taylor used male-to-female bone-marrow transplantation in mice to identify donor-derived cells acquiring endometrial characteristics. In a separate experimentally induced endometriosis model, cells of extrauterine origin entered transplanted lesions and acquired epithelial or stromal characteristics. Because these lesions were created by transplanting uterine tissue, the experiment demonstrated recruitment into existing implants rather than spontaneous initiation of disease. The proposed routes are therefore not mutually exclusive: tissue transplantation can establish a lesion while circulating progenitors subsequently contribute to it, and local cellular transformation or developmental remnants could provide other starting populations. Distinguishing the cells that initiate lesions from those recruited during subsequent growth remains essential when evaluating these hypotheses. (stemcellsjournals.onlinelibrary.wiley.com)

Hormonal Regulation

Estrogen supports the growth and maintenance of endometriotic tissue through estrogen receptors in glandular and stromal cells. Its effects depend not only on ovarian secretion but also on steroid metabolism within lesions. Aromatase, encoded by CYP19A1, converts androgen precursors into estrogens; other enzymes regulate the balance between strongly estrogenic estradiol and less potent estrone. In a 1997 experiment, Luis S. Noble and colleagues found that prostaglandin E2 increased aromatase activity 19–44-fold in cultured endometriosis-derived stromal cells. This was an experimental response, not a measurement of estrogen concentrations in patients. Subsequent cell studies identified a prostaglandin E2–cyclic AMP–steroidogenic factor-1 pathway that activates aromatase and additional steroid-producing genes, providing a mechanism by which local inflammatory signals can sustain estrogen production. (pubmed.ncbi.nlm.nih.gov)

Progesterone normally counteracts estrogen-driven proliferation and promotes differentiation of uterine endometrial tissue. In endometriosis, “progesterone resistance” describes reduced responsiveness to this signal rather than necessarily a deficiency of circulating progesterone. One consequence is impaired estrogen inactivation: in 1998, Khaled Zeitoun and colleagues reported deficient expression of 17β-hydroxysteroid dehydrogenase type 2, which converts estradiol to estrone. Progesterone normally induces this enzyme through communication between stromal and epithelial cells; disruption of that response can prolong estradiol activity. Altered receptor regulation provides another possible mechanism. In 2006, Yan Wu and colleagues identified increased DNA methylation at the promoter controlling progesterone receptor isoform B, but not isoform A, in the tissues studied. These findings describe mechanisms observed in particular samples, not a uniform receptor defect in every lesion. (pubmed.ncbi.nlm.nih.gov)

Lesions respond unevenly to the menstrual cycle and should not be understood as miniature copies of the uterine lining that invariably grow and bleed in synchrony. A 2020 histological study examined superficial peritoneal lesions from 32 patients at different menstrual phases and another 10 receiving hormonal treatment; lesion morphology rarely synchronized with matched uterine endometrium. Hormonal fluctuations can therefore influence lesion activity without producing the orderly proliferative, secretory, and menstrual changes characteristic of uterine tissue. Hemorrhage and tissue breakdown can occur, but their presence does not establish that every implant undergoes monthly menstrual shedding. Local prostaglandin signaling also links inflammatory activity to steroid production rather than making it solely dependent on the circulating hormonal cycle. (academic.oup.com)

Hormonal suppression exploits these dependencies by reducing ovarian estrogen production, limiting menstrual cycling, or activating progesterone receptors with synthetic progestogens. The 2022 European Society of Human Reproduction and Embryology guideline includes combined hormonal contraceptives, progestogens, and gonadotropin-releasing hormone agonists or antagonists among treatments for endometriosis-associated pain; aromatase inhibitors target estrogen synthesis more directly in refractory disease. These approaches act at different points in the hormonal pathway, so reduced responsiveness to progesterone does not imply resistance to every form of hormonal suppression. Their clinical regimens and adverse effects are addressed separately under medical treatment. (academic.oup.com)

Differences between lesion types provide a biological basis for variable responses, although receptor measurements are not established predictors of treatment success. A tissue-microarray study found that ovarian lesions had comparatively low estrogen receptor α and progesterone receptor expression and high estrogen receptor β expression. Heterogeneity also occurs within a single lesion category: a study of 271 superficial peritoneal lesions from 24 patients found substantial variation in estrogen receptor α and progesterone receptor staining, including between lesions from the same patient. A separate analysis of gene expression in 28 ovarian endometriomas, 72 superficial lesions, and 78 deep lesions found subtype-specific associations with hormonal treatment, particularly in endometriomas. These observational findings identify molecular differences but do not establish that one anatomical subtype invariably responds better than another. (pmc.ncbi.nlm.nih.gov)

Immune Dysregulation and Inflammation

Innate immunity in endometriosis can support ectopic tissue rather than eliminate it. Macrophages within lesions and peritoneal fluid participate in inflammatory signaling, tissue remodeling, and the formation of new blood vessels. In a 2009 study, Monica Bacci and colleagues identified macrophages expressing the alternative-activation markers CD163 and CD206 in patients and in experimental mice. Depleting macrophages before introducing endometrial tissue into mice allowed fragments to attach to the peritoneum but prevented organized lesion development; depletion after lesions had formed impaired vascular penetration and stopped further growth. Transferring alternatively activated macrophages enhanced lesion growth, whereas inflammatory macrophages were protective in that model. These experiments establish a functional contribution in mice, rather than simply an association between immune-cell abundance and disease. (pubmed.ncbi.nlm.nih.gov)

Reduced natural killer cell cytotoxicity provides another possible route by which ectopic cells escape clearance. A 1992 study of 44 women undergoing laparoscopy for infertility or pain found lower natural killer activity in peritoneal-fluid cells from women with endometriosis. Cell abundance and killing capacity are nevertheless distinct measurements: a 2024 study of 47 patients and 15 controls found increases in particular natural killer subsets in blood and peritoneal fluid, alongside changes in T-cell subsets associated with disease severity and symptoms. Thus, immune dysregulation cannot be described simply as a shortage of defensive cells; their functional state and anatomical compartment also matter. (pubmed.ncbi.nlm.nih.gov)

Changes in adaptive immunity include altered balances among helper T-cell populations and increased local representation of regulatory T cells, which can suppress immune responses. A 2021 study found higher proportions of CD4-positive, CD25-high, FOXP3-positive regulatory cells in endometriotic peritoneal fluid. Their proportions correlated with IL-10 and transforming growth factor-β concentrations, while migration experiments implicated the chemokine CCL20 in their recruitment. Another 2021 investigation, using fluid from 30 women with and without endometriosis, found that endometriotic fluid promoted regulatory-cell generation and shifted cultured T-cell cytokine production toward a Th2-associated pattern. However, several suppressive effects also occurred with control fluid, without significant differences between groups. Findings are not uniform: a 2020 study detected increased peritoneal Th17 cells in advanced disease but no corresponding differences in blood Th1, Th2, or Th17 populations. These results support compartment-specific alterations rather than a single universal T-cell profile. (pmc.ncbi.nlm.nih.gov)

The peritoneal environment contains both pro-inflammatory and immunoregulatory cytokines and chemokines. The 2021 fluid study found elevated IL-6, IL-10, CCL2, CXCL8, and CXCL9 compared with controls, illustrating how inflammation can coexist with suppression of cellular immune activity. Mechanistic experiments also connect these mediators to tissue growth: a 1998 study involving 40 women found elevated peritoneal IL-8, also called CXCL8, and demonstrated that it stimulated proliferation of cultured endometrial and endometriotic stromal cells. Immune-derived growth factors can additionally contribute to pain. Rachel Forster and colleagues reported in 2019 that macrophage-derived insulin-like growth factor-1 promoted nerve growth and sensitization in experimental systems; its concentration in patients’ peritoneal fluid correlated with pain scores. These observations link the inflammatory environment to lesion remodeling and symptoms, although experimental effects do not establish their relative importance in every patient. (pmc.ncbi.nlm.nih.gov)

Evidence of immune changes outside the pelvis and associations with autoimmune diseases has contributed to discussion of endometriosis as a systemic inflammatory disorder. Nina Shigesi and colleagues’ 2019 systematic review included 26 population-based studies reporting associations with conditions such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Most evidence was graded low or very low quality, although several better-designed studies supported specific associations. Such findings do not establish that endometriosis causes these disorders or is itself an autoimmune disease. Shared susceptibility, confounding, and differences in diagnostic surveillance remain possible explanations; describing systemic effects is therefore distinct from demonstrating autoimmune causation. (pmc.ncbi.nlm.nih.gov)

Genetics and Epigenetics

Family aggregation and twin studies support an inherited component of susceptibility, but endometriosis does not follow a simple single-gene inheritance pattern. In 1999, Susan Treloar and colleagues studied an Australian twin sample with 3,096 questionnaire respondents, validating diagnoses against medical and surgical records where available. The estimated correlation in disease liability was 0.52 for identical twins and 0.19 for non-identical twins; their model attributed approximately 51% of variation in underlying liability to additive genetic influences. This population-level estimate does not mean that half of an individual’s disease is genetically determined. Together with subsequent association studies, it supports a polygenic architecture in which numerous inherited variants contribute to susceptibility alongside non-genetic influences. (pubmed.ncbi.nlm.nih.gov)

Genome-wide association studies (GWAS) compare variant frequencies between affected individuals and controls. A 2023 meta-analysis led by Nilufer Rahmioglu included 60,674 cases and 701,926 controls of European and East Asian ancestry, identifying 42 associated genomic regions containing 49 independent association signals. Associations were generally stronger in stage III/IV disease, particularly ovarian endometriosis. A 2026 multi-ancestry analysis led by Dora Koller expanded the sample to 105,869 cases and 1,282,731 female controls and identified 80 associated regions, including 37 newly reported loci. These findings establish many susceptibility regions rather than a single necessary or sufficient “endometriosis gene.” (pmc.ncbi.nlm.nih.gov)

Associated regions implicate several biological processes. Examples include GREB1 and ESR1 in estrogen-related signaling, FSHB in reproductive hormone regulation, VEZT, which encodes the adherens-junction protein vezatin, in cell adhesion, and WNT4 and the HOXA region in developmental regulation. However, a locus named after a nearby gene does not establish that gene as the causal target. Associated variants may alter distant regulatory elements rather than protein sequences. Integrating GWAS with gene-expression and methylation measurements helps identify plausible targets: the 2023 analysis linked risk signals to expression or methylation changes in endometrium and blood, while its six high-confidence candidate causal variants were all non-coding. (pmc.ncbi.nlm.nih.gov)

Epigenetic studies examine regulatory changes that do not alter the underlying DNA sequence, particularly DNA methylation. A mechanistic example is NR5A1, encoding steroidogenic factor-1 (SF-1), which activates genes involved in estrogen synthesis. In 2007, Qing Xue and colleagues compared stromal cells from eight ovarian endometriotic cysts with endometrial stromal cells from eight disease-free participants. Lesional cells showed reduced methylation around the SF-1 promoter and increased SF-1 expression. Experimental demethylation increased SF-1 messenger RNA in normal endometrial cells, whereas methylating the regulatory region suppressed promoter activity. These experiments connect a specific epigenetic alteration to abnormal transcription, although they do not establish when that alteration arises during disease development. (pubmed.ncbi.nlm.nih.gov)

Epigenetic differences also occur in eutopic endometrium—the uterine lining of affected individuals. A small 2005 study by Yan Wu and colleagues found altered HOXA10 methylation alongside reduced expression of this implantation-related gene. Larger studies reveal a more complex picture: Sally Mortlock and colleagues’ 2023 analysis of endometrial samples from 984 participants identified methylation differences associated with disease subtypes and severity, but menstrual-cycle phase was a major source of variation. The study also identified 51 independent genetic associations with methylation that were associated with endometriosis risk, illustrating that inherited sequence variation and epigenetic regulation are partly interconnected rather than separate explanations. (pubmed.ncbi.nlm.nih.gov)

Individual common variants have small effects, and identified loci explain only part of inherited susceptibility. In the 2023 GWAS, the 49 independent signals explained an estimated 1.98% of overall disease variance, rising to 5.01% for stage III/IV disease. Replication and interpretation are complicated by differences in case ascertainment, lesion subtype, ancestry, and sample size; the 2026 study found significant ancestry-related effect heterogeneity at seven associated loci. Epigenetic comparisons additionally depend on menstrual timing and tissue composition, and cross-sectional differences cannot by themselves distinguish predisposing changes from consequences of established disease. These limitations constrain the translation of association signals into demonstrated causal mechanisms. (pmc.ncbi.nlm.nih.gov)

Mechanisms of Pain

Inflammation around endometriotic lesions can lower the activation threshold of nociceptors, the sensory nerve endings that detect potentially damaging stimuli. This peripheral sensitization allows otherwise modest mechanical or chemical stimulation to generate stronger pain signals. Lesional cells and neighboring immune cells contribute prostaglandins, inflammatory cytokines, and growth factors to this environment. Prostaglandin E2 acts through receptors including EP2, modifying sensory-neuron excitability. In a 2017 mouse study, endometriosis increased prostaglandin E2 concentrations in peritoneal fluid and expression of EP2, the sodium-channel gene Scn11a, and the heat- and chemical-sensitive channel Trpv1 in dorsal root ganglia. EP2 antagonism reduced local and more widespread hypersensitivity, providing experimental evidence for prostaglandin-mediated pain amplification rather than establishing the mechanism in every human case. (pmc.ncbi.nlm.nih.gov)

Lesions also acquire their own nerve supply. In 2006, Natsuko Tokushige and colleagues examined specimens from 40 women with endometriosis and 36 without it, finding significantly more nerve fibers in peritoneal lesions than in normal peritoneum. These included sensory Aδ and C fibers, as well as autonomic fibers; nerve growth factor staining was prominent near endometriotic glands. Such innervation provides a route by which the inflammatory environment can directly stimulate the peripheral nervous system. Immune–nerve interactions can promote both nerve growth and sensitization: Rachel Forster and colleagues showed in 2019 that macrophage-derived insulin-like growth factor 1 stimulated nerve sprouting and increased expression of nociceptive genes in laboratory models. Peritoneal-fluid concentrations correlated with human pain scores, while macrophage depletion or receptor inhibition reduced abnormal pain behavior in mice. These findings distinguish human associations from experimentally demonstrated mechanisms. (pubmed.ncbi.nlm.nih.gov)

Innervation does not, however, translate into a uniform relationship between nerve density and pain intensity. Studies using different nerve markers have produced differing results: a 2001 investigation found no significant differences in its measurements between participants with and without chronic pelvic pain, while some later studies linked sensory-channel expression to symptoms. For example, increased TRPV1 expression in uterosacral lesions was associated with pain severity in one study, whereas a 2011 study of peritoneal lesions found an association with chronic pelvic pain but not with its intensity. Nerve phenotype, excitability, and anatomical relationships therefore require consideration alongside the number of fibers detected in a tissue section. (pubmed.ncbi.nlm.nih.gov)

Repeated peripheral signaling may produce central sensitization: increased responsiveness of pain-processing pathways in the spinal cord and brain. This form of neuroplasticity can amplify incoming signals and contribute to hypersensitivity beyond the pelvis. A study by Sawsan As-Sanie and colleagues, published in 2016, found increased combined glutamate–glutamine concentrations in the anterior insula and stronger connectivity between that region and the medial prefrontal cortex in women with endometriosis-associated chronic pelvic pain. Comparable abnormalities were not detected in participants with endometriosis but without chronic pelvic pain. These observations support altered central processing associated with the pain phenotype, although their observational design does not establish whether the brain changes preceded or followed persistent pain. (pmc.ncbi.nlm.nih.gov)

Central amplification may help explain pain persisting after lesion removal. In Natasha Orr and colleagues’ 2023 prospective cohort of 239 surgical patients, higher preoperative Central Sensitization Inventory scores were associated with worse postoperative pelvic pain, deep dyspareunia, dyschezia, and back pain after adjustment for baseline pain. The inventory measures self-reported symptoms rather than directly measuring neuronal sensitization, so the association is supportive rather than definitive mechanistic evidence. Anatomical disease stage likewise incompletely predicts pain: Paolo Vercellini and colleagues’ 2007 analysis of 1,054 women found only marginal, inconsistent associations between stage and symptom severity, whereas posterior cul-de-sac lesions were more strongly associated with painful intercourse (odds ratio 2.64; 95% confidence interval 1.68–4.24). Lesion location, local nerve signaling, and central amplification are dimensions of pain that lesion size or stage alone cannot capture. (jamanetwork.com)

Diagnosis and Diagnostic Guidance

Laparoscopy with histological examination of sampled lesions historically served as the diagnostic reference standard. It permits direct inspection of the pelvis, while biopsy can demonstrate endometrial-like glands and stroma. The European Society of Human Reproduction and Embryology (ESHRE) explicitly described this combination as the “gold standard” in its 2014 guideline. Its 2022 revision no longer required surgery as the routine first step: imaging and clinical assessment became central to the diagnostic pathway, with laparoscopy considered when imaging is negative or empirical treatment is unsuccessful or inappropriate. When surgery is performed, ESHRE recommends histological confirmation of visually identified lesions, although negative histology does not entirely exclude disease. (academic.oup.com)

A clinical diagnosis draws on symptom patterns, medical and family history, and examination findings rather than requiring immediate surgical proof. Relevant findings include menstrual or persistent pelvic pain, deep pain during intercourse, cyclical bowel or urinary symptoms, and infertility associated with pain. Examination may reveal an adnexal mass, reduced pelvic-organ mobility, or tender nodularity behind the cervix; a normal examination does not exclude endometriosis. The American College of Obstetricians and Gynecologists’ guidance, released on February 20, 2026, supports a presumptive diagnosis from history, symptoms, and examination, allowing empirical medical treatment while imaging evaluation continues. Guideline author Bliss Kaneshiro described this as a means of beginning care without awaiting invasive confirmation. Treatment response, however, does not reliably establish or exclude endometriosis. (academic.oup.com)

Transvaginal ultrasonography is the first-line imaging investigation. In its November 2024 diagnostic update, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended offering it to all people with suspected endometriosis, even when examination is normal. Its purposes include detecting ovarian endometriomas and deep lesions, identifying alternative causes of symptoms, and directing referral. Transabdominal ultrasound is an alternative when the transvaginal approach is unsuitable or declined. A dedicated examination goes beyond identifying ovarian cysts: the Society of Radiologists in Ultrasound’s 2024 consensus recommends assessment of the posterior pelvic compartment, uterine and ovarian positions, and the uterine “sliding sign.” This dynamic maneuver assesses relative movement of pelvic structures and can reveal restricted mobility associated with adhesions. (nice.org.uk)

Specialist ultrasound and pelvic magnetic resonance imaging can map deep disease, including involvement of the bowel, bladder, and ureters. NICE specifies that these examinations should be planned and interpreted by professionals with expertise in gynecological imaging. Imaging performance depends on lesion location and examiner experience; neither modality reliably excludes small superficial peritoneal lesions. Consequently, a normal scan is not equivalent to absence of endometriosis. NICE permits consideration of diagnostic laparoscopy despite normal ultrasound or MRI, whereas ESHRE emphasizes negative imaging and unsuccessful or unsuitable empirical treatment as circumstances for considering surgery. ESHRE found no evidence that diagnostic laparoscopy was superior to imaging combined with empirical hormonal treatment for symptom management; the alternatives therefore require discussion of their respective benefits and disadvantages. (nice.org.uk)

Routine biomarker testing is not part of the guideline-supported diagnostic pathway. NICE specifically advises against using serum cancer antigen 125 (CA125) to diagnose endometriosis; its 2024 evidence review did not establish sufficient diagnostic accuracy to change that recommendation. ESHRE’s 2022 guideline likewise recommends against diagnostic measurement of biomarkers in blood, endometrial tissue, menstrual fluid, or uterine fluid. Such measurements do not replace clinical assessment, specialist imaging, or selectively indicated surgical investigation. (nice.org.uk)

Medical Treatment

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and naproxen, are used for symptomatic pain relief, either alone or alongside hormonal treatment. Their action includes inhibition of prostaglandin synthesis, reducing mediators involved in inflammation and menstrual cramping; they do not suppress ovarian hormone production or eliminate lesions. Endometriosis-specific evidence is limited: a 2017 Cochrane review found only one analysable placebo-controlled trial, involving 24 women, and could not establish whether naproxen improved pain relief. This uncertainty reflects very low-quality evidence rather than proof of ineffectiveness. Gastrointestinal bleeding and renal toxicity are important risks of NSAID treatment, particularly with prolonged exposure. (dailymed.nlm.nih.gov)

Combined hormonal contraceptives and progestins are usual first-line hormonal options when immediate pregnancy is not intended. Combined pills, vaginal rings, and transdermal patches suppress ovarian activity, while their progestin component also reduces endometrial and endometriotic tissue activity. Continuous pill regimens omit the usual hormone-free interval and can reduce menstruation-associated pain. Progestin options include oral dienogest or norethindrone acetate, injectable medroxyprogesterone acetate, the levonorgestrel-releasing intrauterine system, and the etonogestrel implant. The 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline supports both combined contraceptives and progestogens for pain reduction, including intrauterine and implant formulations. These treatments suppress disease activity rather than provide a cure, and symptoms often return after discontinuation; hormonal suppression does not improve endometriosis-associated infertility. (cgf.cochrane.org)

Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, produce an initial stimulation followed by sustained suppression of pituitary gonadotropins and ovarian estrogen production. GnRH antagonists, including oral elagolix and relugolix, directly block pituitary GnRH receptors. ESHRE places both classes principally as second-line options because estrogen deprivation can cause hot flushes, vaginal dryness, and loss of bone mineral density. “Add-back” therapy supplies a progestin, with or without low-dose estrogen, to limit these effects while maintaining pain control. In the United States, leuprolide treatment with norethindrone acetate add-back is limited to a total of 12 months. Elagolix monotherapy has dose-dependent limits: up to 24 months at 150 mg daily or six months at 200 mg twice daily in patients with normal liver function or mild hepatic impairment. (dailymed.nlm.nih.gov)

Relugolix is available as a fixed-dose combination incorporating add-back: relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg. In the SPIRIT 1 and SPIRIT 2 phase III randomized controlled trials, published in 2022, approximately 75% of combination-treated participants met the menstrual-pain responder criteria at 24 weeks, compared with 27% and 30% receiving placebo. Response required a clinically meaningful pain reduction without increased analgesic use, not complete disappearance of pain. United States labeling limits treatment to 24 months because bone loss may continue and may not be fully reversible. The estrogen–progestin component also carries a boxed warning for thrombotic and thromboembolic events. (sciencedirect.com)

Aromatase inhibitors, notably letrozole and anastrozole, inhibit the enzyme responsible for converting androgens into estrogens. They are reserved for pain refractory to other medical or surgical treatment and are generally combined with a progestin, contraceptive, or GnRH-based treatment. Evidence remains limited, especially for long-term outcomes, and adverse effects include hot flushes, vaginal dryness, and diminished bone mineral density. Treatment selection consequently incorporates previous response, bleeding patterns, adverse effects, cost, route of administration, and reproductive intentions. Headache, acne, spotting, weight change, and mood symptoms differ between preparations and individuals; GnRH-antagonist labeling specifically addresses depression and suicidal ideation. The 2022 ESHRE guideline frames these choices as shared decisions rather than a single universally preferred drug sequence. (eshre.eu)

Surgical Treatment

Laparoscopy permits inspection of pelvic lesions, collection of tissue for histopathological examination, and treatment during the same operation. Its diagnostic role is selective: the 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline places it principally after negative imaging or when empirical treatment is unsuccessful or inappropriate. Excision cuts lesions away, providing tissue for examination; ablation destroys them in place using electrosurgery or laser vaporization. ESHRE gives a weak recommendation to consider excision rather than ablation for reducing endometriosis-associated pain, reflecting limited comparative evidence rather than an established superiority for every lesion type. (academic.oup.com)

For ovarian endometriomas, cystectomy separates and removes the cyst wall from the ovary. The 2022 ESHRE guideline favors cystectomy over drainage followed by electrocoagulation because it reduces recurrent cysts and endometriosis-associated pain. This distinction does not establish cystectomy as superior to all ablative techniques: carbon dioxide laser vaporization is another option, with evidence suggesting similar recurrence beyond the first postoperative year, although early recurrence may be lower after cystectomy. The 2017 ESGE–ESHRE–World Endometriosis Society technical recommendations describe combined approaches in which most of the wall is excised but tissue near the ovarian hilum is ablated when further stripping would threaten vessels or functional ovarian tissue. (eshre.eu)

Preserving ovarian reserve—the remaining follicular pool—is a central constraint in endometrioma surgery. Stripping can inadvertently remove follicle-bearing cortex, while excessive coagulation can injure adjacent tissue and its blood supply. Technical recommendations therefore emphasize identifying the dissection plane, avoiding forceful traction when separation is difficult, and limiting thermal hemostasis. Repeat operations compound these trade-offs. In a 2015 prospective controlled study, Ludovico Muzii and colleagues found that surgery for recurrent endometriomas removed more ovarian tissue and produced greater impairment of reserve, assessed through antral follicle count and ovarian volume, than first-time surgery. These findings distinguish removal of a recurrent cyst from restoration of ovarian function: the anatomical intervention itself can incur additional functional loss. (pmc.ncbi.nlm.nih.gov)

Deep disease may require procedures involving the bowel or urinary tract rather than removal of peritoneal lesions alone. The 2020 ESGE–ESHRE–World Endometriosis Society recommendations describe rectal shaving, full-thickness disc excision, and segmental bowel resection, selected according to infiltration, lesion extent, and narrowing of the bowel. Bladder involvement may require partial bladder resection. Ureterolysis frees a ureter from surrounding fibrotic tissue; intrinsic disease or persistent obstruction may require ureteral resection with reconnection or reimplantation into the bladder. These operations carry risks including bowel anastomotic leakage, fistulas, urinary leakage, and pelvic nerve injury affecting bladder or bowel function. Ureteral obstruction can cause hydronephrosis and loss of renal function even without prominent symptoms, making organ preservation a separate surgical objective from pain relief. Complex procedures require coordinated gynecological, colorectal, and urological expertise. (academic.oup.com)

Recurrence estimates depend on whether the outcome is recurrent pain, a cyst detected by imaging, or further surgery; these outcomes are not interchangeable. Andrew Zakhari and colleagues’ meta-analysis, published online in October 2020 and in a 2021 journal issue, included 17 studies with 2,137 participants. In the 14 studies reporting recurrence, postoperative hormonal suppression reduced recurrence relative to placebo or expectant management: the pooled relative risk was $0.41$, with a 95% confidence interval of $0.26–0.65$, among 1,766 participants. Follow-up ranged from 12 to 36 months, with outcomes assessed at a median of 18 months. ESHRE’s 2022 guideline incorporates suppression into postoperative care for patients not immediately seeking pregnancy, including long-term treatment after endometrioma surgery and a 52-mg levonorgestrel intrauterine system or combined hormonal contraception for at least 18–24 months to reduce recurrent dysmenorrhea. (academic.oup.com)

Infertility and Assisted Reproduction

Endometriosis-associated infertility can involve both mechanical obstruction and disturbances of the reproductive environment. Pelvic adhesions may restrict ovarian movement, interfere with oocyte release, or prevent the fallopian tube’s fimbriae from capturing the oocyte. Increased concentrations of prostaglandins and inflammatory cytokines, including interleukin-1, interleukin-6, and tumour necrosis factor, have been reported in peritoneal fluid; these may affect sperm, oocytes, embryos, and tubal function. Altered follicular-fluid composition and endometrial receptivity are additional proposed mechanisms. However, laboratory abnormalities do not establish their contribution to infertility in individual patients, and studies of implantation have produced inconsistent findings. Anatomical disruption provides a clearer explanation in some advanced cases than in minimal disease. (integration.asrm.org)

Evidence that surgery improves unassisted conception is strongest for minimal or mild disease. A 2020 Cochrane review found that operative laparoscopy increased the odds of a viable intrauterine pregnancy compared with diagnostic laparoscopy alone: odds ratio 1.89, with a 95% confidence interval of 1.25–2.86, across three randomized controlled trials involving 528 participants. The evidence was rated moderate certainty, but the review contained no live-birth data for this comparison. These results therefore support an improvement in a pregnancy endpoint, not a demonstrated increase in live births. (pmc.ncbi.nlm.nih.gov) For ovarian endometriomas and deep disease, the 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline describes substantially weaker evidence that surgery improves natural conception, with comparative studies lacking for endometriomas and compelling evidence absent for deep lesions. (academic.oup.com)

Treatment sequencing depends on age, ovarian reserve, previous operations, other infertility factors, and reproductive preferences, rather than lesion stage alone. ESHRE identifies the postoperative Endometriosis Fertility Index as a tool for estimating the prospects of pregnancy without assisted reproduction and informing subsequent treatment. Its guidance permits ovarian stimulation with intrauterine insemination in stage I–II disease, while the value of this approach in stage III–IV disease remains uncertain. In vitro fertilization (IVF) is particularly relevant when tubal function is impaired, a male-factor contribution is present, the fertility index is low, or other treatments have failed. (academic.oup.com)

Surgery undertaken to improve spontaneous conception is distinct from surgery performed before IVF. ESHRE’s 2022 guideline advises against routine endometrioma removal before assisted reproduction solely to improve live-birth rates: available evidence shows no benefit, while surgery may reduce ovarian reserve. Pain or difficulty accessing follicles during egg retrieval can provide separate reasons for intervention. The reproductive benefit of removing deep lesions before IVF remains uncertain because randomized studies are lacking. The guideline also does not recommend prolonged gonadotropin-releasing hormone agonist pretreatment to improve live birth, because its benefit is uncertain. (eshre.eu)

Fertility preservation is relevant to planning care in extensive ovarian disease, especially where ovarian treatment may compromise future reproductive capacity. Oocyte vitrification stores unfertilized eggs for later use; ovarian-tissue storage has also been described, but endometriosis-specific evidence is sparse. ESHRE recommends discussion of preservation’s advantages and disadvantages in extensive ovarian endometriosis, while explicitly stating that its true benefit remains unknown. The guideline does not support routine egg banking for everyone with the disease. (eshre.eu)

In a 2020 observational study, Ana Cobo and colleagues reported outcomes in 485 women with endometriosis who used vitrified oocytes. Oocyte survival after warming was 83.2%, and the cumulative live-birth rate was 46.4%. These figures describe outcomes among women returning to use stored eggs, not the probability that every person undertaking preservation will eventually have a child. The short average storage interval—approximately 1.5 years—also limits interpretation as evidence of long-term preventive benefit: some freezing formed part of near-term infertility treatment rather than preservation against future fertility loss. (pubmed.ncbi.nlm.nih.gov)

Multidisciplinary and Non-Drug Care

Pelvic floor physiotherapy addresses muscle dysfunction accompanying pelvic pain, rather than removing endometriotic lesions. Deep endometriosis can coexist with excessive pelvic floor muscle tone and impaired relaxation; treatment may therefore emphasize relaxation and coordination rather than strengthening alone. Techniques include assessment of resting muscle tone, manual pressure and stretching, and education about pelvic floor function. In a randomized study by Simona Del Forno and colleagues, reported in December 2023, participants received five individual 30-minute sessions incorporating Thiele massage over 11 weeks. Thirty women completed follow-up. Although pelvic floor relaxation, superficial pain during intercourse, and chronic pelvic pain improved, questionnaire scores for urinary, bowel, and overall sexual function did not differ significantly from controls. These findings distinguish improvement in particular pain symptoms from recovery across all pelvic functions. (pmc.ncbi.nlm.nih.gov)

Other rehabilitation approaches target physical conditioning and lumbopelvic impairments. The 2023 Physio-EndEA randomized controlled trial enrolled 31 women whose symptoms had not responded adequately to conventional treatment. Its nine-week supervised exercise programme improved quality of life compared with usual care, both immediately after treatment and at one year. Reported changes included reduced pain during intercourse, increased pressure-pain thresholds, greater abdominal and back strength, and improved lumbopelvic stability. The small sample limits generalization and does not establish an optimal exercise prescription. The 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline had supported discussion of non-medical strategies but found insufficient evidence to recommend any particular physiotherapy or exercise intervention for endometriosis-associated symptoms. (pubmed.ncbi.nlm.nih.gov)

Psychological care addresses coping, emotional distress, and the effects of persistent pain on daily functioning. Cognitive behavioral therapy (CBT) uses techniques for modifying unhelpful thoughts and behaviours and supporting re-engagement in activities. Lilian Donatti and colleagues’ trial, published online in 2024, randomized 52 women and reported improvements in pain perception, depression, stress, and quality of life compared with controls. The larger Healing Pelvic Pain Intervention trial, published in January 2026, randomized 334 participants to telehealth CBT, yoga, or emailed education. After eight weeks, CBT improved endometriosis-specific and general health-related quality of life and several pain outcomes, while reducing pain catastrophizing and increasing confidence in managing pain. It did not significantly improve psychological distress or sleep. Thus, changes in pain-related functioning and changes in mental health are related but distinct outcomes; a pain-focused psychological programme does not necessarily treat every emotional consequence of the disease. (pubmed.ncbi.nlm.nih.gov)

Dietary research similarly distinguishes gastrointestinal symptom relief from effects on endometriosis itself. In the 2025 EndoFOD crossover feeding trial, 35 women with poorly controlled gastrointestinal symptoms received a supplied low-FODMAP diet and a nutritionally matched control diet for 28 days each, separated by a washout period. FODMAPs are fermentable short-chain carbohydrates; reducing their intake targets intestinal effects such as fermentation and osmotic water movement. Sixty percent responded during the low-FODMAP period, compared with 26% during the control period, with improvements in abdominal pain, bloating, stool form, and quality of life. The study did not establish lesion regression or long-term effectiveness after food reintroduction and dietary personalization. Its supplied-food design also leaves uncertainty about effectiveness under ordinary living conditions. (pmc.ncbi.nlm.nih.gov)

Evidence for complementary therapies varies by intervention and outcome. A 2023 multicentre trial randomized 106 women to acupuncture or sham treatment for 12 weeks. Menstrual pain and quality-of-life measures improved more with acupuncture at week 12, but the between-group advantages were absent at week 24, after treatment had stopped. Non-menstrual pelvic pain and pain during intercourse did not differ significantly. In the 2026 telehealth trial, yoga improved menstrual symptoms and sexual pain but not the primary quality-of-life outcome. These results support outcome-specific interpretation rather than treating complementary therapies as a single effective category. (pubmed.ncbi.nlm.nih.gov)

Multidisciplinary services coordinate these approaches with gynecological treatment. NICE’s endometriosis guideline, originally issued in 2017, specifies access to a multidisciplinary pain-management service within gynecology services, and to a service with pelvic-pain expertise within specialist endometriosis centres. Specialist centres also require access to advanced gynecological surgery, colorectal surgery, urology, specialist nursing, imaging, and fertility services. NICE identifies persistent or recurrent symptoms, ineffective or intolerable initial treatment, and substantial interference with daily activities as grounds for gynecological referral. Assessment of support needs includes physical, psychosexual, emotional, work, and study concerns, allowing rehabilitation and psychological care to address functional problems alongside investigation and treatment of the underlying disease. (nice.org.uk)

Comorbidities and Long-Term Risks

Associations with autoimmune diseases are supported by observational studies, but they do not establish that endometriosis is itself an autoimmune disorder. In the Nurses’ Health Study II, Holly Harris and colleagues followed 114,453 women between 1989 and 2011. Laparoscopically confirmed endometriosis was associated with subsequent systemic lupus erythematosus and rheumatoid arthritis, with adjusted hazard ratios of 2.03 and 1.41, respectively. However, further adjustment for hysterectomy, removal of the ovaries, and analgesic use attenuated both associations, and their confidence intervals included no association. Shared hormonal or immune factors, treatment-related effects, and differences in healthcare use therefore remain possible explanations rather than established causal mechanisms. (pmc.ncbi.nlm.nih.gov) Evidence concerning allergic conditions is less secure. A 2012 hospital-based study comparing 501 women with surgically diagnosed endometriosis and 188 controls reported an odds ratio of 4.28 for a history of allergy, including excess medication allergy, allergic rhinitis, and asthma. Its retrospective, single-centre design limits generalization and cannot determine whether endometriosis preceded these conditions. (pubmed.ncbi.nlm.nih.gov)

The association with ovarian cancer is particularly marked for clear-cell and endometrioid carcinomas, although absolute risk remains low. In a Utah population-based cohort published in JAMA in 2024, Mollie Barnard and colleagues compared 78,476 women with endometriosis with 372,430 women without it. The adjusted hazard ratio for epithelial ovarian cancer was 4.20; histotype-specific estimates were 11.15 for clear-cell carcinoma and 7.96 for endometrioid carcinoma. Women with ovarian endometriomas and/or deep infiltrating disease had an adjusted hazard ratio of 9.66. Nevertheless, the adjusted excess amounted to approximately 9.9 ovarian cancers per 10,000 women over a mean follow-up of 12 years. These estimates describe one cohort and follow-up interval, not the probability that an individual lesion will become malignant. (doi.org)

Malignant transformation of endometriotic tissue is rare and is distinct from the broader epidemiological association with cancer. Molecular evidence supports a precursor relationship in some ovarian cancers: a 2010 study identified identical ARID1A mutations in clear-cell carcinoma and contiguous atypical endometriosis in two patients, but not in distant endometriotic lesions. (nejm.org) Such alterations are not sufficient evidence of impending malignancy. Michael Anglesio and colleagues reported in 2017 that 10 of 39 deep endometriotic lesions carried cancer-driver mutations, despite this lesion type rarely undergoing malignant transformation. The mutations were confined to the epithelial component in tested samples, demonstrating that molecular changes associated with cancer can also occur in clinically benign disease. (nejm.org)

Other documented associations include cardiovascular disease and disorders of mental health. A 2023 Ontario cohort study found an adjusted hazard ratio of 1.14 for hospitalization with a major cardiovascular event among women with endometriosis. Chronic inflammation and earlier menopause, including treatment-related loss of ovarian function, were proposed pathways, but the observational design could not establish causation. (pmc.ncbi.nlm.nih.gov) A United States insurance-claims study published in 2021 included 72,677 women with endometriosis and reported adjusted hazard ratios of 1.48 for clinically recognized depression and 1.38 for anxiety. Endometriosis-related pain and other chronic painful conditions were associated with these outcomes; the findings do not imply that pelvic symptoms have a psychiatric origin. (pubmed.ncbi.nlm.nih.gov)

These associations have not produced a universal programme of additional disease screening. The 2022 European Society of Human Reproduction and Embryology guideline states that cancer screening should not routinely exceed existing population-based programmes solely because of endometriosis. Additional assessment may be considered under local guidance when independent risk factors, such as a strong family history or a cancer-predisposing germline mutation, are present. The guideline also distinguishes symptom-driven investigation from screening: a pelvic mass after menopause is evaluated according to oncology guidance. Follow-up is individualized according to symptoms, disease severity, and previous treatment; evidence does not establish that regular long-term surveillance improves early detection of recurrence, complications, or malignancy. (academic.oup.com)

Social and Economic Burden

Delayed diagnosis prolongs the period in which symptoms interfere with education, employment, and family life without a recognized explanation. In a 2011 study led by Kelechi Nnoaham, 1,418 women undergoing laparoscopy were recruited at 16 centres in ten countries; among those diagnosed with endometriosis, the average interval from symptom onset to surgical diagnosis was 6.7 years, with much of the delay occurring in primary care. This measures time to surgical confirmation rather than necessarily time to first treatment. The World Health Organization identifies normalization of menstrual pain, limited public and professional awareness, variable symptoms, and restricted access to diagnostic services as barriers to recognition. These barriers operate both before presentation, when disabling symptoms are regarded as ordinary menstruation, and within the health system, when specialist assessment is difficult to obtain. (pubmed.ncbi.nlm.nih.gov)

Employment losses include absenteeism—time away from work—and presenteeism, reduced effectiveness while working. In Nnoaham and colleagues’ study, employed participants with endometriosis lost an average of 10.8 hours of work productivity per week, predominantly through presenteeism rather than absence. Consequently, sick-leave records alone capture only part of the occupational burden. The monetary value of weekly lost productivity ranged from US$4 in Nigeria to US$456 in Italy within the study, illustrating how wage levels affect economic valuations of similar functional limitations. These findings came from women attending centres for laparoscopy, not a representative sample of everyone with endometriosis, and should not be treated as a universal weekly loss. (pubmed.ncbi.nlm.nih.gov)

Disruption also extends beyond paid employment. Symptoms can prevent school attendance and participation in everyday activities, while painful intercourse and social isolation can affect relationships and quality of life. Educational research requires particular care because menstrual pain does not itself establish endometriosis. A 2025 study of the Australian Periods, Pain and Endometriosis Program, using questionnaires collected from 13,078 students assigned female at birth during July 2022–June 2023, found that 22.9% regularly missed school or work during their periods. This documents the educational burden in the population targeted by menstrual-health awareness programmes, but is not an estimate of absence attributable specifically to diagnosed endometriosis. (who.int)

Costs fall on healthcare providers, patients, households, and employers. Direct medical expenditure and patients’ out-of-pocket payments coexist with indirect losses from reduced work output and income. In Steven Simoens and colleagues’ 2012 study, 909 women with endometriosis-associated symptoms attending 12 referral centres in ten countries had an estimated average annual total cost of €9,579 per patient. Productivity losses averaged €6,298, approximately twice the healthcare costs of €3,113. The study enrolled patients with a relevant healthcare contact in 2008; its estimates describe that selected referral-care population and historical cost setting, rather than current national expenditure. Higher costs were associated with pelvic pain, infertility, greater disease severity, and more years since diagnosis. Household financial strain can additionally arise when treatment requires personal expenditure while symptoms reduce earnings. (pubmed.ncbi.nlm.nih.gov)

Patient advocacy has helped translate concerns about stigma and under-recognition into public-health policy. Australia’s July 2018 National Action Plan explicitly acknowledged contributions from patients, advocacy groups, clinicians, researchers, and parliamentarians, including the Australian Coalition for Endometriosis and its member organizations EndoActive, Endometriosis Australia, and Qendo. Its priorities combined awareness and education with clinical care and research, rather than treating publicity as a substitute for service provision. At the plan’s launch on 26 July 2018, Health Minister Greg Hunt announced A$200,000 for Jean Hailes for Women’s Health to deliver an online awareness campaign during Women’s Health Week that September. The plan also called for school-based education, campaigns co-designed with affected people, and coordinated clinical pathways so that increased awareness could be matched by access to care. (health.gov.au)

History of Research

Nineteenth-century descriptions emerged from microscopic pathology, before endometriosis and adenomyosis were clearly distinguished. Carl von Rokitansky’s 1860 account is frequently cited as an early description, although its terminology and pathological findings do not correspond unambiguously to the modern disease definition. In 1899, William Wood Russell described endometrial-like tissue in an ovary, interpreting it as aberrant Müllerian tissue. Thomas Stephen Cullen subsequently connected microscopic findings with clinical symptoms and anatomical distribution; his Adenomyoma of the Uterus appeared in 1908. These investigations initially grouped several conditions under “adenomyoma,” rather than consistently separating tissue within the uterine muscle from lesions outside the uterus. (applications.emro.who.int)

Early twentieth-century research increasingly relied on operative observations and examination of surgically removed tissue. John Albertson Sampson’s 1921 study of perforating hemorrhagic ovarian cysts related their endometrial-type lining to pelvic implants, initially proposing implantation following leakage from ovarian cysts. In 1927, he developed the better-known retrograde menstruation hypothesis: menstrual material could pass through the fallopian tubes into the peritoneal cavity, where viable endometrial tissue might implant. This was distinct from his earlier cyst-leakage explanation. Sampson also published a separate 1927 account proposing venous dissemination, illustrating that his research considered more than one route by which ectopic tissue could spread. (applications.emro.who.int)

Later research extended beyond anatomical displacement to the biological conditions permitting lesion survival. W. Paul Dmowski, Russell W. Steele, and G. F. Baker published Deficient cellular immunity in endometriosis in 1981, an experimental contribution to investigation of the immune system. In 1996, L. S. Noble, Evan R. Simpson, A. Johns, and Serdar E. Bulun reported aromatase expression in endometriotic tissue, providing molecular evidence for the possibility of estrogen production within implants. Their subsequent 1997 work showed that prostaglandin E2 stimulated aromatase expression in cultured lesion-derived stromal cells. Research also expanded to population-scale genetics: a 2023 genome-wide association meta-analysis involving 60,674 cases and 701,926 controls identified 42 genome-wide significant loci, comprising 49 distinct association signals. (pubmed.ncbi.nlm.nih.gov)

Standardized classifications supplied a common framework for comparing surgical findings. The American Fertility Society introduced its classification in 1979 and revised it in 1985; the American Society for Reproductive Medicine’s revision designated “1996” was published in May 1997. These systems organized observations of lesions and adhesions into severity stages, although anatomical staging remained distinct from measurement of symptoms and treatment outcomes. International guidance developed alongside these classifications: the European Society of Human Reproduction and Embryology (ESHRE) published a diagnostic and treatment guideline in 2005, followed by revisions in 2014 and 2022. (pmc.ncbi.nlm.nih.gov)

Large randomized controlled trials subsequently provided more standardized evidence for medical treatment. Hugh S. Taylor and colleagues reported the phase III Elaris Endometriosis I and II trials in 2017, randomizing 872 and 817 women, respectively, to two doses of the oral gonadotropin-releasing hormone antagonist elagolix or placebo for six months. Participants had surgically diagnosed disease and moderate or severe associated pain. The trials assessed dysmenorrhea and nonmenstrual pelvic pain separately, with response definitions incorporating analgesic use; both doses improved these endpoints relative to placebo, while producing dose-related hypoestrogenic effects. (nejm.org)

Diagnostic guidance documents record a substantial change in the role of laparoscopy. The 2005 ESHRE guideline treated laparoscopic visual inspection as the gold-standard investigation for definitive diagnosis. Its 2022 replacement no longer positioned surgery as a routine prerequisite: symptoms, examination, ultrasonography, and magnetic resonance imaging formed the initial assessment, with empirical treatment an accepted pathway. Laparoscopy remained an option when imaging was negative and empirical treatment unsuccessful or inappropriate. The guideline also explicitly retained the caveat that negative imaging does not exclude disease, particularly superficial peritoneal lesions. (academic.oup.com)

Open Questions and Future Directions

A central unresolved question is why endometrial-like tissue becomes established in some people but not others, and which mechanisms determine its subsequent survival. Research must distinguish factors that initiate lesions from those that maintain inflammation, vascular supply, fibrosis, and altered immune clearance. Genetic associations identify susceptibility pathways but do not, by themselves, establish the causal sequence. Longitudinal observations also challenge the assumption that untreated disease invariably progresses. In a 2023 study by Jure Knez and colleagues, 135 women with deep endometriosis managed without medical or surgical intervention underwent serial ultrasound examinations: 37% showed an increase in nodule number or size, 13% showed regression, and the remainder were stable. These findings concern a selected group with deep disease, not all lesion types; reliable predictors of progression or regression were not identified. (pmc.ncbi.nlm.nih.gov)

Non-invasive biomarkers are being investigated both for diagnosis and for distinguishing disease subtypes and predicting treatment response. A major difficulty is reproducibility: menstrual-cycle phase, hormonal treatment, specimen handling, lesion phenotype, and the choice of control population can change measured signals. In 2019, a technical verification and independent-validation study demonstrated the importance of testing biomarker models beyond their original discovery samples. The 2022 European Society of Human Reproduction and Embryology guideline consequently called for large, multicentre prospective studies with independent validation cohorts rather than adoption of promising discovery results alone. (onlinelibrary.wiley.com)

Salivary microRNAs illustrate both progress and remaining questions. A prospective multicentre validation study published in October 2025 examined 971 symptomatic patients aged 18–43, with an endometriosis prevalence of 77%. Its saliva-based signature achieved 97.3% sensitivity and 94.1% specificity; the negative predictive value was 91.3%. Diagnostic classification used imaging, laparoscopy, or both, and all controls underwent laparoscopy. The study, funded by the test developer Ziwig, provides evidence of performance in that symptomatic cohort. Whether comparable performance and clinical benefit extend to lower-prevalence populations, adolescents, and different diagnostic pathways remains a separate question; these results do not establish its suitability for population screening. (pubmed.ncbi.nlm.nih.gov)

Targeted treatment research seeks mechanisms beyond suppression of reproductive hormones, including inflammatory signalling and abnormal cellular metabolism. In a 2019 study, Andrew Horne and colleagues found that peritoneal mesothelial cells from patients with endometriosis exhibited increased glycolysis, reduced pyruvate dehydrogenase activity, and greater lactate production. Dichloroacetate, which inhibits pyruvate dehydrogenase kinase, reduced lactate secretion and stromal-cell proliferation in laboratory cultures and reduced lesion size in mice. These preclinical effects are not evidence of established clinical efficacy. The University of Edinburgh’s EPiC2 study is designed to investigate dose, painful symptoms, and adverse effects in 100 participants, with recruitment planned for late 2026, to inform a larger efficacy trial. (pure.ed.ac.uk)

Experimental models themselves remain a translational challenge. Rodent studies vary in tissue source, implantation site, induction procedure, hormonal exposure, and recipient strain, potentially producing different answers to the same therapeutic question. Lesion-size reduction also cannot substitute for demonstrated improvement in pain or fertility. The World Endometriosis Research Foundation’s EPHect programme published experimental-model standardisation protocols in 2025, covering homologous and heterologous rodent models, organoids, and pain behaviour. These methods aim to make experiments more reproducible and comparable while retaining models suited to different biological questions. (academic.oup.com)

Persistent pain requires outcomes that distinguish lesion activity from altered pain processing. A 2023 prospective surgical study associated higher preoperative Central Sensitization Inventory scores with worse postoperative pain, but the questionnaire measures symptoms rather than directly measuring central sensitization. Establishing predictive physiological measures remains an important research problem. Trial standardisation has also advanced: the 2020 international consensus study led by James Duffy defined overall pain, improvement in the most troublesome symptom, and quality of life as core outcomes for symptom-treatment trials. Consistent measurement of these outcomes, together with adverse events and patient satisfaction, permits comparison across interventions without equating anatomical lesion removal with recovery. (pmc.ncbi.nlm.nih.gov)

References

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36. Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosispmc.ncbi.nlm.nih.gov
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39. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosispubmed.ncbi.nlm.nih.gov
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41. Gene expression profiles separate endometriosis lesion subtypes and indicate a sensitivity of endometrioma to estrogen suppressive treatments through elevated ESR2 expressionpmc.ncbi.nlm.nih.gov
42. Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease.pubmed.ncbi.nlm.nih.gov
43. The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosispubmed.ncbi.nlm.nih.gov
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45. Endometriotic Peritoneal Fluid Stimulates Recruitment of CD4+CD25highFOXP3+ Treg Cellspmc.ncbi.nlm.nih.gov
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47. Alterations of CD4+T Cell Subsets in Blood and Peritoneal Fluid in Different Stages of Endometriosispmc.ncbi.nlm.nih.gov
48. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosispubmed.ncbi.nlm.nih.gov
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55. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosispubmed.ncbi.nlm.nih.gov
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