{"paper_id":"eea779d7-bdb9-45d3-afe4-18d37d776138","body_text":"npj | women's health Article\nhttps://doi.org/10.1038/s44294-025-00073-z\nUnveiling endometriosis hidden\ncomorbidities using a data-driven\napproach: a retrospective matched\ncohort study\nCheck for updates\nTamar Zelovich1 , Miriam Erenberg2,3,4, Vered Klaitman-Mayer3,4 &C h e nY a n o v e r1\nEndometriosis is a chronic, in flammatory gynecological disease with signi ficant comorbidities. This\nretrospective cohort study utilized a data-driven approach, analyzed a large UK electronic healthcare\ndataset and compared 8299 endometriosis patients with matched controls to explore and uncover\nnovel comorbidities. The analysis con firmed higher prevalence of known comorbidities such as\nmigraines and allergic disorders. Additionally, novel associations were identi fied, including acute\nlaryngitis, sinusitis, viral infections, and sciatica. For each newly identi fied comorbidity, we proposed\npotential mechanisms, suggesting that endometriosis triggers a cascade of events impacting systems\nbeyond the primary affected tissue, thereby reinforcing its characterization as a multi-system disease.\nThese findings underscore the necessity for further research into the pathophysiology of\nendometriosis and its mechanistic links to identified comorbid conditions. Moreover, they highlight the\nimportance of a multidisciplinary approach in the diagnosis and management of endometriosis and its\ncomorbidities, aiming to expand the available treatment strategies and improve patient outcomes.\nEndometriosis is a chronic, estrogen-dependent, in flammatory disease\naffecting 10% of females 1–3, with an average diagnostic delay of about\n12 years4–6. The disease is characterized by cells, similar to those of the inner\nuterine lining (endometrium), that grow outside the uterus, primarily in the\npelvic area, responding to hormonal signals like estrogen, which leads to\ninflammation, scarring, and adhesions. As a multi-system disease, endo-\nmetriosis presents a variety of symptoms\n2,7–10 and is associated with\nnumerous comorbidities7,11–16, including autoimmune diseases16–19,c a r d i o -\nvascular diseases20, allergies16,21,22, chronic-fatigue syndrome7,m i g r a i n e s8,23,\nand infertility24,25. Given the intricate and multifaceted nature of endome-\ntriosis, it is imperative to thoroughly investigate the increased risk of\ncomorbidities in individuals affected by this condition.\nTraditional approaches exploringthe relationship between endome-\ntriosis and its comorbidities are prima rily hypothesis-driven, targeting\nspecific, predefined conditions based on existing knowledge and clinical\nobservations\n7,8,21,22. While these studies have provided valuable insights, they\ninherently limit the discovery of previously unrecognized associations. To\naddress this gap and to identify new correlations, our study takes a com-\nplementary data-driven approach that analyzes a large-scale health dataset\nand explores associations between all recorded diagnoses and\nendometriosis, without prior assu mptions. This method allows for an\nextensive investigation into the broa der health implications of endome-\ntriosis, uncovering novel associations.\nW ed e l v ei n t oaf e we x a m p l e so fc o m o r b i d i t i e si d e n t ified by our ana-\nlysis and propose potential mechanismsto explain these associations. While\nspeculative, these mechanisms suggest that endometriosis may trigger a\ncascade of effects that extend beyond the pelvic region, potentially impacting\ndistant organs or systems. This reinforces the understanding of endome-\ntriosis as a multi-system disease. By demonstrating the multi-systemic\nnature of endometriosis, we aim to deepen our understanding of the disease\nand promote a more holistic approach to the treatment and management of\nendometriosis, ultimately improving the overall health and well-being of\nindividuals affected by the condition.\nResults\nOverview of data-driven analysis\nThe multi-event endometriosis cohort consisted of 11,848 individuals of\nwhich 8299 have been matched to non-endometriosis counterparts. Table1\nprovides an overview of the characteristics of the endometriosis and non-\nendometriosis cohorts. While the median age of participants in both cohorts\n1KI Research Institute, Kfar Malal, Israel. 2Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat Gan, Israel. 3Faculty of Health Sciences, Ben\nGurion University of the Negev, Beer Sheva, Israel. 4Maccabi Health Services South District, Beer Sheva, Israel. e-mail: tamizilo@gmail.com\nnpj Women's Health | (2025)3:30 1\n1234567890():,;\n1234567890():,;\n\nis 34 years, endometriosis patients had signi ficantly more annual visits\ncompared to non-endometriosis individuals (median of 10 [IQR: 7, 15]\nversus 6 [4, 10], respectively). This gap, likely a result of the ongoing medical\nattention required to monitor and treat a chronic and progressive condition,\nattests to the substantial impact of endometriosis on healthcare resource\nutilization.\nWe leveraged SNOMED-CT hierarchy (see Methods for further\ndetails) to identify the most speci fic (lowest-level) conditions that differ\nmeaningfully between cohorts, as th ese often offer the most actionable\ninsights for further investigation. Our data-driven analysis compared the\nprevalence of 4850 conditions and c ondition groups recorded for endo-\nmetriosis and control, non-endometriosis individuals. Of these conditions,\n973 (20.1%) have been signi ficantly ( q-value < 0.05) and meaningfully\n(SMD > 0.1) more prevalent in the endometriosis cohort than in the non-\nendometriosis one. The full results are available in Supplementary Data 1\nand Data 2. Here, we focus on four examples that support the validity of our\nanalysis by reproducing previously reported associations: migraines,fibro-\nmyalgia, allergic disorders, and reflux; and four examples that showcase its\nbreadth and highlight associations that, to the best of our knowledge, have\nnot yet been reported in prior research: sinusitis, laryngitis, herpes virus\ninfection, and sciatica—the latter being a known rare symptom. For each\nexample, we present the prevalence ofthe corresponding condition and its\nhierarchical descendants in the endo metriosis and non-endometriosis\ncohorts and assign measures of statistical significance and clinical meaning\nto their observed difference.\nRepresentative endometriosis comorbidities\nFirst, we examined the prevalence of headache disorders, a known\ncomorbidity of endometriosis, as shown in Supplementary Table S1 and\nFig. S1. Our analysis revealed a signi ficant difference between the\nendometriosis and non-endometriosis cohorts, with 29% and 17%\nexperiencing headache disorders, respectively. Delving deeper, we found\nthat vascular headaches, speci fically migraines\n8,23,26–29, were pre-\ndominant, affecting 24% of the endometriosis cohort and 13% of the\nnon-endometriosis cohort.\nSimilarly, and as has been previously demonstrated, the prevalence of\nfibromyalgia\n7,13,15 is signific a n t l yg r e a t e ri no u re n d o m e t r i o s i sc o h o r tt h a ni n\nthe non-endometriosis one (3.7% vs 1.6%, respectively; Supplementary\nTable S2 and Fig. S2). As a result, the ancestor condition group chronic pain\nis diagnosed in the endometriosis cohort more often than in the non-\nendometriosis cohort (5.9% vs 1.9%, respectively).\nTable 2,F i g .1, and Supplementary Fig. S3 compare the prevalence of\nallergic disorders\n7,11–16,21,22,24,30,31 and sinusitis (i.e., previously reported and\nunreported conditions, respectivel y) and their descendant conditions.\nAllergic disorders are signi ficantly more prevalent in the endometriosis\ncohort (24% versus 18% in the non-end ometriosis cohort), with allergic\nrhinitis contributing most to this difference (22% versus 15%, corre-\nspondingly). For sinusitis, the endometriosis cohort has a prevalence of 32%,\ncompared to 20% in the non-endometriosis cohort, with two meaningful\ncontributing descendant comorbidities: chronic sinusitis (25% versus 16%)\nand acute sinusitis (3.8% versus 1.8%).\nTable 3 and Supplementary Figs. S4-S5 present the top comorbidities\nfinding of esophagus and disorder of the larynx, as well as their descendants.\nFor the former condition group, as previously reported\n28,29,31–33,t h ed i f f e r -\nences between the endometriosis and non-endometriosis cohorts are 20% vs\n12%, respectively. The main contributors to these differences are esophageal\nreflux (12% vs 8%), esophagitis (6.3% versus 3.2%), and gastroesophageal\nreflux disease (4.5% vs 2.3%). The condition group disorder of the larynx\nwas diagnosed in 9.6% of individuals in the endometriosis cohort and 5.9%\nin the non-endometriosis cohort. The main contributor to this difference is\nacute laryngitis, with 8.2% vs 5%, respectively.\nNext, we present the prevalence o f conditions grouped under viral\ndisease in Table 4 and Supplementary Fig. S6, to explore the connection\nbetween endometriosis and the immune system. Our analysis revealed a\nstriking difference between the endometriosis and non-endometriosis\ncohorts, with 55% and 42% experiencing viral infections, respectively.\nDelving deeper, the top categories co ntributing to viral infections were\nherpesvirus infection (23% vs 17%), viral infection of the skin (15% vs 11%),\nviral respiratory tract infection (14%vs 11%), viral infection of the digestive\ntract (12% vs 8.2%), and diseases due to papillomaviridae (18% vs 13%). To\nemphasize the significance of these findings, it is important to note that 12\nother conditions (at the same level of hierarchy) were found to be not\nmeaningful clinically.\nFinally, we compare the prevalence of the condition group neuro-\npathy of lower limb and its descendant conditions in the matched cohorts\n(Supplementary Table S3 and Fig. S7). This group has been diagnosed in\n12% of endometriosis patients, but only 7.7% of non-endometriosis\nindividuals. The condition contributing most to this difference is sciatica\nwith rates of 11% and 7.1% in the endometriosis and non-endometriosis,\nrespectively.\nSensitivity analysis\nAs sensitivity analysis, we expanded the target cohort to include all females\nwith one or more endometriosis-related event and identi fied a matching\ncohort (by sex and year of birth); the characteristics of these single-event\ncohorts are shown in Supplementary Table S4. We then compared the\nprevalence of 7129 conditions and condition groups recorded in these\ncohorts; results for the conditions discussed above appear in Supplementary\nTables S5-S10, and full results can be found in Supplementary Data 1 and\nData 3. Overall, 603 (8.5%) conditions have been signi ficantly (q-value\n< 0.05) and meaningfully (SMD > 0.1) more prevalent in the endometriosis\ncohort than in the non-endometriosis one and, reassuringly, these condi-\ntions overlap with the ones identified in the multi-event analysis. We note\nthat, presumably, the smaller number (and percentage) of clinically\nmeaningful conditions identified in the single-event analysis attests to the\nlower disease severity in the corresponding patients, compared to the multi-\nevent cohort.\nFinally, we note that our analyses identi fied hundreds of conditions\n(522 or 10.8% and 1036 or 14.5% in the mul ti- and single-event analysis,\nrespectively) that are more prevalent in the non-endometriosis cohort, but\nonly “delivery normal” was both statistically significant and (borderline)\nmeaningful.\nTable 1 | Characteristics of the endometriosis and non-\nendometriosis cohorts in the IMRD-THIN database\nEndometriosis Non-\nEndometriosis\nP-valueb\nN 8299\nAge [years]a 34 (28, 39) 34 (28, 39) –\nBaseline period [years] a 4.2 (2.2, 7.7) 4.5 (2.4, 7.9) <0.001\nFollow-up period [years] a 6.6 (3.3, 11.2) 5.6 (2.3, 10.6) <0.001\nAverage annual visit count a 10 (7, 15) 6 (4, 10) <0.001\nCountry of residence\nEngland 5846 (70%) 5814 (70%) 0.6\nScotland 977 (12%) 1107 (13%) 0.002\nWales 936 (11%) 895 (11%) 0.3\nNorthern Ireland 540 (6.5%) 483 (5.8%) 0.066\nTownsend deprivation index\nDeprived\nc 2199 (27%) 2538 (32%) <0.001\nMissing 295 383\naMedian (interquartile range, IQR).\nbWilcoxon rank sum test.\ncTownsend deprivation index was dichotomized into a binary variable, with values ≥ 4 considered\ndeprived.\nBaseline and follow-up periods measure the time span of data available for individuals before and\nafter the index date, respectively; average annual visit count indicates the number of date-distinct\nmedical visit each individual had, divided by their data time span\nhttps://doi.org/10.1038/s44294-025-00073-z Article\nnpj Women's Health | (2025)3:30 2\n\nDiscussion\nOur study utilized a data-driven, hie rarchical approach to analyze com-\nmunity healthcare data, identifying comorbidities more prevalent in indi-\nviduals with endometriosis comparedt oam a t c h e dc o n t r o lc o h o r t .W e\nfound hundreds of statistically signi ficant and clinically meaningful\ncomorbidities, some of wh ich corroborate existing literature, thereby\naffirming the validity of our methodology, while others are novelfindings.\nNotably, our analysis revealed a significant association between endome-\ntriosis and migraines8,23,26–29 (SMD = 0.3), aligning with previous studies that\nsuggest overlapping factors such as chronic pain, hormonal fluctuations,\nTable 2 | Comparison of the prevalence of allergic disorders and sinusitis conditions in the endometriosis and matched control\ncohorts\nCondition Endometriosis Non-Endometriosis q-value SMD\nAllergic disorders\nAllergic disorder 2027 (24%) 1479 (18%) <0.001 0.2\n–Allergic disorder caused by substance 1397 (17%) 960 (12%) <0.001 0.2\n––Allergic rhinitis due to pollen 1396 (17%) 959 (12%) <0.001 0.2\n–IgE-mediated allergic disorder 1804 (22%) 1264 (15%) <0.001 0.2\n––Atopic IgE-mediated allergic disorder 1804 (22%) 1264 (15%) <0.001 0.2\n–––Allergic rhinitis 1804 (22%) 1264 (15%) <0.001 0.2\n–Allergic disorder of respiratory system 1812 (22%) 1286 (15%) <0.001 0.2\n––Allergic disorder of respiratory tract 1812 (22%) 1286 (15%) <0.001 0.2\n–––Allergic asthma 52 (0.6%) 39 (0.5%) 0.3 0.021\n–Non-IgE-mediated allergic disorder 44 (0.5%) 25 (0.3%) 0.05 0.036\n––Allergic contact dermatitis 44 (0.5%) 24 (0.3%) 0.037 0.038\n–Allergic disorder of skin 94 (1.1%) 74 (0.9%) 0.2 0.024\n––Allergic urticaria 51 (0.6%) 50 (0.6%) >0.9 0.002\n–Allergic conjunctivitis 304 (3.7%) 233 (2.8%) 0.006 0.048\n––Chronic allergic conjunctivitis 11 (0.1%) 11 (0.1%) >0.9 0\n––Atopic conjunctivitis 292 (3.5%) 218 (2.6%) 0.003 0.052\n–––Acute atopic conjunctivitis 32 (0.4%) 30 (0.4%) 0.9 0.004\nSinusitis\nSinusitis 2652 (32%) 1670 (20%) <0.001 0.3\n–Chronic sinusitis 319 (3.8%) 152 (1.8%) <0.001 0.12\n–Acute sinusitis 2096 (25%) 1288 (16%) <0.001 0.2\n––Acute frontal sinusitis 26 (0.3%) 18 (0.2%) 0.3 0.019\n––Acute maxillary sinusitis 66 (0.8%) 34 (0.4%) 0.004 0.05\n––Acute rhinosinusitis 20 (0.2%) 10 (0.1%) 0.13 0.028\n–Rhinosinusitis 20 (0.2%) 10 (0.1%) 0.13 0.028\n–Maxillary sinusitis 95 (1.1%) 49 (0.6%) <0.001 0.06\n–Frontal sinusitis 47 (0.6%) 26 (0.3%) 0.034 0.038\nHyphen length preceding each condition name indicates its SNOMED-CT hierarchical depth (relative to the top condition); descendants are shown up to depth 3. Rows are ordered by depth first search;\nmeaningful differences (SMD > 0.1) are shown in bold face. See Fig. 1 and Supplementary Fig. S3 for a graphical presentation.\n0\n0.1\n0.2\n0.3\n0.4\n0.5\nSMD\nAllergic\nurticariac\nAllergic rhinitis tis\npollendue to polleollen\nAllergic\nrhinitisn is\nAcute atopic\nctivitisconjun\nChronic allergicer\nconjunctivitiscti\nAllergic contactct\ndermatitisitis\nAllergic\nasthmah\nAllergic disorder\ncaused by substancey bstance\nAtopic IgE-mediatedA\nallergic disorderd\nIgE-mediatedIg\nallergic disordersorde\nAllergic disorderor\nof respiratory systemory\nNon-IgE-mediatedIg\nallergic disorderc \nAllergic\ndisorder of skindisor\nAtopic\nconjunctivitisun\nAllergic\ndisorder\nAllergic disorderd\nof respiratory tract\nAllergic\nconjunctivitisco\nFig. 1 | SNOMED-CT hierarchical presentation of allergic disorders and its descendant conditions, as shown in Table 2. Nodes are colored by standardized mean\ndifference (SMD); statistically signi ficant and clinically meaningful conditions (or condition groups) are highlighted in boldface.\nhttps://doi.org/10.1038/s44294-025-00073-z Article\nnpj Women's Health | (2025)3:30 3\n\nand inflammatory processes may contribute to this correlation. Addition-\nally, we confirmed a higher prevalence of fibromyalgia34 in endometriosis\npatients7,13,15 (SMD = 0.13), suggesting a complex interplay between these\nchronic pain conditions, potentially linked by mechanisms like central\nsensitization. Alternatively, it may indicate misdiagnosis of fibromyalgia\nwhen endometriosis is the underlying cause.\nOur research suggests a higher prevalence of allergic disorders in\nindividuals with endometriosis 7,11,16,21,22,24,30,31, potentially involving pro-\ninflammatory cytokines in the peritonealfluid, which stimulate histamine-\nreleasing factors, or activated mast cells in endometriosis lesions, con-\ntributing to hypersensitivity reactions\n35.\nIntriguingly, our study also unveiled a higher prevalence of sinusitis\namong individuals with endometriosis (SMD = 0.3). This finding aligns\nwith a previous survey-based research, indicating a link between endome-\ntriosis and sinusitis symptoms\n36 and can potentially be explained through\nthe association between endometriosi s and allergies: allergic symptoms\noften lead to nasal mucosal edema, i ncreased secretions, and impaired\nmucociliary function, potentially resulting in sinus obstruction which, in\nturn, may lead to stagnant debris that becomes infected. From an immu-\nnologic point of view, the presence of eosinophils that are more prevalent in\nallergic rhinitis flares can also cause chronic inflammation of the mucosa\neven without bacteria, and cause sinusitis37. High levels of IgE antibodies, a\nhallmark of allergic reactions, have also been associated with severe chronic\nsinusitis38.\nAnother comorbidity identified in our study was gastroesophageal\nreflux disease (GERD), which showed a notably higher prevalence among\nindividuals with endometriosis (SMD = 0.13), con firming a previously\nrecognized comorbidity28,29,31–33. A potential underlying mechanism sug-\ngests that estrogen may induce relaxation of the lower esophageal sphincter\nand thereby exacerbate gastroesophageal reflux symptoms39.A d d i t i o n a l l y ,\nimmune system dysregulation and in flammatory mediators, which play\ncritical roles in both endometriosis and GERD, may contribute to this\nassociation\n40.\nWe also uncovered a significant increase in the prevalence of laryngitis\nand acute laryngitis (SMD = 0.13), an association that has not been pre-\nviously studied. This observation ma y be related to the established link\nbetween endometriosis and GERD. Research has shown that GERD and\nlaryngopharyngeal reflux are closely connected conditions\n41.D i g e s t i v e\nenzymes, such as activated pepsin, can in flame the laryngopharyngeal\nmucosa, resulting in edema, erythema, and laryngeal damage 42,43.A d d i -\ntionally, acid in the lower esophagus may cause repeated neural stimulation\nof the vagus nerve, which subsequently activates mast cells. The degranu-\nlation of mast cells can lead to laryngeal in flammation and associated\nsymptoms\n44.\nTable 3 | Comparison of the prevalence of finding of esophagus and disorders of the larynx in the endometriosis and matched\ncontrol cohorts\nCondition Endometriosis Non-Endometriosis q-value SMD\nFinding of esophagus\nFinding of esophagus 1696 (20%) 1027 (12%) <0.001 0.2\n–Disorder of esophagus 936 (11%) 490 (5.9%) <0.001 0.2\n––Candidiasis of the esophagus 108 (1.3%) 66 (0.8%) 0.004 0.05\n–––Candidiasis of mouth and esophagus 108 (1.3%) 66 (0.8%) 0.004 0.05\n––Esophagitis 520 (6.3%) 264 (3.2%) <0.001 0.15\n–––Gastro-esophageal reflux dis w/ esophagitis 399 (4.8%) 195 (2.3%) <0.001 0.13\n––Gastroesophageal reflux disease 376 (4.5%) 188 (2.3%) <0.001 0.13\n––Laceration of esophagus 21 (0.3%) 11 (0.1%) 0.14 0.027\n–––Serosal tear of esophagus 21 (0.3%) 11 (0.1%) 0.14 0.027\n––Esophageal injury 21 (0.3%) 11 (0.1%) 0.14 0.027\n–Pain in esophagus 618 (7.4%) 430 (5.2%) <0.001 0.093\n––Heartburn 618 (7.4%) 428 (5.2%) <0.001 0.094\n–Finding of esophageal function 1034 (12%) 660 (8.0%) <0.001 0.15\n––Esophageal reflux finding 1034 (12%) 660 (8.0%) <0.001 0.15\n–––Gastric reflux 182 (2.2%) 115 (1.4%) <0.001 0.061\n–––Acid reflux 281 (3.4%) 138 (1.7%) <0.001 0.11\n–Lesion of esophagus 41 (0.5%) 19 (0.2%) 0.013 0.044\n–Swallowing symptoms 32 (0.4%) 24 (0.3%) 0.4 0.017\nDisorder of the larynx\nDisorder of the larynx 795 (9.6%) 492 (5.9%) <0.001 0.14\n–Laryngitis 754 (9.1%) 468 (5.6%) <0.001 0.13\n––Acute laryngitis 679 (8.2%) 412 (5.0%) <0.001 0.13\n–––Acute laryngotracheitis 35 (0.4%) 20 (0.2%) 0.088 0.031\n––Infective laryngitis 58 (0.7%) 40 (0.5%) 0.13 0.028\n–––Croup 44 (0.5%) 31 (0.4%) 0.2 0.023\n––Laryngotracheitis 103 (1.2%) 67 (0.8%) 0.015 0.043\n–––Laryngotracheobronchitis 52 (0.6%) 34 (0.4%) 0.1 0.03\n–Infection of larynx 58 (0.7%) 40 (0.5%) 0.13 0.028\nSee Table 2 for more info; meaningful differences (SMD > 0.1) are shown in bold face and borderline clinically meaningful (0.08 < SMD ≤ 0.1) entities are shown in italics. See Figs. S4 and S5 for a graphical\npresentation.\nhttps://doi.org/10.1038/s44294-025-00073-z Article\nnpj Women's Health | (2025)3:30 4\n\nPrevious studies observed transient vocal changes such as loss of high\ntones, pitch uncertainty, and submucous hemorrhages in singers before and\nduring menstruation, correlati ng these symptoms with hormonal\nfluctuations45. Given that endometriosis is also driven by hormonal changes,\nit is plausible that this condition could exacerbate menstrual-related vocal\ncord alterations, increasing the suscep tibility to laryngitis or vocal dys-\nfunction during critical phases of the menstrual cycle.\nAdditionally, we discovered a signi ficant increase in various viral\ninfections within the endometriosis cohort. These associations raise\nimportant questions about the role of the immune system in the patho-\ngenesis of endometriosis. Given that e n d o m e t r i o s i si sc h a r a c t e r i z e db ya n\naltered immune response, the presence of these viral infections may further\ncomplicate the immune landscape, potentially exacerbating symptoms or\ninfluencing disease progression.\nHormones, particularly estrogen, play a key role in modulating the\nimmune system\n46,47,i n fluencing immune responses by promoting the\nproliferation of immune cells and modulating cytokines production. This\nhormonal influence can lead to an altered immune environment, which\nmay contribute to the pathogenesis of endometriosis. Hormonal fluc-\ntuations throughout the menstrual cycle can further impact the immune\nsystem, potentially exacerbating inflammation and pain in affected indi-\nviduals. A deeper understanding of the intricate relationship between\nhormones, immune function, viral infections and endometriosis could\nyield valuable insights into the disease ’s underlying mechanisms. Future\nresearch should focus on elucidating the immunological factors involved\nand exploring how viral infections may interact with the disease ’s\ninflammatory process.\nA final example is sciatic pain, which clinically manifests as limiting\npain in the hip and gluteal region, radiating down the lower leg and foot, and\nmay include tingling and numbness within the affected nerve ’s\ndermatome\n48. Nerve involvement in endometriosis is uncommon, with the\nsacral plexus and sciatic nerve being the most frequently affected nerves49.\nDeep lesions within the nerve roots of the pelvis are rare, estimated to occur\nin approximately 0.1% of cases\n50. Our study reveals a much higher\nprevalence of sciatica at 11%, suggest ing additional pathophysiological\nmechanisms beyond direct neural involvement.\nCross-organ sensitization offers one possible mechanism, character-\nized by the propagation of noxious i nputs from a diseased organ to an\nadjacent, healthy organ through sensory projections into dorsal root ganglia\nand subsequent spinal cord integra tion. This phenomenon may lead to\nsensations of pain or discomfort in unaffected organs, anatomically distant\nfrom the origin of the pathology51,52. Alternatively, prolonged exposure to\nnoxious stimuli may trigger neural adaptations which eventually manifest in\ninstability and a hypertonic contractile state within the muscles53. Several\nstudies have demonstrated hypertonicity and spasms in the pelvic floor\nmuscles, lower limb muscles, and the piriformis muscle among individuals\nwith endometriosis\n54–56. These muscular changes, particularly the hyperto-\nnicity and spasms of the piriformis muscle, are implicated in the onset of\nsciatica symptoms57,58.\nThe coexistence of endometriosis with other conditions arises from\npathophysiological mechanisms, ass u g g e s t e di nt h i ss t u d y ,a sw e l la sa\ncomplex interplay of environmental f actors and genetic predisposition.\nComplementary genetic studies 20,23,28,33,40 suggest biological links and\npotential shared mechanisms between endometriosis and various comor-\nbidities, including migraine, cancer, and depression. Exploring the diverse\nmechanisms underlying endometrio sis and its comorbidities not only\ndeepens our understanding of endometriosis but may also pave the way for\nnew therapeutic strategies, by repurposing existing drugs for related\ncomorbidities\n23,59,60 or developing novel targeted therapies, ensuring that\ntreatment approaches address the root causes of comorbidities rather than\njust managing symptoms.\nOur study leverages a novel approach and a large routinely collected\ndataset to test links between endometriosis and all data-reported conditions.\nIt has, however, several limitations.First, the community data resource we\nanalyzed has incomplete informati on on surgeries and imaging, thus\nendometriosis diagnosis could not be ascertained. Note, however, that\nendometriosis misclassification is expected to reduce the difference between\ncases and controls. Second, conditions recorded during a typical multi-year\nTable 4 | Comparison of the prevalence of Viral diseases in the endometriosis and matched control cohorts; shown are\nconditions with SMD > 0.08 (meaningful and borderline meaningful)\nCondition Endometriosis Non-Endometriosis q-value SMD\nViral disease\nViral disease 4571 (55%) 3525 (42%) <0.001 0.3\n–Herpesvirus infection 1922 (23%) 1381 (17%) <0.001 0.2\n––Disease due to Alphaherpesvirinae 1707 (21%) 1234 (15%) <0.001 0.15\n–––Herpes simplex 814 (9.8%) 573 (6.9%) <0.001 0.11\n–––Varicella-zoster virus infection 1055 (13%) 734 (8.8%) <0.001 0.12\n–Viral infection of skin 1247 (15%) 936 (11%) <0.001 0.11\n––Verruca vulgaris of skin of lower extremity 695 (8.4%) 517 (6.2%) <0.001 0.083\n–––Verruca plantaris 695 (8.4%) 517 (6.2%) <0.001 0.083\n–Viral respiratory infection 1195 (14%) 873 (11%) <0.001 0.12\n––Viral upper respiratory tract infection 869 (10%) 677 (8.2%) <0.001 0.08\n––Influenza 385 (4.6%) 235 (2.8%) <0.001 0.1\n–Viral infection of the digestive tract 976 (12%) 684 (8.2%) <0.001 0.12\n––Viral enteritis 348 (4.2%) 216 (2.6%) <0.001 0.088\n–––Viral gastroenteritis 342 (4.1%) 207 (2.5%) <0.001 0.091\n––Viral gastritis 342 (4.1%) 207 (2.5%) <0.001 0.091\n–Disease due to Papillomaviridae 1470 (18%) 1103 (13%) <0.001 0.12\n––Disease due to Papilloma virus 1470 (18%) 1103 (13%) <0.001 0.12\n–––Human Papilloma virus infection 1470 (18%) 1103 (13%) <0.001 0.12\n–Disease due to Orthomyxoviridae 388 (4.7%) 237 (2.9%) <0.001 0.1\nSee Table 2 for more info; meaningful differences (SMD > 0.1) are shown in bold face, borderline clinically meaningful entities are shown in italics. See Fig. S6 f or a graphical presentation.\nhttps://doi.org/10.1038/s44294-025-00073-z Article\nnpj Women's Health | (2025)3:30 5\n\njourney to endometriosis diagnosis m ay be recognized, in retrospect, as\ninaccurate, and as information is not typically removed from healthcare\nrecords, these spurious reports may inflate ourfindings. The long time-span\nof patient data alleviates, to some extent, this concern. Finally, the closer and\nmore frequent monitoring of indivi duals with endometriosis by their\nhealthcare providers, compared to th eir non-endometriosis counterparts\n(see Table 1 and S1), may lead to surveillance bias. Our analysis primarily\nfocused on testable and treatable conditions, that are likely recorded for all\nsuffering individuals. Future work will focus on speci fic comorbidities\nidentified in this study and attempt to correct for these potential biases, e.g.,\nby considering the relative timing of endometriosis and each comorbidity\ndiagnosis.\nThis study significantly advances our understanding of the complex\nrelationships between endometriosis a nd its comorbidities, highlighting\ntheir contribution to the overall health burden of individuals with endo-\nmetriosis. To the best of our knowledge, this is the first data-driven inves-\ntigation that uses a large datase t to explore these associations\ncomprehensively, rather than focusing on specificp r e d efined conditions,\nbased on existing knowledge. We focused on several comorbidities—known\nand novel —and explored potential mechanisms explaining the links\nbetween endometriosis and these comorbidities. Future studies are required\nto further investigate the hun dreds of comorbidities identi fied in this\nresearch, particularly to elucidate the underlying mechanisms linking these\nconditions and endometriosis. Importantly, our research emphasizes that\nendometriosis is a multi-system disease capable of affecting distant organ\nsystems, potentially triggering a cascade of events that influence other areas\nof the body. This underscores the need for a comprehensive, multi-\ndisciplinary approach to the diagn osis, management, and treatment of\nendometriosis.\nMethods\nStudy design\nA retrospective, matched cohort study using routinely collected healthcare\ndata, standardized to the Observati onal Medical Outcomes Partnership\n(OMOP) Common Data Model (CDM) 61. The study adheres to the\nSTROBE (Strengthening the Reportingof Observational Studies in Epide-\nmiology) guidelines62.\nData sources\nIQVIA™ Medical Research Data (IMRD), formerly known as The Health\nImprovement Network (THIN), contains longitudinal non-identi fied\npatient electronic health records (EHR) collected from clinical systems of\ngeneral practitioners (GP) in the U K (incorporating data from THIN, a\nCegedim database). IMRD-THIN contains records of over 13 million\npatients, including demographic information, prescribed medication, vital\nsigns, diagnoses, lab tests, and additional information such as lifestyle fac-\ntors, BMI, and vaccinations as recorded in GP practices. It has been pre-\nviously shown to be representative of the UK population, in terms of\ndemographics and condition prevalence\n63.\nStudy population\nThe endometriosis cohort includes females aged 14–50 years who had at\nleast two endometriosis-related events—that is, a diagnosis of endometriosis\nor an endometriosis-related procedure (e.g., laparoscopic laser destruction\nof endometriosis)—in separate dates. Individuals in the endometriosis\ncohort were matched 1:1 to counterpar ts with no endometriosis-related\nevent, by birth year and sex. The index date of each matched pair is the date\nof the first endometriosis-related event. Eligible pairs were required to have\nat least 1 year of prior observation on the index date. Additionally, as\nsensitivity analysis, we repeated the comorbidity prevalence comparison in a\nless stringent endometriosis cohort, requiring a single related event.\nComorbidities\nWe took a data-driven approach and analyzed the prevalence of all con-\nditions recorded for individuals in th e cohorts of interest (rather than\nfocusing on a pre-specified, limited set of comorbidities). Moreover, we used\nthe hierarchical structure of Systematized Nomenclature of Medicine\nClinical Terms (SNOMED-CT), a standard OMOP vocabulary\n61,t og r o u p\ntogether conditions into broader categories64 (for example, Fig. 1 demon-\nstrates the hierarchical structure of allergies disorders and its descendants).\nWe then used OHDSI’s FeatureExtraction package65 to extract a feature for\neach medical condition (or condition group) recorded in the dataset, indi-\ncating whether individuals had a reco rd of the corresponding condition.\nConditions with less than ten individuals, in either the endometriosis or the\nmatched cohorts, were excluded from the analysis.\nStatistical analysis\nWe computed the prevalence of each condition (or condition group) in the\nendometriosis and the matched non-endometriosis cohorts and assessed its\nstatistical significance using Pearson’s Chi-squared test, corrected for multiple\ntesting with Benjamini and Hochberg’s false discovery rate method\n66 (q-value;\nvalues smaller than 0.05 were considered significant). The magnitude of the\ndifferences was reported using standardized mean difference (SMD), which\ncompares the difference in prevalence, in units of the pooled standard\ndeviation\n67 (values greater than 0.1 were considered meaningful67,a n d0 . 0 8t o\n0.1—borderline meaningful). We depict the results as hierarchical graphs,\nwith nodes representing conditions (or condition groups) and edges con-\nnecting ancestor (upper) and descendant (lower) entities.\nData availability\nAll comorbidity prevalence data are available in Supplementary Data 1. The\ndata that support the findings of this study are available to license from\nIQVIA, at https://www.iqvia.com/solutions/real-world-evidence/real-\nworld-data-and-insights.\nReceived: 15 December 2024; Accepted: 14 April 2025;\nPublished online: 13 May 2025\nReferences\n1. Parente Barbosa, C., Bentes De Souza, A. M., Bianco, B. &\nChristofolini, D. M. The effect of hormones on endometriosis\ndevelopment. 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FeatureExtraction: Generating Features for a\nCohort. https://github.com/OHDSI/FeatureExtraction (2024).\n66. Benjamini, Y. & Hochberg, Y. Controlling the False Discovery Rate: A\nPractical and Powerful Approach to Multiple Testing. J. R. Stat. Soc.\nSer. B57, 289–300 (1995).\n67. Austin, P. C. An introduction to propensity score methods for reducing\nthe effects of confounding in observational studies. Multivar. Behav.\nRes. 46, 399–424 (2011).\nAuthor contributions\nT.Z. and C.Y. developed the methodology, analyzed, and interpreted the\ndata. M.E. and V.K.M. provided the clinical interpretation of the results. All\nauthors were major contributors to writing the manuscript. All authors read\nand approved the final manuscript.\nCompeting interests\nThe authors declare no competing interests.\nEthical approval\nUse of IQVIA Medical Research Data (IMRD) was approved by the NHS\nLondon–Southeast Research Ethics Committee (REC reference: 18/LO/\n0441); in accordance with this approval, the study protocol was reviewed\nand approved by an independent Scientific Review Committee (SRC) of\nIQVIA Inc. (reference number: 23SRC021). Patients’ written informed\nconsent was waived by the London–Southeast Research Ethics Committee\nas the study used data from anonymized electronic health records.\nAdditional information\nSupplementary informationThe online version contains\nsupplementary material available at\nhttps://doi.org/10.1038/s44294-025-00073-z.\nCorrespondenceand requests for materials should be addressed to\nTamar Zelovich.\nReprints and permissions informationis available at\nhttp://www.nature.com/reprints\nPublisher’s note Springer Nature remains neutral with regard to\njurisdictional claims in published maps and institutional affiliations.\nOpen Access This article is licensed under a Creative Commons\nAttribution-NonCommercial-NoDerivatives 4.0 International License,\nwhich permits any non-commercial use, sharing, distribution and\nreproduction in any medium or format, as long as you give appropriate\ncredit to the original author(s) and the source, provide a link to the Creative\nCommons licence, and indicate if you modi fied the licensed material. You\ndo not have permission under this licence to share adapted material\nderived from this article or parts of it. The images or other third party\nmaterial in this article are included in the article ’s Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material\nis not included in the article’s Creative Commons licence and your intended\nuse is not permitted by statutory regulation or exceeds the permitted use,\nyou will need to obtain permission directly from the copyright holder. To\nview a copy of this licence, visit http://creativecommons.org/licenses/by-\nnc-nd/4.0/\n.\n© The Author(s) 2025, corrected publication 2025\nhttps://doi.org/10.1038/s44294-025-00073-z Article\nnpj Women's Health | (2025)3:30 8","source_license":"CC0","license_restricted":false}