{"paper_id":"e64cdf97-0ba4-4706-ae77-5a2c9eb3f5e2","body_text":"npj | women's health Review\nhttps://doi.org/10.1038/s44294-026-00128-9\nRethinking endometriosis recurrence:\nfrom clinical challenge to biological\nopportunity\nCheck for updates\nCarina Masferrer-Ferragutcasas1, Raquel Delgado-Gil1,2 &E v aC o l a s1,2\nEndometriosis postoperative recurrence remains a major clinical challenge and a poorly understood\nbiological process, directly impacting long-term care. This narrative review integrates current\nknowledge on recurrence de finitions, patterns, risk factors, and prevention strategies; potential\npredictive models and candidate biomarkers; and surgical and biological contributors to recurrence.\nWe propose that recurrent endometriosis represents a valuable model that may help uncover disease\nmechanisms and guide future research toward personalized, mechanism-based management\nstrategies.\nEndometriosis is a complex, estrogen-dependent in flammatory disorder\nthat affects approximately 10% of women of reproductive age1. Character-\nized by pelvic pain, infertility, and fatigue, it has a profound impact on\npatients’ physical, reproductive, and emotional health 2.D e s p i t ei t sh i g h\nprevalence, there is no definitive or causal treatment for endometriosis, as\nthe pathophysiology of the disease remains poorly understood. As a result,\nendometriosis is considered a chronic condition that requires long-term,\nmultidisciplinary management.\nCurrent therapeutic approaches are symptomatic and include medical\ntreatments (mainly nonsteroidal anti-inflammatory drugs and hormonal\nsuppression) and/or surgical removalof lesions. Since both hormonal and\nsurgical therapies seem to achieve comparable pain improvement overall3,\nthere has been a growing tendency to wards a less invasive management,\nreserving laparoscopic resection for patients who decline or fail to respond\nto medical treatments, in cases involving large endometriomas (>5 cm), or\nwhen ultrasoundfindings suggest malignancy or risk of obstruction in the\nurinary or intestinal tract, among others\n4–6.\nWhile surgical resection of endometriosis lesions can provide symp-\ntom relief for many patients, postoperative recurrence is common, with pain\nrelapse generally reported in 20–26% of patients within the first year after\nsurgery7–9, and lesion reappearance rates ranging from 12 to 29%, 1 and 2\nyears postoperatively, respectively7,9,10. The term postoperative recurrence is\ngenerally used across the literature to refer to both events indistinctively,\nwhich adds to the variability of reported outcomes. When integrating these\nheterogeneous definitions, the estimated mean 2-year recurrence of 21.5%\n11.\nThe high rates of postoperative recurrence of both pain symptoms and\nendometriosis lesions are importantcontributors to the complexity of the\nlong-term management of endometriosis11,12. In fact, recurrence has been\nidentified as a top research priority by both patients and healthcare\nprofessionals, who call for more effective strategies to prevent disease pro-\ngression following treatment13,14.\nAlthough this issue is widely acknowledged in clinical practice, it has\nreceived little attention and is frequently framed as surgical failure, rather\nthan as a biological phenomenon worth investigating. As a result, the\nmechanisms that drive disease recurrence remain poorly understood. To\nimprove long-term outcomes, it is essential to understand why endome-\ntriosis lesions and symptoms reappear in some individuals despite see-\nmingly adequate treatment, and wha t biological factors underlie such\npredisposition.\nThis review aims to (1) provide an updated and integrative synthesis of\nthe literature on endometriosis recurrence definitions, rates, and risk factors;\n(2) explore the biological processes that may contribute to lesion recurrence,\nin light of current knowledge on the pathogenesis of endometriosis; and (3)\npropose recurrent endometriosis as aconceptual model to gain insights into\ndisease mechanisms, while outlining future directions for translational\nresearch.\nConceptual and clinical heterogeneity in endometriosis\nrecurrence definitions\nDespite being an important concern in endometriosis care, there is currently\nno standardized de finition of postoperative recurrence. In a conceptual\nsense, recurrence refers to the return of disease after a period of remission. In\nendometriosis, recurrence can describe two distinct phenomena: the\ndetection of endometriotic lesions after complete surgical resection, which\nrepresents the reappearance of the disease itself and is considered the most\nobjective and biologically informative endpoint, or the return of\nendometriosis-associated pain symptoms, which is more relevant to patient\nmanagement.\n1Group of Biomedical Research in Gynaecology, Vall d ’ Hebron Institute of Research (VHIR), CIBERONC, Barcelona, Spain. 2Department of Biochemistry and\nMolecular Biology, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain. e-mail: eva.colas@vhir.org\nnpj Women's Health |             (2026) 4:4 1\n1234567890():,;\n1234567890():,;\n\nAlthough they often overlap, lesion regrowth and symptom relapse are\nnot always equivalent15–17. This lack of correlation is generally reflected in the\nrecurrent rates reported for both outcomes, where pain recurrence is typi-\ncally higher than lesion recurrence. For example, in a retrospective study of\n115 patients with deep infiltrating endometriosis (DIE), relapse of pain 3\nand 5 years after surgery was 20.5 and 43.5%, and the lesion recurrence rates\nwere 9 and 28%, respectively\n18. Similarly, another retrospective study of 401\npatients reported pain recurrence at 34% and lesion recurrence detected by\ntransvaginal ultrasonography (TVUS) at 16%, both within a median follow-\nup of 24 months\n19.\nThis highlights that endometriosis-associated symptoms can be driven\nby pathways unrelated to anatomical lesion regrowth, such as central sen-\nsitization, pain comorbidities, or factors secondary to the surgical procedure\nitself, including fibrosis or the formation of new adhesions 1,20,21.C e n t r a l\nsensitization refers to an increased exc itability of central pain pathways,\nleading to pain amplification and persistence even in the absence of per-\nipheral noxious stimuli. This mechanism has been associated with poor\nresponse to surgery and hormonal therapies, and may contribute to post-\noperative pain recurrence in the absence of visible disease\n20.A d d i t i o n a l l y ,\npersistent symptoms can be related to undetected peritoneal implants not\nremoved during surgery\n22. It is also worth noting that studies often fail to\ndifferentiate between symptom persist ence (indicating initial treatment\nfailure) and relapse (the return of pain after a period of relief, potentially\nlinked), further complicating the understanding of these outcomes from a\npathophysiological standpoint.\nConversely, lesion reappearance does not always entail symptom\nrelapse: retrospective studies on recurrent endometriomas have reported\nthat 24-30% of patients with imaging-con firmed recurrence remained\nasymptomatic\n19,23. Therefore, recurrence should be considered a multi-\ndimensional phenomenon involving both lesion regrowth and symptom\nreappearance, which likely involve distinct underlying mechanisms\n24.\nMeasuring recurrence in endometriosis: proxies and\nmethodological variability\nThe lack of consensus in de fining, assessing, and consequently\nreporting recurrence is a persistent methodological challenge fre-\nquently highlighted by systematic reviews and meta-analyses\n25–27.\nNotably, Ceccaroni et al. 28 systematically compiled the de finitions used\nacross observational studies and clini cal trials, illustrating this hetero-\ngeneity and the limited comparabilit y across studies. There is currently\nno commonly agreed, well-de fined, and consistently applied set of\noutcomes to evaluate postoperativ er e c u r r e n c ei ne n d o m e t r i o s i s .\nInstead, a diverse range of clinical and imaging-based assessment cri-\nteria are used, each with its own limitations.\nImaging modalities such as TVUS and magnetic resonance imaging\n(MRI) are the most widely used tools to assess lesion reappearance. As in the\ndiagnostic process, the accuracy of these tools depends on subtype, lesion\nlocalization and size, and operator expertise\n29.S i n c eb o t hT V U Sa n dM R I\nare highly reliable in detecting ovarian endometriosis, it is the most studied\nsubtype in terms of postoperative recurrence, although specificc y s ts i z ec u t -\noffs and sonographic features re main variable between studies 27,30,31.A\nrecent meta-analysis by Veth et al.31 has demonstrated a progressive increase\nin endometrioma recurrence risk over time, with rates of 4% at 3 months\npost-surgery, 14% at 6 months, 17% at 17 months, and 27% at 24 months\nwhen not using postoperative hormonal treatment.\nHowever, as in diagnosis, a negative imaging result does not necessarily\nrule out the presence of disease, so histological con firmation of endome-\ntriotic lesions is the most rigorous approach to confirm lesion recurrence,\nalthough highly invasive and unsuit able for longitudinal assessment.\nAdditionally, repeated surgeries are generally discouraged due to the asso-\nciated loss of ovarian reserve, poten tial surgical complications, and the\nformation of new adhesions\n4,32–34. Consequently, not all recurrence cases are\nmanaged surgically, and recurrence rates might be underestimated.\nBeyond imaging, the longitudinal assessment of endometriosis recur-\nrence is further limited by the absence of a reliable, non-invasive biomarker\nthat could serve as a dynamic indicator of disease activity over time. In a\nchronic condition likeendometriosis, where repeated surgical verification is\nneither feasible nor ethical, such a biomarker would be key to monitoring\nrecurrence and disease progression.\nSymptom recurrence is usually assessed through patient-reported\noutcomes, primarily pain scores. Whilethese are clinically meaningful, they\nare inherently subjective and prone to reporting and attrition bias, especially\nin long-term follow-up studies 7.D e finitions vary widely: some studies\ndichotomize pain as“present” or “absent,” while others use changes in visual\nanalog scale scores or relative improvement thresholds35.\nBoth lesion and symptom recurrence can prompt subsequent changes\nin clinical management, and many retrospective studies rely on reoperation\nor starting a second-line hormonal therapy as indirect indicators of\nrecurrence\n25,36,37. Although practical, these proxies cannot distinguish\nbetween treatment failure and true recurrence after remission and usually\ndo not con firm the presence of lesions histologically, so they should be\ninterpreted carefully.\nThe inconsistent use of diverse outcomes to assess recurrence across\nstudies severely limits comparability and complicates the interpretation of\nrecurrence rates, risk factors, and therapeutic outcomes. Moreover, recur-\nrence estimates are influenced by cohort characteristics, disease subtype and\nseverity, surgical technique, follow-up length, and the use (or absence) of\npostoperative hormonal therapy. Col lectively, this variability not only\nexplains the wide range of recurrence rates reported in the literature\n11 but\nalso limits our understanding of the b iological and clinical dynamics of\nrecurrence.\nRisk factors for lesion and symptom recurrence\nUnderstanding which factors predi spose patients to postoperative\nrecurrence is essential to identify p atients at higher risk of recurrence,\nto ultimately guide individualized management. However, as\nemphasized above, the substantial heterogeneity in how recurrence is\ndefined across the literature complicates the interpretation and com-\nparison of findings. Table 1 summarizes the main clinical, surgical,\nand patient-related determinants in fluencing the likelihood of recur-\nrence reported in the literature, dis tinguishing between risk factors for\nlesion and symptom recurrence, and including studies using broader\ndefinitions as well. Because imaging reliably detects ovarian endo-\nmetriomas, it has naturally become the most extensively studied\nsubtype in terms of recurrence, and this predominance should be\nconsidered when interpreting risk factors.\nNevertheless, several consistent patterns can be identified across stu-\ndies. Younger age at the time of surgery is associated with a higher risk of\nrecurrence\n38. Although the absolute differences in mean age between\nrecurrent and non-recurrent groups are small, this consistent trend9,18,19,39–51\nsuggests a biologically meaningful eff ect likely related to longer lifetime\nestrogen exposure. Preoperative pain symptoms, including dysmenorrhea\nand chronic pelvic pain, have been linked to both lesion\nreappearance\n19,43,52–56 and pain persistence and recurrence 19,47,57, possibly\nreflecting pre-existing inflammatory and nociplastic factors not resolved by\nsurgery.\nDisease-related factors such as extensive adhesions 49,54,58,59,l a r g e r\ncysts42,54,55,60–65, coexistent deep infiltrating lesions61,66 and adenomyosis47,66\nor higher preoperative revised AmericanS o c i e t yf o rR e p r o d u c t i v eM e d i c i n e\n(rASRM) scores18,19,24,39,41,42,48,50,58,59,67–70 are associated with increased lesion\nrecurrence risk mainly, likely due to incomplete lesion resection.\nSurgical approach and postoperative care also impact outcomes.\nConservative surgery is widely associated with earlier\nrecurrence\n25,41,48,52,58,71–74. Conversely, the use of postoperative hormonal\ntherapy has been consistently fou nd as a protective factor against\nrecurrence9,26,50,69,70,75–77. However, an insuf ficient duration or poor adher-\nence to treatment over the long term can diminish the protective effects of\nthese therapies\n10,44,61,74,78–82. Similarly, achieving pregnancy after surgery\nappears to lower recurrence risk, likely due to prolonged ovarian\nsuppression\n19,40,41,44,48,51,56,59,63,67,70,81,83.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 2\n\nThe role of postoperative hormonal treatment in\nrecurrence prevention and management\nAmong the risk factors for endometr iosis recurrence mentioned above,\nperiods of ovarian suppression or amenorrhea, whether pharmacologically\ninduced or occurring during pregnancy and lactation, are associated with a\nreduced risk of both lesion and symptom recurrence. In this hypo-\nestrogenic environment, the growth of residual lesions is suppressed, new\nlesion development is prevented, and associated pain symptoms persisting\nor reappearing after surgery are controlled.\nPostoperative medical therapy represents a cornerstone in endome-\ntriosis recurrence prevention. Systematic reviews and meta-analyses have\nreported that the risk of lesion reappearance is reduced by 59 –70%, and\nsymptom recurrence by 30% after 12 months, if using hormonal treatment\npostoperatively, compared to surgery alone\n7,26. Comparative studies asses-\nsing different hormonal agents and regimens for recurrence prevention have\nreported heterogeneous results 26,60,79,82,84–87. Variability in study design,\ninclusion criteria, treatment duration, adherence, and f ollow-up compli-\ncates comparisons and limits definitive conclusions. Overall, no hormonal\nagent has been consistently demonstrated to be better than others,\nsuggesting that the protective effect primarily derives from sustained\novarian suppression rather than from a specific drug class. In line with this, a\nrandomized controlled trial by Seracchioli et al.10 demonstrated that con-\ntinuous oral contraceptive use was associated with lower rates of dysme-\nnorrhea relapse and severity compared to cyclic use. Accordingly, the\nEuropean Society of Human Reproduction and Embryology guideline on\nendometriosis recommends the long-term use of continuous combined oral\ncontraceptives or levonorgestrel-releasing intrauterine systems following\nlaparoscopy for the prevention of dysmenorrhea relapse\n6.\nDespite its bene fits, hormonal therapy is not without limitations.\nSymptom relapse occurs shor tly after discontinuation60, and recurrence\nrates among patients treated for less than 12 months are similar to those of\nuntreated individuals within 1–2y e a r s\n88.T h i ss u g g e s t sap r e d o m i n a n t l y\nsuppressive effect, requiring sustained use to maintain bene fit. However,\nlong-term use is associated with relevant side effects and is not appropriate\nfor patients with immediate pregnancy desire, so discontinuation rates are\nhigh\n89–91. Additionally, treatment failure in this context may be amplified by\nthe fact that patients referred to surgery may be less responsive to medical\ntherapy as a first-line approach\n4,92.\nTable 1 | Risk factors for endometriosis postoperative recurrence\nRisk factor References\nLesion recurrence Symptom recurrence Other de finitions\nPatient-related risk factors\nYoung age Coccia et al. 19\nOMA: Liu et al. 39, Sengoku et al. 40, Yuan et al. 41, Moini\net al.42, Han et al. 43, Choi et al. 44\nDIE: Nirgianakis et al. 45\nVignali et al. 18, Vercellini et al. 9,\nUccella et al. 46, Yang et al. 47\nBusacca et al. 48, Yun\net al.49\nOMA: Su and Xie 50\nDIE: Fedele et al. 51\nPreoperative pain Coccia et al. 19, Zhong et al. 52\nOMA: Chon et al. 53, Küçükbas et al. 54, Yu et al. 56, Han\net al.55\nCoccia et al. 19, Yang et al. 47 Ngernprom et al. 74\nOMA: Li et al. 83, Huang\net al.67\nDisease-related risk factors\nPresence of adhesions Holdsworth-Carson et al. 58\nOMA: Porpora et al. 59, Küçükbas et al. 54\nPorpora et al. 59 Yun et al. 49\nLarger cyst size a OMA: Koga et al.63, Moini et al.42, Küçükbas et al.54, Lee\net al.62, Candiani et al. 61, Han et al. 55\nOMA: Saleh et al. 64,\nBusacca et al. 65\nBilaterality of cysts OMA: Han et al. 55 Yun et al. 49\nOMA: Su and Xie 50\nCoexistent adenomyosis OMA: Sun et al. 66 Yang et al. 47\nHigher preoperative staging (rASRM or\nrAFS scores)\nBusacca et al. 48, Coccia et al. 19, Holdsworth-Carson\net al.58\nOMA: Liu et al. 39, Takamura et al. 69, Porpora et al. 59,\nHayasaka et al. 70, Moini et al. 42, Yuan et al. 41, Tobiume\net al.24, Li et al. 68\nLiu et al. 39 OMA: Huang et al. 67,S u\nand Xie50\nManagement-related risk factors\nConservative surgical technique Zhong et al. 52, Holdsworth-Carson et al. 58\nOMA: Yuan et al. 41\nDIE: Bendifallah et al. 71, Xu et al. 72\nAfors et al. 73 Busacca et al. 48\nOMA: Ngernprom et al. 74\nPrior surgery for endometriosis OMA: Porpora et al. 59 Fedele et al. 51, Porpora et al. 59 Busacca et al. 65\nDIE: Fedele et al. 51\nAbsence, poor adherence, or insuf ficient\nduration of postoperative hormonal therapy\nVercellini et al. 9\nOMA: Vercellini et al. 79, Takamura et al. 69, Seracchioli\net al.78, Hayasaka et al. 70, Seong et al. 80, Choi et al. 44\nDIE: Yela et al. 75\nVercellini et al. 76, Sesti et al. 77,\nSeracchioli et al.10, Candiani et al.61\nNgernprom et al. 74, Kwok\net al.81\nOMA: Del Forno et al.82,S u\nand Xie50\nPregnancy and/or breastfeeding\n(protective)\nCoccia et al.\n19\nOMA: Koga et al. 63, Porpora et al. 59, Hayasaka et al. 70,\nSegonku et al. 40, Yuan et al. 41, Yu et al. 56, Choi et al. 44\nFedele et al. 51, Porpora et al. 59 Busacca et al. 48, Kwok\net al.81\nOMA: Li et al. 83, Huang\net al.67\nDIE: Fedele et al. 51\nLesion recurrence refers to radiologic or surgical con firmation of lesion reappearance; symptom recurrence refers to postoperative pain relapse; other de finitions include studies reporting recurrence\nthrough mixed (e.g., lesion and/or pain recurrence) or unspeci fied criteria (e.g., management change). Within each cell, studies including all endometriosis subtypes are listed first, followed by those\nspecifically focused on ovarian endometriomas (OMA) or deep in filtrating endometriosis (DIE).\nOMA endometrioma, DIE deep infiltrating endometriosis, rASRM revised American Society for Reproductive Medicine, rAFS revised American Fertility Society.\naLarger cyst size: De fined variably across studies: some report larger mean cyst diameters in recurrent cases (Koga et al. 63; Küçükbas et al. 54; Moini et al. 42), while others apply size cut-offs of 5 cm (Han\net al.55; Candiani et al. 61) or 5.5 cm (Lee et al. 62).\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 3\n\nBeyond adherence and tolerance, growing evidence suggests that some\npatients may develop resistance to postoperative hormonal therapy, parti-\ncularly progestins93,94.T h i sm a yr eflect lesion-level progesterone resistance\nor, in the case of persistent pain, the predominance of centrally mediated\nmechanisms that are less responsive to hormonal suppression. Because\nhormonal therapy primarily acts on le sion-related, peripheral pain path-\nways, its benefit may be limited in such patients.\nTherefore, long-term managemen t of endometriosis recurrence\nremains an important challenge. As mentioned above, reoperation is\nincreasingly discouraged due to th e associated risks and the fact that a\nhistory of previous endometriosis-related surgeries is itself a risk factor for\nfuture recurrence\n51,59,65,95,96, creating a vicious cycle that further complicates\nlong-term management97.\nThese challenges highlight the need to identify new preventive and\ntherapeutic strategies to manage endometriosis recurrence, ideally beyond\nhormonal suppression. To develop such strategies and better tailor the long-\nterm management of endometriosis, itis essential to better understand the\nbiological basis of recurrence and to develop tools to identify patients at\nhigher risk.\nPredicting recurrence: clinical models and emerging\nbiomarkers\nAccurately predicting postoperative recurrence in endometriosis is key to\nadvancing personalized care and guiding long-term treatment strategies. A\nlimited number of predictive models have been developed based on clinical,\nsurgical, and molecular variables, but their performance and applicability\nTable 2 | Potential biomarkers for endometriosis postoperative recurrence published in the literature\nBiomarker Reference Sample N (R/NR) Measurement\ntechnique\nRecurrence assessmenta Follow-up\n(months)b\nExpression\n(p value)\nlncRNA UCA1 Huang\net al.\n100\nSerum 98 (28/70) qRT-PCR Pelvic exam 24 ↓ (p < 0.05)\nlncRNA\nLINC01465\nSong\net al.101\nSerum 80 (40/40) qRT-PCR Pelvic exam 36 ↓ (p < 0.01)\nmiR-20a Abdoli\net al.103\nEndometrioma\ntissue\n20 (9/11) qRT-PCR TVUS or MRI 24 ↑ (p < 0.001)\nNANOG Abdoli\net al.\n103\nEndometrioma\ntissue\n20 (9/11) qRT-PCR TVUS or MRI 24 ↑ (p < 0.01)\nlncRNA H19 Liu et al.\n104 Endometrioma\ntissue\n104\n(22/82)\nqRT-PCR At least two of the following:\n• Symptomatic\n• Pelvic exam\n• CA125 > 35 U/mL\n• Ultrasonography\n24 ↑ (p = 0.001)\nEV-LGMNP1 Sun et al. 102 Serum 52 (15/37) qRT-PCR Pelvic exam or CA125 > 35 U/mL or\nUltrasonography\n46 ± 13 ↑ (p < 0.001)\nCOX2 Yuan\net al.105\nEndometrioma\ntissue\n109\n(53/56)\nIHC Ultrasonography or Laparoscopy 32 ↑ (p < 0.001)\nNFkB-p65 Shen\net al.\n106\nEndometrioma\ntissue\n109\n(53/56)\nIHC TVUS or Laparoscopy 32 ↑ (p = 0.001)\nHan et al.\n111 Endometrioma\ntissue\n134\n(27/107)\nIHC TVUS 24 ↓ (p < 0.05)\nPRB Shen\net al.106\nEndometrioma\ntissue\n109\n(53/56)\nIHC TVUS or Laparoscopy 32 ↓ (p = 0.01)\nHan et al.\n111 Endometrioma\ntissue\n134\n(27/107)\nIHC TVUS 24 ↑ (p < 0.05)\nTarumi\net al.112\nEndometrioma\ntissue\n132\n(36/96)\nIHC Ultrasonography or MRI 24 ↓ (p < 0.01)\nROBO1 Shen\net al.\n107\nEndometrioma\ntissue\n88 (43/45) IHC TVUS or Laparoscopy 32 ↑ (p < 0.05)\nSLIT Shen\net al.\n107\nEndometrioma\ntissue\n88 (43/45) IHC TVUS or Laparoscopy 32 ↑ (p < 0.01)\nKi-67 Yalcin\net al.\n113\nEndometrioma\ntissue\n50 (24/26) IHC TVUS 6 ↑ (p < 0.01)\nE-cadherin Wu et al.\n114 Endometrioma\ntissue\n49 (34/15) IHC NA Max. 80 ↓ (p < 0.05)\nMMP9 Wu et al. 114 Endometrioma\ntissue\n49 (34/15) IHC NA Max. 80 ↑ (p = 0.001)\nEMMPRIN Wu et al. 114 Endometrioma\ntissue\n49 (34/15) IHC NA Max. 80 ↑ (p < 0.05)\nuPA Wu et al. 114 Endometrioma\ntissue\n49 (34/15) IHC NA Max. 80 ↑ (p < 0.05)\nS100A8 Zhu et al. 115 Endometrioma\ntissue\n50 (25/25) IHC Symptomatic\nTVUS\n24 ↑ (p < 0.01)\nS100A9 Zhu et al. 115 Endometrioma\ntissue\n50 (25/25) IHC Symptomatic\nTVUS\n24 ↑ (p < 0.01)\nR recurrent, NR non-recurrent, TVUS transvaginal ultrasonography, IHC immunohistochemistry, qRT-PCR real-time quantitative PCR, NA not reported.\naSymptomatic refers to the return of pelvic pain to the same or higher intensity levels as before surgery, after an initial postoperative relief.\nbFollow-up refers to the minimum time of observation required before patients were classi fied in recurrent and non-recurrent, unless otherwise speci fied.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 4\n\nremain modest, partly due to the variable criteria used to define recurrent\npatients.\nMost clinically based models rely on established risk factors, such as\nadhesions or high rASRM scores, and their use primarily relates to the risk of\nlesion recurrence, since they re flect the anatomical severity of endome-\ntriosis. For example, Huang et al. 67 proposed a logistic regression model\nusing rASRM >70 as a single predictor (AUC = 0.79), but its applicability is\nconstrained by a short follow-up and a strict recurrence definition, requiring\nlesion recurrence (detected by TVUS and pelvic exam), high CA125 levels,\nand symptom return. Broader criteria are used by Su and Xie\n50,w h oc o m -\nbined clinical and inflammatory parameters and achieved higher accuracy\n(AUC = 0.895) in detecting symptomatic recurrence, supported by either\nhigh CA125 levels, pelvic exam, or TVUSfindings. However, the inclusion\nof CA125 as a predictor in these models limits their reliability, given its low\nspecificity and poor sensitivity in early-stage disease\n28,98, and considering\nthat recent clinical guidelines discourage its use for detecting endometriosis\nin routine practice99. Lastly, a model by Li et al.68 showed good performance\n(AUC = 0.80), which still requires validation in larger cohorts and with\nlonger follow-up durations.\nLooking ahead, the growing availability of large-scale electronic health\nrecord data provides an opportunity to develop machine learning-based\npredictive scores for endometriosis outcomes with excellent statistical\npower. For example, Mustard et al.\n57 used national and research databases to\ndevelop predictive models of pain reduction following endometriosis sur-\ngery, identifying the removal of ovarian and uterosacral ligament endo-\nmetriosis as important predictors of pain relief, although pending on\nexternal validation. Although still in early stages and focused on pain out-\ncomes, integrating such datasets with molecular and imaging data could\nopen promising avenues for individualized recurrence risk assessment.\nIn parallel, exploratory studies have identi fied candidate RNA and\nprotein biomarkers differing between recurrent and non-recurrent patients\nin serum or endometrioma tissue (Table2). Although promising, none of\nthese biomarkers have yet been validated in independent cohorts, and their\nutility in predicting recurrence remains to be established.\nAt the RNA level, decreased circulating levels of the long non-coding\nRNAs UCA1\n100 and LINC01465101 have been linked to a higher risk of\nrecurrence at 2 –3 years post-surgery, whereas elevated serum LGMNP1\ncarried by extracellular vesicles in recurrent patients achieved an AUC of\n0.869, and was shown to promoteM2 macrophagepolarization102.I nl e s i o n\nsamples, overexpression of miR-20 a, the stemness-associated gene\nNANOG103, and lncRNA H19 have been associated with recurrence, with\nH19 achieving an AUC of 0.728104. However, many of these studies did not\ncontrol for important confounders like the use of postoperative therapy,\nwhich limits their interpretation.\nTissue-based immunohistochemical (IHC) biomarkers have also\nshown potential. Studies from Prof. Guo ’sg r o u pi d e n t ified differential\nexpression of COX2, NFkB-p65, PRB, SLIT, and ROBO1 in recurrent\nendometriomas, which served to develop predictive models with high\nreported sensitivity and speci ficity (up to 86% and 87%, respectively)\n(Table 3)\n105–107. Building on these results, perioperative treatment with non-\nspecific β-blockers or NFκB inhibitors reduced recurrence rates in mouse\nmodels, suggesting therapeutic relevance 108,109. Additionally, Slit2\nTable 3 | Predictive models for endometriosis postoperative recurrence published in the literature\nRecurrence\npredictive model\nSample size\n(R/NR)\nRecurrence assessmenta Follow-upb\n(months)\nParameters included in\nthe model\nSens.\n(%)\nSpec.\n(%)\nAUC Accur.\n(%)\nBased on patient characteristics\nHoldsworth-Carson\net al.58\n503 (221/282) Laparoscopy (with self-reported previous laparoscopy) NA Age\nER attendance\nAdhesions\nEczema\nPararectal space lesion\nNA NA 0.668 NA\nHoldsworth-Carson\net al.\n58\n382 (94/288) Laparoscopy NA Adenomyosis\nDiastolic blood pressure\nUterine fibroids\nAdhesions\nAge of menarche\nNA NA 0.617 NA\nHuang et al.\n67 289 (49/240) Symptomatic\nPelvic exam\nCA125 > 35 U/mL\nTVUS\n12 rASRM score 57.1 94.2 0.79 87.9\nSu and Xie\n50 212 (36/176) Symptomatic, supported by pelvic exam or ultrasonography\nor CA125 increase\n24 Age\nBilateral cysts\nrASRM staging\nTNFα serum levels\nPostop. medication\n89.4 83.7 0.895 NA\nLi et al.68 164 (46/118) TVUS\nPelvic exam\n12 History of abortion\nAbnormal uterine bleeding\nrASRM staging\nPosterior fornix tenderness\n71 76 0.802 73\nIncorporating proteomic biomarkers\nShen et al.\n106 109 (53/56) TVUS or Laparoscopy 32 PRB levels (IHC)\nNFκB-p65 levels (IHC)\n80 82 NA NA\nShen et al.107 88 (43/45) TVUS or Laparoscopy 32 SLIT levels (IHC)\nPresence of adhesions\nPRB levels (IHC)\nNFκB-p65 levels (IHC)\n86 87 NA NA\nYuan et al.105 109 (53/56) Ultrasonography or Laparoscopy 32 COX2 levels (IHC)\nPrevious medication\nPresence of adhesion\n72.5 72.4 NA NA\nR recurrent; NR non-recurrent; Sens. sensitivity; Spec. specificity; AUC area under the curve; Accur. accuracy; TVUS transvaginal ultrasonography; IHC immunohistochemistry; ER emergency room;\nrASRM revised American Society for Reproductive Medicine, NA not reported.\naSymptomatic refers to the return of pelvic pain to the same or higher intensity levels as before surgery, after an initial postoperative relief.\nbFollow-up refers to the minimum time of observation required before patients were classi fied in recurrent and non-recurrent.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 5\n\noverexpression increased lesion size and vascularization in mice, supporting\nits role in endometriosis angiogenesis 110. However, independent studies\nhave reported opposite expression patterns of NF κB-p65 and PRB in\nrecurrent lesions, likely reflecting differences in study design, marker loca-\nlization (epithelial vs stromal), and patient characteristics111,112. This high-\nlights the urgent need for harmonized protocols and replication in larger,\nwell-characterized cohorts, ideally in corporating single-cell and spatial\nomics technologies to capture the cellular heterogeneity of endometriotic\ntissue.\nAdditional candidates include markers of proliferation (Ki-67)\n113,a n d\nadhesion and extracellular matrix remodeling (E-cadherin, uPA, MMP9,\nand EMMPRIN)114,a sw e l la si n flammatory mediators (S100A8/A9)115,\nassessed in endometriomas by IHC. Although biologically plausible, these\nfindings are preliminary, as they have been performed in small cohorts and\ntheir predictive performance remains untested.\nDeveloping robust prognostic tools for recurrence risk prediction will\nbe essential to stratify patients, optimize postoperative care, and improve\nlong-term outcomes. Beyond risk prediction, validated biomarkers may also\nreveal biological mechanisms driving recurrence and serve as novel ther-\napeutic targets.\nThe role of incomplete surgery and minimal residual\ndisease in endometriosis lesion recurrence\nThe mechanisms driving the reappearance of endometriotic lesions after\nsurgery are not fully understood and are likely multifactorial. While surgical\nfactors are well-established contributors to recurrence, it may also result\nfrom biological processes intrinsic to the disease and its interaction with the\nhost environment. Figure 1 presents a visual summary of the main\nmechanisms contributing to endometriosis lesion recurrence described in\nthe following sections.\nIncomplete surgical removal is one of the most established contributors\nto recurrence18,116. Minimal residual disease, whether due to conservative\napproaches or incomplete surgery, significantly increases the risk of recur-\nrence across all endometriosis subtypes (reviewed in refs.11,109,117). Fac-\ntors influencing the completeness of excision, such as lesion location, disease\nseverity, the presence of adhesions, and surgical expertise118,119 have been\ndiscussed above. And even when surgery seems macroscopically complete,\nresidual microscopic implants may go undetected, which may partly explain\nwhy recurrent lesions often appearin the same anatomical location\n23,120.\nThis is particularly relevant in the case of DIE, where the complexity of\nsurgery can make complete excision challenging. Some studies have iden-\ntified positive resection margins in DIE as a major risk factor for early\nrecurrence, especially when lesions are located in anatomically complex\nareas such as the bowel\n25,45,58,71,72. However,findings from Roman et al. point\nout that small palpable satellite noduleslocated near the resection site, rather\nthan microscopic occult endometriosis at bowel resection margins, carry\ngreater clinical relevance\n121,122. Surgical complications may further increase\nthis risk72. Similarly, conservative procedures to treat ovarian endometriosis\nare associated with higher recurrence rates. A recently updated Cochrane\nreview\n123 reported that cystectomy of endometriomas significantly reduced\nlesion recurrence (from 37 to 5 –17%) and pain recurrence (from 49 to\n10–34%) rates compared to more conserv ative approaches. Nevertheless,\nultrasound-guided ethanol sclerotherapy has gained interest as a less inva-\nsive alternative, with recent series using standardized protocols reporting\nrecurrence rates comparable to cystectomy\n124,125.\nAltogether, thesefindings support the widely accepted interpretation\nthat residual disease is responsible for early lesion recurrence and lesion-\nrelated pain relapse observed within months after surgery126. These minimal\nor invisible lesions can remain dormant for some time, especially if post-\noperative hormonal suppression is used briefly. Once hormonal treatment is\nMinimal residual disease\nRecurrence due to de novo lesionsRecurrence due to surgical factors\nUnintentional \ndissemination of viable \nendometrial material\nImpaired immune \nclearance of remaining \ntissue debris\nSurgical scars as favorable \nimplantation sites \nInvisible peritoneal \nlesions\nIncomplete \nexcision of tissue\nSpillage of \nendometrioma \nStem cell \ninvolvement\nMain theories and mechanisms \nproposed to explain primary disease\nImmune \ndysregulation\nRetrograde \nmenstruation\nStem-like \nendometriotic cells\nImmunotolerant \nperitoneal niche\nFig. 1 | Potential biological mechanisms of endometriosis recurrence. The left\npanel illustrates surgery-related mechanisms contributing to lesion recurrence,\nincluding minimal residual disease (resulting from incomplete excision, invisible\nperitoneal lesions, or impaired immune clearance of remaining endometriotic cells\nas a result of surgical transient immunosuppression) as well as the unintentional\ndissemination of viable endometrial material with the capacity to implant in the\nperitoneal cavity and give rise to recurrent lesions. The right panel depicts potential\nmechanisms of de novo lesion formation, integrating several hypotheses described\nin the literature. Surgical scars are also represented as favorable implantation sites for\ndisseminated endometriotic cells or menstrual debris, potentially facilitating lesion\nestablishment. Created in BioRender. Delgado, R. (2026) https://BioRender.com/\n1s91uhu.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 6\n\ndiscontinued, dormant cells may re- grow, leading to recurrence in the\nmedium term. Indeed, while many experts support continuous hormonal\nsuppression, it is often acknowledged that such treatments may only delay,\nrather than prevent, recurrence\n34,60,117,127.\nThe temporal dynamics of recurrence reinforce this view11. Recurrence\ncommonly shows an early peak, and then enters a plateau of apparent\nstability, probably representing successful interventions, and rises again in\nthe long term. However, this pattern is difficult to assess consistently in the\nliterature due to the heterogeneity i n follow-up durations and reporting,\nwith most studies providing only short- to medium-term follow-up, typi-\ncally up to 2 years, although median time to repeat surgery has been reported\nbetween 30 and 36 months\n39,120.\nThese observations suggest that recurrence due to incomplete or\nsuboptimal surgery tends to manifest earlier, while later recurrences may\nreflect the slow progression of residual disease or the formation of new\nlesions.\nOther recurrence-promoting effects of surgery\nBeyond residual disease, the surgical procedure itself may contribute to\nlesion reappearance. Some authors have suggested that the dissemination of\nviable endometrial cells during surgery may facilitate the development of\nnew lesions. For example, spi llage of endometrioma cyst fluid during\nexcision has been shown to release endometrial cells capable of implanting\non surrounding tissues, potentially forming new lesions\n128.\nSimilarly, uterine trauma, such as that caused by cesarean section, has\nbeen associated with increased risk of endometriosis development129,130,a n d\nin patients with a prior diagnosis of endometriosis, with a two-fold higher\nrisk of recurrence compared to vaginal births131. This may be a consequence\nof the intra-abdominal dissemination of endometrial cells131, together with\nthe protective effect of cervical dilat ion and enhanced uterine drainage\noccurring in vaginal delivery, reducing retrograde menstruation132.\nThis association has led researche rs to consider the role of surgical\ntrauma and wound healing in lesion formation. It has been proposed that\nnewly formed surgical scars may provide a favorable microenvironment for\nendometriotic lesion development, facilitating cell adhesion and prolifera-\ntion through extracellular matrix remodeling, angiogenesis, and the release\nof growth factors\n133. Incisional endometriosis (i.e., endometriosis appearing\nin the cesarean section, episiotomy, or trocar site scars) is a well-\ndocumented phenomenon supporting this hypothesis52,134–136.T h e s ea r e a s\nof surgical trauma could be potential sites where endometrial cells, either\nspread during surgery or regurgitated in retrograde menstruation, could\nimplant and develop into new lesions\n109,128,135.\nCoincidentally, perioperative immune suppression, triggered by sur-\ngical stress, may further impair the body’s ability to clear minimal residual\ndisease and disseminated endometrial tissue109. Together, transient immu-\nnosuppression and local trauma may s ynergistically create a permissive\nenvironment for lesion establishment and recurrence137.\nDe novo lesion formation as a potential contributor to\nlate endometriosis recurrence\nSurgical factors alone cannot fully explain why some patients experience\ndelayed or multiple recurrences despite apparently complete excision.\nRecurrence rates remain high over time despite advances in surgical\ntechniques\n138–140, raising the possibility thatsome recurrent lesions may not\nstem from residual disease, but rather form de novo. Since surgery does not\naddress the underlying pathophysiology of endometriosis, it is plausible that\nthe disease reappears through the same mechanisms that led to its initial\ndevelopment, representing a progression of the natural course of the disease\nin susceptible individuals, rather than merely a consequence of incomplete\ntreatment.\nS e v e r a lo b s e r v a t i o n ss u p p o r tt h eh y p o t h e s i so fd en o v ol e s i o nf o r m a -\ntion. First, recurrent lesions can appear in previously unaffected anatomical\nsites, including the contralateral ovary or other pelvic locations\n18,23,120. Sec-\nond, recurrence rates tend to increase with longer follow-up periods25,44,120.\nThis long-term progression has b een interpreted by some authors as\nsupporting de novo lesion formation, hypothesizing that endometriosis may\neventually recur in all operated patients128,141. However, there is currently no\nconsensus on whether reported timeframes are enough for the full devel-\nopment of new lesions and symptoms\n11,39. Lastly, the association between\nyounger age and increased recurrence risk also supports this view, as it\nimplies a longer time period for lesions to reappear before menopause38.\nAssuming that endometriotic lesion recurrence not necessarily stems\nfrom residual disease shifts the focus towards the biological processes\nimplicated in lesion initiation. Sampson’s theory of retrograde menstruation\nremains the most widely accepted explanation for the development of\nendometriotic lesions\n142 and is compatible with de novo recurrence.\nMechanisms proposed to explain primary disease in this context, such as\nimmune dysregulation\n143, stem cell involvement 144, or pro-angiogenic,\nimmunotolerant peritoneal niche145,146, may also be relevant in the context of\nrecurrence. In this setting, implantation of regurgitated menstrual debris in\nthe peritoneal cavity may be further facilitated by the permissive local\nenvironment created by tissue trauma and transient immunosuppression,\nas discussed above. From this perspective, late recurrence may re flect an\nindividual’s biological predisposition to lesion formation.\nFuture directions: recurrence as a conceptual window\ninto endometriosis pathophysiology\nCurrent evidence indicates that endometriosis recurrence is a result of\nmultiple, overlapping processes, including residual disease, surgery-related\neffects, and de novo lesion formation, whose relative contributions may vary\ndepending on each patient’s surgical context and baseline biology. Under-\nstanding the biological basis of disease recurrence is essential to move\nbeyond its clinical characterization and towards identifying the core pro-\ncesses sustaining endometriosis. T o date, however, most research has\nfocused on surgical determinants, leaving these underlying susceptibilities\nlargely unexplored.\nIt is plausible that women prone to recurrence may harbor intrinsic\nbiological traits that favor lesion re-establishment, such as impaired\nimmune clearance of menstrual debris\n143, epigenetic alterations that\nenhance cell survival and adhesion 147, increased presence of endometrial\nstem cells 144, and a peritoneal microenvironment more permissive to\nimplantation145,146. These mechanisms, proposed as contributors to disease\nonset, may similarly promote lesion reappearance in biologically susceptible\nindividuals, a hypothesis that warrants future investigation.\nHence, viewed through this lens, recurrence becomes not just a clini-\ncally relevant outcome, but also a c onceptual and biological model for\ninvestigating the core processes of endometriosis. Patients who develop\nrecurrence despite apparently complete excision may represent an infor-\nmative subgroup in whom disease drivers remain active or re-emerge after\nsurgery. Their disease course could provide insights into key drivers of lesion\ninitiation, including microenvironmental, immunological, or molecular\nalterations that facilitate the growth of residual cells or the implantation of\ndisseminated or regurgitated endometrial cells. Understanding these path-\nways could help clarify whether recurrence is more a reflection of disease\nprogression than surgical failure, and whether some patients exhibit a more\naggressive disease phenotype.\nA deeper understanding of the biological basis of recurrence could also\ninform prevention and treatment strategies. If early postoperative or base-\nline characteristics could predict recurrence, they might guide surgical\ndecisions, follow-up intensity, and duration of hormonal suppression.\nMoreover, identifying mechanistically relevant molecular signatures may\nprovide not only predictive tools but also functional biomarkers, enabling\npatient stratification, precise monitoring of disease progression, and the\ndevelopment of targeted, mechanism-based therapies, potentially beyond\nhormonal treatment.\nIn this light, recurrence of endometriosis lesions should be reframed\nnot only as a clinical challenge, but also as a conceptual opportunity to\ninvestigate the pathogenic mechanisms of endometriosis: a natural stress\ntest that reveals the processes most essential to lesion survival and reap-\npearance, opening a window into the pathogenesis of the disease itself.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 7\n\nConclusions\nRecurrence remains a major challenge in the clinical management of\nendometriosis and a source of uncertainty for both patients and profes-\nsionals. Conceptual and methodological differences across studies compli-\ncate the accurate interpretation of clinical outcomes. The adoption of a\nstandardized, multidimensional definition of recurrence, together with\nuniform outcome measures systematically collected during long follow-ups,\nwill be crucial to improve research comparability. These efforts should\nideally build on and expand the existing Endometriosis Phenome and\nBiobanking Harmonisation Project (EPHect) surgical standard operating\nprocedures\n148 to incorporate longitudinal outcome reporting and facilitate\nmulticentric studies on endometriosis recurrence.\nBeyond methodological improvement, endometriosis recurrence\nrepresents a biologically informative event and offers a unique opportunity\nto uncover key pathways involved in lesion initiation and survival. 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This\nwork was supported by La Fundació La Marató 2024 through the project\n“202407-10,” the CP22/00147 granted to E.C., and the CIBERONC\nnetwork grant number CB16/12/00328. The funders had no role in study\ndesign, data collection, data analysis, data interpretation, or writing of the\nmanuscript.\nAuthor contributions\nC.M.F. and E.C. conceived and designed the review. C.M.F. conducted the\nliterature search, performed data curation, drafted the initial manuscript,\nfigure, and tables, and addressed revisions. R.D.G. contributed tofigure and\ntable construction and data validation. E.C. secured funding and provided\nfeedback and editorial input. All authors critically reviewed and approved the\nfinal version.\nCompeting interests\nThe authors declare no competing interests.\nAdditional information\nCorrespondenceand requests for materials should be addressed to\nEva Colas.\nReprints and permissions informationis available at\nhttp://www.nature.com/reprints\nPublisher’s noteSpringer Nature remains neutral with regard to jurisdictional\nclaims in published maps and institutional affiliations.\nhttps://doi.org/10.1038/s44294-026-00128-9 Review\nnpj Women's Health |             (2026) 4:4 11\n\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. 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