Rethinking endometriosis recurrence: from clinical challenge to biological opportunity

and biologically informative endpoint, or the return of endometriosis-associated pain symptoms, which is more relevant to patient management. 1Group of Biomedical Research in Gynaecology, Vall d ’ Hebron Institute of Research (VHIR), CIBERONC, Barcelona, Spain. 2Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain. e-mail: [email protected] npj Women's Health | (2026) 4:4 1 1234567890():,; 1234567890():,; Although they often overlap, lesion regrowth and symptom relapse are not always equivalent15–17. This lack of correlation is generally reflected in the recurrent rates reported for both outcomes, where pain recurrence is typi- cally higher than lesion recurrence. For example, in a retrospective study of 115 patients with deep infiltrating endometriosis (DIE), relapse of pain 3 and 5 years after surgery was 20.5 and 43.5%, and the lesion recurrence rates were 9 and 28%, respectively 18. Similarly, another retrospective study of 401 patients reported pain recurrence at 34% and lesion recurrence detected by transvaginal ultrasonography (TVUS) at 16%, both within a median follow- up of 24 months 19. This highlights that endometriosis-associated symptoms can be driven by pathways unrelated to anatomical lesion regrowth, such as central sen- sitization, pain comorbidities, or factors secondary to the surgical procedure itself, including fibrosis or the formation of new adhesions 1,20,21.C e n t r a l sensitization refers to an increased exc itability of central pain pathways, leading to pain amplification and persistence even in the absence of per- ipheral noxious stimuli. This mechanism has been associated with poor response to surgery and hormonal therapies, and may contribute to post- operative pain recurrence in the absence of visible disease 20.A d d i t i o n a l l y , persistent symptoms can be related to undetected peritoneal implants not removed during surgery 22. It is also worth noting that studies often fail to differentiate between symptom persist ence (indicating initial treatment failure) and relapse (the return of pain after a period of relief, potentially linked), further complicating the understanding of these outcomes from a pathophysiological standpoint. Conversely, lesion reappearance does not always entail symptom relapse: retrospective studies on recurrent endometriomas have reported that 24-30% of patients with imaging-con firmed recurrence remained asymptomatic 19,23. Therefore, recurrence should be considered a multi- dimensional phenomenon involving both lesion regrowth and symptom reappearance, which likely involve distinct underlying mechanisms 24. Measuring recurrence in endometriosis: proxies and methodological variability The lack of consensus in de fining, assessing, and consequently reporting recurrence is a persistent methodological challenge fre- quently highlighted by systematic reviews and meta-analyses 25–27. Notably, Ceccaroni et al. 28 systematically compiled the de finitions used across observational studies and clini cal trials, illustrating this hetero- geneity and the limited comparabilit y across studies. There is currently no commonly agreed, well-de fined, and consistently applied set of outcomes 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 . Instead, a diverse range of clinical and imaging-based assessment cri- teria are used, each with its own limitations. Imaging modalities such as TVUS and magnetic resonance imaging (MRI) are the most widely used tools to assess lesion reappearance. As in the diagnostic process, the accuracy of these tools depends on subtype, lesion localization and size, and operator expertise 29.S i n c eb o t hT V U Sa n dM R I are highly reliable in detecting ovarian endometriosis, it is the most studied subtype in terms of postoperative recurrence, although specificc y s ts i z ec u t - offs and sonographic features re main variable between studies 27,30,31.A recent meta-analysis by Veth et al.31 has demonstrated a progressive increase in endometrioma recurrence risk over time, with rates of 4% at 3 months post-surgery, 14% at 6 months, 17% at 17 months, and 27% at 24 months when not using postoperative hormonal treatment. However, as in diagnosis, a negative imaging result does not necessarily rule out the presence of disease, so histological con firmation of endome- triotic lesions is the most rigorous approach to confirm lesion recurrence, although highly invasive and unsuit able for longitudinal assessment. Additionally, repeated surgeries are generally discouraged due to the asso- ciated loss of ovarian reserve, poten tial surgical complications, and the formation of new adhesions 4,32–34. Consequently, not all recurrence cases are managed surgically, and recurrence rates might be underestimated. Beyond imaging, the longitudinal assessment of endometriosis recur- rence is further limited by the absence of a reliable, non-invasive biomarker that could serve as a dynamic indicator of disease activity over time. In a chronic condition likeendometriosis, where repeated surgical verification is neither feasible nor ethical, such a biomarker would be key to monitoring recurrence and disease progression. Symptom recurrence is usually assessed through patient-reported outcomes, primarily pain scores. Whilethese are clinically meaningful, they are inherently subjective and prone to reporting and attrition bias, especially in long-term follow-up studies 7.D e finitions vary widely: some studies dichotomize pain as“present” or “absent,” while others use changes in visual analog scale scores or relative improvement thresholds35. Both lesion and symptom recurrence can prompt subsequent changes in clinical management, and many retrospective studies rely on reoperation or starting a second-line hormonal therapy as indirect indicators of recurrence 25,36,37. Although practical, these proxies cannot distinguish between treatment failure and true recurrence after remission and usually do not con firm the presence of lesions histologically, so they should be interpreted carefully. The inconsistent use of diverse outcomes to assess recurrence across studies severely limits comparability and complicates the interpretation of recurrence rates, risk factors, and therapeutic outcomes. Moreover, recur- rence estimates are influenced by cohort characteristics, disease subtype and severity, surgical technique, follow-up length, and the use (or absence) of postoperative hormonal therapy. Col lectively, this variability not only explains the wide range of recurrence rates reported in the literature 11 but also limits our understanding of the b iological and clinical dynamics of recurrence. Risk factors for lesion and symptom recurrence Understanding which factors predi spose patients to postoperative recurrence is essential to identify p atients at higher risk of recurrence, to ultimately guide individualized management. However, as emphasized above, the substantial heterogeneity in how recurrence is defined across the literature complicates the interpretation and com- parison of findings. Table 1 summarizes the main clinical, surgical, and patient-related determinants in fluencing the likelihood of recur- rence reported in the literature, dis tinguishing between risk factors for lesion and symptom recurrence, and including studies using broader definitions as well. Because imaging reliably detects ovarian endo- metriomas, it has naturally become the most extensively studied subtype in terms of recurrence, and this predominance should be considered when interpreting risk factors. Nevertheless, several consistent patterns can be identified across stu- dies. Younger age at the time of surgery is associated with a higher risk of recurrence 38. Although the absolute differences in mean age between recurrent and non-recurrent groups are small, this consistent trend9,18,19,39–51 suggests a biologically meaningful eff ect likely related to longer lifetime estrogen exposure. Preoperative pain symptoms, including dysmenorrhea and chronic pelvic pain, have been linked to both lesion reappearance 19,43,52–56 and pain persistence and recurrence 19,47,57, possibly reflecting pre-existing inflammatory and nociplastic factors not resolved by surgery. Disease-related factors such as extensive adhesions 49,54,58,59,l a r g e r cysts42,54,55,60–65, coexistent deep infiltrating lesions61,66 and adenomyosis47,66 or 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 (rASRM) scores18,19,24,39,41,42,48,50,58,59,67–70 are associated with increased lesion recurrence risk mainly, likely due to incomplete lesion resection. Surgical approach and postoperative care also impact outcomes. Conservative surgery is widely associated with earlier recurrence 25,41,48,52,58,71–74. Conversely, the use of postoperative hormonal therapy has been consistently fou nd as a protective factor against recurrence9,26,50,69,70,75–77. However, an insuf ficient duration or poor adher- ence to treatment over the long term can diminish the protective effects of these therapies 10,44,61,74,78–82. Similarly, achieving pregnancy after surgery appears to lower recurrence risk, likely due to prolonged ovarian suppression 19,40,41,44,48,51,56,59,63,67,70,81,83. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 2 The role of postoperative hormonal treatment in recurrence prevention and management Among the risk factors for endometr iosis recurrence mentioned above, periods of ovarian suppression or amenorrhea, whether pharmacologically induced or occurring during pregnancy and lactation, are associated with a reduced risk of both lesion and symptom recurrence. In this hypo- estrogenic environment, the growth of residual lesions is suppressed, new lesion development is prevented, and associated pain symptoms persisting or reappearing after surgery are controlled. Postoperative medical therapy represents a cornerstone in endome- triosis recurrence prevention. Systematic reviews and meta-analyses have reported that the risk of lesion reappearance is reduced by 59 –70%, and symptom recurrence by 30% after 12 months, if using hormonal treatment postoperatively, compared to surgery alone 7,26. Comparative studies asses- sing different hormonal agents and regimens for recurrence prevention have reported heterogeneous results 26,60,79,82,84–87. Variability in study design, inclusion criteria, treatment duration, adherence, and f ollow-up compli- cates comparisons and limits definitive conclusions. Overall, no hormonal agent has been consistently demonstrated to be better than others, suggesting that the protective effect primarily derives from sustained ovarian suppression rather than from a specific drug class. In line with this, a randomized controlled trial by Seracchioli et al.10 demonstrated that con- tinuous oral contraceptive use was associated with lower rates of dysme- norrhea relapse and severity compared to cyclic use. Accordingly, the European Society of Human Reproduction and Embryology guideline on endometriosis recommends the long-term use of continuous combined oral contraceptives or levonorgestrel-releasing intrauterine systems following laparoscopy for the prevention of dysmenorrhea relapse 6. Despite its bene fits, hormonal therapy is not without limitations. Symptom relapse occurs shor tly after discontinuation60, and recurrence rates among patients treated for less than 12 months are similar to those of untreated individuals within 1–2y e a r s 88.T h i ss u g g e s t sap r e d o m i n a n t l y suppressive effect, requiring sustained use to maintain bene fit. However, long-term use is associated with relevant side effects and is not appropriate for patients with immediate pregnancy desire, so discontinuation rates are high 89–91. Additionally, treatment failure in this context may be amplified by the fact that patients referred to surgery may be less responsive to medical therapy as a first-line approach 4,92. Table 1 | Risk factors for endometriosis postoperative recurrence Risk factor References Lesion recurrence Symptom recurrence Other de finitions Patient-related risk factors Young age Coccia et al. 19 OMA: Liu et al. 39, Sengoku et al. 40, Yuan et al. 41, Moini et al.42, Han et al. 43, Choi et al. 44 DIE: Nirgianakis et al. 45 Vignali et al. 18, Vercellini et al. 9, Uccella et al. 46, Yang et al. 47 Busacca et al. 48, Yun et al.49 OMA: Su and Xie 50 DIE: Fedele et al. 51 Preoperative pain Coccia et al. 19, Zhong et al. 52 OMA: Chon et al. 53, Küçükbas et al. 54, Yu et al. 56, Han et al.55 Coccia et al. 19, Yang et al. 47 Ngernprom et al. 74 OMA: Li et al. 83, Huang et al.67 Disease-related risk factors Presence of adhesions Holdsworth-Carson et al. 58 OMA: Porpora et al. 59, Küçükbas et al. 54 Porpora et al. 59 Yun et al. 49 Larger cyst size a OMA: Koga et al.63, Moini et al.42, Küçükbas et al.54, Lee et al.62, Candiani et al. 61, Han et al. 55 OMA: Saleh et al. 64, Busacca et al. 65 Bilaterality of cysts OMA: Han et al. 55 Yun et al. 49 OMA: Su and Xie 50 Coexistent adenomyosis OMA: Sun et al. 66 Yang et al. 47 Higher preoperative staging (rASRM or rAFS scores) Busacca et al. 48, Coccia et al. 19, Holdsworth-Carson et al.58 OMA: Liu et al. 39, Takamura et al. 69, Porpora et al. 59, Hayasaka et al. 70, Moini et al. 42, Yuan et al. 41, Tobiume et al.24, Li et al. 68 Liu et al. 39 OMA: Huang et al. 67,S u and Xie50 Management-related risk factors Conservative surgical technique Zhong et al. 52, Holdsworth-Carson et al. 58 OMA: Yuan et al. 41 DIE: Bendifallah et al. 71, Xu et al. 72 Afors et al. 73 Busacca et al. 48 OMA: Ngernprom et al. 74 Prior surgery for endometriosis OMA: Porpora et al. 59 Fedele et al. 51, Porpora et al. 59 Busacca et al. 65 DIE: Fedele et al. 51 Absence, poor adherence, or insuf ficient duration of postoperative hormonal therapy Vercellini et al. 9 OMA: Vercellini et al. 79, Takamura et al. 69, Seracchioli et al.78, Hayasaka et al. 70, Seong et al. 80, Choi et al. 44 DIE: Yela et al. 75 Vercellini et al. 76, Sesti et al. 77, Seracchioli et al.10, Candiani et al.61 Ngernprom et al. 74, Kwok et al.81 OMA: Del Forno et al.82,S u and Xie50 Pregnancy and/or breastfeeding (protective) Coccia et al. 19 OMA: Koga et al. 63, Porpora et al. 59, Hayasaka et al. 70, Segonku et al. 40, Yuan et al. 41, Yu et al. 56, Choi et al. 44 Fedele et al. 51, Porpora et al. 59 Busacca et al. 48, Kwok et al.81 OMA: Li et al. 83, Huang et al.67 DIE: Fedele et al. 51 Lesion 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 through 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 specifically focused on ovarian endometriomas (OMA) or deep in filtrating endometriosis (DIE). OMA endometrioma, DIE deep infiltrating endometriosis, rASRM revised American Society for Reproductive Medicine, rAFS revised American Fertility Society. aLarger 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 et al.55; Candiani et al. 61) or 5.5 cm (Lee et al. 62). https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 3 Beyond adherence and tolerance, growing evidence suggests that some patients may develop resistance to postoperative hormonal therapy, parti- cularly progestins93,94.T h i sm a yr eflect lesion-level progesterone resistance or, in the case of persistent pain, the predominance of centrally mediated mechanisms that are less responsive to hormonal suppression. Because hormonal therapy primarily acts on le sion-related, peripheral pain path- ways, its benefit may be limited in such patients. Therefore, long-term managemen t of endometriosis recurrence remains an important challenge. As mentioned above, reoperation is increasingly discouraged due to th e associated risks and the fact that a history of previous endometriosis-related surgeries is itself a risk factor for future recurrence 51,59,65,95,96, creating a vicious cycle that further complicates long-term management97. These challenges highlight the need to identify new preventive and therapeutic strategies to manage endometriosis recurrence, ideally beyond hormonal suppression. To develop such strategies and better tailor the long- term management of endometriosis, itis essential to better understand the biological basis of recurrence and to develop tools to identify patients at higher risk. Predicting recurrence: clinical models and emerging biomarkers Accurately predicting postoperative recurrence in endometriosis is key to advancing personalized care and guiding long-term treatment strategies. A limited number of predictive models have been developed based on clinical, surgical, and molecular variables, but their performance and applicability Table 2 | Potential biomarkers for endometriosis postoperative recurrence published in the literature Biomarker Reference Sample N (R/NR) Measurement technique Recurrence assessmenta Follow-up (months)b Expression (p value) lncRNA UCA1 Huang et al. 100 Serum 98 (28/70) qRT-PCR Pelvic exam 24 ↓ (p < 0.05) lncRNA LINC01465 Song et al.101 Serum 80 (40/40) qRT-PCR Pelvic exam 36 ↓ (p < 0.01) miR-20a Abdoli et al.103 Endometrioma tissue 20 (9/11) qRT-PCR TVUS or MRI 24 ↑ (p < 0.001) NANOG Abdoli et al. 103 Endometrioma tissue 20 (9/11) qRT-PCR TVUS or MRI 24 ↑ (p 35 U/mL • Ultrasonography 24 ↑ (p = 0.001) EV-LGMNP1 Sun et al. 102 Serum 52 (15/37) qRT-PCR Pelvic exam or CA125 > 35 U/mL or Ultrasonography 46 ± 13 ↑ (p < 0.001) COX2 Yuan et al.105 Endometrioma tissue 109 (53/56) IHC Ultrasonography or Laparoscopy 32 ↑ (p < 0.001) NFkB-p65 Shen et al. 106 Endometrioma tissue 109 (53/56) IHC TVUS or Laparoscopy 32 ↑ (p = 0.001) Han et al. 111 Endometrioma tissue 134 (27/107) IHC TVUS 24 ↓ (p < 0.05) PRB Shen et al.106 Endometrioma tissue 109 (53/56) IHC TVUS or Laparoscopy 32 ↓ (p = 0.01) Han et al. 111 Endometrioma tissue 134 (27/107) IHC TVUS 24 ↑ (p < 0.05) Tarumi et al.112 Endometrioma tissue 132 (36/96) IHC Ultrasonography or MRI 24 ↓ (p < 0.01) ROBO1 Shen et al. 107 Endometrioma tissue 88 (43/45) IHC TVUS or Laparoscopy 32 ↑ (p < 0.05) SLIT Shen et al. 107 Endometrioma tissue 88 (43/45) IHC TVUS or Laparoscopy 32 ↑ (p < 0.01) Ki-67 Yalcin et al. 113 Endometrioma tissue 50 (24/26) IHC TVUS 6 ↑ (p < 0.01) E-cadherin Wu et al. 114 Endometrioma tissue 49 (34/15) IHC NA Max. 80 ↓ (p < 0.05) MMP9 Wu et al. 114 Endometrioma tissue 49 (34/15) IHC NA Max. 80 ↑ (p = 0.001) EMMPRIN Wu et al. 114 Endometrioma tissue 49 (34/15) IHC NA Max. 80 ↑ (p < 0.05) uPA Wu et al. 114 Endometrioma tissue 49 (34/15) IHC NA Max. 80 ↑ (p < 0.05) S100A8 Zhu et al. 115 Endometrioma tissue 50 (25/25) IHC Symptomatic TVUS 24 ↑ (p < 0.01) S100A9 Zhu et al. 115 Endometrioma tissue 50 (25/25) IHC Symptomatic TVUS 24 ↑ (p < 0.01) R recurrent, NR non-recurrent, TVUS transvaginal ultrasonography, IHC immunohistochemistry, qRT-PCR real-time quantitative PCR, NA not reported. aSymptomatic refers to the return of pelvic pain to the same or higher intensity levels as before surgery, after an initial postoperative relief. bFollow-up refers to the minimum time of observation required before patients were classi fied in recurrent and non-recurrent, unless otherwise speci fied. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 4 remain modest, partly due to the variable criteria used to define recurrent patients. Most clinically based models rely on established risk factors, such as adhesions or high rASRM scores, and their use primarily relates to the risk of lesion recurrence, since they re flect the anatomical severity of endome- triosis. For example, Huang et al. 67 proposed a logistic regression model using rASRM >70 as a single predictor (AUC = 0.79), but its applicability is constrained by a short follow-up and a strict recurrence definition, requiring lesion recurrence (detected by TVUS and pelvic exam), high CA125 levels, and symptom return. Broader criteria are used by Su and Xie 50,w h oc o m - bined clinical and inflammatory parameters and achieved higher accuracy (AUC = 0.895) in detecting symptomatic recurrence, supported by either high CA125 levels, pelvic exam, or TVUSfindings. However, the inclusion of CA125 as a predictor in these models limits their reliability, given its low specificity and poor sensitivity in early-stage disease 28,98, and considering that recent clinical guidelines discourage its use for detecting endometriosis in routine practice99. Lastly, a model by Li et al.68 showed good performance (AUC = 0.80), which still requires validation in larger cohorts and with longer follow-up durations. Looking ahead, the growing availability of large-scale electronic health record data provides an opportunity to develop machine learning-based predictive scores for endometriosis outcomes with excellent statistical power. For example, Mustard et al. 57 used national and research databases to develop predictive models of pain reduction following endometriosis sur- gery, identifying the removal of ovarian and uterosacral ligament endo- metriosis as important predictors of pain relief, although pending on external validation. Although still in early stages and focused on pain out- comes, integrating such datasets with molecular and imaging data could open promising avenues for individualized recurrence risk assessment. In parallel, exploratory studies have identi fied candidate RNA and protein biomarkers differing between recurrent and non-recurrent patients in serum or endometrioma tissue (Table2). Although promising, none of these biomarkers have yet been validated in independent cohorts, and their utility in predicting recurrence remains to be established. At the RNA level, decreased circulating levels of the long non-coding RNAs UCA1 100 and LINC01465101 have been linked to a higher risk of recurrence at 2 –3 years post-surgery, whereas elevated serum LGMNP1 carried by extracellular vesicles in recurrent patients achieved an AUC of 0.869, and was shown to promoteM2 macrophagepolarization102.I nl e s i o n samples, overexpression of miR-20 a, the stemness-associated gene NANOG103, and lncRNA H19 have been associated with recurrence, with H19 achieving an AUC of 0.728104. However, many of these studies did not control for important confounders like the use of postoperative therapy, which limits their interpretation. Tissue-based immunohistochemical (IHC) biomarkers have also shown potential. Studies from Prof. Guo ’sg r o u pi d e n t ified differential expression of COX2, NFkB-p65, PRB, SLIT, and ROBO1 in recurrent endometriomas, which served to develop predictive models with high reported sensitivity and speci ficity (up to 86% and 87%, respectively) (Table 3) 105–107. Building on these results, perioperative treatment with non- specific β-blockers or NFκB inhibitors reduced recurrence rates in mouse models, suggesting therapeutic relevance 108,109. Additionally, Slit2 Table 3 | Predictive models for endometriosis postoperative recurrence published in the literature Recurrence predictive model Sample size (R/NR) Recurrence assessmenta Follow-upb (months) Parameters included in the model Sens. (%) Spec. (%) AUC Accur. (%) Based on patient characteristics Holdsworth-Carson et al.58 503 (221/282) Laparoscopy (with self-reported previous laparoscopy) NA Age ER attendance Adhesions Eczema Pararectal space lesion NA NA 0.668 NA Holdsworth-Carson et al. 58 382 (94/288) Laparoscopy NA Adenomyosis Diastolic blood pressure Uterine fibroids Adhesions Age of menarche NA NA 0.617 NA Huang et al. 67 289 (49/240) Symptomatic Pelvic exam CA125 > 35 U/mL TVUS 12 rASRM score 57.1 94.2 0.79 87.9 Su and Xie 50 212 (36/176) Symptomatic, supported by pelvic exam or ultrasonography or CA125 increase 24 Age Bilateral cysts rASRM staging TNFα serum levels Postop. medication 89.4 83.7 0.895 NA Li et al.68 164 (46/118) TVUS Pelvic exam 12 History of abortion Abnormal uterine bleeding rASRM staging Posterior fornix tenderness 71 76 0.802 73 Incorporating proteomic biomarkers Shen et al. 106 109 (53/56) TVUS or Laparoscopy 32 PRB levels (IHC) NFκB-p65 levels (IHC) 80 82 NA NA Shen et al.107 88 (43/45) TVUS or Laparoscopy 32 SLIT levels (IHC) Presence of adhesions PRB levels (IHC) NFκB-p65 levels (IHC) 86 87 NA NA Yuan et al.105 109 (53/56) Ultrasonography or Laparoscopy 32 COX2 levels (IHC) Previous medication Presence of adhesion 72.5 72.4 NA NA R recurrent; NR non-recurrent; Sens. sensitivity; Spec. specificity; AUC area under the curve; Accur. accuracy; TVUS transvaginal ultrasonography; IHC immunohistochemistry; ER emergency room; rASRM revised American Society for Reproductive Medicine, NA not reported. aSymptomatic refers to the return of pelvic pain to the same or higher intensity levels as before surgery, after an initial postoperative relief. bFollow-up refers to the minimum time of observation required before patients were classi fied in recurrent and non-recurrent. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 5 overexpression increased lesion size and vascularization in mice, supporting its role in endometriosis angiogenesis 110. However, independent studies have reported opposite expression patterns of NF κB-p65 and PRB in recurrent lesions, likely reflecting differences in study design, marker loca- lization (epithelial vs stromal), and patient characteristics111,112. This high- lights the urgent need for harmonized protocols and replication in larger, well-characterized cohorts, ideally in corporating single-cell and spatial omics technologies to capture the cellular heterogeneity of endometriotic tissue. Additional candidates include markers of proliferation (Ki-67) 113,a n d adhesion and extracellular matrix remodeling (E-cadherin, uPA, MMP9, and EMMPRIN)114,a sw e l la si n flammatory mediators (S100A8/A9)115, assessed in endometriomas by IHC. Although biologically plausible, these findings are preliminary, as they have been performed in small cohorts and their predictive performance remains untested. Developing robust prognostic tools for recurrence risk prediction will be essential to stratify patients, optimize postoperative care, and improve long-term outcomes. Beyond risk prediction, validated biomarkers may also reveal biological mechanisms driving recurrence and serve as novel ther- apeutic targets. The role of incomplete surgery and minimal residual disease in endometriosis lesion recurrence The mechanisms driving the reappearance of endometriotic lesions after surgery are not fully understood and are likely multifactorial. While surgical factors are well-established contributors to recurrence, it may also result from biological processes intrinsic to the disease and its interaction with the host environment. Figure 1 presents a visual summary of the main mechanisms contributing to endometriosis lesion recurrence described in the following sections. Incomplete surgical removal is one of the most established contributors to recurrence18,116. Minimal residual disease, whether due to conservative approaches or incomplete surgery, significantly increases the risk of recur- rence across all endometriosis subtypes (reviewed in refs.11,109,117). Fac- tors influencing the completeness of excision, such as lesion location, disease severity, the presence of adhesions, and surgical expertise118,119 have been discussed above. And even when surgery seems macroscopically complete, residual microscopic implants may go undetected, which may partly explain why recurrent lesions often appearin the same anatomical location 23,120. This is particularly relevant in the case of DIE, where the complexity of surgery can make complete excision challenging. Some studies have iden- tified positive resection margins in DIE as a major risk factor for early recurrence, especially when lesions are located in anatomically complex areas such as the bowel 25,45,58,71,72. However,findings from Roman et al. point out that small palpable satellite noduleslocated near the resection site, rather than microscopic occult endometriosis at bowel resection margins, carry greater clinical relevance 121,122. Surgical complications may further increase this risk72. Similarly, conservative procedures to treat ovarian endometriosis are associated with higher recurrence rates. A recently updated Cochrane review 123 reported that cystectomy of endometriomas significantly reduced lesion recurrence (from 37 to 5 –17%) and pain recurrence (from 49 to 10–34%) rates compared to more conserv ative approaches. Nevertheless, ultrasound-guided ethanol sclerotherapy has gained interest as a less inva- sive alternative, with recent series using standardized protocols reporting recurrence rates comparable to cystectomy 124,125. Altogether, thesefindings support the widely accepted interpretation that residual disease is responsible for early lesion recurrence and lesion- related pain relapse observed within months after surgery126. These minimal or invisible lesions can remain dormant for some time, especially if post- operative hormonal suppression is used briefly. Once hormonal treatment is Minimal residual disease Recurrence due to de novo lesionsRecurrence due to surgical factors Unintentional dissemination of viable endometrial material Impaired immune clearance of remaining tissue debris Surgical scars as favorable implantation sites Invisible peritoneal lesions Incomplete excision of tissue Spillage of endometrioma Stem cell involvement Main theories and mechanisms proposed to explain primary disease Immune dysregulation Retrograde menstruation Stem-like endometriotic cells Immunotolerant peritoneal niche Fig. 1 | Potential biological mechanisms of endometriosis recurrence. The left panel illustrates surgery-related mechanisms contributing to lesion recurrence, including minimal residual disease (resulting from incomplete excision, invisible peritoneal lesions, or impaired immune clearance of remaining endometriotic cells as a result of surgical transient immunosuppression) as well as the unintentional dissemination of viable endometrial material with the capacity to implant in the peritoneal cavity and give rise to recurrent lesions. The right panel depicts potential mechanisms of de novo lesion formation, integrating several hypotheses described in the literature. Surgical scars are also represented as favorable implantation sites for disseminated endometriotic cells or menstrual debris, potentially facilitating lesion establishment. Created in BioRender. Delgado, R. (2026) https://BioRender.com/ 1s91uhu. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 6 discontinued, dormant cells may re- grow, leading to recurrence in the medium term. Indeed, while many experts support continuous hormonal suppression, it is often acknowledged that such treatments may only delay, rather than prevent, recurrence 34,60,117,127. The temporal dynamics of recurrence reinforce this view11. Recurrence commonly shows an early peak, and then enters a plateau of apparent stability, probably representing successful interventions, and rises again in the long term. However, this pattern is difficult to assess consistently in the literature due to the heterogeneity i n follow-up durations and reporting, with most studies providing only short- to medium-term follow-up, typi- cally up to 2 years, although median time to repeat surgery has been reported between 30 and 36 months 39,120. These observations suggest that recurrence due to incomplete or suboptimal surgery tends to manifest earlier, while later recurrences may reflect the slow progression of residual disease or the formation of new lesions. Other recurrence-promoting effects of surgery Beyond residual disease, the surgical procedure itself may contribute to lesion reappearance. Some authors have suggested that the dissemination of viable endometrial cells during surgery may facilitate the development of new lesions. For example, spi llage of endometrioma cyst fluid during excision has been shown to release endometrial cells capable of implanting on surrounding tissues, potentially forming new lesions 128. Similarly, uterine trauma, such as that caused by cesarean section, has been associated with increased risk of endometriosis development129,130,a n d in patients with a prior diagnosis of endometriosis, with a two-fold higher risk of recurrence compared to vaginal births131. This may be a consequence of the intra-abdominal dissemination of endometrial cells131, together with the protective effect of cervical dilat ion and enhanced uterine drainage occurring in vaginal delivery, reducing retrograde menstruation132. This association has led researche rs to consider the role of surgical trauma and wound healing in lesion formation. It has been proposed that newly formed surgical scars may provide a favorable microenvironment for endometriotic lesion development, facilitating cell adhesion and prolifera- tion through extracellular matrix remodeling, angiogenesis, and the release of growth factors 133. Incisional endometriosis (i.e., endometriosis appearing in the cesarean section, episiotomy, or trocar site scars) is a well- documented phenomenon supporting this hypothesis52,134–136.T h e s ea r e a s of surgical trauma could be potential sites where endometrial cells, either spread during surgery or regurgitated in retrograde menstruation, could implant and develop into new lesions 109,128,135. Coincidentally, perioperative immune suppression, triggered by sur- gical stress, may further impair the body’s ability to clear minimal residual disease and disseminated endometrial tissue109. Together, transient immu- nosuppression and local trauma may s ynergistically create a permissive environment for lesion establishment and recurrence137. De novo lesion formation as a potential contributor to late endometriosis recurrence Surgical factors alone cannot fully explain why some patients experience delayed or multiple recurrences despite apparently complete excision. Recurrence rates remain high over time despite advances in surgical techniques 138–140, raising the possibility thatsome recurrent lesions may not stem from residual disease, but rather form de novo. Since surgery does not address the underlying pathophysiology of endometriosis, it is plausible that the disease reappears through the same mechanisms that led to its initial development, representing a progression of the natural course of the disease in susceptible individuals, rather than merely a consequence of incomplete treatment. S 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 - tion. First, recurrent lesions can appear in previously unaffected anatomical sites, including the contralateral ovary or other pelvic locations 18,23,120. Sec- ond, recurrence rates tend to increase with longer follow-up periods25,44,120. This long-term progression has b een interpreted by some authors as supporting de novo lesion formation, hypothesizing that endometriosis may eventually recur in all operated patients128,141. However, there is currently no consensus on whether reported timeframes are enough for the full devel- opment of new lesions and symptoms 11,39. Lastly, the association between younger age and increased recurrence risk also supports this view, as it implies a longer time period for lesions to reappear before menopause38. Assuming that endometriotic lesion recurrence not necessarily stems from residual disease shifts the focus towards the biological processes implicated in lesion initiation. Sampson’s theory of retrograde menstruation remains the most widely accepted explanation for the development of endometriotic lesions 142 and is compatible with de novo recurrence. Mechanisms proposed to explain primary disease in this context, such as immune dysregulation 143, stem cell involvement 144, or pro-angiogenic, immunotolerant peritoneal niche145,146, may also be relevant in the context of recurrence. In this setting, implantation of regurgitated menstrual debris in the peritoneal cavity may be further facilitated by the permissive local environment created by tissue trauma and transient immunosuppression, as discussed above. From this perspective, late recurrence may re flect an individual’s biological predisposition to lesion formation. Future directions: recurrence as a conceptual window into endometriosis pathophysiology Current evidence indicates that endometriosis recurrence is a result of multiple, overlapping processes, including residual disease, surgery-related effects, and de novo lesion formation, whose relative contributions may vary depending on each patient’s surgical context and baseline biology. Under- standing the biological basis of disease recurrence is essential to move beyond its clinical characterization and towards identifying the core pro- cesses sustaining endometriosis. T o date, however, most research has focused on surgical determinants, leaving these underlying susceptibilities largely unexplored. It is plausible that women prone to recurrence may harbor intrinsic biological traits that favor lesion re-establishment, such as impaired immune clearance of menstrual debris 143, epigenetic alterations that enhance cell survival and adhesion 147, increased presence of endometrial stem cells 144, and a peritoneal microenvironment more permissive to implantation145,146. These mechanisms, proposed as contributors to disease onset, may similarly promote lesion reappearance in biologically susceptible individuals, a hypothesis that warrants future investigation. Hence, viewed through this lens, recurrence becomes not just a clini- cally relevant outcome, but also a c onceptual and biological model for investigating the core processes of endometriosis. Patients who develop recurrence despite apparently complete excision may represent an infor- mative subgroup in whom disease drivers remain active or re-emerge after surgery. Their disease course could provide insights into key drivers of lesion initiation, including microenvironmental, immunological, or molecular alterations that facilitate the growth of residual cells or the implantation of disseminated or regurgitated endometrial cells. Understanding these path- ways could help clarify whether recurrence is more a reflection of disease progression than surgical failure, and whether some patients exhibit a more aggressive disease phenotype. A deeper understanding of the biological basis of recurrence could also inform prevention and treatment strategies. If early postoperative or base- line characteristics could predict recurrence, they might guide surgical decisions, follow-up intensity, and duration of hormonal suppression. Moreover, identifying mechanistically relevant molecular signatures may provide not only predictive tools but also functional biomarkers, enabling patient stratification, precise monitoring of disease progression, and the development of targeted, mechanism-based therapies, potentially beyond hormonal treatment. In this light, recurrence of endometriosis lesions should be reframed not only as a clinical challenge, but also as a conceptual opportunity to investigate the pathogenic mechanisms of endometriosis: a natural stress test that reveals the processes most essential to lesion survival and reap- pearance, opening a window into the pathogenesis of the disease itself. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 7

Recurrence remains a major challenge in the clinical management of endometriosis and a source of uncertainty for both patients and profes- sionals. Conceptual and methodological differences across studies compli- cate the accurate interpretation of clinical outcomes. The adoption of a standardized, multidimensional definition of recurrence, together with uniform outcome measures systematically collected during long follow-ups, will be crucial to improve research comparability. These efforts should ideally build on and expand the existing Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) surgical standard operating procedures 148 to incorporate longitudinal outcome reporting and facilitate multicentric studies on endometriosis recurrence. Beyond methodological improvement, endometriosis recurrence represents a biologically informative event and offers a unique opportunity to uncover key pathways involved in lesion initiation and survival. Inte- grating clinical and molecular data f rom well-annotated longitudinal cohorts could drive the development of predictive tools, mechanistically relevant biomarkers, and novel therapeutic targets, not only laying the foundation for patient risk stratification and personalized long-term man- agement but also improving our broader understanding of endometriosis pathogenesis. Data availability No datasets were generated or analyzed during the current study. R e c e i v e d :2 5J u l y2 0 2 5 ;A ccepted: 5 January 2026;

1. As-Sanie, S. et al. Endometriosis: a review. JAMA 334, 64 (2025). 2. Maulenkul, T. et al. Understanding the impact of endometriosis on women’ s life: an integrative review of systematic reviews. BMC Women’s Health 24, 524 (2024). 3. Chaichian, S. et al. Comparing the ef ficacy of surgery and medical therapy for pain management in endometriosis: a systematic review and meta-analysis. Pain Physician 20, 185–195 (2017). 4. Mijatovic, V. & Vercellini, P. Towards comprehensive management of symptomatic endometriosis: beyond the dichotomy of medical versus surgical treatment. Hum. Reprod. 39, 464–477 (2024). 5. Singh, S. S. & Suen, M. W. H. Surgery for endometriosis: beyond medical therapies. Fertil. Steril. 107, 549–554 (2017). 6. Becker, C. M. et al. ESHRE guideline: endometriosis. Hum. Reprod. Open. 2022, hoac009 (2022). 7. Chen, I. et al. Pre- and postsurgical medical therapy for endometriosis surgery. Cochrane Database Syst. Rev. 11, CD003678 (2020). 8. Abbott, J. et al. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial.Fertil. Steril.82, 878–884 (2004). 9. Vercellini, P. et al. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classi fication system. Hum. Reprod. 21, 2679–2685 (2006). 10. Seracchioli, R. et al. Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. Fertil. Steril. 94, 464–471 (2010). 11. Guo, S.-W. Recurrence of endometriosis and its control. Hum. Reprod. Update 15, 441–461 (2009). 12. Vercellini, P. et al. Post-operative endometriosis recurrence: a plea for prevention based on pathogenetic, epidemiological and clinical evidence. Reprod. Biomed. Online 21, 259–265 (2010). 13. As-Sanie, S. et al. Assessing research gaps and unmet needs in endometriosis. Am. J. Obstet. Gynecol. 221,8 6–94 (2019). 14. Hanton, T. et al. Women's health research priorities in the UK: a consensus statement from RCOG. the lancet 1, e249– e250 (2025). 15. Wei, Y., Liang, Y., Lin, H., Dai, Y. & Yao, S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J. Neuroinflammation 17, 80 (2020). 16. Kobayashi, H. et al. Mechanism of pain generation for endometriosis- associated pelvic pain. Arch. Gynecol. Obstet. 289,1 3–21 (2014). 17. Yoshino, O. et al. Bradykinin system is involved in endometriosis- related pain through endothelin-1 production. Eur. J. Pain 22, 501–510 (2018). 18. Vignali, M. et al. Surgical treatment of deep endometriosis and risk of recurrence. J. Minim. Invasive Gynecol. 12, 508–513 (2005). 19. Coccia, M. E., Rizzello, F., Palagiano, A. & Scarselli, G. Long-term follow-up after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometriotic lesions and pain. Eur. J. Obstet. Gynecol. Reprod. Biol. 157,7 8–83 (2011). 20. Orr, N. L. et al. Association of Central Sensitization Inventory Scores With Pain Outcomes After Endometriosis Surgery. JAMA Netw. Open 6, e230780 (2023). 21. Tucker, D. R. et al. Pelvic pain comorbidities associated with quality of life after endometriosis surgery. Am. J. Obstet. Gynecol. 229, 147.e1–147.e20 (2023). 22. Khan, K. N. et al. Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions. Hum. Reprod. 28, 109–118 (2013). 23. Exacoustos, C. et al. Recurrence of endometriomas after laparoscopic removal: Sonographic and clinical follow-up and indication for second surgery. J. Minim. Invasive Gynecol. 13, 281–288 (2006). 24. Tobiume, T. et al. Determinant factors of postoperative recurrence of endometriosis: difference between endometrioma and pain. Eur. J. Obstet. Gynecol. Reprod. Biol. 205,5 4–59 (2016). 25. Ianieri, M. M., Mautone, D. & Ceccaroni, M. Recurrence in deep infiltrating endometriosis: a systematic review of the literature. J. Minim. Invasive Gynecol. 25, 786–793 (2018). 26. Zakhari, A. et al. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis. Hum. Reprod. Update 27,9 6–107 (2021). 27. Nati, I.-D. et al. Endometriosis reccurence — Is ultrasound the solution?. Curr. Med. Imaging Rev. 20 , e050423215451 (2023). 28. Ceccaroni, M., Bounous, V. E., Clarizia, R., Mautone, D. & Mabrouk, M. Recurrent endometriosis: a battle against an unknown enemy. Eur. J. Contracept. Reprod. Health Care 24, 464–474 (2019). 29. Nisenblat, V., Bossuyt, P. M. M., Farquhar, C., Johnson, N. & Hull, M. L. Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database Syst. Rev. 2, CD009591 (2016). 30. Guerra, A. et al. Imaging of postoperative endometriosis. Diagn. Interv. Imaging 100, 607–618 (2019). 31. Veth, V. B. et al. Recurrence after surgery for endometrioma: a systematic review and meta-analyses.Fertil. Steril.122, 1079–1093 (2024). 32. Muzii, L. et al. Second surgery for recurrent endometriomas is more harmful to healthy ovarian tissue and ovarian reserve than first surgery. Fertil. Steril. 103, 738–743 (2015). 33. Canis, M. & Guo, S.-W. In the thicket of fears, doubts, and murky facts: some reflections on treatment modalities for endometriosis- associated pain. Hum. Reprod. 38, 1245–1252 (2023). 34. Vercellini, P. et al. Repetitive surgery for recurrent symptomatic endometriosis: what to do?. Eur. J. Obstet. Gynecol. Reprod. Biol. 146,1 5–21 (2009). 35. Singh, S. S., Gude, K., Perdeaux, E., Gattrell, W. T. & Becker, C. M. Surgical outcomes in patients with endometriosis: a systematic review. J. Obstet. Gynaecol. Can. 42, 881–888.e11 (2020). 36. Bougie, O., McClintock, C., Pudwell, J., Brogly, S. B. & Velez, M. P. Long-term follow-up of endometriosis surgery in Ontario: a population-based cohort study. Am. J. Obstet. Gynecol. 225, 270.e1–270.e19 (2021). https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 8 37. Capezzuoli, T. et al. Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence. Reprod. Biomed. Online 42, 451–456 (2021). 38. Seo, J.-W., Lee, D.-Y., Yoon, B.-K. & Choi, D. The age-related recurrence of endometrioma after conservative surgery. Eur. J. Obstet. Gynecol. Reprod. Biol. 208,8 1–85 (2017). 39. Liu, X. et al. Patterns of and risk factors for recurrence in women with ovarian endometriomas. Obstet. Gynecol. 109, 1411–1420 (2007). 40. Sengoku, K. et al. Clinicopathologic risk factors for recurrence of ovarian endometrioma following laparoscopic cystectomy. Acta Obstet. Gynecol. Scand. 92, 278–284 (2013). 41. Yuan, M. et al. Risk factors for recurrence of ovarian endometriomas after surgical excision. J. Huazhong Univ. Sci. Technol. Med. Sci.34, 213–219 (2014). 42. Moini, A., Arabipoor, A. & Ashra finia, N. Risk factors for recurrence rate of ovarian endometriomas following a laparoscopic cystectomy. Minerva Med. 105, 295–301 (2014). 43. Han, S. et al. Risk factors related to the recurrence of endometrioma in patients with long-term postoperative medical therapy. Ginekol. Pol. 89, 611–617 (2018). 44. Choi, S. H. et al. Recurrence, reoperation, pregnancy rates, and risk factors for recurrence after ovarian endometrioma surgery: long- term follow-up of 756 women. Yonsei Med. J. 64, 204–212 (2023). 45. Nirgianakis, K. et al. Laparoscopic management of bowel endometriosis: resection margins as a predictor of recurrence. Acta Obstet. Gynecol. Scand. 93, 1262–1267 (2014). 46. Uccella, S. et al. Laparoscopy for ureteral endometriosis: surgical details, long-term follow-up, and fertility outcomes.Fertil. Steril. 102, 160–166.e2 (2014). 47. Yang, X. et al. Status and related factors of postoperative recurrence of ovarian endometriosis: a cross-sectional study of 874 cases. Arch. Gynecol. Obstet. 307, 1495–1501 (2023). 48. Busacca, M. et al. Determinants of long-term clinically detected recurrence rates of deep, ovarian, and pelvic endometriosis. Am. J. Obstet. Gynecol. 195, 426–432 (2006). 49. Yun, B. H. et al. The prognostic value of individual adhesion scores from the revised American Fertility Society Classification System for Recurrent Endometriosis. Yonsei Med. J. 56 , 1079 (2015). 50. Su, H. & Xie, Z. In fluencing factors and prediction model construction for recurrence in patients with ovarian endometriosis after laparoscopic conservative surgery. Am. J. Transl. Res. 16, 7458–7466 (2024). 51. Fedele, L., Bianchi, S., Zanconato, G., Bettoni, G. & Gotsch, F. Long- term follow-up after conservative surgery for rectovaginal endometriosis. Am. J. Obstet. Gynecol. 190, 1020–1024 (2004). 52. Zhong, Q., Qin, S., Lai, H., Yao, S. & Chen, S. Risk factors for postoperative recurrence of cesarean scar endometriosis. AJOG Glob. Rep. 4, 100349 (2024). 53. Chon, S. J., Lee, S. H., Choi, J. H. & Lee, J. S. Preoperative risk factors in recurrent endometrioma after primary conservative surgery. Obstet. Gynecol. Sci. 59, 286–294 (2016). 54. Küçükba ş, M. et al. Which factors are associated with the recurrence of endometrioma after cystectomy?. J. Obstet. Gynaecol. J. Inst. Obstet. Gynaecol. 38, 372–376 (2018). 55. Han, J. & Zheng, L. Analysis of risk factors for bleeding and recurrence of ovarian endometriomas after laparoscopic surgery and its impact on pregnancy outcomes. Clin. Exp. Obstet. Gynecol. 51, 5 (2024). 56. Yu, L., Sun, Y. & Fang, Q. Ef ficacy of laparoscopic surgery combined with leuprorelin in the treatment of endometriosis associated with infertility and analysis of in fluencing factors for recurrence. Front. Surg. 9, 873698 (2022). 57. Mustard, C. et al. Predicting pain reduction following laparoscopic surgery for endometriosis: a retrospective cohort study using UK national and research databases. BMJ Open 15, e099374 (2025). 58. Holdsworth-Carson, S. J. et al. Predicting disease recurrence in patients with endometriosis: an observational study. BMC Med. 22, 320 (2024). 59. Porpora, M. G. et al. Pain and ovarian endometrioma recurrence after laparoscopic treatment of endometriosis: a long-term prospective study. Fertil. Steril. 93, 716–721 (2010). 60. Koga, K., Takamura, M., Fujii, T. & Osuga, Y. Prevention of the recurrence of symptom and lesions after conservative surgery for endometriosis. Fertil. Steril. 104, 793–801 (2015). 61. Candiani, M. et al. Recurrence rate after ‘ One-Step’ CO 2 fiber laser vaporization versus cystectomy for ovarian endometrioma: a 3-year follow-up study. J. Minim. Invasive Gynecol. 27, 901–908 (2020). 62. Lee, N. et al. The recurrence rate of ovarian endometrioma in women aged 40-49 years and impact of hormonal treatment after conservative surgery. Sci. Rep. 10, 16461 (2020). 63. Koga, K. et al. Recurrence of ovarian endometrioma after laparoscopic excision. Hum. Reprod. 21, 2171–2174 (2006). 64. Saleh, A. & Tulandi, T. Reoperation after laparoscopic treatment of ovarian endometriomas by excision and by fenestration.Fertil. Steril. 72, 322–324 (1999). 65. Busacca, M. et al. Recurrence of ovarian endometrioma after laparoscopic excision. Am. J. Obstet. Gynecol.180, 519–523 (1999). 66. Sun, M. et al. Extrinsic adenomyosis is associated with postoperative recurrence of ovarian endometrioma. Front. Med. 8, 815628 (2022). 67. Huang, G., Fan, X. & Zhu, P. Analysis of recurrence factors associated with conservative surgery for ovarian-type endometriosis. Ann. Transl. Med. 10, 255 (2022). 68. Li, F. et al. Construction of a clinical predictive model for risk factors after laparoscopic surgery in patients with endometriosis based on pathologic characteristics.Am. J. Transl. Res.17, 3392–3403 (2025). 69. Takamura, M. et al. Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. Hum. Reprod. 24, 3042–3048 (2009). 70. Hayasaka, S. et al. Risk factors for recurrence and re-recurrence of ovarian endometriomas after laparoscopic excision. J. Obstet. Gynaecol. Res. 37, 581–585 (2011). 71. Bendifallah, S. et al. Recurrence after surgery for colorectal endometriosis: a systematic review and meta-analysis. J. Minim. Invasive Gynecol. 27, 441–451.e2 (2020). 72. Xu, P., Wang, J., Zhang, Y., Zhu, L. & Zhang, X. Factors affecting the postoperative bowel function and recurrence of surgery for intestinal deep endometriosis. Front. Surg. 9, 914661 (2022). 73. Afors, K. et al. Segmental and discoid resection are preferential to bowel shaving for medium-term symptomatic relief in patients with bowel endometriosis. J. Minim. Invasive Gynecol. 23, 1123–1129 (2016). 74. Ngernprom, P., Klangsin, S., Suwanrath, C. & Peeyananjarassri, K. Risk factors for recurrent endometriosis after conservative surgery in a quaternary care center in southern Thailand. PLoS ONE 18, e0289832 (2023). 75. Yela, D. A., Vitale, S. G., Vizotto, M. P. & Benetti-Pinto, C. L. Risk factors for recurrence of deep infiltrating endometriosis after surgical treatment. J. Obstet. Gynaecol. Res. 47, 2713–2719 (2021). 76. Vercellini, P. et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil. Steril. 80, 305–309 (2003). 77. Sesti, F. et al. Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III –IV. A randomized comparative trial. Fertil. Steril. 88, 1541–1547 (2007). 78. Seracchioli, R. et al. Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil. Steril. 93,5 2–56 (2010). https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 9 79. Vercellini, P. et al. Postoperative oral contraceptive exposure and risk of endometrioma recurrence. Am. J. Obstet. Gynecol. 198, 504.e1–5 (2008). 80. Seong, S. J. et al. Role of hormone therapy after primary surgery for endometrioma: a multicenter retrospective cohort study. Reprod. Sci. 23, 1011–1018 (2016). 81. Kwok, H. et al. Risk factors for postoperative recurrence of deep infiltrating endometriosis during a 6- to 12-year follow-up. Sci. Rep. 15, 37544 (2025). 82. Del Forno, S. et al. Long-term medical therapy after laparoscopic excision of ovarian endometriomas: Can we reduce and predict the risk of recurrence?. Gynecol. Obstet. Investig. 86, 170–176 (2021). 83. Li, X.-Y. et al. Risk factors for postoperative recurrence of ovarian endometriosis: long-term follow-up of 358 women. J. Ovarian Res. 12, 79 (2019). 84. Gibbons, T., Georgiou, E. X., Cheong, Y. C. & Wise, M. R. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst. Rev. 2021, CD005072 (2021). 85. Grandi, G. et al. Hormonal contraception in women with endometriosis: a systematic review. Eur. J. Contracept. Reprod. Health Care 24,6 1–70 (2019). 86. Ceccaroni, M. et al. Dienogest vs GnRH agonists as postoperative therapy after laparoscopic eradication of deep in filtrating endometriosis with bowel and parametrial surgery: a randomized controlled trial. Gynecol. Endocrinol. 37, 930–933 (2021). 87. Chen, Y.-J. et al. Postoperative maintenance levonorgestrel- releasing intrauterine system and endometrioma recurrence: a randomized controlled study. Am. J. Obstet. Gynecol. 216, 582.e1–582.e9 (2017). 88. Muzii, L. et al. Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial. Am. J. Obstet. Gynecol. 183, 588–592 (2000). 89. Lee, K. H. et al. Comparison of the ef ficacy of diegnogest and levonorgestrel-releasing intrauterine system after laparoscopic surgery for endometriosis. J. Obstet. Gynaecol. Res. 44, 1779–1786 (2018). 90. Drechsel-Grau, A. et al. Long-term follow-up regarding pain relief, fertility, and re-operation after surgery for deep endometriosis. J. Clin. Med. 13, 5039 (2024). 91. Cooper, K. G. et al. Preventing recurrence of endometriosis-related pain by means of long-acting progestogen therapy: the PRE-EMPT RCT. Health Technol. Assess. 28,1 –77 (2024). 92. Leyland, N. et al. Endometriosis: diagnosis and management. J. Obstet. Gynaecol. Can. 32,S 1–S3 (2010). 93. Zhang, P. & Wang, G. Progesterone resistance in endometriosis: current evidence and putative mechanisms.Int. J. Mol. Sci. 24, 6992 (2023). 94. Tang, H., Lin, T., Wu, M. & Tsai, S. Progesterone resistance in endometriosis: a pathophysiological perspective and potential treatment alternatives. Reprod. Med. Biol. 23, e12588 (2024). 9 5 . J i a n g ,D . ,Z h a n g ,X . ,S h i ,J . ,T a o ,D .&N i e ,X .R i s kf a c t o r sf o ro v a r i a n endometrioma recurrence following surgical excision: a systematic review and meta‑analysis.Arch. Gynecol. Obstet.304,5 8 9–598 (2021). 96. Su, C., Yang, J., Ding, J. & Ding, H. Factors that increase the likelihood of ovarian endometriosis relapsing after surgical excision: a systematic review and meta-analysis. Clin. Exp. Obstet. Gynecol. 50, 182 (2023). 97. Long, Q., Liu, X. & Guo, S.-W. Surgery accelerates the development of endometriosis in mice. Am. J. Obstet. Gynecol. 215, 320.e1–320.e15 (2016). 98. Sasamoto, N. et al. Evaluation of CA125 in relation to pain symptoms among adolescents and young adult women with and without surgically-confirmed endometriosis. PLoS ONE 15, e0238043 (2020). 99. NICE Women ’ s and Reproductive Health Suite Endometriosis Committee. Endometriosis: diagnosis and management https:// www.nice.org.uk/guidance/ng73 (National Institute for Health and Care Excellence, 2024). 100. Huang, H., Zhu, Z. & Song, Y. Downregulation of lncRNA UCA1 as a diagnostic and prognostic biomarker for ovarian endometriosis. Rev. Assoc. Méd. Bras. 65, 336–341 (2019). 101. Song, Y. et al. Downregulation of lncRNA LINC01465 predicts ovarian endometriosis and its prognosis. Wien. Klin. Wochenschr. 136, 163–168 (2024). 102. Sun, S. G. et al. The extracellular vesicular pseudogene LGMNP1 induces M2-like macrophage polarization by upregulating LGMN and serves as a novel promising predictive biomarker for ovarian endometriosis recurrence. Hum. Reprod. 37, 447–465 (2022). 103. Abdoli, M. et al. Endometriotic lesions and their recurrence: a study on the mediators of immunoregulatory (TGF- β/miR-20a) and stemness (NANOG/miR-145). J. Reprod. Immunol. 166, 104336 (2024). 104. Liu, S. et al. LncRNA H19 overexpression in endometriosis and its utility as a novel biomarker for predicting recurrence. Reprod. Sci. 27, 1687–1697 (2020). 105. Yuan, L., Shen, F., Lu, Y., Liu, X. & Guo, S.-W. Cyclooxygenase-2 overexpression in ovarian endometriomas is associated with higher risk of recurrence. Fertil. Steril. 91, 1303–1306 (2009). 106. Shen, F. et al. Immunoreactivity of progesterone receptor isoform B and nuclear factor kappa-B as biomarkers for recurrence of ovarian endometriomas.A m .J .O b s t e t .G y n e c o l .199,4 8 6 . e 1–486.e10 (2008). 107. Shen, F., Liu, X., Geng, J.-G. & Guo, S.-W. Increased immunoreactivity to SLIT/ROBO1 in ovarian endometriomas. Am. J. Pathol. 175, 479–488 (2009). 108. Long, Q., Zheng, H., Liu, X. & Guo, S.-W. Perioperative intervention by β-blockade and NF-κB suppression reduces the recurrence risk of endometriosis in mice due to incomplete excision. Reprod. Sci. 26, 697–708 (2019). 109. Guo, S.-W. & Martin, D. C. The perioperative period: a critical yet neglected time window for reducing the recurrence risk of endometriosis?. Hum. Reprod. 34, 1858–1865 (2019). 110. Guo, S.-W., Zheng, Y., Lu, Y., Liu, X. & Geng, J.-G. Slit2 overexpression

in increased microvessel density and lesion size in mice with induced endometriosis.Reprod. Sci. 20,2 8 5–298 (2013). 111. Han, A. R., Lee, T. H., Kim, S. & Lee, H. Y. Risk factors and biomarkers for the recurrence of ovarian endometrioma: about the immunoreactivity of progesterone receptor isoform B and nuclear factor kappa B. Gynecol. Endocrinol. 33,7 0–74 (2017). 112. Tarumi, Y. et al. Progesterone receptor status of epithelial cells as a predictive marker for postoperative recurrence of endometriosis. J. Clin. Endocrinol. Metab. 107, 1552–1559 (2022). 113. Yalcin, S. E. et al. Evaluation of the Ki-67 proliferation index and urocortin expression in women with ovarian endometriomas. Eurasia. J. Med. 49, 107–112 (2017). 114. Wu, T., Zhang, R., Jiang, Q., Li, Z. & Wu, R. Expression of cellular adherent and invasive molecules in recurrent ovarian endometriosis. J. Int. Med. Res. 48, 0300060520971993 (2020). 115. Zhu, G. et al. Identi fication of differentially expressed proteins associated with recurrence in ovarian endometriotic cysts. Syst. Biol. Reprod. Med. 66,5 9–69 (2020). 116. Stepniewska, A. et al. Colorectal endometriosis: bene fits of long- term follow-up in patients who underwent laparoscopic surgery. Fertil. Steril. 93, 2444–2446 (2010). 117. Bozdag, G. Recurrence of endometriosis: risk factors, mechanisms and biomarkers. Women’s Health 11, 693–699 (2015). https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 10 118. Carmona, F. et al. Does the learning curve of conservative laparoscopic surgery in women with rectovaginal endometriosis impair the recurrence rate?. Fertil. Steril. 92, 868–875 (2009). 119. Bougie, O. et al. Impact of surgeon characteristics on endometriosis surgery outcomes. J. Minim. Invasive Gynecol. 32, 709–717.e6 (2025). 120. Nirgianakis, K., Ma, L., McKinnon, B. & Mueller, M. D. Recurrence patterns after surgery in patients with different endometriosis subtypes: a long-term hospital-based cohort study. J. Clin. Med. 9, 496 (2020). 121. Roman, H. et al. Bowel occult microscopic endometriosis in resection margins in deep colorectal endometriosis specimens has no impact on short-term postoperative outcomes. Fertil. Steril. 105, 423–429.e7 (2016). 122. Roman, H. et al. Nonvisualized palpable bowel endometriotic satellites. Hum. Reprod. 36, 656–665 (2021). 123. Kalra, R. et al. Excisional surgery versus ablative surgery for ovarian endometrioma.Cochrane Database Syst. Rev.11, CD004992 (2024). 124. Mohtashami, S., Jabarpour, M., Aleyasin, A., Aghahosseini, M. & Najafian, A. Ef ficacy of ethanol sclerotherapy versus laparoscopic excision in the treatment of ovarian endometrioma. J. Obstet. Gynecol. India 74,6 0–66 (2024). 125. García-Tejedor, A. et al. Ultrasound-guided ethanol sclerotherapy versus laparoscopic surgery for endometriomas: a randomized clinical trial in a real-world setting. Arch. Gynecol. Obstet. 312, 2199–2210 (2025). 126. Sar ıdoğan, E. & Mueller, M. D. Recurrent Endometriosis. in Endometriosis and Adenomyosis: Global Perspectives Across the Lifespan (ed. Oral, E.) 235–242. https://doi.org/10.1007/978-3-030- 97236-3_19 (Springer International Publishing, 2022). 127. Vercellini, P. et al. A gonadotrophin-releasing hormone agonist compared with expectant management after conservative surgery for symptomatic endometriosis. Br. J. Obstet. Gynaecol. 106, 672–677 (1999). 128. Xu, X. et al. The presence of living endometrial cells in ovarian endometriotic cyst fluid may contribute to the recurrence of endometriosis after surgical excision of endometriomas. J. Ovarian Res. 15, 89 (2022). 129. Andolf, E., Thorsell, M. & Källén, K. Caesarean section and risk for endometriosis: a prospective cohort study of Swedish registries. BJOG Int. J. Obstet. Gynaecol. 120, 1061–1065 (2013). 130. Liu, X., Long, Q. & Guo, S.-W. Surgical history and the risk of endometriosis: a hospital-based case-control study. Reprod. Sci. 23 , 1217–1224 (2016). 131. Carpini, G. D. et al. Effect of the mode of delivery on the risk of endometriosis recurrence: a retrospective cohort study.Fertil. Steril. 118, 1080–1087 (2022). 132. Bulletti, C. et al. Vaginal parturition decreases recurrence of endometriosis. Fertil. Steril. 94, 850–855 (2010). 133. Canis, M. et al. Trauma and endometriosis. A review. May we explain surgical phenotypes and natural history of the disease?. J. Gynecol. Obstet. Hum. Reprod. 46, 219–227 (2017). 134. Gunes, M., Kayikcioglu, F., Ozturkoglu, E. & Haberal, A. Incisional endometriosis after cesarean section, episiotomy and other gynecologic procedures.J. Obstet. Gynaecol. Res.31,4 7 1–475 (2005). 135. Canis, M., Bourdel, N., Chauvet, P., Gremeau, A. S. & Botchorishvili, R. Recurrences of endometriosis after surgery may be the consequence of retrograde menstruation on the postoperative scar. Hum. Reprod. 35, 1246–1247 (2020). 136. Ananias, P. et al. Cesarean section: a potential and forgotten risk for abdominal wall endometriosis. Cureus 13, e17410 (2021). 137. Guo, S.-W. & Martin, D. C. Reply: Perioperative intervention vs. postoperative menstruation suppression in preventing recurrence of endometriosis. Hum. Reprod. 35, 1247–1248 (2020). 138. Baraki, D., Richards, E. G. & Falcone, T. Treatment of endometriomas: Surgical approaches and the impact on ovarian reserve, recurrence, and spontaneous pregnancy. Best. Pract. Res. Clin. Obstet. Gynaecol. 92, 102449 (2024). 139. Gordts, S. & Campo, R. Modern approaches to surgical management of endometrioma. Best. Pract. Res. Clin. Obstet. Gynaecol. 59,4 8–55 (2019). 140. Dulemba, J. F., Pelzel, C. & Hubert, H. B. Retrospective analysis of robot-assisted versus standard laparoscopy in the treatment of pelvic pain indicative of endometriosis. J. Robot. Surg. 7, 163–169 (2013). 141. Evers, J. L., Dunselman, G. A., Land, J. A. & Bouckaert, P. X. Is there a solution for recurrent endometriosis?. Br. J. Clin. Pract. 72,4 5–50 (1991). 142. Sampson, J. A. The development of the implantation theory for the origin of peritoneal endometriosis. Am. J. Obstet. Gynecol. 40, 549–557 (1940). 143. Symons, L. K. et al. The Immunopathophysiology of Endometriosis. Trends Mol. Med. 24, 748–762 (2018). 144. Sasson, I. E. & Taylor, H. S. Stem cells and the pathogenesis of endometriosis. Ann. N. Y. Acad. Sci. 1127, 106–115 (2008). 145. Tan, Y. et al. Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues. Nat. Cell Biol. 24, 1306–1318 (2022). 146. Chen, S. et al. Peritoneal immune microenvironment of endometriosis: role and therapeutic perspectives. Front. Immunol. 14, 1134663 (2023). 147. Koninckx, P. R. et al. Pathogenesis of endometriosis: the genetic/ epigenetic theory. Fertil. Steril. 111, 327–340 (2019). 148. Becker, C. M. et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research.Fertil. Steril. 102, 1213–1222 (2014).

The authors are grateful to the clinical and research teams whose ongoing efforts continue to support and advance endometriosis research. This work was supported by La Fundació La Marató 2024 through the project “202407-10,” the CP22/00147 granted to E.C., and the CIBERONC network grant number CB16/12/00328. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. Author contributions C.M.F. and E.C. conceived and designed the review. C.M.F. conducted the literature search, performed data curation, drafted the initial manuscript, figure, and tables, and addressed revisions. R.D.G. contributed tofigure and table construction and data validation. E.C. secured funding and provided feedback and editorial input. All authors critically reviewed and approved the final version. Competing interests The authors declare no competing interests. Additional information Correspondenceand requests for materials should be addressed to Eva Colas. Reprints and permissions informationis available at http://www.nature.com/reprints Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 11 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modi fied the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party

in this article are included in the article ’ s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’ s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by- nc-nd/4.0/ . © The Author(s) 2026 https://doi.org/10.1038/s44294-026-00128-9 Review npj Women's Health | (2026) 4:4 12