{"paper_id":"8674b8d2-c6f3-47a7-ad0c-2a9bf0fa6c90","body_text":"Beyond staging: Potentially divergent trajectories of pain, quality of life, and fertility in \nendometriosis – prospective observational cohort study. \n \nMichael Fanta1, Zdeňka Lisá1, Kristýna Hlinecká1, Michal Mára1, Radoslav Janoštiak2,* \n \n1 – Department of Gyneacology, Obstetrics and Neonatology, General University Hospital in \nPrague, First Faculty of Medicine, Prague, 128 08, Czech Republic,    \n2 – First Faculty of Medicine, BIOCEV , Charles University, Prague, 121 08, Czech Republic \n* - corresponding author  \n \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\nAbstract:   \nBackground \nEndometriosis is a heterogeneous disease in which anatomical lesion burden often shows poor \ncorrelation with pain severity and quality-of-life impairment. While classification systems such \nas the revised American Society for Reproductive Medicine (r-ASRM) and Enzian score \naccurately describe anatomical disease extent, their relationship to symptom burden and \nreproductive outcomes remains incompletely understood. \nObjective(s) \nThis study aimed to investigate the relationships between anatomical disease extent, pain \nseverity, quality-of-life impairment, and fertility outcomes across ovarian, deep, and peritoneal \nendometriosis in a prospective cohort of women undergoing surgical treatment. \nStudy Design \nThis prospective observational cohort study included women aged 18–45 years undergoing \nlaparoscopic surgery between 2023 and 2025 at a tertiary endometriosis center. Participants were \ncategorized into ovarian (OE), deep (DE), or peritoneal (PE) endometriosis based on imaging \nand intraoperative findings. Pain severity was assessed using numeric rating scales across \nmultiple domains, and quality of life was evaluated using the Endometriosis Health Profile \n(EHP-30+23). Anatomical disease burden was determined using r-ASRM and Enzian \nclassifications. Patients were followed for 12 months after surgery to assess symptom \ntrajectories, pregnancy outcomes, and surgical complications. A subset of lesion samples \nunderwent RNA sequencing to explore molecular signatures associated with pain severity. \nResults \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nA total of 145 women were included (OE n=33, DE n=55, PE n=25, controls n=32). Pain \nseverity showed limited correlation with anatomical staging across subtypes. In contrast, \ninfertility and the need for ureter surgery were strongly associated with higher Enzian scores and \nstructural disease burden. Quality-of-life impairment closely paralleled pain intensity rather than \nanatomical stage. Transcriptomic analysis identified a molecular signature associated with high \npain burden characterized by increased expression of inflammatory mediators (IL6, CCL8, \nSPP1), endocannabinoid system components (PENK, CNR1) and nociceptive transcription \nfactors (NR4A3, EGR3). Longitudinal follow-up demonstrated substantial postoperative \nimprovement in pain and quality of life independent of pregnancy outcomes. \nConclusions \nPain severity, quality-of-life impairment, and reproductive dysfunction in endometriosis \nrepresent partially independent dimensions of disease activity. While neuroinflammatory \nmechanisms appear to drive pain and quality-of-life impairment, fertility outcomes and organ-\nthreatening complications are primarily determined by structural disease burden. Integrating \nanatomical staging with multidimensional symptom assessment and molecular profiling may \nenable more personalized management strategies for women with endometriosis. \n \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nIntroduction \nEndometriosis is a chronic, inflammatory and estrogen-dependent disease affecting \napproximately 10–15% of women of reproductive age and up to 50% of women with infertility1. \nIt is characterized by the presence of endometrium-like tissue outside the uterine cavity and \npresents with a highly heterogeneous clinical phenotype, ranging from asymptomatic disease to \nsevere pelvic pain, organ dysfunction and impaired fertility2. The most frequently reported \nsymptoms include dysmenorrhea, dyspareunia, chronic pelvic pain and bowel or urinary \ncomplaints, all of which may significantly reduce physical, sexual and professional activity and \nnegatively impact quality of life3. \nDespite decades of research, the relationship between anatomical disease extent and clinical \nsymptom burden remains incompletely understood. The revised American Society for \nReproductive Medicine (r-ASRM) classification has been widely used to stage endometriosis \nbased on surgical findings4; however, multiple studies have demonstrated poor correlation \nbetween r-ASRM stage and pain severity5,6. Similarly, the Enzian and its updated version \n#Enzian were developed to provide a more detailed description of deep infiltrating endometriosis \n(DE) and compartment-specific involvement7. Although these systems improve and facilitate \nanatomical mapping and surgical planning, their correlation with patient-reported pain remains \ninconsistent6,8.  \nRecent prospective analyses have shown that the intensity of dysmenorrhea, dyspareunia and \nchronic pelvic pain does not systematically increase with more extensive compartment \ninvolvement in deep endometriosis8,9. Likewise, ultrasound-based Enzian (ENZIAN(u)) staging \ndemonstrated that dysmenorrhea shows no clear compartment-specific pattern, while \ndyspareunia and bowel symptoms show only selective associations, primarily with retrocervical \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nor uterosacral ligament involvement8–10. These findings support the concept that pain in \nendometriosis is multifactorial and not solely determined by lesion size or anatomical \ndistribution. \nIn contrast, pathophysiology of fertility in endometriosis is very complex, and it appears more \nclosely associated with anatomical disease burden. Warzecha et al. reported that infertility \nprevalence increases significantly with advanced r-ASRM stage, even though pain severity does \nnot11. Severe disease was associated with prolonged time to conception and higher infertility \nrates, suggesting that reproductive prognosis depends more strongly on structural distortion, \nadhesions and deep compartment involvement than on symptom intensity11. This mismatch \nbetween anatomical extent and reproductive outcomes suggests that pain, quality-of-life \nimpairment, and fertility may represent partially distinct (though interrelated) aspects of disease \nburden. \nFurthermore, endometriosis is increasingly viewed as a multidimensional condition with \nsystemic and psychosocial components. Chronic pelvic pain is associated with reduced quality of \nlife and a higher prevalence of depressive symptoms, yet depressive symptom severity appears to \ncorrelate more strongly with pain burden than with disease stage12–14. These data highlight the \nlimitation of purely lesion-based classifications and support the need for integrated clinical \nmodels that simultaneously consider anatomical, symptomatic and reproductive outcomes. \nAlthough prior studies have evaluated classification systems, symptom correlations, or quality-\nof-life impairment individually, few investigations have examined these domains concurrently \nacross endometriosis subtypes or assessed their evolution longitudinally after laparoscopic \nsurgical treatment. In particular, limited data exist comparing ovarian endometriosis (OE), deep \nendometriosis (DE), and peritoneal endometriosis (PE) with respect to pain trajectories, quality-\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nof-life improvement, postoperative anatomical scores, and subsequent pregnancy outcomes \nwithin the same cohort. \nGiven the increasing emphasis on individualized management and fertility preservation \nstrategies, a comprehensive analysis integrating anatomical staging, symptom burden, quality-of-\nlife impairment and reproductive outcomes across endometriosis subtypes is warranted. \nClarifying whether symptom improvement translates into improved fertility, and whether \nresidual anatomical disease burden predicts reproductive success independent of pain, has direct \nimplications for patient counseling and treatment planning. \nThe aim of the present study was therefore to investigate the relationships between (1) \nanatomical disease extent assessed by r-ASRM and Enzian classification, (2) pain severity and \nmultidimensional quality-of-life impairment, and (3) postoperative pregnancy outcomes across \novarian, deep and peritoneal endometriosis. By integrating these domains in a longitudinal \nframework, we sought to clarify whether pain, quality of life and fertility represent convergent or \nindependent axes of disease activity and to identify subtype-specific patterns that may inform \npersonalized management strategies.  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nMaterials and Methods \nStudy Design and Setting \nThis study was designed as a prospective observational cohort analysis with longitudinal follow-\nup. Women diagnosed with endometriosis were consecutively recruited at General University \nHospital in Prague (2023-2025). The study included both cross-sectional baseline assessment and \nfollow-up evaluation at 3 and 12 months after surgical intervention. The primary objective was to \nevaluate the relationship between anatomical disease burden, symptom severity, quality-of-life \nimpairment, and reproductive outcomes across endometriosis subtypes. Secondary objectives \nincluded assessment of sterility status and predictors of ureter surgery. \nThe study was conducted in accordance with the Declaration of Helsinki and approved by the \nlocal Ethics committee of General University Hospital, Department of Gyneacology, Obstetrics \nand Neonatology (Ethical approval ID: Ref. No. 3/23 Grant GIP) on 16/02/2023. The recruitment \nof the patients for the study started on 01/04/2023. All participants provided written informed \nconsent prior to inclusion. \n \nParticipants \nInclusion criteria \n• Women aged 18–45 years \n• Availability of complete baseline pain and quality-of-life data \n• Available r-ASRM and/or Enzian classification \nAdditional inclusion criteria – endometriosis group \n• Laparoscopically and histologically confirmed diagnosis of endometriosis \nAdditional inclusion criteria – healthy controls \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\n• No endometriosis detected intra-operatively or histologically \n• Undergoing planned laparoscopic or hysteroscopic procedure for another benign \nindication \nExclusion criteria (both groups) \n• Age <18 or >45 years \n• Refusal to participate or withdrawal of consent \n• Non-fulfilment of group-specific criteria at the time of surgery \n• Active malignancy \n• Severe systemic or psychiatric comorbidities that could independently affect quality of \nlife \n• Incomplete staging or missing follow-up data \nHealthy controls were recruited among women undergoing gynecological laparoscopic surgery \nfor other benign indications and had no clinical, imaging, or surgical evidence of endometriosis.  \nEndometriosis Phenotyping \nParticipants were categorized into three subtypes based on dominant lesion type: \n1. Ovarian endometriosis (OE) \n2. Deep endometriosis (DE) \n3. Peritoneal endometriosis (PE) \nSubtype classification was determined preoperatively by expert sonographers using high-\nresolution transvaginal ultrasound according to the International Deep Endometriosis Analysis \n(IDEA) consensus criteria and intraoperatively by the operating surgeon. \nAnatomical Staging \nDisease severity was assessed using: \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\n• Revised American Society for Reproductive Medicine (r-ASRM) staging (I–IV) \n• #Enzian classification - Enzian scores were recorded both preoperatively based on \nultrasound (u) and intraoperatively based on surgical findings (s).) \nEnzian compartments and severity grades were systematically documented as Enzian (u) by \nexpert sonographers in the preoperative transvaginal ultrasound report and as surgical Enzian \n[Enzian (s)] by the operating surgeon in the operative report. \nSurgical Management \nAll surgeries were performed by experienced endometriosis surgeons within a multidisciplinary \nteam. The surgical goal was complete excision of macroscopically visible lesions while \npreserving organ function and fertility when possible. Ureter surgery (e.g., ureterolysis or \nresection) was documented separately. Indications were based on intraoperative findings of \nureteral involvement or obstruction. \nPain Assessment \nPain was evaluated using an 11-point Numeric Rating Scale (NRS, 0–10) for the following \ndomains: \n• Chronic pelvic pain \n• Dysmenorrhea (painful menstruation) \n• Dyspareunia (painful sexual intercourse) \n• Dysuria (painful urination) \n• Dyschezia (painful defecation) \nA composite pain score was calculated as the mean of individual pain domain scores. \nPain assessment was performed: \n• At baseline (preoperatively) \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\n• At 3 months postoperatively \n• At 12 months postoperatively \nEnzian score calculation: \nEnzian (u) and (s) scores were recorded by assigning compartment-specific severity grades (1–3) \naccording to lesion size/extent for each affected compartment, including peritoneal (P), ovarian \n(O), tubal (T), and deep infiltrating compartments A, B, and C. \nQuality-of-Life Assessment \nQuality of life was assessed using a structured questionnaire comprising four arbitrary domains: \n• Physical and functional impairment \n• Symptom burden and perceived control \n• Emotional and psychological distress \n• Social identity and stigma \nThe Endometriosis Health Profile-30+23 (EHP-30+23) was scored on a standardized scale; item \nscores were averaged to derive domain-specific and overall quality-of-life (QoL) impairment \nscores. \n \nFertility and Reproductive Outcomes \nSterility status was defined as failure to conceive after ≥12 months of regular unprotected \nintercourse. \nPregnancy outcomes were assessed at 12-month follow-up. Both spontaneous conception and \nconception via assisted reproductive technologies (ART) were recorded. \nAnti-Müllerian hormone (AMH) levels were documented where available, both preoperatively \nand at 3 months postoperatively. \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nLongitudinal Follow-up \nPatients were reassessed at: \n• 3 months postoperatively \n• 12 months postoperatively \nThe following were recorded at follow-up: \n• Pain scores \n• Quality-of-life (QoL) scores \n• Clinical gynecological examination and Enzian (u) score \n• Conception attempts and Pregnancy status \n \nPain-associated biomarker analysis. \nA subset of patient tissue samples included in this study was subjected to transcriptomic profiling \nto explore molecular signatures associated with pain severity and endometriosis subtype. RNA \nsequencing (RNA-seq) was performed as previously described15, with raw sequencing data \ndeposited in the ArrayExpress database under accession number E-MTAB-15117. Sample \nselection was performed without clinical pre-stratification and was based solely on chronological \nprocurement and fulfillment of predefined RNA quality criteria. The final cohort included \nsamples from ovarian, deep, and peritoneal endometriosis lesions, as summarized in \nSupplementary Figure 1A. For exploratory analysis of pain-associated molecular signatures, \npatients were stratified into high-pain and low-pain groups based on composite pain scores \nderived from standardized numeric rating scale assessments at baseline. High-pain group \ncorresponds to samples from women with composite pain score above median (>15.5), while \nlow-pain group corresponds samples from women with composite pain score below median \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\n(<15.5). Pain stratification thresholds were predefined to ensure separation of clinically \nmeaningful phenotypes while maintaining adequate statistical power. Gene expression was \nanalyzed using standard bioinformatics pipeline in R (4.4.2) using Bioconductor package \nDEseq216. Final p values were adjusted using the Benjamini and Hochberg method and genes \nwith p-adjusted value <0.05 were considered significantly differentially expressed.  \n \nStatistical Analysis \nBetween-group comparisons \nKruskal–Wallis tests were used for comparisons between groups followed by Dunn’s multiple \ncomparisons test for comparison between individual groups.  Fisher’s exact test was used for \ncategorical variables. \nCorrelation analyses \nSpearman correlation coefficients were calculated to assess relationships between: \n• Pain scores and anatomical staging \n• QoL scores and pain \n• Fertility outcomes and anatomical parameters \n• Longitudinal analysis \nA p-value <0.05 was considered statistically significant. Statistical analyses were performed \nusing Prism software (GraphPad). \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nResults \nPatient characteristics \nA total of 145 women were included: ovarian endometriosis (n = 33), deep endometriosis (n = \n55), peritoneal endometriosis (n = 25), and healthy controls (n = 32). Age, BMI, age at \nmenarche, and cycle length were comparable across groups. Pain profiles differed by phenotype: \ndysmenorrhea was most pronounced in deep endometriosis, while non-cyclic pelvic pain and \ndyspareunia were highest in peritoneal disease. Dyschezia was markedly elevated in deep and \nperitoneal endometriosis compared to ovarian disease and controls. Infertility was substantially \nmore frequent in deep endometriosis (62%) than in ovarian (27%) or peritoneal endometriosis \n(32%), and lowest among controls (22%). Deep endometriosis was predominantly associated \nwith advanced r-ASRM stage IV disease and extensive multi-compartment involvement on \nEnzian classification, whereas ovarian and peritoneal phenotypes were characterized by more \nlocalized disease patterns. \n \nPain burden differs by subtype and demonstrates distinct internal structure \nPain scores for pelvic pain, dysmenorrhea, dyspareunia, dysuria, and dyschezia are shown in \nFigure 1A. Pain scores for pelvic pain, dysmenorrhea, dyspareunia and dyschezia were \nsignificantly different among the groups, while dysuria pain scores were not (Fig. 1A). The most \nprominent difference was in pain score for dysmenorrhea where patients with all endometriosis \nsubtypes reported significantly higher pain scores compared to healthy control. In other \nindividual pain scores, there were apparent differences between subtypes. Women with \nperitoneal endometriosis reported significantly higher pain scores across all pain domains \n(except dysuria), while women with deep endometriosis reported higher pain scores for pelvic \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\npain and for dyschezia with even higher magnitude than women with peritoneal endometriosis. \nCorrelation heatmaps (Fig. 1B) revealed subtype-specific pain architecture. In OE, correlations \nbetween domains were generally weak to moderate, with the strongest association observed \nbetween pelvic pain and dyspareunia (Fig. 1B, top left). Similarly in DE, correlations remained \nmodest with strongest correlation between dyspareunia, dysuria and dyschezia (Fig. 1B, top \nright). In contrast, PE exhibited strong positive correlations across most pain domains, \nindicating a more globally coherent pain phenotype (Fig. 1B, bottom left). Healthy controls \ndemonstrated moderate inter-domain correlations at lower absolute pain levels (Fig. 1B, bottom \nright). \n \nPain shows limited correlation with anatomical staging and imaging findings \nFigure 2 illustrates correlation matrices between pain scores and ultrasound and laparoscopic \nstaging parameters across OE, DE, and PE. The correlation heatmap allows to draw several \nconclusions. In OE and DE, the pain scores do not correlated with Enzian scores (ultrasound or \nlaparoscopic) or with r-ASRM stage, while in PE, we can see a correlation between individual \npain scores and Enzian compartment A and B involvement assessed using ultrasound. The \ndissociation was most evident in OE and DE, where high anatomical burden did not correspond \nto proportional increases in symptom severity. Interestingly, there are differences in scoring \ncorrelation between ultrasound and laparoscopic Enzian scores. In OE, there is significant \nconcordance between ultrasound and laparoscopic Enzian scores for compartments A, B and C \ninvolvement as well as for ovarian involvement (Fig 2A). Similarly, in DE, strongest correlation \nis seen in ultrasound and laparoscopic Enzian score for ovarian and tube involvement, and \nweaker correlation for compartments A, B and C (Fig 2B). Finally, in PE, we see again the \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nstrongest correlation between ultrasound and laparoscopic Enzian scores for ovarian and tube \ninvolvement, and much weaker and inconsistent between scores for compartment A, B and C \n(Fig. 2C). When looking at the correlation between r-ASRM stage and other features, the results \nare fairly consistent between subtypes. There is a positive correlation between r-ASRM and \nlaparoscopic Enzian scores for compartments A, B, C and tube involvement in all three subtypes, \nwith strongest correlation in PE, followed by OE and DE (Fig. 2A-C). Similarly, there is positive \ncorrelation between between r-ASRM and laparoscopic Enzian scores for compartments A, B, C \nand tube involvement in PE and OE, while in DE the correlation is weak and not significant (Fig. \n2A-C). Finally, we compared the symptom severity and Enzian score-informed disease extent \nwith r-ASRM stages (Fig. 3). Ultrasound and laparoscopic Enzian scores increased progressively \nwith advancing r-ASRM stage across OE and DE, confirming structural concordance between \nstaging systems (Fig. 3A-B), while in PE, r-ASRM staging was correlated only with \nlaparoscopy-informed Enzian score reflecting higher difficulty with ultrasound assessment of \nperitoneal endometriosis (Fig. 3C). In contrast, pain domains and composite pain score showed \nsubstantial overlap across stages without consistent escalation. \n \nQuality of life impairment is primarily pain-driven \nQuality-of-life domain scores are presented in Figure 4A. All endometriosis groups demonstrated \nsignificantly worse physical and functional impact, symptom burden, emotional distress, and \nsocial identity impairment compared with controls. Women with DE and PE reported \nsignificantly increased QoL impairment scores across all 4 domains, with symptom burden and \nperceived control impairment being the most significant (Fig. 4A). In contrast, women with OE \nreported modestly increased QoL burden across the domains compared to healthy individuals, \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nwith symptom burden and perceived control impairment being the only one significantly \nincreased (Fig. 4A). Correlation heatmaps (Fig. 4B) showed notable variability between \nsubtypes. The strongest correlation was observed between QoL impairment and dysmenorrhea in \nwomen with OE, while there was no correlation between QoL impairment and general pelvic \npain or dyschezia, and only a weak and inconsistent correlation with dysuria (Fig. 4B). Similar to \nwomen with OE, women with DE reported significant correlation between QoL impairment and \ndysmenorrhea, but also high correlation with general pelvic pain and dyschezia to a certain \ndegree (Fig. 4B). On the other hand, women with PE consistently reported strong correlation \nbetween QoL impairment across all domains and symptoms severity, with strongest correlation \nbetween dysmenorrhea and dyspareunia with physical impact and symptoms burden (Fig. 4B) \nTo explore the association between pain severity and molecular alterations within endometriotic \nlesions, we reanalyzed RNA sequencing data as previously described15. Eligible samples were \nstratified into high- and low-pain groups based on composite pain scores, and differential gene \nexpression analysis was performed. Despite the relatively small cohort size (high pain: n = 13; \nlow pain: n = 13), we identified a distinct set of genes significantly overexpressed in lesions from \nwomen with high pain burden (Supplementary Figure 1B; Fig. 4C). Among the most strongly \nupregulated transcripts were several genes with established roles in inflammatory signaling and \npain perception. Notably, IL6, OSM, CCL8 and SPP1 were significantly increased, consistent \nwith enhanced inflammatory cytokine signaling (Fig. 4C, top row). The immediate early \ntranscription factors NR4A3 and EGR3 associated with nociception were also markedly elevated, \nsuggesting increased transcriptional activation associated with nociceptive signaling (Fig. 4C, \nbottom left). Finally, upregulation of endocannabinoid system-associated genes PENK and \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nCNR1 further supports engagement of neurobiological pathways within high-pain lesions (Fig \n4C). \n \nInfertility is associated with structural disease burden but not with pain \nInfertility analyses are shown in Figure 5. Across OE, DE, and PE, women with confirmed \ninfertility did not exhibit higher pain scores or composite pain burden compared with non-sterile \nwomen in the same subgroup (Fig. 5A-C). Similarly, AMH levels showed no consistent \nassociation with infertility status across the groups. In contrast, sterile women demonstrated \nconsistently higher laparoscopic Enzian scores across subtypes, however reaching statistical \nsignificance only in women with DE (Fig. 5A-C). There was a trend showing higher ultrasound \nEnzian scores in women with confirmed infertility however not reaching statistical significance \nin any of the subtypes. On the other hand, r-ASRM stages were not correlated with infertility in \nwomen with OE and DE, while the women with PE with higher r-ASRM stages exhibited \nsignificantly higher proportion of infertility (Fig. 5C). These findings indicate that reproductive \nimpairment is structurally mediated rather than symptom-driven. \n \nLongitudinal follow-up demonstrates symptom improvement independent of pregnancy \nTo investigate the functional, symptomatic and emotional recovery after laparoscopic removal of \nendometriotic lesions, we conducted a follow-up analysis at 3 and 12 months after surgery (Fig. \n6A-C). Across all the subtypes, the trend was consistent with subtle differences. Pain perception \nacross all the domains was most significantly decreased in women with higher r-ASRM (III/IV) \nstaging at baseline with consistent decrease of follow up ultrasound Enzian scores (Fig. 6A). \nInterstingly, in women with lower r-ASRM stage (I/II) the pain perception decrease was rather \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nmodest or not evident, even though baseline pain scores were comparable high to women with \nhigher stages and the follow up ultrasound Enzian score was lowered (Fig. 6A). On the other \nhand, quality-of-life scores improved consistently across subtypes and stages, further supporting \na disconnection between symptoms, disease extent and quality of life scores (Fig. 6B). \nAdditional analysis of reproductive health improvement showed that despite objective disease \nremoval,  pregnancy rates at 12 months did not significantly improved and pregnancy occurred \nin 6/11 women with OE, 9/30 with DE, and 4/10 with PE, without statistically significant \ndifferences across subtypes (Fig. 6C). Additional correlation analysis of pregnancy predictors \nshowed overall poor correlation between recorded metrics (symptoms, stage, Enzian, QoL) at \nbaseline or at 12 months follow up (Supplementary Table 1).  Only statistical significant \npredictors were discovered in women with DE, where the pregnancy was associated with lower \n12-month ultrasound Enzian score and significantly lower impairment in physical and functional \nimpact, symptom burden, emotional distress, and social identity domains.  \n \nUreter surgery is driven by anatomical extent rather than symptoms \nSince one of the major complication of deep endometriosis is possible renal failure, we \ninvestigated if there are any predictors of the necessity for ureter surgery. As shown in Figure 7, \nlaparoscopic composite Enzian score as well as laparoscopic individual Enzian scores for tube \ninvolvement showed strong positive correlation for the need for ureter surgery, while right and \nleft tubal involvement, compartment B lesions, ovarian involvement, showed significant yet \nmuch weaker association (Fig. 7A-B). Interestingly dyschezia and dyspareunia demonstrated \nmedium negative associations but did not reach the statistical significance observed for structural \nparameters (Fig. 7A-B).  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nComments \nPrincipal findings \nIn this study, we show that the clinical severity of endometriosis cannot be explained by a single \nanatomical continuum. Instead, our findings support the presence of two partially independent \nbiological axes that shape disease manifestations: a neuroinflammatory axis governing pain \nseverity and quality-of-life impairment, and a structurally driven fibrotic axis determining \nfertility outcomes, surgical complexity, and risk of organ compromise. Pain intensity and quality-\nof-life measures were largely independent of anatomical staging, whereas reproductive outcomes \nand surgical interventions were strongly associated with disease extent measured by r-ASRM \nand Enzian scores. Transcriptomic analysis further identified a molecular program associated \nwith severe pain characterized by endocannabinoid system activation, inflammatory cytokine \nsignaling, extracellular matrix remodeling, and activation of nociceptive transcriptional \npathways. Together, these findings provide a biological framework that explains the longstanding \ndiscordance between lesion burden and symptom severity in endometriosis. \nResults  \nThe weak association between anatomical staging and pain severity observed in our cohort is \nconsistent with prior studies demonstrating poor correlation between r-ASRM stage and \ndysmenorrhea, chronic pelvic pain, or dyspareunia8–10. Pain in endometriosis arises from a \ncomplex interaction of inflammatory mediators, neuroangiogenesis, nerve fiber infiltration, and \ncentral sensitization. These mechanisms are not captured by lesion-based staging systems17. \nFibrotic remodeling appears to be a central component of disease progression18,19. Deep \ninfiltrating lesions are characterized by dense collagen deposition, myofibroblast activation, \nsmooth muscle metaplasia, and extracellular matrix stiffening. These changes can mechanically \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nstimulate nociceptors and alter local mechanotransduction20,21. Importantly, fibrotic remodeling \ndoes not necessarily correlate with total lesion burden. Small but highly fibrotic nodules may \ngenerate substantial mechanical tension and nerve entrapment, potentially explaining the \nheterogeneity of pain severity among patients with similar anatomical stages.  Consistent with \nthis model, transcriptomic analysis identified a distinct molecular signature associated with high \npain burden across lesion subtypes. Lesions from patients with severe pain showed increased \nexpression of inflammatory mediators including IL6, OSM, CCL8, and SPP1, suggesting a \ncytokine-driven microenvironment capable of directly sensitizing peripheral nociceptors through \nJAK/STAT and MAPK signaling pathways22–24. Elevated expression of the immediate early \ntranscription factor NR4A3 and EGR3 further suggests activation of nociceptive transcriptional \nprograms, as NR4A family members and EGR3 are rapidly induced in sensory neurons during \ninflammatory stimulation and contribute to persistent neuronal sensitization. Alongside this \nactivation signal, we observed consistent upregulation of PENK, encoding the precursor of \nendogenous opioid peptides, and CNR1, encoding the cannabinoid receptor type 1. Both \npathways are central components of intrinsic pain-modulatory systems and are commonly \nactivated in response to chronic nociceptive stimulation25,26. Their upregulation therefore likely \nreflects a compensatory neuroregulatory response, in which endogenous opioid and \nendocannabinoid signaling attempts to counterbalance persistent inflammatory activation of \nsensory pathways. The simultaneous presence of inflammatory mediators and endogenous \nanalgesic signaling suggests that painful lesions represent dynamic neuroimmune \nmicroenvironments characterized by both nociceptive activation and intrinsic attempts at pain \nmodulation. \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nQuality-of-life impairment in our cohort closely paralleled pain severity and showed minimal \nassociation with anatomical staging. This observation is consistent with previous studies \ndemonstrating that psychosocial distress and functional impairment in endometriosis are \nprimarily mediated by chronic pain rather than lesion burden6,11. These results underscore the \nimportance of incorporating validated patient-reported outcome measures into clinical \nevaluation. In contrast, fertility outcomes were strongly associated with anatomical disease \nburden. Higher Enzian scores and advanced r-ASRM stages were associated with sterility and \nreduced probability of pregnancy. This finding aligns with previous reports linking advanced \nendometriosis to infertility. Structural distortion caused by fibrosis and adhesions likely underlies \nthis relationship. Progressive collagen deposition restricts fimbrial mobility, impairs tubal \npatency, and disrupts the spatial relationship between the ovary and fallopian tube necessary for \nefficient oocyte capture27–29. \nDeep infiltrating endometriosis represents a clinical context in which structural and symptomatic \naxes may converge. In this subgroup, pregnancy within 12 months was associated with lower \nresidual Enzian scores and improved quality-of-life measures. These findings suggest that \ncomplete surgical excision may alleviate both fibrotic mechanical distortion and sustained \nnociceptive signaling. However, the benefits of extensive surgical intervention must be balanced \nagainst potential risks, including repeated procedures and impacts on ovarian reserve. \nUreteral involvement represents one of the most clinically significant manifestations of the \nstructural axis. In our cohort, ureter surgery was strongly predicted by compartmental disease \nextent rather than symptom severity. Ureteral endometriosis often develops through extrinsic \ncompression by parametrial or uterosacral fibrotic nodules (extrinsic) or by infiltration of ureteral \nwall (intrinsic form), leading to progressive luminal narrowing, impaired peristalsis, and \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nhydronephrosis30,31. Because this process frequently progresses without prominent symptoms, \nreliance on pain severity alone may delay diagnosis. Chronic obstruction can result in \nhydronephrosis, renal cortical thinning, irreversible nephron loss, and ultimately renal failure. \nThese findings highlight the importance of careful anatomical assessment and imaging \nsurveillance in patients with deep compartment involvement. \nClinical implications \nThese findings have several implications for clinical management. First, anatomical staging \nalone cannot reliably estimate symptom burden. Patients with limited visible disease may \nexperience severe pain, whereas individuals with extensive lesions may remain relatively \nasymptomatic. Routine integration of validated patient-reported outcome measures and \nmultidimensional pain assessment is therefore essential. \nSecond, the molecular characteristics associated with severe pain suggest that therapies targeting \nprostaglandin synthesis, such as nonsteroidal anti-inflammatory drugs, may be less effective in \npatients whose symptoms are driven predominantly by cytokine-mediated nociceptor \nsensitization and fibrotic tissue remodeling. Instead, the transcriptional profile observed in high-\npain lesions—characterized by inflammatory mediators (IL6, OSM, CCL8, SPP1) and neuronal \nactivation markers (NR4A3, EGR)—together with increased expression of endogenous pain-\nmodulatory pathways including PENK and CNR1, suggests an active neuroimmune pain \nphenotype. In this context, neuromodulatory agents such as gabapentinoids or serotonin–\nnorepinephrine reuptake inhibitors, which reduce neuronal hyperexcitability and enhance \ndescending inhibitory pathways, may represent biologically rational therapeutic options. \nThird, careful anatomical evaluation remains critical for identifying patients at risk of structural \ncomplications. Classification systems that capture compartmental disease extent, such as the \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nEnzian score, provide valuable information for anticipating surgical complexity and guiding \nsurveillance for complications including ureteral obstruction and infertility. \nResearch implications \nThese findings highlight the need for integrated disease classification frameworks that capture \nboth structural burden and biological activity. Current staging systems quantify anatomical extent \nbut do not measure neuroinflammatory activity or fibrotic remodeling. Conversely, pain scales \ncapture symptom intensity but do not indicate structural risk. Future research should therefore \nfocus on multidimensional phenotyping strategies that combine anatomical staging, symptom \nprofiling, and molecular biomarkers. The transcriptional programs identified in this study also \nsuggest potential therapeutic targets. Modulation of inflammatory signaling, extracellular matrix \nremodeling, and myofibroblast activation may represent promising approaches for addressing \nboth symptom burden and disease progression. \nStrengths and limitations \nThis study integrates detailed clinical phenotyping with molecular analysis of lesion tissue, \nallowing simultaneous evaluation of anatomical disease burden, symptom severity, and \ntranscriptional programs associated with pain. The inclusion of longitudinal reproductive \noutcomes and surgical variables further strengthens the clinical relevance of our findings. \nHowever several limitations should be acknowledged. Transcriptomic analyses were performed \nin a subset of samples and may not capture the full molecular heterogeneity of endometriosis. \nPain assessment relied on patient-reported measures and may be influenced by individual \ndifferences in perception and reporting. In addition, the observational design limits causal \ninference regarding the mechanistic relationships between fibrosis, neuroinflammation, and \nclinical outcomes. \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nConclusions \nEndometriosis severity cannot be adequately conceptualized as a single lesion-based continuum. \nInstead, disease manifestations arise from the interaction of two partially independent biological \nprograms: a neuroinflammatory axis governing pain and quality-of-life impairment and a fibrotic \nstructural axis determining fertility outcomes, surgical complexity, and risk of organ \ncompromise. Recognizing these distinct yet intersecting dimensions helps explain the \nlongstanding disconnect between lesion burden and symptom severity. Integrating anatomical \nand biological phenotyping into clinical practice may enable more precise management strategies \naimed at alleviating pain while preventing progressive structural complications, including organ-\nthreatening manifestations such as ureteral obstruction and renal failure. \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure Legends: \nFigure 1. Pain score distribution and inter-domain correlations. (A) Boxplots showing pain \nscores for pelvic pain, dysmenorrhea, dyspareunia, dysuria and dyschezia in ovarian \nendometriosis (OE), deep endometriosis (DE), peritoneal endometriosis (PE), and healthy \ncontrols (CTRL). P-value represents Kruskal-Wallis test results, and asterisks represent Dunn’s \ntest scores between control group and individual endometriosis subtypes as follows: *  <0.05, ** \n<0.01, *** <0.001, **** <0.0001.  (B) Spearman correlation heatmaps illustrating relationships \nbetween pain domains within each group. \n \nFigure 2. Correlation between pain, ultrasound, and laparoscopic findings. (A-C) Spearman \ncorrelation matrices for OE, DE, and PE demonstrating relationships between pain scores and \nultrasound and laparoscopic Enzian parameters, including compartmental involvement and r-\nASRM stage. \n \nFigure 3. Pain and structural scores stratified by r-ASRM stage. (A-C) Bar graphs showing \npain domain scores, composite pain score, ultrasound Enzian score, and laparoscopic Enzian \nscore across r-ASRM stages I–IV within OE, DE, and PE. Asterisks represent Student’s t-test \nscores between control group and individual endometriosis subtypes as follows: *  <0.05, ** \n<0.01, *** <0.001, **** <0.0001.   \n \nFigure 4. Quality of life and its association with pain. (A) Boxplots showing average Quality \nof life composite scores for 4 distinct domain, namely physical & functional impact, symptom \nburden & perceived control, emotional & psychological distress, stigma & self-image in ovarian \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nendometriosis (OE), deep endometriosis (DE), peritoneal endometriosis (PE), and healthy \ncontrols (CTRL). P-value represents Kruskal-Wallis test results, and asterisks represent Dunn’s \ntest scores between control group and individual endometriosis subtypes as follows: *  <0.05, ** \n<0.01, *** <0.001, **** <0.0001.  (B) Spearman correlation heatmaps illustrating relationships \nbetween pain domains QoL domains within each group. (C) Box plots showing counts per \nmillion (cpm) distribution for selected genes in high and low pain groups. P-value represents \nadjusted p-values calculated using Wald test followed by Benjamini and Hochberg adjustment. \n \nFigure 5. Association between sterility and clinical parameters. (A) Bar charts representing \npain scores,  AMH, ultrasound Enzian score, laparoscopic Enzian score, and r-ASRM stage in \ninfertile (YES) versus non-infertile (NO) women across subtypes. Asterisks represent Student’s t-\ntest scores between control group and individual endometriosis subtypes as follows: *  <0.05, ** \n<0.01, *** <0.001, **** <0.0001.   \n \nFigure 6. Follow-up trends and pregnancy outcomes. (A) Bar charts representing changes in \npain scores and ultrasound Enzian score from diagnosis to 3 and 12 months follow up, grouped \nby rASRM stage and subtype. (B) Bar charts representing changes in QoL domain scores and \nultrasound Enzian score from diagnosis to 3 and 12 months, follow up grouped by rASRM stage \nand subtype. (C) Bar charts representing number of pregnancies recorded at 12-month follow-up \nstratified by subtype. Asterisks represent Student’s t-test scores between control group and \nindividual endometriosis subtypes as follows: *  <0.05, ** <0.01, *** <0.001, **** <0.0001.   \n \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure 7. Ureter surgery outcomes. (A) V olcano plot showing characteristics associated with \nureter surgery (difference vs –log(q value)). (B) Bar chart shows comparison of structural and \nsymptom variables between patients with and without ureter surgery. Asterisks represent \nStudent’s t-test scores between control group and individual endometriosis subtypes as follows: *  \n<0.05, ** <0.01, *** <0.001, **** <0.0001.  [LAP] – laparoscopy, [US] - ultrasound \n \nTable 1: Recruited patients’ characteristics. Baseline characteristics, symptom severity, \nreproductive parameters, and anatomical classification across ovarian endometriosis, deep \nendometriosis, peritoneal endometriosis, and healthy control groups. Continuous variables are \npresented as mean ± standard deviation. Categorical variables are shown as absolute numbers or \npercentages, as indicated. Disease stage was classified according to the revised American Society \nfor Reproductive Medicine (rASRM) system. Deep infiltrating lesions were described using the \nEnzian classification based on laparoscopic findings. AMH, anti-Müllerian hormone; BMI, body \nmass index; rASRM, revised American Society for Reproductive Medicine. \n \nSupplementary Figure 1. Pain-associated biomarkers. (A) Table showing sample grouping \ninto high and low pain groups and individual pain domain average scores for endometriosis \nsubtypes. (B) V olcano plot depicting the distribution of differentially expressed genes between \naggregated endometriosis subtypes in low and high pain groups. The x-axis represents the log2 \nfold change, while the y-axis represents -log10(p-value). Each point corresponds to a gene, with \nsignificantly upregulated genes shown in red, downregulated genes in blue, and non-significant \ngenes in gray. The dashed horizontal line indicates the significance threshold (p-value < 0.05), \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nand the vertical dashed lines denote the fold-change cut-off (log2FC > 1 or < -1). Labeled points \nindicate key genes of interest. \n \nSupplementary Table 1. Predictors of pregnancy at diagnosis and 12-month follow-up. P \nvalues, effect differences, and q values for associations between pain domains, structural scores, \nQoL domains, and pregnancy across OE, DE, and PE. Green highlight indicates significant \nassociation between pregnancy and respective characteristics.  \n  \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nReferences \n1. Alson, S., Jokubkiene, L., Henic, E. & Sladkevicius, P. Prevalence of endometrioma and \ndeep infiltrating endometriosis at transvaginal ultrasound examination of subfertile \nwomen undergoing assisted reproductive treatment. Fertil. Steril. 118, 915–923 (2022). \n2. Saunders, P. T. K. & Horne, A. W. Endometriosis: Etiology, pathobiology, and therapeutic \nprospects. Cell 184, 2807–2824 (2021). \n3. Smolarz, B., Szyłło, K. & Romanowicz, H. 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(which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nTable 1: Patient characteristics table\nOvarian Endometriosis Deep Endometriosis Peritoneal Endometriosis Healthy control\nSample size 33 55 25 32\nAge 30.6 (+/-5.8) 32.6 (+/-5.9) 32.52 (+/-6.1) 32.5 (+/-6)\nBMI 24.2 (+/-5.7) 24.4 (+/-4.1) 24.5 (+/-4.8) 26.4 (+/-5.8)\nMenarche 12.9 (+/- 0.9) 12.8 (+/- 1.4) 12.5 (+/-1.6) 12.6 (+/- 1.2)\nCycle length 28.3 (+/-1.9) 27.8 (+/- 2.3) 27.7 (+/-2.6) 28.2 (+/-1.7)\nPelvic pain 2.7 (+/-2.6) 2.4 (+/-2.1) 3.9 (+/-2.8) 1.1 (+/-2.5)\nDysmenorhea 6.4 (+/-3.1) 7.1 (+/-2.5) 6.5 (+/-2.6) 3.9(+/-3.2)\nDyspareunia 3.5 (+/-3.2) 3.2 (+/-3) 4.4 (+/-3.6) 2.1 (+/-2.5)\nDysuria 1.9 (+/-2.7) 2.1 (+/- 2.7) 2.2(+/-2.1) 1.9 (+/-3)\nDyschezia 0.97 (+/-2.2) 2.9 (+/-3) 2.9 (+/-3.3) 0.84 (+/-2)\nInfertility 27% 62% 32% 22%\nAMH (ng/ml) 5.5 (+/-3.6) 3.2 (+/-3.4) 4.1 (+/-2.8) 4.5 (+/-3.1)\nTotal number of pregnancies\n0 26 39 19 24\n1 5 8 5 7\n2 1 5 1 1\n3 1 3 0 0\nTotal number of births\n0 28 45 22 29\n1 4 9 3 3\n2 0 1 0 0\n3 1 0 0 1\nDisease stage (rAFS)\nStage I (Minimal) 1-5 2 1 12 N/A\nStage II (Mild) 6-15 8 2 7 N/A\nStage III (Moderate) 16-40 18 3 6 N/A\nStage IV (Severe) over 40 5 46 0 N/A\nUndetermined 0 3 0 N/A\nEnzian score (laparoscopic)\nP- peritoneum\nP1 18% 35% 40% N/A\nP2 24% 24% 44% N/A\nP3 12% 5% 8% N/A\nO- ovary Left\nO1 12% 20% 16% N/A\nO2 48% 22% 4% N/A\nO3 21% 18% 0% N/A\nO- ovary Right\nO1 18% 18% 8% N/A\nO2 33% 15% 4% N/A\nO3 0% 9% 0% N/A\nT- tube Left\nT1 27% 15% 12% N/A\nT2 3% 13% 8% N/A\nT3 18% 53% 12% N/A\nT- tube Right\nT1 18% 16% 12% N/A\nT2 3% 16% 4% N/A\nT3 12% 36% 0% N/A\nA \nA1 12% 22% 4% N/A\nA2 6% 35% 0% N/A\nA3 3% 35% 0% N/A\nB (left)\nB1 21% 35% 24% N/A\nB2 3% 47% 0% N/A\nB3 0% 9% 0% N/A\nB right\nB1 15% 44% 20% N/A\nB2 3% 24% 4% N/A\nB3 0% 5% 0% N/A\nC\nC1 6% 13% 0% N/A\nC2 6% 15% 0% N/A\nC3 0% 51% 0% N/A\nF A 0% 13% 0%\nF B 0% 9% 0%\nF I 6% 2% 0%\nF U 3% 11% 0%\nF O 0% 2% 4%\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure 1: Pain score in the group & correlation\nA\nB\n0 5 10 15\nCTRL\nPE\nDE\nOE\n0 5 10 15\n0 5 10 15\n0 5 10 15\n0 5 10 15\nPelvic pain\n(p-value 0.0005)\nDysmenorrhea\n(p-value <0.0001)\nDyspareunia\n(p-value 0.039)\nDysuria\n(p-value 0.49)\nDyschezia\n(p-value <0.0001)\nOvarian Endometriosis Deep Endometriosis\nPeritoneal Endometriosis Healthy \nPain score Pain score Pain score Pain score Pain score\n***\n*\n**\n**\n****\n* **\n****\n0.22\n0.09\n0.09\n0.08\n1.00\n-0.02\n0.19\n0.36\n1.00\n0.08\n0.50\n0.25\n1.00\n0.36\n0.09\n0.12\n1.00\n0.25\n0.19\n0.09\n1.00\n0.12\n0.50\n-0.02\n0.22\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\n-1.0\n-0.5\n0\n0.5\n1.0\n0.19\n0.19\n0.34\n0.36\n1.00\n0.01\n0.23\n0.05\n1.00\n0.36\n0.07\n0.20\n1.00\n0.05\n0.34\n0.32\n1.00\n0.20\n0.23\n0.19\n1.00\n0.32\n0.07\n0.01\n0.19\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\n-1.0\n-0.5\n0\n0.5\n1.0\n0.27\n0.38\n0.39\n0.33\n1.00\n0.40\n0.47\n0.64\n1.00\n0.33\n0.52\n0.72\n1.00\n0.64\n0.39\n0.42\n1.00\n0.72\n0.47\n0.38\n1.00\n0.42\n0.52\n0.40\n0.27\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\n-1.0\n-0.5\n0\n0.5\n1.0\n0.42\n0.51\n0.50\n0.47\n1.00\n0.57\n0.32\n0.39\n1.00\n0.47\n0.51\n0.50\n1.00\n0.39\n0.50\n0.47\n1.00\n0.50\n0.32\n0.51\n1.00\n0.47\n0.51\n0.57\n0.42\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\n-1.0\n-0.5\n0\n0.5\n1.0\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO Peritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO r-AFS \nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nr-AFS \n-1.0\n-0.5\n0\n0.5\n1.0\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO Peritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO r-AFS \nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nr-AFS \n-1.0\n-0.5\n0\n0.5\n1.0\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO Peritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA FB FI FU FO r-AFS \nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nPeritoneum\nOvary (left)\nOvary (right)\nTube (left)\nTube (right)\nCompartment A\nCompartment B (right)\nCompartment B (left)\nCompartment C\nFA\nFB\nFI\nFU\nFO\nr-AFS \n-1.0\n-0.5\n0\n0.5\n1.0\nDeep EndometriosisPeritoneal Endometriosis Ovarian Endometriosis\nUltrasound Laparoscopy\nUltrasound\nLaparoscopy\nUltrasound\nLaparoscopy\nUltrasound\nLaparoscopy\nFigure 2: Pain score, \nultrasound and laparoscopy \nscore correlation\nA\nB\nC\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nComposite score\nUltrasound Enzian Score\nLaparoscopy Enzian Score\n0\n5\n10\n15\n20\nStage I\nStage II\nStage III\nStage IV\nFigure 3: Pain, Enzian, rAFS score\nDeep Endometriosis\nPeritoneal Endometriosis\nOvarian Endometriosis\nScore ScoreScore\n*\n*\n**\n*\n****\nA\nB\nC\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nComposite score\nUltrasound Enzian Score\nLaparoscopy Enzian Score\n0\n5\n10\n15\n20\nStage I\nStage II\nStage III\nStage IV\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nComposite score\nUltrasound Enzian Score\nLaparoscopy Enzian Score\n0\n5\n10\n15\n20\nStage I\nStage II\nStage III\nStage IV\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\n0 1 2 3 4 5\nCTRL\nPE\nDE\nOE\n0 1 2 3 4 5\n0 1 2 3 4 5\n0 1 2 3 4 5\nPhysical & \nFunctional Impact\n(p-value 0.0093)\nSymptom Burden & \nPerceived Control\n(p-value 0<.0001)\nEmotional & \nPsychological Distress\n(p-value 0.0093)\nStigma & \nSelf-Image\n(p-value 0.026)\nFigure 4: Quality of life and pain score\nAverage QoL score Average QoL score Average QoL score Average QoL score\nA\nOvarian Endometriosis Deep Endometriosis Peritoneal Endometriosis Healthy \nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity\n0\n0.2\n0.4\n0.6\n0.8\n1.0B\n*\n**\n***\n****\n*\n*\n**\n*\n*\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity\nPelvic Pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nComposite score\nEndocannabinoid system\nLow pain\nHigh pain\n0\n5\n10\n15\n20\nLow pain\nHigh pain\n0\n10\n20\n30\nLow pain\nHigh pain\n0\n200\n400\n600\nLow pain\nHigh pain\n0\n20\n40\n60\nLow pain\nHigh pain\n0\n200\n400\n600\nLow pain\nHigh pain\n0\n200\n400\n600\n800\n1000\nInflammatory signaling\nNociceptive signaling\nPENK CNR1\nSPP1IL6 CCL8\nNR4A3\nCounts per Million\nCounts per Million\nCounts per Million\nCounts per Million\nCounts per MillionCounts per Million\nC\nLow pain\nHigh pain\n0\n10\n20\n30\n40\n50\nOSM\nLow pain\nHigh pain\n0\n200\n400\n600\n800\nCounts per Million\np-adj: 0.012 p-adj: 0.003 p-adj: 0.023 p-adj: 0.039 \nEGR3\nCounts per Million\np-adj: 0.004 p-adj: 0.025 p-adj: 0.048 p-adj: 0.012 \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure 5: Infertility association\nDeep Endometriosis\nPeritoneal Endometriosis\nOvarian Endometriosis\nScore ScoreScore\nA\n**\n**\nB\nC\nPelvic pain\nDysmenorrhea\nDyspareunie\nDysuria\nDyschezia\nComposite pain score\nAMH\nUltrasound Enzian Score\nLaparoscopy Enzian Score\nrAFS\n0\n5\n10\n15\n20\nYES\nNO\nPelvic pain\nDysmenorrhea\nDyspareunie\nDysuria\nDyschezia\nComposite pain score\nAMH\nUltrasound Enzian Score\nLaparoscopy Enzian Score\nrAFS\n0\n5\n10\n15\n20\nYES\nNO\nPelvic pain\nDysmenorrhea\nDyspareunie\nDysuria\nDyschezia\nComposite pain score\nAMH\nUltrasound Enzian Score\nLaparoscopy Enzian Score\nrAFS\n0\n5\n10\n15\n20\nYES\nNO\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure 6: Follow up trends, pregnancy and recurrence\n0\n5\n10\n15 Diagnosis\n3 Months FU\n12 Months FU\n0\n5\n10\n15\n0\n5\n10\n15\n0\n20\n40\n60\nDiagnosis\n3 Months FU\n12 Months FU\n0\n10\n20\n30\n0\n10\n20\n30\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity, Stigma & Self-Image\n0\n10\n20\n30\n0\n5\n10\n15 Diagnosis\n3 Months FU\n12 Months FU\n0\n5\n10\n15\n0\n5\n10\n15\n0\n10\n20\n30\n0\n10\n20\n30\n0\n20\n40\n60\nDiagnosis\n3 Months FU\n12 Months FU\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity, Stigma & Self-Image\n0\n10\n20\n30\n0\n5\n10\n15 Diagnosis\n3 Months FU\n12 Months FU\n0\n5\n10\n15\n0\n20\n40\n60 Diagnosis\n3 Months FU\n12 Months FU\n0\n10\n20\n30\n40\nPhysical & Functional Impact\nSymptom Burden & Perceived Control\nEmotional & Psychological Distress\nSocial Identity, Stigma & Self-Image\n0\n10\n20\n30\n40\n0\n5\n10\n15\n20\n25 YES\nNO\nNumber of patients\nC\nOE DE PE\nB\nA\nr-ASRM Stage Ir-ASRM Stage IIr-ASRM Stage IIIr-ASRM Stage IVr-ASRM Stage Ir-ASRM Stage IIr-ASRM Stage IIIr-ASRM Stage IV\nOvarian Endometriosis Deep Endometriosis Peritoneal Endometriosis\nOvarian Endometriosis Deep Endometriosis Peritoneal Endometriosis\nPregnancy after 12 M  FU\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nUltrasound Enzian Score\n0\n5\n10\n15\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nUltrasound Enzian Score\n0\n5\n10\n15\nPelvic pain\nDysmenorrhea\nDyspareunia\nDysuria\nDyschezia\nUltrasound Enzian Score\n0\n5\n10\n15\n**********\n***\n**\n**\n**\n*\n*\n***\n***\n****\n***\n**\n***\n**\n***\n*\n**\n*\n****\n****\n****\n**\n****\n****\n****\n**\n*\n*\n*\n*\n**\n*\n*\n*\n*\n**\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nFigure 7: Outcomes: Ureter operation\n-5 0 5\n0\n1\n2\n3\n4\n5\nDifference\n-log(q value)\nA B\nLAP: Enzian score\nLAP: Tube (right)\nLAP: Tube (left)\nLAP: Compartment B\nLAP: Ovary (right)\nLAP: Peritoneum\nLAP: Ovary (left)\nUS: Ovary (right)\nLAP: Compartment A\nPainful defecation\nDyspareunia\nUreter operation (yes/no)Ureter operation correlation with features\n0 5 10 15 20\nLAP: Enzian score \nLAP: Tube (right)\nLAP: Tube (left)\nLAP: Compartment B\nLAP: Ovary (right)\nDyschezia\nDyspareunia\nLAP: Peritoneum\nLAP: Ovary (left)\nUS: Ovary (right)\nLAP: Compartment A\nYES\nNO\n****\n*\n*\n*\n*\n*\n*\n*\n**\n***\n****\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nSupplementary table 1: 12 M FU pregnancy predictors\nP value Difference q value P value Difference q value P value Difference q value\nPelvic pain 0.017 -3.267 0.431 0.845 0.175 0.945 0.939 0.167 0.980\nDysmenorrhea 0.075 -2.833 0.489 0.877 0.143 0.947 0.263 -2.083 0.980\nDyspareunia 0.194 -2.533 0.553 0.623 -0.587 0.751 0.614 -1.333 0.980\nDysuria 0.701 -0.667 0.985 0.278 -1.349 0.580 0.776 -0.500 0.980\nDyschezia 0.881 0.167 0.985 0.603 0.635 0.751 0.861 0.417 0.980\nUltrasound Enzian Score 0.783 -0.667 0.985 0.602 -0.841 0.751 0.838 0.583 0.980\nStage 0.297 -0.400 0.596 0.137 -0.413 0.389 0.432 0.500 0.980\nPhysical & Functional Impact 0.913 -0.433 0.985 0.594 -2.333 0.751 0.706 2.750 0.980\nSymptom Burden & Perceived Control0.665 -1.600 0.985 0.734 -0.857 0.851 0.881 0.917 0.980\nEmotional & Psychological Distress0.325 -2.867 0.599 0.374 2.000 0.615 0.697 1.583 0.980\nSocial Identity, Stigma & Self-Image0.415 -2.967 0.722 0.937 -0.222 0.977 0.644 2.667 0.980\nPelvic pain 0.041 -1.667 0.431 0.265 -0.778 0.580 0.242 0.917 0.980\nDysmenorrhea 0.078 -2.000 0.489 0.064 -2.556 0.224 0.088 -2.833 0.980\nDyspareunia 0.867 -0.200 0.985 0.151 -1.333 0.393 0.657 -0.833 0.980\nDysuria 0.220 -1.333 0.574 0.348 -1.333 0.605 0.242 -0.833 0.980\nDyschezia 0.855 0.133 0.985 0.597 -0.556 0.751 0.467 0.833 0.980\nUltrasound Enzian Score 0.041 -3.067 0.431 0.049 -2.079 0.218 0.275 -0.500 0.980\nPhysical & Functional Impact 0.178 -1.867 0.553 0.030 -7.270 0.218 0.485 3.500 0.980\nSymptom Burden & Perceived Control0.119 -1.600 0.496 0.014 -5.651 0.213 0.911 -0.583 0.980\nEmotional & Psychological Distress0.257 -2.133 0.596 0.037 -4.762 0.218 >0.999999 0.000 >0.999999\nSocial Identity, Stigma & Self-Image0.105 -2.600 0.496 0.045 -5.746 0.218 0.892 -0.750 0.980\n12 Months Follow Up\nOvarian endometriosis Deep endometriosis Peritoneal endomeriosis\nDiagnosis\n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint \n\nSupplementary Figure 1: Pain association\nA B\nAll Ovarian \nendometriosis\nDeep \nendometriosis\nPeritoneal \nendometriosis\nN 13 7 3 3\nPelvic pain 2.6 +/- 2.1 2.6 +/- 2 1.7-/+2.1 3.7 +/- 2.5\nDysmenorrhea 5.4 +/- 3.3 4.4 +/-3.9 8 5 +/- 2.6\nDyspareunia 2.5 +/- 2.8 3.3 +/-3.4 0.3 +/- 0.6 2.7 +/- 1.5\nDysuria 0.7 +/- 1.2 0.8 +/- 1.6 0.3 +/- 0.6 0.7 +/- 0.6\nDyschezia 0.5 +/- 0.8 0.4 +/- 0.8 0.7 +/- 1.2 0.3 +/- 0.6 \nSum 11.6 +/- 2.6 11.6 +/- 2.5 11 +/- 2.6 12.3 +/- 3.8\nN 13 3 8 2\nPelvic pain 2.2 +/- 1.6 1.7 +/-2.1 1.9 +/- 0.8 4.5 +/- 2.1\nDysmenorrhea 7.8 +/- 1.5 7.3 +/- 1.5 7.6 +/- 1.5 9.5 +/- 0.7\nDyspareunia 3.7 +/- 3.6 3.3 +/- 3.1 2.5 +/- 3.1 9\nDysuria 3.1 +/- 2.9 4 +/- 4 2.5 +/- 2.8 4 +/- 2.8\nDyschezia 5 +/- 3.6 3 +/- 3 5.1 +/- 4 7.5 +/- 0.7\nSum 21.8 +/- 6.2 19.3 +/- 3.2 19.6 +/- 3.1 34.5 +/- 0.7\nLow pain \nHigh pain \n . CC-BY-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 10, 2026. ; https://doi.org/10.64898/2026.03.09.26347925doi: medRxiv preprint","source_license":"CC0","license_restricted":false}