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To assess the prevalence of pelvic pain worsened by orgasm in patients with endometriosis and its associated clinical features, focusing on those related to pelvic floor myalgia, central sensitization, and surgical findings. Prospectively collected data were analysed. Data were collected at three timepoints: pre-appointment patient questionnaire, initial appointment, and surgery. Surgery was done by gynecologists specializing in endometriosis. Tertiary referral centre for pelvic pain and endometriosis. Participants included were aged 18 to 50, pre-menopausal, diagnosed with endometriosis via specified criteria, and underwent surgery at our centre. A total of 358 participants referred to our centre between January 2018 and December 2019 completed the study. The median follow-up (duration between pre-appointment questionnaire and surgery) was 6 months, range 0-28 months. Participants who reported that orgasm worsened their pelvic or lower abdominal pain were compared to those who did not. Among 358 participants, 14% (n=49) reported pelvic pain worsened by orgasm. Pain with orgasm was significantly associated with pelvic floor myalgia (p = 0.01), higher scores on the Central Sensitization Inventory (p < 0.001), Patient Health Quality-9 (p < 0.001), and Generalized Anxiety Disorder-7 (p = 0.002). For surgical findings, there was no difference between the two groups for revised American Society for Reproductive Medicine scores (p=0.07). There was a trend towards ovarian endometriosis more commonly seen in participants without orgasm-associated pain (p=0.049). However, the prevalence of superficial peritoneal endometriosis, deep infiltrating endometriosis, and cul-de-sac obliteration were similar between the two groups. Pelvic pain worsened by orgasm in people with endometriosis may be associated with concurrent pelvic floor myalgia and central sensitization. Interventions targeting these factors may alleviate the symptom. There were no associations with more anatomically severe endometriosis found at surgery. Further research is needed to identify effective treatments. [ABSTRACT FROM AUTHOR]

Study Question: Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes?, Summary Answer: Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity., What Is Known Already: Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear., Study Design, Size, Duration: This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013-2017), with a follow-up period of 5-9 years., Participants/materials, Setting, Methods: PTEN and ARID1A loss was assessed using established immunohistochemistry (IHC) methods as proxies for somatic loss by two independent raters. PTEN and ARID1A status for each participant was defined as loss (loss in at least one sample for a participant) or retained (no loss in all samples for a participant). Primary analyses examined associations between PTEN and ARID1A loss and disease burden based on anatomic subtype (superficial peritoneal endometriosis (SUP), deep endometriosis (DE), ovarian endometrioma (OMA)) and rASRM stage (I-IV). Secondary analyses explored associations of PTEN and ARID1A loss with demographics, surgical difficulty, and pain scores (baseline and follow-up). Additionally, using previously published data on KRAS codon 12 mutations for this cohort, we investigated associations between variables in the primary and secondary analyses and acquiring two or more somatic events (PTEN loss, ARID1A loss, or KRAS mutation) in this cohort. The risk of reoperation over the 5-9 years was also examined., Main Results and the Role of Chance: PTEN loss (68.3%; 86 participants) exceeded ARID1A loss (24.6%; 31 participants). Inter-rater reliability was substantial for PTEN (k = 0.69; 95% CI: 0.62-0.77) and ARID1A (k = 0.64; 95% CI: 0.51-0.77). PTEN loss was significantly associated with more severe anatomic subtypes (P < 0.001; participants with SUP only = 46.4%; participants with DE only or OMA only = 72.7%; participants with mixed subtypes = 85.1%), and higher stages (P = 0.024; Stage I = 47.8%; Stage II = 73.7%; Stage III = 80.8%; Stage IV = 81.0%). Results were similar for ARID1A loss, albeit with smaller sample size limiting power. PTEN loss was further associated with non-White ethnicities (P = 0.017) and greater surgical difficulty (more frequent need for ureterolysis) (P = 0.02). There were no differences in pain scores (baseline or follow-up) based on PTEN or ARID1A status. Reoperation was uncommon (13.5% of the cohort), and patterns in reoperation rates based on the presence of somatic alterations did not reach statistical significance., Limitations, Reasons for Caution: Sequencing was not performed to determine the type of PTEN and ARID1A somatic mutations resulting in loss of expression., Wider Implications of the Findings: These results demonstrate a link between PTEN somatic loss and greater endometriosis disease burden. These findings underscore the potential relevance of PTEN loss and other somatic driver mutations in a future molecular classification of endometriosis., Study Funding/competing Interest(s): This study was funded by Canadian Institutes of Health Research (CIHR) project grant (MOP-142273 and PJT-156084). P.J.Y. was supported by a Health Professional Investigator award from Michael Smith Health Research BC, Canada, and a Canada Research Chair (Tier 2) in Endometriosis and Pelvic Pain. M.S.A. was supported by a Michael Smith Health Research BC Scholar award, and CIHR project grants (369990, 462997, and 456767). The sponsors did not play any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. C.A. declares receiving payment from Pfizer for a symposium; being on advisory boards for AbbVie and Pfizer; being President and past President of the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE), co-lead of EndoAct Canada, and a board member of IPPS. M.A.B. has received consulting fees from AbbVie and Pfizer and grants from Ferring outside the scope of this work. D.G.H. is the founder of Canxeia Health but has no current affiliation. M.K. has received consulting fees from Helix Biopharma outside the scope of this work. M.S.A. received reimbursement of travel and registration fees to attend and present at the 2023 and 2024 annual meetings for the Society for Reproductive Investigation (SRI). P.J.Y. declares receiving: payment for a lecture from the International Society for the Study of Women's Sexual Health (ISSWSH); honoraria from the CIHR; support to attend meetings from CanSAGE, ISSWSH, the International Pelvic Pain Society, the World Endometriosis Society (WES), the Society for the Study of Reproduction, and the Vulvodynia Summit; and discounted devices from Ohnut Wearable for a clinical trial. P.J.Y. is a data safety monitoring board member of a clinical trial funded by CIHR; and a strategic advisory board member for the Women's Health Research Institute. P.J.Y. served as a board of directors member for CanSAGE and ISSWSH; was a junior board of directors member for WES; is a current board of directors member for WES; and was a committee chair for the Society of Obstetricians and Gynaecologists of Canada. A subset of these results was presented by the first author at the 71st Society for Reproductive Investigation Annual Scientific Meeting on 15 March 2024. Other authors have nothing to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Pelvic pain worsened by orgasm is a poorly understood symptom in patients with endometriosis., Aim: To assess the prevalence of pelvic pain worsened by orgasm in patients with endometriosis and explore its association with potential etiologic factors, including pelvic floor myalgia, uterine tenderness and adenomyosis, and central nervous system sensitization., Methods: An analysis was done of a prospective data registry based at a tertiary referral center for endometriosis. Eligible participants were patients aged 18 to 50 years who were referred between January 1, 2018, and December 31, 2019, diagnosed with endometriosis, and subsequently underwent surgery at the center. Clinical features were compared between participants reporting worsening pelvic pain with orgasm and those without worsening pain with orgasm, including patient-reported variables, physical examination findings, and anatomic phenotyping at the time of surgery. Pelvic floor myalgia and uterine tenderness were assessed by palpation on pelvic examination, adenomyosis by ultrasound, and central nervous system sensitization via the Central Sensitization Inventory (range, 0-100)., Outcomes: Outcomes included pelvic or lower abdominal pain in the last 3 months that worsened with orgasm (yes/no)., Results: Among 358 participants with endometriosis, 14% (49/358) reported pain worsened by orgasm while 86% (309/358) did not. Pain with orgasm was significantly associated with pelvic floor myalgia (55% [27/49] vs 35% [109/309]; Cohen's h = 0.40, P = .01) and higher scores on the Central Sensitization Inventory (mean ± SD, 53.3 ± 17.0 vs 42.7 ± 18.2; Cohen's d = 0.60, P < .001) but not with uterine tenderness or adenomyosis. Other clinical features associated with pain with orgasm were poorer sexual health (higher scores: deep dyspareunia, Cohen's h = 0.60; superficial dyspareunia, Cohen's h = 0.34; and Female Sexual Distress Scale-Revised, Cohen's d = 0.68; all P < .05) and poorer mental health (higher scores: Patient Health Questionnaire-9, 12.9 ± 6.7 vs 9.1 ± 6.3, Cohen's d = 0.59, P < .001; Generalized Anxiety Disorder-7, 9.4 ± 5.6 vs 6.8 ± 5.5, Cohen's d = 0.48, P = .002). Anatomic findings at the time of surgery did not significantly differ between the groups., Clinical Implications: Interventions targeting pelvic floor myalgia and central nervous system sensitization may help alleviate pain worsened by orgasm in patients with endometriosis., Strengths and Limitations: A strength is that pain worsened by orgasm was differentiated from dyspareunia. However, pain with orgasm was assessed by only a binary question (yes/no). Also, the study is limited to a single center, and there were limited data on sexual function., Conclusion: Pelvic pain exacerbated by orgasm in people with endometriosis may be related to concurrent pelvic floor myalgia and central sensitization., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Background: Deep dyspareunia affects 50% of people with endometriosis. The Ohnut is a set of interlocking rings that fit over the penis/insertive object. One or more rings can be used to limit insertion depth and reduce deep dyspareunia., Aim: We conducted a pilot, parallel, open-label randomized controlled trial (RCT) to investigate the feasibility of the study design and the acceptability and preliminary efficacy of the Ohnut., Method: Participants were recruited from a tertiary center for endometriosis. Eligibility criteria were surgically confirmed endometriosis, age 19-49 years, monogamous sexual relationship with a partner willing to participate in the study, and no comorbid superficial dyspareunia, anxiety, or depression. Couples were randomized into an intervention group or a waitlist control group using a 1:1 allocation ratio. All couples had sex as normal during weeks 1 to 4 (baseline period), and couples in the intervention group used the Ohnut with sex during weeks 5 to 10 (intervention period) while controls had sex as normal. Patient participants used daily diaries to record sexual activity and deep dyspareunia score (0-10) for the 10-week study. Intervention group participants completed an acceptability questionnaire at the end of the study., Outcomes: The primary outcomes were feasibility of the study and acceptability of the Ohnut. We also assessed differences in deep dyspareunia scores in the participants who used the Ohnut compared to the control participants who did not., Results: We recruited approximately 5 couples per month of active recruitment. Of 864 potentially eligible participants, we successfully contacted 44.7% (n = 386), of whom 8.0% (n = 31) consented, 64.8% (n = 250) were ineligible, and 27.2% (n = 105) declined. Thirty-one couples were randomly assigned to the intervention or control group, and 17 couples completed the study. Intervention group couples used the Ohnut for an average of 72.4% (32.7%) of sexual encounters during the intervention period. The mean acceptability index score for the Ohnut was 0.83 (0.078) among patients and 0.83 (0.049) among partners (index between 0 and 1). After controlling for baseline deep dyspareunia, there was a significant difference in the intervention period mean deep dyspareunia scores between the control and intervention group (4.69 (2.44) vs 2.46 (1.82), P = .012)., Clinical Implications: We identified preliminary evidence for the acceptability and efficacy of the Ohnut among both patients and partners, suggesting that the Ohnut may be a useful stand-alone or adjuvant management tool for endometriosis-associated deep dyspareunia., Strengths and Limitations: Strengths of this study were the "real-world" use of the Ohnut and data collection from both patients and partners. Limitations of the study design included the strict eligibility criteria that affected feasibility and generalizability., Conclusion: This pilot RCT indicated that the Ohnut may be an acceptable and effective intervention to reduce endometriosis-associated deep dyspareunia. We identified opportunities to improve design for a larger RCT., Clinical Trial Registration: This clinical trial was registered with clinicaltrials.gov (#NCT04370444)., Competing Interests: R.F. is co-owner of Teumo Health Technologies Inc, a digital health company in sexual medicine., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine.)

Objectives: To evaluate whether endometriosis and menstrual health education improves knowledge and attitudes among adolescents and is acceptable., Methods: We conducted a cluster-randomised controlled trial in a Canadian school district. Eligible classes were grades 8-12, co-educational, and English. Classes were randomly assigned either to a 60-minute virtual menstrual health and endometriosis education program before (intervention) or after (waitlist control) primary data collection. The primary outcome was change in endometriosis knowledge from baseline to follow-up (∼4 weeks later, 6-item questionnaire). Secondary outcomes were changes in confidence in endometriosis knowledge, prioritisation of menstrual health knowledge, and comfort in discussing menstrual health, as well as intervention acceptability. The sexual health educator and statistician were masked., Results: In April and May 2021, 2 intervention classes and 2 control classes completed the study. In total, 71 students enrolled, and 48 were present on both baseline and follow-up days. Mean age was 15.7 ± 1.6 years, 55% identified as non-White ethnicities, and 53% were female. The knowledge score increased by 1.86 points in the intervention classes compared with 0.30 points in the control classes, with an estimated mean difference of 1.56 (95% CI 1.12-2.00). The intervention classes showed increased confidence in endometriosis knowledge, prioritisation of menstrual health knowledge, and comfort in discussing menstrual health, compared to the control classes. The mean acceptability index was 80 (SD = 10) in the intervention classes and 70 (SD = 20) in the control classes., Conclusions: A brief menstrual health and endometriosis education program improved knowledge and attitudes among adolescents, who considered the program acceptable., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Background: Approximately half of people with endometriosis experience deep dyspareunia; however, there is no means of objective self-testing of endometriosis-associated deep dyspareunia., Aim: The aim of this study was to assess the acceptability, test-retest reliability, and validity of a vaginal insert for a self-assessment of endometriosis-associated deep dyspareunia., Methods: Participants were recruited from a tertiary endometriosis center. Inclusion criteria were: 19 to 49 years of age, self-reported deep dyspareunia of ≥4 of 10, and surgically confirmed endometriosis. Participants completed 2 self-assessments using the vaginal insert to self-assess tenderness at the right and left pelvic floor, bladder, cervix-uterus, and posterior cul-de-sac (vaginal fornix). The participants recorded tenderness at each pelvic site and completed a questionnaire regarding the acceptability of the vaginal insert to assess deep dyspareunia. Test-retest reliability was assessed by correlating the tenderness scores between the 2 assessment dates. Over a 4-week period, the participants also recorded deep dyspareunia severity at each penetrative vaginal sex encounter. Validity was assessed by correlating vaginal insert tenderness to deep dyspareunia severity, and also to tenderness reported on a prior gynecologic pelvic examination., Outcomes: The main outcome measures were the acceptability index score, tenderness (0-10) at each pelvic site, and prospective deep dyspareunia scores (0-10) over 4 weeks., Results: There were 19 participants (mean age 34 ± 7 years) who completed the study. The majority identified as female (94.7%), heterosexual (89.5%), and white (89.5%). The median acceptability index score was 0.72 (interquartile range, 0.66-0.81). For test-retest reliability, the intraclass correlation coefficients were 0.79 (P = .001) for the left pelvic floor, 0.82 (P < .001) for the right pelvic floor, 0.54 (P = .07) for the bladder, 0.89 (P < .001) for the cervix-uterus, and 0.77 (P = .003) for the cul-de-sac. The correlation between the highest self-assessed mean tenderness in each participant and self-reported deep dyspareunia over 4 weeks was r = 0.32, but correlations for each pelvic site varied significantly. Tenderness at each site on prior gynecologist pelvic exam was associated with higher self-assessed mean tenderness with the vaginal insert in each participant (effect sizes = 0.42-0.88)., Clinical Implications: The vaginal insert is acceptable and reliable for the objective self-assessment of endometriosis-associated deep dyspareunia, with initial evidence of validity., Strengths and Limitations: A strength was the inclusion of participants who were avoiding sexual activity and a limitation was the small sample size., Conclusion: Future studies with larger sample sizes are required to further establish the validity of the vaginal insert for the self-assessment of endometriosis-associated deep dyspareunia., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We propose a standardized protocol for measurement of nerve bundle density in endometriosis as a potential biomarker, including in deep endometriosis (DE), ovarian endometriomas (OMA) and superficial peritoneal endometriosis (SUP)., Methods: This was a prospective cohort of surgically excised endometriosis samples from Dec 1st 2013 and Dec 31st 2017 at a tertiary referral center for endometriosis in Vancouver, BC, Canada. Surgical data were available from linked patient registry. Protein gene product 9.5 (PGP9.5) was used to identify nerve bundles on immunohistochemistry. PGP9.5 nerve bundles were counted visually. To calculate nerve bundle density, PGP9.5 nerve bundle count was divided by the tissue surface area (total on the slide). All samples were assessed using NHS Elements software for semi-automated measurement of the tissue surface area. For a subset of samples, high power fields (HPFs) were also counted as manual measurement of the tissue surface area. Intraclass correlation was used to assess intra observer and inter observer reliability. Generalized linear mixed model (GLMM) with random intercepts only was conducted to assess differences in PGP9.5 nerve bundle density by endometriosis type (DE, OMA, SUP)., Results: In total, 236 tissue samples out of 121 participants were available for analysis in the current study. Semi-automated surface area measurement could be performed in 94.5% of the samples and showed good correlation with manually counted HPFs (Spearman's rho = 0.781, p  < 0.001). To assess intra observer reliability, 11 samples were assessed twice by the same observer; to assess inter observer reliability, 11 random samples were blindly assessed by two observers. Intra observer reliability and inter observer reliability for nerve bundle density were excellent: 0.979 and 0.985, respectively. PGP9.5 nerve bundle density varied among samples and no nerve bundles could be found in 24.6% of the samples. GLMM showed a significant difference in PGP9.5 nerve bundle density between the different endometriosis types (X 2  = 87.6, P  < 0.001 after adjusting for hormonal therapy, with higher density in DE and SUP in comparison to OMA)., Conclusion: A standardized protocol is presented to measure PGP9.5 nerve bundle density in endometriosis, which may serve as a biomarker reflecting local neurogenesis in the endometriosis microenvironment., Competing Interests: MK is a consultant for Helix Biopharma, which has no relation to the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zoet, Tucker, Orr, Alotaibi, Liu, Noga, Köbel and Yong.)

The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5-9 years of follow-up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I-IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re-operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02-2.11) and non-Caucasian ethnicity (RR = 0.64, 95% CI: 0.47-0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow-up. Re-operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66-4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer-driver mutations may inform a future molecular classification of endometriosis., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Endometriosis-associated deep dyspareunia is associated with reduced sexual quality of life, lower self-esteem, and impaired sexual function., Objective: The primary objective is to assess the acceptability of a phallus length reducer (brand name: Ohnut [OhnutCo]), which is a buffer worn over the penis or a penetrating object to reduce endometriosis-associated deep dyspareunia, and the feasibility of a definitive randomized controlled trial (RCT). The secondary objective is to obtain estimates of the effectiveness of the buffer. An embedded substudy will explore the acceptability and the preliminary validity and reliability of a vaginal insert for the self-assessment of deep dyspareunia., Methods: Ours is an investigator-initiated, 2-arm RCT. We will recruit 40 patient participants with diagnosed endometriosis between the ages of 19 and 49 years, as well as their sexual partners. The participating couples will be randomized in a 1:1 ratio into the experimental arm or the waitlist control arm. The length of the study period will be 10 weeks, during which time all participants will record deep dyspareunia severity following each episode of sexual intercourse. In weeks 1 to 4, all patient participants will record deep dyspareunia severity at each sexual encounter. In weeks 5 to 10, participants in the experimental arm will use the buffer during vaginal penetration; participants in the waitlist control arm will continue engaging in vaginal penetration as usual. Participants will complete questionnaires for assessing measures of anxiety, depression, and sexual function at baseline, at 4 weeks, and at 10 weeks. In the substudy, patient participants will self-assess dyspareunia by using a vaginal insert on 2 occasions, at least 1 week apart. The primary outcomes-the acceptability and feasibility of the buffer-will be assessed with descriptive statistics, and the secondary outcome-phallus length reducer effectiveness-will be assessed by using an analysis of covariance-based approach. For the vaginal insert, we will assess acceptability, test-retest reliability, and convergent validity via correlation analyses comparing the use of the insert to clinical examination in terms of dyspareunia assessment outcomes., Results: Our pilot will provide initial data on the acceptability and effectiveness of the buffer and the feasibility of the study methodology. The results from our study are expected to be submitted for publication by the spring of 2023. As of September 2021, we have consented 31 couples into the study., Conclusions: Our study will provide preliminary evidence for the self-assessment and management of endometriosis-associated deep dyspareunia. The findings will inform the decision to proceed to a definitive RCT., Trial Registration: ClinicalTrials.gov NCT04370444; https://clinicaltrials.gov/ct2/show/NCT04370444., International Registered Report Identifier (irrid): DERR1-10.2196/39834., (©Sandy X J Zhang, Rebecca G K MacLeod, Gurkiran Parmar, Natasha L Orr, Kate J Wahl, Heather Noga, Arianne Albert, Ryan Flannigan, Lori A Brotto, Paul J Yong. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 27.03.2023.)

Importance: A subset of people who undergo surgery for endometriosis have persistent pain, suggesting that other factors besides the endometriosis, such as central sensitization, may play a role in this pain. The Central Sensitization Inventory, a validated self-reported questionnaire of central sensitization symptoms, may identify individuals with endometriosis who have more pain after surgery due to pain sensitization., Objective: To examine whether greater baseline Central Sensitization Inventory scores are associated with postsurgical pain outcomes., Design, Setting, and Participants: This prospective, longitudinal cohort study performed at a tertiary center for endometriosis and pelvic pain in British Columbia, Canada, included all patients aged 18 to 50 years with diagnosed or suspected endometriosis and a baseline visit between January 1, 2018, and December 31, 2019, who underwent surgery after the baseline visit. Individuals who were menopausal, had a prior hysterectomy, or were missing data for outcomes or measures were excluded. Data analysis was performed from July 2021 to June 2022., Main Outcomes and Measures: The primary outcome was chronic pelvic pain at follow-up measured on a scale of 0 to 10, with 0 to 3 indicating no pain or mild pain, 4 to 6 indicating moderate pain, and 7 to 10 indicating severe pain. Secondary outcomes were deep dyspareunia, dysmenorrhea, dyschezia, and back pain at follow-up. The main variable of interest was baseline Central Sensitization Inventory score (measured from 0 to 100, consisting of 25 self-reported questions rated from 0 to 4 [never, rarely, sometimes, often, and always, respectively])., Results: A total of 239 patients (mean [SD] age, 34 [7] years; 189 [79.1%] White [11 (5.8%) identified as White mixed with another ethnicity], 1 [0.4%] Black or African American, 29 [12.1%] Asian, 2 [0.8%] Native Hawaiian or Pacific Islander, 16 [6.7%] other, and 2 [0.8%] mixed race or ethnicity) with follow-up data at more than 4 months after surgery were included in this study (71.0% follow-up rate). The mean (SD) baseline Central Sensitization Inventory score was 43.8 (18.2), and the mean (SD) follow-up was 16.1 (6.1) months. Higher baseline Central Sensitization Inventory scores were significantly associated with higher chronic pelvic pain (odds ratio [OR], 1.02; 95% CI, 1.00-1.03; P = .02), deep dyspareunia (OR, 1.03; 95% CI, 1.01-1.04; P = .004), dyschezia (OR, 1.03; 95% CI, 1.01-1.04; P < .001), and back pain (OR, 1.02; 95% CI, 1.00-1.03; P = .02) at follow-up, when controlling for baseline pain scores. The Central Sensitization Inventory scores themselves decreased slightly from baseline to follow-up (mean [SD] score, 43.8 [18.2] vs 41.7 [18.9]; P = .05); however, individuals with high baseline Central Sensitization Inventory scores still had high scores at follow-up., Conclusions and Relevance: In this cohort study of 239 patients with endometriosis, higher Central Sensitization Inventory scores at baseline were associated with worse pain outcomes after endometriosis surgery, when controlling for baseline pain scores. The Central Sensitization Inventory could be used to counsel patients with endometriosis on their expected outcomes after surgery.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: A key clinical problem is identifying the patient with endometriosis whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (eg, hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cutoff in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes [CSS]) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18 to 50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0 ± 7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (P < 0.001), and with the CSI score (0-100) (r = 0.731, P < 0.001). Receiver operating characteristic analysis indicated that a CSI cutoff of 40 had a sensitivity of 78% (95% CI: 72.7%-84.6%) and a specificity of 80% (95% CI: 70.3%-84.5%) for identifying a patient with endometriosis with ≥3 CSS. In the group with CSI ≥ 40, 18% retrospectively self-reported pain nonresponsive to hormonal therapy and 40% self-reported daily pain, compared with 6% and 20% in the CSI < 40 group (P = 0.003 and 0.002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify patients with endometriosis with pain contributors related to central nervous system sensitization., (Copyright © 2021 International Association for the Study of Pain.)

Background: Endometriosis is a complex condition that can negatively affect a woman's quality of life, including her sleep. This study aims to assess the multifactorial variables associated with poorer quality of sleep in women with endometriosis. Materials and Methods: Data from the Endometriosis Pelvic Pain Interdisciplinary Cohort (EPPIC) data registry were analyzed for women who underwent surgery at the BC Women's Center for Pelvic Pain and Endometriosis with histopathological confirmation of endometriosis (June 2015 to June 2017). The primary outcome was quality of sleep preoperatively, from the Chronic Pain Sleep Inventory (0-100 VAS). Bivariate analysis and multivariable linear regression were done to determine any significant associations between preoperative patient variables and overall quality of sleep, based on p -value of 0.05. Results: Two hundred and seventy-five women met the study criteria. Poorer overall quality of sleep was independently associated with poorer functional quality of life (EHP-30) (b = -0.18, p  = 0.0026), more depressive symptoms (PHQ-9) (b = -1.62, p  < 0.001), and painful bladder syndrome (PBS) (b = -5.82, p  = 0.035). This indicates that a 1 point increase in the EHP-30 (worsening quality of life), a 1 point increase in the PHQ-9 (worsening depression), and the presence of PBS increased the primary outcome ( i.e ., toward poorer quality of sleep) by 0.18, 1.62, and 5.82 points. Conclusions: Poorer quality of sleep in women with endometriosis is associated with poorer quality of life, more depressive symptoms, and bladder pain. Research into interventions that improve sleep is warranted as part of the management of some women with endometriosis.

Introduction: Deep dyspareunia is a cardinal symptom of endometriosis, and as many as 40% of people with this condition experience comorbid superficial dyspareunia., Aim: To evaluate the relationship between sexual pain and infertility concerns among women with endometriosis., Methods: This is a cross-sectional study conducted at a university-based tertiary center for endometriosis. 300 reproductive-aged participants in the prospective Endometriosis Pelvic Pain Interdisciplinary Cohort (ClinicalTrials.gov Identifier: NCT02911090) with histologically confirmed endometriosis were included (2013-2017)., Main Outcome Measure: The total score on the infertility concerns module of the Endometriosis Health Profile-30 categorized into 5 groups (0, 1-4, 5-8, 9-12, 13-16)., Results: The odds of infertility concerns did not increase with severity of deep dyspareunia (odds ratio = 1.02, 95% CI: 0.95-1.09, P = .58). However, the odds of infertility concerns increased with severity of superficial dyspareunia (odds ratio = 1.09, 95% CI: 1.02-1.16, P = .011); this relationship persisted after adjusting for endometriosis-specific factors, infertility risk factors, reproductive history, and demographic characteristics (adjusted odds ratio [AOR] = 1.14, 95% CI: 1.06-1.24, P < .001). Other factors in the model independently associated with increased infertility concerns were previous difficulty conceiving (AOR = 2.09, 95% CI 1.04-4.19, P = .038), currently trying to conceive (AOR = 5.23, 95% CI 2.77-9.98, P < .001), nulliparity (AOR = 3.21, 95% CI 1.63-6.41, P < .001), and younger age (AOR = 0.94, 95% CI: 0.89-0.98, P = .005)., Conclusion: Severity of superficial dyspareunia, but not deep dyspareunia, was associated with increased odds of infertility concerns among women with endometriosis. Strengths of the study included the use of a validated measure of infertility concerns and disaggregation of sexual pain into deep and superficial dyspareunia. Limitations included the setting of a tertiary center for pelvic pain, which affects generalizability to fertility clinic and primary care settings. Women experiencing introital dyspareunia, who can have difficulties with achieving penetrative intercourse, may be concerned about their future fertility and should be counselled appropriately. Wahl KJ, Orr NL, Lisonek M, et al. Deep Dyspareunia, Superficial Dyspareunia, and Infertility Concerns Among Women With Endometriosis: A Cross-Sectional Study. Sex Med 2020;8:274-281., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Deep dyspareunia, a common symptom in endometriosis, has previously been associated with bladder and/or pelvic floor tenderness (BPFT), which suggests a role for central nervous system sensitization. The Central Sensitization Inventory (CSI, 0-100) is a validated self-reported scale for patients with central sensitization., Aim: The objective of this study was to phenotype deep dyspareunia using BPFT and the CSI., Methods: The methods included cross-sectional analysis from a prospective registry from January 2018 to June 2018 at a tertiary center for endometriosis (ClinicalTrials.gov #NCT02911090). Included were women aged 18-50 years with endometriosis (previously surgically diagnosed, current visualized endometrioma on ultrasound, or current palpable or visualized nodule on ultrasound), who were newly or re-referred to the center. Severity of deep dyspareunia was self-reported using an 11-point numeric rating scale (0 = no pain; 10 = worst pain imaginable), categorized as no or low deep dyspareunia (0-4) and high deep dyspareunia (5-10). We identified the subgroup with high deep dyspareunia and presence of BPFT, where we hypothesized a central component of the sexual pain. This subgroup was compared with 2 other subgroups: no or low deep dyspareunia and high deep dyspareunia but no BPFT. The CSI was compared between the groups using analysis of variance, followed by post hoc testing (P < .05)., Main Outcome Measure: The main outcome measure was the CSI score ranging from 0 to 100., Results: Data from 163 women with endometriosis were analyzed. The mean age of this cohort was 36.4 ± 6.8 years, and the mean CSI score was 41.0 ± 18.6. 37 percent (61/163) had high deep dyspareunia and BPFT; 29% (47/163) had high deep dyspareunia and no BPFT; and 34% (55/163) had no or low deep dyspareunia. The CSI significantly differed between the 3 groups (analysis of variance: F = 22.4, P < .001). In post hoc testing, the CSI was higher in women with high deep dyspareunia and BPFT (51.3 ± 16.9), compared with women with no or low deep dyspareunia (30.9 ± 15.4, P < .001) and compared with women with high deep dyspareunia but no BPFT (39.4 ± 17.2, P = .001)., Clinical Implications: The CSI could be used to classify and phenotype patients with endometriosis-associated sexual pain., Strength & Limitations: Strengths include a prospective registry with integrated pain scores, validated questionnaires, and physical examination findings. Limitations include the lack of quantitative sensory testing for central sensitization., Conclusions: In women with endometriosis, the subgroup with high deep dyspareunia and bladder and/or pelvic floor tenderness had a significantly higher score on the CSI than other subgroups, suggesting that this group may have a central component to their sexual pain. Orr NL, Wahl KJ,Noga H, et al. Phenotyping Sexual Pain in Endometriosis Using the Central Sensitization Inventory. J Sex Med 2020;17:761-770., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: This study sought to identify factors independently associated with a negative impression of the medical profession in patients with endometriosis who were presenting to a tertiary referral centre., Methods: A cross-sectional analysis was conducted on a prospective data registry between December 2013 and June 2017 at a tertiary referral centre for pelvic pain and endometriosis. The main outcome variable, negative impression about the medical profession, was measured with the four-item subscale of the Endometriosis Health Profile-30 and divided into three groups: no (0), some (1-8), and many (9-16) negative impressions. Patients with a surgical and histological diagnosis of endometriosis were included. Postmenopausal women were excluded. Bivariate analyses determined significant associations (P < 0.05) between variables from the registry and the main outcome. Variables with a significant association were put into ordinal logistic regression with sequential backwards elimination., Results: Negative impression of the medical profession was independently associated with previous surgery that did not help symptoms (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI] 1.09-2.87; P = 0.021), presentation to an emergency room in the past 3 months (aOR 1.90; 95% CI 1.17-3.07; P = 0.009), and previous visits to a complementary health care provider (aOR 2.16; 95% CI 1.42-3.29; P < 0.0005), while controlling for an endometriosis pain-related morbidity composite variable., Conclusion: Negative perception of the medical profession in women with endometriosis was associated with surgical treatment failure, emergency room use, and accessing complementary health care. Each identified factor offers an opportunity for intervention to improve the perception of the medical profession among women with endometriosis., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Introduction: Hepatic artery pseudoaneurysm is a rare and potentially fatal complication of liver transplantation with a reported incidence of 0.3-2.6% and associated mortality approaching 75%. Clinical presentation typically includes sudden hypotension, gastrointestinal bleed or abnormal liver function tests within two months of transplantation. We report a series of four cases of hepatic artery pseudoaneurysm in adult liver transplant recipients with the goal of identifying factors that may aid in early diagnosis, prior to the development of life threatening complications., Methods: A retrospective chart review at a high volume transplant center revealed 4 cases of hepatic artery pseudoaneurysm among 553 liver transplants (Incidence 0.72%) between March 2013 and March 2017., Results: Two of the four patients died immediately after intervention, one patient survived an additional 151 days prior to death from an unrelated condition and one patient survived at two years follow up. All cases utilized multiple imaging modalities that failed to identify the pseudoaneurysm prior to diagnosis with computed tomography angiography (CTA). Two cases had culture proven preoperative intrabdominal infections, while the remaining two cases manifested a perioperative course highly suspicious for infection (retransplant for hepatic necrosis after hepatic artery thrombosis and infected appearing vessel at reoperation, respectively). Three of the four cases either had a delayed biliary anastomosis or development of a bile leak, leading to contamination of the abdomen with bile. Additionally, three of the four cases demonstrated at least one episode of hypotension with acute anemia at least 5 days prior to diagnosis of the hepatic artery pseudoaneurysm., Conclusions: Recognition of several clinical features may increase the early identification of hepatic artery pseudoaneurysm in liver transplant recipients. These include culture proven intrabdominal infection or high clinical suspicion for infection, complicated surgical course resulting either in delayed performance of biliary anastomosis or a biliary leak, and an episode of hypotension with acute anemia. In combination, the presence of these characteristics can lead the clinician to investigate with appropriate imaging prior to the onset of life threatening complications requiring emergent intervention. This may lead to increased survival in patients with this life threatening complication., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 David P. St. Michel et al.)

Purpose: Deep infiltrating endometriosis (DIE) is defined as an endometriotic lesion penetrating to a depth of >5 mm and is associated with pelvic pain, but the underlying mechanisms are unclear. Our objective is to investigate whether plasminogen activator inhibitor-1 expression (PAI-1) in endometriotic tissues is increased in women with DIE., Methods: In this blinded in vitro study, immunohistochemistry and Histoscore were used to examine the expression of PAI-1 in glandular epithelium (GECs) and stroma (SCs) in a total of 62 women: deep infiltrating uterosacral/rectovaginal endometriosis (DIE; n = 13), ovarian endometrioma (OMA; n = 14), superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP; n = 23), uterine (eutopic) endometrium from women with endometriosis (UE; n = 6), and non-endometriosis eutopic endometrium (UC; n = 6). The following patient characteristics were also collected: age, American Fertility Society stage, hormonal suppression, phase of menstrual cycle, dysmenorrhea score and deep dyspareunia score., Results: PAI-1 expression in GECs and SCs of the DIE group was significantly higher than that of SUP group (p = 0.01, p = 0.01, respectively) and UE group (p = 0.03, p = 0.04, respectively). Interestingly, increased PAI-1 expression in GECs and SCs was also significantly correlated with increased dysmenorrhea (r = 0.38, p = 0.01; r = 0.34, p = 0.02, respectively)., Conclusions: We found higher expression of PAI-1 in DIE, and an association between PAI-1 and worse dysmenorrhea., Competing Interests: Dr. Bedaiwy received lecture fees and served on advisory boards for Abbvie and Allergan, and received funding for research unrelated to the present study from Allergan (CAPTURE fibroid registry). This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

Study Question: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations?, Summary Answer: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways., What Is Known Already: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations., Study Design, Size, Duration: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy., Participants/materials, Setting, Methods: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins., Main Results and the Role of Chance: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE., Limitations, Reasons for Caution: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established., Wider Implications of the Findings: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted., Study Funding/competing Interest(s): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare., Trial Registration Number: Not applicable.

Introduction: The etiology of endometriosis-associated deep dyspareunia may include direct endometriosis-specific factors (eg, stage or invasiveness of disease) and/or indirect contributors such as bladder/pelvic floor dysfunction (eg, related to myofascial mechanisms or nervous system sensitization)., Aim: This study aimed to determine whether bladder/pelvic floor tenderness and painful bladder syndrome were associated with severity of deep dyspareunia in women with endometriosis, regardless of Stage (I/II vs III/IV) or other endometriosis-specific factors., Methods: Observational study from a prospective patient registry (January 2014 to December 2016) at a tertiary centre for endometriosis. Included were women aged 18 to 49 years who had surgical removal and histopathologic confirmation of endometriosis at the centre. Cases with Stage I/II vs Stage III/IV endometriosis were analyzed separately. Bivariate associations with the primary outcome (severity of deep dyspareunia) were tested for bladder/pelvic floor tenderness, painful bladder syndrome, as well as endometriosis-specific factors identified at the time of laparoscopic surgery (eg, deep infiltrating endometriosis) and demographic factors (eg, age). Multivariable ordinal logistic regression was carried out to adjust for factors associated with the primary outcome., Main Outcome Measure: Primary outcome was severity of deep dyspareunia on an 11-point numeric rating scale, categorized as none/mild (0-3), moderate (4-6), and severe (7-10), from a preoperative self-reported questionnaire., Results: Overall, 411 women had surgically confirmed endometriosis: 263 had Stage I/II and 148 had Stage III/IV endometriosis. Among women with Stage I/II endometriosis, severity of deep dyspareunia was associated with both bladder/pelvic floor tenderness and painful bladder syndrome (AOR = 1.94, 95% CI: 1.11-3.38, P = .019 and AOR = 1.99, 95% CI: 1.15-3.44, P = .013, respectively), independent of endometriosis-specific factors or other factors associated with deep dyspareunia severity. Similar associations were found in women with Stage III/IV endometriosis (bladder/pelvic floor tenderness AOR =2.51, 95% CI: 1.25-5.02, P = .01, painful bladder syndrome: AOR = 1.90, 95% CI: 1.01-3.57, P = .048)., Clinical Implications: Myofascial or nervous system mechanisms may be important for deep dyspareunia in women with endometriosis, even in those with moderate-to-severe disease (Stage III/IV)., Strengths & Limitations: Strengths include the prospective registry, and histological confirmation of endometriosis and staging by experienced endometriosis surgeons. Limitations include assessment of only one pelvic floor muscle (levator ani)., Conclusion: In women with Stage I/II or Stage III/IV endometriosis, severity of deep dyspareunia was strongly associated with bladder/pelvic floor tenderness and painful bladder syndrome, independent of endometriosis-specific factors, which suggests the role of myofascial or sensitization pain mechanisms in some women with deep dyspareunia. Orr NL, Noga H, Williams C, et al. Deep Dyspareunia in Endometriosis: Role of the Bladder and Pelvic Floor. J Sex Med 2018;15:1158-1166., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)