Elevated basophil count is associated with increased risk of endometriosis.

Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analysed two targeted study cohorts: a tertiary centre cohort (Endometriosis at Oxford University [ENDOX] study, 325 cases/177 controls) and a large-scale population study (UK Biobank [UKBB], 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils and basophils analysed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 x10^9/L: OR 1.65 [95%CI:1.06-2.57], P trend = 0.025) and replicated in the UKBB dataset (basophils >0.04 x10^9/L: OR 1.26 [95%CI:1.09-1.45], P trend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI [1.25 to 4.22], P trend = 0.007; UKBB study (OR = 1.40, 95% CI [1.07 to 1.85], P trend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal.

Enhancing Genetic Association Power in Endometriosis through Unsupervised Clustering of Clinical Subtypes Identified from Electronic Health Records.

Background: Endometriosis affects 10% of reproductive-age women, and yet, it goes undiagnosed for 3.6 years on average after symptoms onset. Despite large GWAS meta-analyses (N > 750,000), only a few dozen causal loci have been identified. We hypothesized that the challenges in identifying causal genes for endometriosis stem from heterogeneity across clinical and biological factors underlying endometriosis diagnosis. Methods: We extracted known endometriosis risk factors, symptoms, and concomitant conditions from the Penn Medicine Biobank (PMBB) and performed unsupervised spectral clustering on 4,078 women with endometriosis. The 5 clusters were characterized by utilizing additional electronic health record (EHR) variables, such as endometriosis-related comorbidities and confirmed surgical phenotypes. From four EHR-linked genetic datasets, PMBB, eMERGE, AOU, and UKBB, we extracted lead variants and tag variants 39 known endometriosis loci for association testing. We meta-analyzed ancestry-stratified case/control tests for each locus and cluster in addition to a positive control (Total N endometriosis cases = 10,108). Results: We have designated the five subtype clusters as pain comorbidities, uterine disorders, pregnancy complications, cardiometabolic comorbidities, and EHR-asymptomatic based on enriched features from each group. One locus, RNLS , surpassed the genome-wide significant threshold in the positive control. Thirteen more loci reached a Bonferroni threshold of 1.3 x 10 -3 (0.05 / 39) in the positive control. The cluster-stratified tests yielded more significant associations than the positive control for anywhere from 5 to 15 loci depending on the cluster. Bonferroni significant loci were identified for four out of five clusters, including WNT4 and GREB1 for the uterine disorders cluster, RNLS for the cardiometabolic cluster, FSHB for the pregnancy complications cluster, and SYNE1 and CDKN2B-AS1 for the EHR-asymptomatic cluster. This study enhances our understanding of the clinical presentation patterns of endometriosis subtypes, showcasing the innovative approach employed to investigate this complex disease.

Crimson clues: advancing endometriosis detection and management with novel blood biomarkers.

Endometriosis is an inflammatory condition affecting approximately 10% of the female-born population. Despite its prevalence, the lack of noninvasive biomarkers has contributed to an established global diagnostic delay. The intricate pathophysiology of this enigmatic disease may leave signatures in the blood, which, when detected, can be used as noninvasive biomarkers. This review provides an update on how investigators are utilizing the established disease pathways and innovative methodologies, including genome-wide association studies, next-generation sequencing, and machine learning, to unravel the clues left in the blood to develop blood biomarkers. Many blood biomarkers show promise in the discovery phase, but because of a lack of standardized and robust methodologies, they rarely progress to the development stages. However, we are now seeing biomarkers being validated with high diagnostic accuracy and improvements in standardization protocols, providing promise for the future of endometriosis blood biomarkers.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

BACKGROUND: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function.

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

STUDY QUESTION: Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? SUMMARY ANSWER: Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. WHAT IS KNOWN ALREADY: Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. STUDY DESIGN, SIZE, DURATION: This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. MAIN RESULTS AND THE ROLE OF CHANCE: Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). LIMITATIONS, REASONS FOR CAUTION: We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Predictors and trends of Caesarean section and breastfeeding in the Eastern Mediterranean region: Data from the cross-sectional Cyprus Women's Health Research (COHERE) Initiative.

INTRODUCTION: Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population. METHODS: Using self-reported data from the representative Cyprus Women's Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration. RESULTS: C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14-2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06-1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length. CONCLUSION: Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.

Shared genetic architecture of hernias: A genome-wide association study with multivariable meta-analysis of multiple hernia phenotypes.

Abdominal hernias are common and characterised by the abnormal protrusion of a viscus through the wall of the abdominal cavity. The global incidence is 18.5 million annually and there are limited non-surgical treatments. To improve understanding of common hernia aetiopathology, we performed a six-stage genome-wide association study (GWAS) of 62,637 UK Biobank participants with either single or multiple hernia phenotypes including inguinal, femoral, umbilical and hiatus hernia. Additionally, we performed multivariable meta-analysis with metaUSAT, to allow integration of summary data across traits to generate combined effect estimates. On individual hernia analysis, we identified 3404 variants across 38 genome-wide significant (p < 5×10-8) loci of which 11 are previously unreported. Robust evidence for five shared susceptibility loci was discovered: ZC3H11B, EFEMP1, MHC region, WT1 and CALD1. Combined hernia phenotype analyses with additional multivariable meta-analysis of summary statistics in metaUSAT revealed 28 independent (seven previously unreported) shared susceptibility loci. These clustered in functional categories related to connective tissue and elastic fibre homeostasis. Weighted genetic risk scores also correlated with disease severity suggesting a phenotypic-genotypic severity correlation, an important finding to inform future personalised therapeutic approaches to hernia.

Correction: Obesity and risk of female reproductive conditions: A Mendelian randomisation study.

[This corrects the article DOI: 10.1371/journal.pmed.1003679.].

Genome-wide association analysis and replication in 810,625 individuals with varicose veins.

Varicose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery.

Endometriosis Classification Systems: An International Survey to Map Current Knowledge and Uptake.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed, but do clinicians routinely use these classification systems, which system do they use and what are the clinicians' motivations? DATA SOURCES: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. Of particular focus were three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the Endometriosis Fertility Index (EFI), and the ENZIAN classification. Data were analysed by SPSS. A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: The final dataset included the replies of 1178 clinicians, including surgeons, gynecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting, and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. CONCLUSION: Even with a high uptake of the existing endometriosis classification systems (rASRM, ENZIAN and EFI), most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis.

Endometriosis classification systems: an international survey to map current knowledge and uptake.

STUDY QUESTION: Which classification system for endometriosis do clinicians use most frequently, and why? SUMMARY ANSWER: Even with a high uptake of the three existing endometriosis classification systems, most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis. WHAT IS KNOWN ALREADY: In the field of endometriosis, several classifications, staging and reporting systems have been developed and published, but there are no data on the uptake of these systems in clinical practice. STUDY DESIGN SIZE DURATION: A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. PARTICIPANTS/MATERIALS SETTING METHODS: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. The particular focus was on the three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the endometriosis fertility index (EFI), and the ENZIAN classification. Data were analysed to detect statistically significant differences among user groups. MAIN RESULTS AND THE ROLE OF CHANCE: The final dataset included the replies of 1178 clinicians, including surgeons, gynaecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, while the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The vast majority of respondents replied positively to the question on whether they would use a simple surgical descriptive system available for endometriosis, if available. LIMITATIONS REASONS FOR CAUTION: While the total number of respondents was acceptable, some regions/professions were not sufficiently represented to draw conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. STUDY FUNDING/COMPETING INTERESTS: The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, ESHRE and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, and consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. He is Chair of TSC for STOP-OHSS and CERM trials and Chair of RCOG Academic Board 2018-2021. M.A. reports being member of the executive board and vice president of AAGL. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants from AbbVie, DoD, NIH and Marriot Family Foundation, honoraria from University British Columbia and WERF, support for speaking at conferences (ESHRE, CanSAGE, Endometriosis UK, UEARS, IFFS, IASP, National Endometriosis Network UK) participation on Advisory Boards from AbbVie and Roche, outside the submitted work. She also discloses having a leadership or fiduciary role in SWHR, WERF, WES, ASRM and ESHRE. C.T. reports grants, consulting and speakers' fees non-financial support and other from Merck SA, non-financial support and other consulting fees from Gedeon Richter and Nordic Pharma, and support for meeting attendance non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Volition Rx, and Evotec (Lab282-Partnership programme with Oxford University), non-financial support from AbbVie Ltd, all outside the submitted work; and is a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation. J.P. reports personal fees from Hologic, Inc., outside the submitted work; he is also a member of the executive boards of ASRM and SRS. The other authors had nothing to disclose.

The role of endometrial B cells in normal endometrium and benign female reproductive pathologies: a systematic review.

STUDY QUESTION: What are the similarities and differences in endometrial B cells in the normal human endometrium and benign reproductive pathologies? SUMMARY ANSWER: Endometrial B cells typically constitute <5% of total endometrial CD45+ lymphocytes, and no more than 2% of total cells in the normal endometrium, and while their relative abundance and phenotypes vary in benign gynaecological conditions, current evidence is inconsistent. WHAT IS KNOWN ALREADY: B cells are vitally important in the mucosal immune environment and have been extensively characterized in secondary lymphoid organs and tertiary lymphoid structures (TLSs), with the associated microenvironment germinal centre. However, in the endometrium, B cells are largely overlooked, despite the crucial link between autoimmunity and reproductive pathologies and the fact that B cells are present in normal endometrium and benign female reproductive pathologies, scattered or in the form of lymphoid aggregates (LAs). A comprehensive summary of current data investigating B cells will facilitate our understanding of endometrial B cells in the endometrial mucosal immune environment. STUDY DESIGN SIZE DURATION: This systematic review retrieved relevant studies from four databases (MEDLINE, EMBASE, Web of Science Core Collection and CINAHL) from database inception until November 2021. PARTICIPANTS/MATERIALS SETTING METHODS: The search strategy combined the use of subject headings and relevant text words related to 'endometrium', 'B cells' and B-cell derivatives, such as 'antibody' and 'immunoglobulin'. Non-benign diseases were excluded using cancer-related free-text terms, and searches were limited to the English language and human subjects. Only peer-reviewed research papers were included. Each paper was graded as 'Good', 'Fair' or 'Poor' quality based on the NEWCASTLE-OTTAWA quality assessment scale. Only 'Good' quality papers were included. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-seven studies met the selection criteria and were included in this review: 10 cross-sectional studies investigated B cells in the normal endometrium; and 17 case-control studies compared the characteristics of endometrial B cells in control and benign female reproductive pathologies including endometritis, endometriosis, infertility, abnormal uterine bleeding, endometrial polyps and uterine fibroids. In all studies, B cells were present in the endometrium, scattered or in the form of LAs. CD20+ B cells were more abundant in patients with endometritis, but the data were inconsistent as to whether B-cell numbers were increased in endometriosis and patients with reproductive pathologies. LIMITATIONS REASONS FOR CAUTION: Although only 'good' quality papers were included in this systematic review, there were variations in patients' age, diagnostic criteria for different diseases and sample collection time among included studies. Additionally, a large number of the included studies only used immunohistochemistry as the identification method for endometrial B cells, which may fail to provide an accurate representation of the numbers of endometrial B cells. WIDER IMPLICATIONS OF THE FINDINGS: Histological studies found that endometrial B cells are either scattered or surrounded by T cells in LAs: the latter structure seems to be under hormonal control throughout the menstrual cycle and resembles TLSs that have been observed in other tissues. Further characterization of endometrial B cells and LAs could offer insights to endometrial B-cell function, particularly in the context of autoimmune-associated pathologies, such as endometriosis. Additionally, clinicians should be aware of the limited value of diagnosing plasma cell infiltration using only CD138. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Finox Biotech. The authors have no conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: This systematic review was registered in PROSPERO in January 2020 (PROSPERO ID: CRD42020152915).

Obesity and risk of female reproductive conditions: A Mendelian randomisation study.

BACKGROUND: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. METHODS AND FINDINGS: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. CONCLUSIONS: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.