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Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

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.

Endometriosis may exert a profound negative influence on the lives of individuals with the disorder, adversely affecting quality of life, participation in daily and social activities, physical and sexual functioning, relationships, educational and work productivity, mental health, and well-being. Over the course of a lifetime, these daily challenges may translate into limitations in achieving life goals such as pursuing or completing educational opportunities; making career choices or advancing in a chosen career; forming stable, fulfilling relationships; or starting a family, all of which ultimately alter one's life trajectory. The potential for endometriosis to impact the life course is considerable, as symptom onset generally occurs at a time of life (menarche through menopause, adolescence through middle age) when multiple life-changing and trajectory-defining decisions are made. Using a life-course approach, we examine how the known effects of endometriosis on life-domain satisfaction may impact health and well-being across the life course of affected individuals. We provide a quasi-systematic, narrative review of the literature as well as expert opinion on recommendations for clinical management and future research directions.

Background Tubal ectopic pregnancies can cause significant morbidity or even death. Current treatment is with methotrexate or surgery. However, methotrexate treatment can fail in approximately 30% of women. Gefitinib, an epidermal growth factor receptor inhibitor, may improve the effects of methotrexate. We assessed the efficacy of administering oral gefitinib with methotrexate, versus methotrexate alone, to treat a tubal ectopic pregnancy. Objectives To test the hypothesis a combination of gefitinib with methotrexate can increase resolution of stable tubal ectopic pregnancy without the need for surgery, compared with methotrexate alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting Fifty UK hospitals. Participants A target of 328 women with a stable, tubal ectopic pregnancy. Intervention Women were randomised to combination of methotrexate and gefitinib or methotrexate and placebo. All participants received a single intramuscular dose of methotrexate 50 mg/m2 and were randomised in a 1:1 ratio of oral gefitinib (250 mg daily for 7 days) or placebo. Main outcome measures The primary outcome was surgical intervention for resolution of ectopic pregnancy. Secondary outcomes were the need for an additional dose of methotrexate, time to resolution of the ectopic pregnancy, number of treatment-associated hospital visits, safety and tolerability, acceptability of treatment and return to menses. Results Between 2 November 2016 and 6 October 2021, 328 women were randomly allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three women in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval 0.85 to 1.58; adjusted risk difference −0.01, 95% confidence interval −0.10 to 0.09; p = 0.37). Without surgical intervention, median time to resolution was 28.0 days in the gefitinib group and 28.0 days in the placebo group (subdistribution hazard ratio 1.03, 95% confidence interval 0.75 to 1.40). The need for additional methotrexate doses, number of additional hospital visits, participant acceptability, time to return of menses and serious adverse events were similar in both groups. Diarrhoea and rash were more common in the gefitinib group. Conclusions The addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Limitations We were unable to investigate how different gefitinib doses or modes of delivery would impact on the results. Future work Questions that remain unaddressed relate to the use of methotrexate and gefitinib combination treatment for other extrauterine and uterine ectopic pregnancy, such as caesarean scar pregnancies, or in the management of choriocarcinoma. Trial registration This trial is registered as ISRCTN 67795930 and EudraCT 2015-005013-76. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and will be published in full in Efficacy and Mechanistic Evaluation; Vol. 10, No. 1. The gefitinib and placebo were supplied by Astra Zeneca. See the NIHR Journals Library website for further project information. Plain language summary What was the question? A tubal ectopic pregnancy is where a fertilised egg is not growing in the womb. The pregnancy cannot be saved and the woman is at risk of losing her fallopian tube and if this pregnancy is left to grow can even die. Current treatment is with methotrexate or surgery. An operation can happen because either the ectopic pregnancy has ruptured and caused internal bleeding, the medical treatment has not worked and the ectopic pregnancy needs to be removed or the patient can chose to have an operation. However, methotrexate treatment can fail in approximately 30% of women. We carried out research to see if the addition of a new drug (gefitinib, a drug used for lung cancer) to methotrexate could lower the number of women needing an operation to remove their ectopic pregnancy. What did we do? We involved 328 women with a stable tubal ectopic pregnancy, who were being treated medically with methotrexate, and randomly assigned them to have methotrexate alone or a combination of methotrexate and gefitinib. The gefitinib was taken in tablet form for 7 days, and the methotrexate was given as an injection. We followed the women up in line with their clinical care until their ectopic pregnancy resolved or they had surgery to remove the ectopic pregnancy. What did we find? The addition of gefitinib to methotrexate did not reduce the number of women who required surgery to remove their ectopic pregnancy. More women taking gefitinib experienced side effects, such as a facial rash or diarrhoea. What does this mean? Treatment with methotrexate remains the only drug treatment option for ectopic pregnancy. More research is needed. Scientific summary Background Tubal ectopic pregnancy (EP) can cause significant morbidity or even death. Current treatment is with methotrexate (MTX) or surgery. However, MTX treatment can fail in approximately 30% of women. Preclinical studies have shown that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments MTX-induced regression of pregnancy-like tissue. Clinical evidence from uncontrolled phase I and II trials has raised the possibility that a combination of MTX and gefitinib could be a more effective medical treatment than MTX alone to treat stable tubal EP. Objectives To test the hypothesis, a combination of gefitinib with MTX can increase resolution of stable tubal EP without the need for surgery, compared with MTX alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting This trial took place in 50 hospitals in the UK. Participants A target of 328 women with a stable, tubal EP. Intervention Participants were randomly assigned in a 1:1 ratio to receive either gefitinib and MTX or matched placebo and MTX with the use of minimisation to balance trial-group assignments according to baseline human chorionic gonadotropin levels (

STUDY QUESTION How does pre-diagnosis use of hospital care differentiate between women later diagnosed with endometriosis and age-matched controls without a diagnosis? SUMMARY ANSWER Women with hospital-diagnosed endometriosis had more frequent hospital contacts in the 10 years leading up to the diagnosis compared to women without a diagnosis of endometriosis, and the contacts were related to registered diagnoses in nearly all of the included ICD-10 chapters for the entire period. WHAT IS KNOWN ALREADY Only a few studies have investigated the utilization of health care among women with endometriosis in the time before diagnosis, but current research shows that women with endometriosis have a higher utilization compared to women without diagnosed endometriosis. To our knowledge, no study has investigated the type of contact related to the higher utilization by using the ICD-10 diagnoses registered to the hospital contact. STUDY DESIGN, SIZE, DURATION This study was conducted as a national Danish registry-based case–control study of 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 Using density sampling, we identified 21 616 cases. Each case was matched on age at the date of diagnosis (index date) to five women without hospital-diagnosed endometriosis (n = 108 080) at the time of matching. The utilization and registered ICD-10 diagnoses related to the hospital contact were included for the 10 years before the index date. MAIN RESULTS AND THE ROLE OF CHANCE The probability of having a high number of hospital contacts (six or more) was more common among women with endometriosis (68.6%) compared to women without endometriosis (55.7%) In general, women without endometriosis were more likely to have fewer than six contacts. The diagnoses registered to the contact among cases were related to a greater variety of ICD-10 chapters when compared to controls with the same number of contacts. For nearly all of the included ICD-10 chapters, women with endometriosis were more likely to have a diagnosis over the entire period compared to controls, with the only exception being in the chapter related to pregnancy. LIMITATIONS, REASONS FOR CAUTION Our results are only applicable for women with hospital-based diagnosed endometriosis since we were not able to include women diagnosed at the general practitioner or private gynecologists. We were not able to make a causal interpretation, as we do not have information on the onset of symptoms of the included diseases. The association may be overestimated due to detection bias. However, a sensitivity analysis only changed the results slightly, indicating a low risk of this bias. WIDER IMPLICATIONS OF THE FINDINGS This study is in accordance with previous studies on the subject, indicating that the utilization of health care prior to endometriosis is not necessarily restricted to endometriosis-related symptoms and that endometriosis can be associated with many other diseases. Future studies may explore hospital contacts and causes/diagnoses following the endometriosis diagnosis to further shed light on whether our results are due to a pattern of multiple pathologies or rather an expression of misdiagnoses among women with endometriosis before 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). A.W.H. received grant funding from NIHR, CSO, Roche Diagnostics, and Wellbeing of Women. A.W.H.'s institution received consultation fees from Theramex, Joii, Gesynta, and Gedeon Richter. A.W.H.'s institution received honoraria for lectures from Theramex and Gedeon Richter. A.W.H. is listed as co-inventor on a patent application (UK Patent App No. 2217921.2, International Patent App No. PCT/GB2023/053076). P.T.K.S.'s institution (University of Edinburgh) received consultation fees from Gesynta Pharma AB and BenevolentAI Bio Ltd. P.T.K.S's institution (University of Edinburgh) declares a patent application (UK Patent Application No. 2310300.5. Androgens in diagnostic strategies for endometriosis). P.T.K.S. is a treasurer of the World Endometriosis Society, Fellowship in the Royal Society of Edinburgh, and a Scientific Advisor of the Royal College of Obstetrics and Gynaecology. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pelvic pain affects up to 24% of women worldwide and for up to 55% of these there is no associated pathology. Despite this there are no established treatments in this cohort. This is a secondary analysis of a randomised-controlled trial (GaPP2) to explore if there are measures which enable us to predict treatment outcome. Methods: GaPP2 recruited women with chronic pelvic pain and no identified pathology and compared the response to gabapentin and placebo. This analysis used variables collected at baseline including validated questionnaires. Binary logistic regression was used to create models to explore whether baseline variables predicted treatment response. Treatment response was determined using 30% reduction in average pain intensity, 30% reduction in worst pain intensity and the Patient Global Impression of Change ('marked' or 'very marked' improvement) individually. We also explored whether baseline variables predicted the occurrence of side-effects (dizziness, visual disturbances and drowsiness). Results: Using the Patient Global Impression of Change questionnaire, we found a significant binary logistic regression (p = 0.029, explaining 31% of the variance), with those with lower worst pain intensity (odds ratio (OR) of 0.393, 95% CI [0.217, 0.712]), lower bladder symptom score (OR = 0.788, CI [0.628, 0.989]), and higher mental component quality of life score (OR = 0.911, CI [0.840, 0.988]), more likely to have 'marked' or 'very marked' improvement when treated with gabapentin. We could not identify predictors of experiencing side-effects to gabapentin. However, we did find predictors of these in the placebo group (binary logistic regression (p = 0.009) and explained 33% of the variance). Worse mental health (OR = 1.247, CI [1.019, 1.525]) and lower baseline pain interference (OR = 0.687, CI [0.483, 0.978]) were associated with having side effects, whilst the use of hormones reduced the risk of experiencing side effects (OR = 0.239, CI [0.084, 0.676]). Discussion: Researchers and clinicians are increasingly aware of the importance of personalised medicine and treatment decisions being driven by knowledge of what treatments work for whom. Our data suggests an important role of the Patient Global Impression of Change in clinical trials as it may better reflect balance between symptoms reduction and side-effects and therefore be more useful in clinician-patients joint decision making. [ABSTRACT FROM AUTHOR]

Objective: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). Design: Cross‐sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. Setting: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). Population or Sample: A total of 100 participants. Methods: Descriptive and comparative analysis from flares questionnaire. Main Outcome Measures: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. Results: We received 100 responses of 104 questionnaires sent. Seventy‐six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non‐painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. Conclusions: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden. [ABSTRACT FROM AUTHOR]

Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis. [ABSTRACT FROM AUTHOR]

The 3rd International Consensus Workshop on Research Priorities in Endometriosis was held in São Paulo on May 4, 2014, following the 12th World Congress on Endometriosis. The workshop was attended by 60 participants from 19 countries and was divided into 5 main sessions covering pathogenesis/pathophysiology, symptoms, diagnosis/classification/prognosis, disease/symptom management, and research policy. This research priorities consensus statement builds on earlier efforts to develop research directions for endometriosis. Of the 56 research recommendations from the 2011 meeting in Montpellier, a total of 41 remained unchanged, 13 were updated, and 2 were deemed to be completed. Fifty-three new research recommendations were made at the 2014 meeting in Sao Paulo, which in addition to the 13 updated recommendations resulted in a total of 66 new recommendations for research. The research recommendations published herein, as well as those from the 2 previous papers from international consensus workshops, are an attempt to promote high-quality research in endometriosis by identifying and agreeing on key issues that require investigation. New areas included in the 2014 recommendations include infertility, patient stratification, and research in emerging nations, in addition to an increased focus on translational research. A revised and updated set of research priorities that builds on this document will be developed at the 13th World Congress on Endometriosis to be held on May 17-20, 2017, in Vancouver, British Columbia, Canada.