Lay summary:Endometriosis is a chronic pain condition that affects >190 million people worldwide. It is recommended in clinical guidelines to remove the most common type of endometriosis, 'superficial peritoneal endometriosis' (SPE), if it is diagnosed at laparoscopy (keyhole surgery). However, the evidence to support removal of SPE is based on small studies with short-term follow-up. The aim of this small feasibility trial was to determine what proportion of women with pelvic pain undergoing laparoscopy for suspected endometriosis would be willing to be randomly allocated to have surgical removal of SPE or not have it treated surgically straightaway (sham surgery). Of the eligible patients that were approached, 31% consented to take part, demonstrating that people with endometriosis are willing to take part in a sham surgical trial. We are now leading a similar, but much larger UK-wide trial, to determine whether removal of SPE truly improves painful endometriosis symptoms.

SUMMARY Background Endometriosis is a chronic pain condition in which hormonal therapies form the cornerstone of long-term management. Treatment tolerability is critical for adherence and therapeutic success, but most comparative studies and reviews have focused on their ability to reduce menstrual pain, while their impact on non-menstrual pelvic pain (NMPP), bleeding patterns, adverse events (AEs), treatment discontinuation and quality of life (QoL) remain poorly characterised. This systematic review and meta-analysis evaluate these outcomes across currently available hormonal therapies, providing practical evidence for clinical decision-making. Methods PubMed/MEDLINE, Scopus, and Embase were searched up to November 2025 for randomised controlled trials comparing at least two active first- or second-line hormonal treatments for endometriosis. Studies without confirmed endometriosis, treatment duration less than three months and comparing therapies to placebo only were excluded. Data were extracted by two reviewers from reports. Pain outcomes were pooled as mean differences (MD, 95% CI), with bleeding patterns, AEs, and discontinuations as proportions. Analyses were performed in R. PROSPERO: CRD420251137785. Findings Of 1892 records screened, 48 trials (5583 women) met our inclusion criteria. Overall pelvic pain (0-10 scale) was significantly reduced across all treatment categories ( p <0·001): combined oral contraceptives (COCs) (MD 3·17), oral and long-acting progestogens (MD 3·83; MD 4·29), and GnRH-analogues (MD 3·81). Sensitivity analyses restricted to studies reporting NMPP yielded comparable results. GnRH-agonists showed the most favourable bleeding profile, followed by continuous COCs. However, all regimens reported class-specific AEs, including mood changes, nausea, headache, weight gain, and decreased libido (pooled proportions >10%). Overall discontinuation due to AEs was 7·7%, and vaginal bleeding was the leading cause. Heterogeneity across meta-analyses was high. Risk of bias (RoB2) was moderate to high. Interpretation Given similar reductions in overall pelvic pain across hormonal therapies, treatment decisions should prioritise differences in bleeding profiles, therapy-specific AEs, and QoL. Funding None. Panel: Research in context Evidence before this study Hormonal therapies are widely recommended as first-line treatment for endometriosis-associated pain and several randomised controlled trials (RCTs), systematic reviews, and network meta-analyses have demonstrated their effectiveness. However, the available evidence is limited by small study populations, few direct head-to-head comparisons, heterogeneous outcome measures, and short follow-up. Most original studies and reviews focus primarily on pain outcomes (particularly menstrual pain or “dysmenorrhea”), whereas overall pelvic pain and patient-centred outcomes, such as quality of life, treatment satisfaction, acceptability, and tolerability are infrequently assessed, leaving uncertainty about the comparative safety and tolerability profiles of commonly used medical treatments. We searched PubMed/MEDLINE, Scopus, and Embase up to November 2025 using terms related to endometriosis, adenomyosis, and hormonal treatments. We included 48 RCTs comparing two or more first- or second-line hormonal therapies. Exclusion criteria were non-English articles, endometriosis not confirmed by imaging or surgery, placebo-controlled trials, therapy length less than three months. Added value of this study This systematic review and meta-analysis provide a comprehensive comparison of the most commonly used hormonal therapies for endometriosis. Unlike most previous syntheses, we evaluated overall pelvic pain and non-menstrual pelvic pain (NMPP) as primary pain outcomes (not only menstrual pain or ‘dysmenorrhea’), as a more clinically relevant measure of endometriosis-associated pain, and conducted the first systematic comparisons of continuous versus cyclic combined oral contraceptive (COC) regimens. We also evaluated safety, tolerability, bleeding patterns, treatment discontinuation, and other patient-centred outcomes. In addition to confirming the effectiveness of hormonal therapies in reducing overall pelvic pain and NMPP, our findings highlight important differences in bleeding profiles and adverse events across regimens. Implications of all the available evidence The findings of this review reinforce the need for an individualised, patient-centred approach to hormonal management of endometriosis, weighing efficacy alongside safety, tolerability, bleeding profiles, and patient preferences. To better inform treatment decisions, future research should prioritise longer-term head-to-head comparisons of hormonal therapies and include a range of validated patient-reported outcomes among the endpoints assessed.

Graphical abstract Abstract Current endometriosis treatments primarily focus on pain management, despite many patients also experiencing fatigue, which significantly impacts their quality of life. This study aimed to evaluate the perceived effectiveness of endometriosis treatments in managing fatigue. An international anonymous survey was conducted using the Qualtrics platform, with participants (aged 16 years and over) and a self-reported diagnosis of endometriosis. The survey collected demographic information, the brief fatigue inventory, and perceived impact of treatments on fatigue over the past 5 years. Ethical approval was granted by the Edinburgh Medical School Research Ethics Committee. Data analysis was performed using R, with results presented as medians and interquartile ranges. From 12 April to 25 May 2023, 2,907 responses were collected. Our results showed that fatigue was significantly worsened during menstruation (median: −2, IQR: −3 to −1) and slightly worsened during ovulation (median: −1, IQR: −2 to 0). Analysis revealed limited associations between common medical treatments, such as analgesics or hormonal therapy, and improvements in fatigue symptoms. Use of gonadotrophin-releasing hormone (GnRH) agonists was linked to a worsened fatigue, reported by 54% users. Surgical interventions and changes in rest patterns showed minimal improvement, while other behavioural modifications showed little to no effect. These findings suggest that current endometriosis treatments are largely ineffective in addressing fatigue. Limitations of this study include recall bias and confounding factors, which may influence perceived effectiveness of endometriosis therapies on fatigue. This underscores the need for more comprehensive management strategies to better support patients experiencing endometriosis-associated fatigue. Lay summary Endometriosis is a common chronic pain condition affecting 180 million women worldwide. Many women with endometriosis also report that fatigue significantly impacts their quality of life. Despite this, fatigue management has been largely neglected, and there are limited studies that have evaluated the benefit of current endometriosis treatments on fatigue. This international survey aimed to evaluate the perceived effectiveness of various therapies for endometriosis on fatigue, including pain medication, hormonal medication, surgery and behavioural changes. Pain medication and most hormonal therapies provided limited relief. However, gonadotrophin-releasing hormone (GnRH) agonists worsened fatigue in more than half of the users. These results suggest that existing endometriosis treatments are largely ineffective in addressing fatigue, highlighting the need for improved strategies to address this symptom to enhance quality of life for women with endometriosis.

Background There is an unmet need for non-hormonal treatments for endometriosis. Peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that favours formation and survival of endometriosis lesions. Our preclinical data show that correcting this metabolic phenotype using dichloroacetate is possible, but this approach has not been evaluated in humans. We aimed to determine the feasibility of a clinical trial using dichloroacetate to treat endometriosis-associated pain. Methods We performed a single-arm, open-label, single-site study in 30 pre-menopausal women with chronic pelvic pain and surgically confirmed American Society of Reproductive Medicine Stage I–II endometriosis. Participants were recruited from a tertiary-referral endometriosis centre based within the Royal Infirmary of Edinburgh. Potentially eligible patients were approached by their attending clinician for their possible interest in participating and then were followed-up by the study team. Participants were prescribed oral dichloroacetate for 12 weeks (ie, 6·25 mg/kg total bodyweight twice daily, optional increase to 12·5 mg/kg total bodyweight twice daily after 6 weeks). Genotyping was performed on a subset of participants to explore the effect of the dichloroacetate-metabolising enzyme (GSTZ1) haplotype on side-effects. The primary outcome was recruitment and retention, based on multiple timepoints, with rates of 50% or more for recruitment and 80% or more for retention deemed acceptable for progression to a subsequent trial. Retention was assessed based on the proportion of recruited participants who at visits 3 and 5 submitted their average numerical rating scale scores, completed the questionnaires, and attended per-protocol blood testing. Adverse events were assessed at each study visit by the study team in addition to ad hoc reporting by participants. This trial was registered with ClinicalTrials.gov (NCT04046081) and is completed. Findings Between Nov 19, 2019, and Aug 13, 2021, 93 women were screened for the study, of whom 77 were approached. Of these, 54 (70%) were eligible and 30 (56%) were recruited. Therefore, the prespecified recruitment rate was met. Five of six retention metrics met the prespecified threshold. Overall retention was 19 (66%) of 29 participants who met all retention metrics, which did meet the prespecified criterion for overall retention. 18 (60%) participants completed all 12 weeks of treatment, and all completing participants reported taking all, or almost all (75–99%), of the prescribed dichloroacetate. 19 (86%) of 22 participants described the trial as a positive experience. Side-effects were common but typically mild as jointly judged by participants and the study team. Six participants developed a transient peripheral neuropathy, of whom two consequently stopped treatment. Both these individuals had a GSTZ1 haplotype associated with slow metabolism of dichloroacetate. Interpretation Recruitment to clinical trials of dichloroacetate for endometriosis appears feasible. Genotyping to inform dosage could have the potential to mitigate side-effects. Dichloroacetate is a promising treatment for endometriosis-associated pain but requires assessment in placebo-controlled trials. This study has supported funding for a double-blind, placebo-controlled trial (EPiC2). Funding Medical Research Council Confidence in Concept Scheme and Chief Scientist Office.

Endometriosis is a common, chronic condition associated with debilitating pain, fatigue, and heterogeneous symptom presentation. In this exploratory study, 68 participants with confirmed endometriosis were monitored for up to three 4-6-week smartwatch cycles. We collected daily self-reports of pain and fatigue as well as retrospective questionnaires assessing quality of life, and we extracted daily measures of physical activity (PA), sleep, and diurnal rhythms from wrist-worn actigraphy data. We found that daily PA was strongly negatively correlated with self-reported fatigue (repeated measures correlations R < - 0.3 ) and that participants with more severe or variable symptom trajectories displayed lower levels of PA, greater sleep disturbance, and more disrupted sleep and activity rhythms (Spearman's |R| > 0.3 ). Lastly, we found evidence of sleep and PA changes following surgery for endometriosis that reflected change in self-reported symptoms. Collectively, our findings suggest that passive data collection using wrist-worn wearables in endometriosis could facilitate individualized objective insights into symptom trajectories.

Endometriosis is a common, chronic, incurable condition the hallmark of which is the presence of lesions (tissue resembling endometrium) in sites outside the womb, with symptoms including chronic debilitating pain and fatigue. However, current therapeutic options are limited. Recent advances in our understanding of the mechanisms that contribute to the development of lesions and pain experience in endometriosis as well as surveys of patients have increased interest in testing recently approved formulations containing cannabidiol (CBD) in this patient group. In this review, we summarise data from patient samples and animals models focussed on the pathophysiology of endometriosis, including pathways where CBD has activity. We consider the available formulations of CBD-containing products, their pharmacokinetics (PK), and their use in ongoing clinical trials in endometriosis and other pain conditions.

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 (NRG3) (p = 2·11×10-8; OR = 18·82 (95% CI 4·86-72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment.

Endometriosis is a chronic disorder with debilitating symptoms that is difficult to diagnose and treat. Advances in imaging technologies and strategies for the management of symptoms are improving the quality of life of patients by reducing the time taken for diagnosis and offering a more balanced approach to therapy.

Abstract STUDY QUESTION What is the capacity of the change between Day 1 and Day 4 post-treatment serum human chorionic gonadotropin (hCG) levels for predicting single-dose methotrexate treatment success in tubal ectopic pregnancy? SUMMARY ANSWER Any fall in Days 1–4 serum hCG signified an 85% (95% CI 76.8–90.6) likelihood of treatment success for women with tubal ectopic pregnancy (initial hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate. WHAT IS KNOWN ALREADY For those with tubal ectopic pregnancy managed by single-dose methotrexate, current guidelines advocate intervention if Days 4–7 hCG fails to fall by >15%. The trajectory of hCG over Days 1–4 has been proposed as an early indicator that predicts treatment success, allowing early reassurance for women. However, almost all prior studies of Days 1–4 hCG changes have been retrospective. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study of women with tubal ectopic pregnancy (pre-treatment hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate. The data were derived from a UK multicentre randomized controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tubal ectopic pregnancy (GEM3). For this analysis, we include data from both treatment arms. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were categorized according to single-dose methotrexate treatment success or failure. Treatment success for this analysis was defined as complete and uneventful resolution of tubal ectopic pregnancy to serum hCG <30 IU/l following single-dose methotrexate treatment without additional treatment. Patient characteristics of the treatment success and failure groups were compared. Changes in Days 1–4, 1–7, and 4–7 serum hCG were evaluated as predictors of treatment success through receiver operating characteristic curve analysis. Test performance characteristics were calculated for percentage change ranges and thresholds including optimal classification thresholds. MAIN RESULTS AND THE ROLE OF CHANCE A total of 322 women with tubal ectopic pregnancy were treated with single-dose methotrexate. The overall single-dose methotrexate treatment success rate was 59% (n = 189/322). For any fall in serum hCG on Days 1–4, likelihood ratios were >3, while for any fall of serum hCG >20% on Days 1–7, likelihood ratios reached 5. Any rise of serum hCG on Days 1–7 and 4–7 strongly reduced the chance of success. Any fall in Days 1–4 hCG predicted single-dose methotrexate treatment success with a sensitivity of 58% and specificity 84%, resulting in positive and negative predictive values of 85% and 57%, respectively. Any rise in Days 1–4 serum hCG <18% was identified as an optimal test threshold that predicted treatment success with 79% sensitivity and 74% specificity, resulting in 82% positive predictive value and 69% negative predictive value. LIMITATIONS, REASONS FOR CAUTION Our findings may be limited by intervention bias resulting from existing guidelines which influences evaluation of hCG changes reliant on Day 7 serum hCG levels. WIDER IMPLICATIONS OF THE FINDINGS Examining a large prospective cohort, we show the value of Days 1–4 serum hCG changes in predicting single-dose methotrexate treatment success in tubal ectopic pregnancy. We recommend that clinicians provide early reassurance to women who have a fall or only a modest (<18%) rise in Days 1–4 serum hCG levels, that their treatment will likely be effective. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by funding from the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant reference number 14/150/03). A.W.H. has received honoraria for consultancy for Ferring, Roche, Nordic Pharma and AbbVie. W.C.D. has received honoraria from Merck and Guerbet and research funding from Galvani Biosciences. L.H.R.W. has received research funding from Roche Diagnostics. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. also reports consultancy for ObsEva and Merck and travel support from Merck. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER This study is a secondary analysis of the GEM3 trial (ISRCTN Registry ISRCTN67795930).

Graphical abstract Abstract Patients with chronic pelvic pain (CPP) may experience pain exacerbations requiring hospital admissions. Due to the effects of backlogged elective surgeries and outpatient gynaecology appointments resulting from the COVID-19 pandemic, we hypothesised that there would be an increased number of women admitted with CPP flares. We conducted a retrospective review of all acute gynaecology admissions at the Royal Infirmary of Edinburgh from July to December 2018 (pre-COVID) and 2021 (post-COVID lockdown). We collected information on the proportion of emergency admissions due to CPP, inpatient investigations and subsequent management. Average total indicative hospital inpatient costs for women with CPP were calculated using NHS National Cost Collection data guidance. There was no significant difference in the number of emergency admissions due to pelvic pain before (153/507) and after (160/461) the COVID-19 pandemic. As high as 33 and 31% had a background history of CPP, respectively. Across both timepoints, investigations in women with CPP had low diagnostic yield: <25% had abnormal imaging findings and 0% had positive vaginal swab cultures. Women with CPP received significantly more inpatient morphine, pain team reviews and were more likely to be discharged with strong opioids. Total yearly inpatient costs were £170,104 and £179,156 in 2018 and 2021, respectively. Overall, emergency admission rates for managing CPP flares was similar before and after the COVID-19 pandemic. Inpatient resource use for women with CPP remains high, investigations have low diagnostic yield and frequent instigation of opiates on discharge may risk dependence. Improved community care of CPP is needed to reduce emergency gynaecology resource utilisation. Lay summary Existing treatments for chronic pelvic pain (CPP) and endometriosis focus on surgery or hormone medication, but these are often ineffective or associated with unacceptable side-effects. As a result, women continue to experience chronic pain and often have ‘flares’ of worsening pain that may lead to hospital admission. The COVID-19 pandemic resulted in backlogged gynaecology clinics and surgeries. The aim of this study was to compare the management of emergency pelvic pain admissions for women with CPP before and after COVID-19. We also aimed to better understand their in-hospital management and estimate their hospital length of stay costs. We did not find an increase in CPP patients admitted for pelvic pain flares after the COVID-19 lockdown. Women with CPP often undergo multiple hospital tests and are often prescribed with strong pain medications which can cause long-term problems. Efforts are needed to improve long-term pain management for women with CPP.

Background Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy.Methods We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930.Findings Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1middot15, 95% CI 0middot85 to 1middot58; adjusted risk difference -0middot01, 95% CI -0middot10 to 0middot09; p=0middot37). Without surgical intervention, median time to resolution was 28middot0 days in the gefitinib group and 28middot0 days in the placebo group (subdistribution hazard ratio 1middot03, 95% CI 0middot75 to 1middot40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group.Interpretation In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions.Funding National Institute of Health Research.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background:Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods:This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings:Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation:Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding:UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843.

Abstract Background Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. Methods We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons’ preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants’ preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. Discussion This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. Trial registration ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

STUDY QUESTION Does application of an unbiased method for analysis of magnetic resonance (MR) images reveal any effect on uterine or fibroid volume from treatment of heavy menstrual bleeding (HMB) with three 12-week courses of the selective progesterone receptor modulator ulipristal acetate (SPRM-UPA)? SUMMARY ANSWER Application of an unbiased method for analysis of MR images showed that treatment of HMB with SPRM-UPA was not associated with a significant reduction in the volume of the uterus or in the volume of uterine fibroids. WHAT IS KNOWN ALREADY SPRM-UPA shows therapeutic efficacy for treating HMB. However, the mechanism of action (MoA) is not well understood and there have been mixed reports, using potentially biased methodology, regarding whether SPRM-UPA has an effect on the volume of the uterus and fibroids. STUDY DESIGN, SIZE, DURATION In a prospective clinical study (with no comparator), 19 women with HMB were treated over a period of 12 months with SPRM-UPA and uterine and fibroid size were assessed with high resolution structural MRI and stereology. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 19 women aged 38-52 years (8 with and 11 without fibroids) were treated with three 12-week courses of 5 mg SPRM-UPA given daily, with four weeks off medication in-between treatment courses. Unbiased estimates of the volume of uterus and total volume of fibroids were obtained at baseline, and after 6 and 12 months of treatment, by using the Cavalieri method of modern design-based stereology in combination with magnetic resonance imaging (MRI). MAIN RESULTS AND THE ROLE OF CHANCE Bland-Altman plots showed good intra-rater repeatability and good inter-rater reproducibility for measurement of the volume of both fibroids and the uterus. For the total patient cohort, two-way ANOVA did not show a significant reduction in the volume of the uterus after two or three treatment courses of SPRM-UPA (P = 0.51), which was also the case when the groups of women with and without fibroids were considered separately (P = 0.63). One-way ANOVA did not show a significant reduction in total fibroid volume in the eight patients with fibroids (P = 0.17). LIMITATIONS, REASONS FOR CAUTION The study has been performed in a relatively small cohort of women and simulations that have subsequently been performed using the acquired data have shown that for three time points and a group size of up to 50, with alpha (Type I Error) and beta (Type II Error) set to 95% significance and 80% power, respectively, at least 35 patients would need to be recruited in order for the null hypothesis (that there is no significant reduction in total fibroid volume) to be potentially rejected. WIDER IMPLICATIONS OF THE FINDINGS The imaging protocol that we have developed represents a generic paradigm for measuring the volume of the uterus and uterine fibroids that can be readily incorporated in future studies of medical treatments of HMB. In the present study, SPRM-UPA failed to produce a significant reduction in the volume of the uterus or the total volume of fibroids (which were present in approximately half of the patients) after either two or three 12-week courses of treatment. This finding represents a new insight in respect of the management of HMB using treatment strategies that target hormone-dependence. STUDY FUNDING/COMPETING INTEREST(S) The UPA Versus Conventional Management of HMB (UCON) trial was funded by the EME Programme (Medical Research Council (MRC) and National Institutes of Health Research (NIHR)) (12/206/52). The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. H.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (All paid to Institution) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., and Myovant Sciences GmbH. H.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. L.W. has received grant funding from Roche Diagnostics (Paid to Institution). All other authors have no conflicts to declare.

Endometriosis is a chronic pain condition affecting 1 in 10 women. There is an unmet need for better medical treatments for endometriosis. We spotlight trials of a single preparation combined HRT-GnRH antagonist (Relugolix) by Giudice et al.,1 for endometriosis-associated pain.

BACKGROUND:The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS:In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION:ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION:Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING:UK MRC DCS/DPFS grant MR/J003611/1.