HORMONAL THERAPIES FOR ENDOMETRIOSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED HEAD-TO-HEAD TRIALS

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.

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. 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. Competing Interest Statement AWH receives grant funding from the NIHR, UKRI, Chief Scientists Office, Wellbeing of Women, European Union, and Roche. AWHs institution has received honoraria for consultancy from Gedeon Richter and Theramex, and he has received lecture fees from Gedeon Richter and Theramex. AWHs institution has received grant funding from Roche Diagnostics and honoraria for teaching from Gedeon Richter. LHRW receives grant funding the NIHR, MRC, Chief Scientist's Office and Wellbeing of Women. LHRWs institution has received grant funding from Roche Diagnostics, honoraria for consultancy from Thermax, Absci, Hirundo and F-prime and honoraria for teaching from Gedeon Richter and Theramex. KV receives grant funding from the NIHR, MRC, Medical Research Foundation, European Union and NIH. KV's institution has received honoraria for consultancy and talks and associated travel costs from Gedeon Richter, Bayer Healthcare, Reckitt, Organon and Gesynta. RM previously received an honorarium from Roche Diagnostics for consultancy work. PV is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica, and has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate. NS reports relationships with the World Endometriosis Society (WES), the European Society of Human Reproduction and Embryology (ESHRE), and the Society for Endometriosis and Uterine Disorders (SEUD), including travel reimbursement. VB declare no conflicts of interest. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data extracted from the included studies and used for the analyses are available in the main manuscript or appendix. No individual participant data were collected or generated for this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript and supplementary appendix. Protocol registered on PROSPERO.