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