Efficacy of antioxidant supplementation in alleviating endometriosis-related pain: insights from a systematic review and meta-analysis of RCTs

Endometriosis, a chronic inflammatory disorder, is a leading cause of pelvic pain and reduced quality of life in women, with oxidative stress implicated in its pathogenesis. While antioxidant supplementation has been proposed as a potential therapeutic strategy, its clinical efficacy remains controversial. This systematic review and meta-analysis evaluate the impact of antioxidants on endometriosis-related pain outcomes. We conducted a systematic review and meta-analysis. A comprehensive search of PubMed, Scopus, Cochrane, Web of Science, and clinical trial registries (2000–January 2025) was conducted for randomized controlled trials (RCTs) investigating the effect of any oral antioxidant supplement, without dose or duration restrictions, in endometriosis patients and reporting quantitative data on at least one of the primary pain outcomes (dysmenorrhea, dyspareunia, or chronic pelvic pain). Primary outcomes included dysmenorrhea, dyspareunia, and chronic pelvic pain. Study risk of bias was assessed using the Cochrane RoB 2 tool, and evidence certainty was graded via the GRADE framework. Random-effects meta-analyses were performed to estimate pooled effects. Meta-analysis of available RCTs suggested a potential reduction in pain scores for dysmenorrhea (SMD = − 1.26, 95% CI: −2.19 to − 0.32) and chronic pelvic pain (SMD = − 1.07, 95% CI: −1.71 to − 0.42); however, extreme heterogeneity (I² > 90%) in these analyses indicates that these average effects are highly uncertain and should not be generalized specific clinical contexts. No significant effect was observed for dyspareunia. Subgroup analyses indicated that melatonin may be associated with the most consistent potential pain reduction. Current low- to very low-certainty evidence suggests that antioxidant supplementation, particularly melatonin, may be associated with improvements in dysmenorrhea and chronic pelvic pain in endometriosis. However, due to considerable inconsistency and methodological limitations across studies, these findings must be interpreted with caution. The results underscore the urgent need for high-quality, large-scale RCTs to confirm any potential benefits and define the clinical role of antioxidants in endometriosis management.