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

The short version

This systematic review and meta-analysis combined 17 randomized controlled trials (15 pooled, 996 women) to ask whether antioxidant supplements ease the pain of endometriosis, a chronic inflammatory condition in which tissue like the uterine lining grows outside the uterus. Oxidative stress (damage from unstable oxygen molecules called free radicals) is thought to feed the inflammation and pain, so antioxidants such as melatonin, vitamins C, D, and E, curcumin (from turmeric), garlic, silymarin (from milk thistle), and resveratrol have been tested. Results across individual trials have been inconsistent, and earlier reviews were narrower, so this one searched seven sources through January 2025 and graded the certainty of the evidence. Included trials enrolled women aged 18 to 49 with confirmed endometriosis, mostly in Iran, plus Egypt, Brazil, the United States, China, and Sweden. Women took an oral antioxidant or a comparator (placebo, standard care, or nothing) for 8 to 24 weeks. The review pooled three pain outcomes using standardized mean differences (a way to combine different pain scales into one measure): painful periods (dysmenorrhea), painful intercourse (dyspareunia), and chronic pelvic pain. Study quality was graded with Cochrane RoB 2, and evidence certainty with GRADE. For painful periods, 12 trials (706 women) showed lower pain with antioxidants (SMD -1.26; 95% CI -2.19 to -0.32, equal to about 3 points on a 0 to 10 scale), but results varied enormously between trials (I² = 90.1%), so the evidence was rated low certainty. Melatonin stood out (SMD -1.89; 95% CI -2.48 to -1.31), while vitamin D, vitamins C plus E, omega-3, resveratrol, and curcumin did not reach significance. Painful intercourse showed no significant effect (SMD -1.01; 95% CI -2.27 to 0.24). Chronic pelvic pain fell in the pooled analysis (SMD -1.07; 95% CI -1.71 to -0.42), but the evidence was very low certainty and the effect vanished when trials with conflicts of interest were removed. Single trials of garlic powder and silymarin reported lower pain, whereas curcumin did not. Only 7 of 17 trials had low risk of bias. The authors say the findings do not support routine antioxidant use for endometriosis pain, and describe melatonin as the most promising candidate for painful periods, pending confirmation. Limitations include very high heterogeneity, small trials, different antioxidants and doses, bigger effects in weaker studies, and little control of baseline vitamin levels or diet. The paper did not report adverse events. The garlic and silymarin findings come from single trials, and publication-bias testing found no small-study effects for chronic pelvic pain. The authors call for larger, standardized trials.

Key findings

• A meta-analysis (a statistical combination of results from several trials) of 15 randomized trials with 996 women tested oral antioxidant supplements for endometriosis-related pain, and 17 trials were included in the systematic review overall.
• For period pain (dysmenorrhea), antioxidants were associated with a lower pain score (standardized mean difference -1.26; 95% CI -2.19 to -0.32, about 3 points on a 0 to 10 scale), but the evidence was low certainty because results differed greatly between trials.
• Melatonin showed the clearest effect on period pain (four trials; standardized mean difference -1.89; 95% CI -2.48 to -1.31), while vitamin D, vitamins C plus E, omega-3, resveratrol, and curcumin did not reach statistical significance.
• Painful intercourse (dyspareunia) did not improve significantly, and the chronic pelvic pain result (standardized mean difference -1.07) was very low certainty and lost significance when trials with conflicts of interest were excluded.
• The authors state that current evidence does not support routine antioxidant use for endometriosis pain, and they call for larger, standardized, high-quality trials.

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