Antioxidants in male infertility: from empirical supplementation to phenotype directed therapy

Oxidative stress is a biologically plausible contributor to male infertility, and antioxidant supplementation has been investigated for decades. Yet clinical evidence has not converged on a reproducible benefit in reproductive outcomes. The 2025 World Health Organization (WHO) infertility guideline made no recommendation for or against antioxidant supplementation in men with infertility and one or more semen parameters outside WHO reference ranges, reflecting uncertainty rather than proof of universal inefficacy. A Cochrane review identified 90 randomized controlled trials involving 10,303 men, but live birth was reported in only 12 trials with very low certainty. Contemporary randomized trials have not resolved the uncertainty: MOXI found no improvement in semen parameters, sperm DNA fragmentation, pregnancy, or live birth with a multicomponent antioxidant formulation; FAZST found no benefit of folic acid and zinc on semen quality or live birth with an increase in sperm DNA fragmentation; and SUMMER found no improvement in ongoing pregnancy with a combined antioxidant supplement. These findings make routine empirical supplementation difficult to justify but do not establish universal inefficacy of redox modulating interventions. Most trials have enrolled men according to clinical infertility or semen criteria rather than a prospectively defined standardized redox phenotype and have rarely tested treatment effect modification. Biological and clinical heterogeneity, differences among interventions, physiological roles of reactive oxygen species, and reliance on surrogate endpoints may dilute true effects. Future trials should determine which biologically defined men, if any, benefit from which redox modulating intervention, using standardized phenotyping, target engagement measures, prespecified treatment by phenotype interaction testing, and clinically meaningful reproductive outcomes.