Smart Cryopreservation: Antioxidants as Molecular Guardians of Fertility

Significance: Ovarian tissue cryopreservation (OTC) has emerged as an important fertility-preservation strategy for patients undergoing gonadotoxic treatment. However, this approach remains vulnerable to freeze–thaw-associated cellular injury driven by oxidative stress, mitochondrial dysfunction, cryoprotectant toxicity, and ischemia–reperfusion damage. Antioxidants have demonstrated potential as redox modulators, but clinical use necessitates careful consideration of dosage, timing, and tissue-specific redox biology. Importantly, excessive antioxidant supplementation may induce reductive stress, interfering with physiological redox signaling. Recent Advances: Enzymatic antioxidants, including catalase and superoxide dismutase, and nonenzymatic antioxidants, including resveratrol, melatonin, N -acetylcysteine, and vitamins C and E, have been evaluated in OTC models. Studies using human ovarian tissue, including ex vivo and xenograft models, have reported promising effects on follicular morphology, steroidogenic activity, angiogenesis, and post-thaw apoptosis. Melatonin and resveratrol have demonstrated protective effects in preclinical models; however, direct evidence from cryopreserved human ovarian tissue remains limited. Because these agents act through distinct mechanisms, antioxidant selection should be matched to the specific oxidative-stress phenotype. Critical Issue: Considerable heterogeneity persists in antioxidant selection, concentration, timing, and delivery, and no standardized protocols are currently available. Antioxidant overexposure may cause paradoxical pro-oxidant effects or reductive stress, thereby disrupting redox-dependent signaling. Ethical and regulatory considerations require particular attention in pediatric fertility preservation. Future Direction: Future studies need to compare antioxidant therapy with conventional treatments using clinically relevant endpoints such as graft survival, hormonal recovery, and live-birth rates. Combining patient features with redox analysis could allow for personalized therapy. Future studies also need to address the chromosomal integrity of oocytes. Antioxid. Redox Signal. 00, 000–000.