Stem cell-based therapy for premature ovarian insufficiency: From mechanisms to clinical translation

Premature ovarian insufficiency (POI) is a major cause of diminished fertility and premature reproductive aging.POI is accompanied by vasomotor, physical, psychosocial, and sexual symptoms that substantially affect women's health and quality of life.Hormone replacement therapy remains the cornerstone of symptomatic management; however, it does not restore ovarian reserve or reproductive potential.Thus, stem cell-based therapies have emerged as novel regenerative strategies, supported by preclinical evidence of improved ovarian function, follicular development, and microenvironmental remodeling.This review critically summarizes current evidence from in vitro studies, animal models, and clinical trials, focusing on mesenchymal stem cells, human amniotic epithelial cells, embryonic stem cells, and induced pluripotent stem cells.Proposed mechanisms include ovarian homing, paracrine signaling, immunomodulation, anti-apoptotic and antioxidant effects, angiogenesis, extracellular vesicle-mediated communication, and the regulation of follicular development.Early clinical studies suggest feasibility and an acceptable short-term safety profile, with preliminary evidence showing improvements in ovarian endocrine function, menstrual recovery, and selected reproductive outcomes.However, evidence remains preliminary, limited and heterogeneous, with substantial challenges related to cell sources, manufacturing, dosing, delivery, mechanisms of action, long-term safety, potency, and clinical endpoints.Future research should prioritize mechanism-guided, standardized strategies and well-designed randomized controlled trials to establish safety and efficacy.