Abstract
Primary ovarian insufficiency (POI) affects up to 3% of reproductive-aged women and is a critical yet underrecognized contributor to infertility and systemic accelerated aging. While most cases remain idiopathic, advances in genomics increasingly reveal a genetic basis, implicating pathways that govern DNA repair, meiosis, chromosomal stability, and folliculogenesis. This review synthesizes the multifactorial etiology of POI, integrating genetic contributions with emerging evidence on epigenetic dysregulation, mitochondrial dysfunction, and environmental influences such as toxins and lifestyle factors. These mechanisms converge on core cellular processes, driving premature follicular depletion and shortening reproductive lifespan. We also highlight racial and ethnic disparities in POI prevalence and research representation, alongside the profound psychosocial burden experienced by affected individuals. Addressing these challenges through integrative strategies that unite mechanistic insight with equity is essential, not only for improving POI care but also for advancing precision approaches to ovarian aging and safeguarding reproductive health across the lifespan.