From subclinical ovarian damage to reproductive outcomes: a translational perspective on PI3K/AKT/mTOR signaling in fertility preservation.

Gonadotoxic cancer therapies have significantly improved patient survival but frequently compromise female reproductive potential, leading to diminished ovarian reserve and infertility. Although ovarian damage is traditionally assessed using clinical indicators such as anti-Müllerian hormone levels and menstrual irregularities, accumulating evidence suggests that injury may begin at a subclinical level before functional decline becomes apparent. Early alterations include histological changes, granulosa cell apoptosis, oxidative stress, and activation of DNA damage responses. Dysregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway may further contribute to premature follicular recruitment and ovarian reserve depletion. However, much of this mechanistic evidence derives from experimental models, and direct prospective human evidence remains limited. This review proposes a unifying "subclinical damage-signaling-outcome axis" linking early molecular injury and signaling dysregulation with subsequent reproductive consequences, including impaired oocyte quality and adverse fertility outcomes. By integrating experimental and clinical evidence, this framework provides a translational perspective on gonadotoxic ovarian injury and highlights potential opportunities for early detection and targeted fertility preservation. Further prospective studies are required to validate its clinical utility and determine whether these molecular insights can inform individualized fertility preservation strategies.