Ovarian gonadotoxicity and gonadoprotection: a narrative review

Chemotherapy-induced gonadotoxicity is a serious concern for cancer survivors, particularly children and women of reproductive age. The mechanisms by which chemotherapy depletes the ovarian reserve and impairs fertility are multifactorial. Chemotherapy can induce apoptosis of growing and primordial follicles, as well as excessive activation of primordial follicles, leading to burnout of the ovarian reserve. Stromal damage may further exacerbate these effects. Preclinical studies have aimed to safeguard the ovary against chemotherapy by targeting follicular apoptosis through inhibition of specific pathway mediators (tyrosine kinase inhibitors, serine/threonine kinase inhibitors, sphingolipids) or use of mesenchymal-stem-cell-derived factors, specific microRNA and antioxidant molecules. Other studies have focused on inhibiting follicular activation by targeting direct pathways (e.g. phosphatidylinositol 3-kinase and mammalian target of rapamycin modulators) or indirect regulators (e.g. anti-Müllerian hormone). Finally, some approaches aim to protect the ovarian stroma, which may be crucial to preserving ovarian function. The objective of this article is to provide an updated overview of the effects of chemotherapy on the ovary, and summarize current and emerging gonadoprotective strategies. Although numerous preclinical studies have reported encouraging results, further research is needed before these approaches can be considered safe and suitable for clinical application.