Does gonadotoxic chemotherapy deplete the ovarian reserve through activation of primordial follicles?

Despite significant advances in fertility preservation, no proven pharmacological options exist to protect ovarian primordial follicle reserve from chemotherapy-induced damage. Developing targeted gonadoprotective treatments will require an improved understanding of the molecular mechanisms underlying chemotherapy-induced primordial follicle depletion. While there is robust evidence that gonadotoxic chemotherapy induces primordial follicle death by causing DNA double-strand breaks which trigger apoptotic death, follicle activation leading to 'burn-out' of the ovarian reserve has been suggested as an alternative mechanism. Here, we critically evaluated whether primordial follicle activation is a significant mechanism of chemotherapy-induced ovarian reserve depletion in humans. We assessed the causal relationship between chemotherapy exposure and primordial follicle activation by applying the Bradford Hill criteria.