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.