Chemotherapy can cause premature ovarian failure and infertility. This study showed that the anticancer drug cyclophosphamide induces follicle loss in mice by triggering the growth of dormant primordial follicles (which represent the non-renewable 'ovarian reserve') through activation of the PI3K (phosphoinositide 3-kinase)–PTEN (phosphatase and tensin homolog)–AKT pathway. Administration of AS101, which modulates the PI3K–PTEN–AKT pathway, increased the follicle reserve and rescued fertility after cyclophosphamide treatment. So AS101, which is currently in clinical trials, could be used to preserve fertility in female patients with cancer.