Reproduction Abstracts

A common side-effect of standard cytotoxic cancer therapy is infertility and pre-mature menopause resulting from collateral damage sustained by the ovaries during treatment. The survival rates for many cancers has improved greatly during recent years and consequently there has been considerable interest in the development of new and innovative strategies to protect the fertility and health of women post-cancer treatment. Towards this end, we are investigating the cellular mechanisms that regulate oocyte apoptosis and primordial follicle loss during cancer treatment. We have identified the pro-apoptotic BH3-only proteins, PUMA and NOXA, as essential regulators of oocyte death and primordial follicle loss following exposure to γ-irradiation. Furthermore, our studies in mice demonstrate that elimination of PUMA, either alone or together with NOXA, protects a cohort of primordial follicles from γ-irradiation induced loss and preserves fertility without compromising the health of offspring. We are now extending our findings to determine if PUMA and NOXA are also responsible for the loss of primordial follicles that occurs during exposure to commonly used chemotherapy agents, such as cyclophosphamide, cisplatin and doxorubicin. Our work provides support for the concept that preventing oocyte death, by blocking key members of the apoptotic pathway, such as PUMA and NOXA, may represent a viable new stategy for protecting future fertility and ovarian function in girls and women being treated for cancer.