Multidose 5-Fluorouracil is Highly Toxic to Growing Ovarian Follicles in Mice

With increasing improvements in cancer survival rates, it is critical to reduce the significant long-term side effects that afflict patients following treatment. For women, consequences of chemotherapy-induced damage to the reproductive system include infertility and premature menopause, which adversely effects cognition, mood, cardiovascular, bone, and sexual health, and increases the risk of early mortality. These long-term effects impact patient's life quality and highlight a significant and on-going burden on the health system after treatment. However, the precise mechanisms through which chemotherapeutic agents induce ovarian damage and primordial follicle depletion remain to be characterized. Hence, preventing the development of effective pharmacological methods to preserve fertility and improve quality of life after treatment. The chemotherapeutic agent 5-Fluorouracil (5FU) is not deemed cytotoxic to the ovary, however, risks to longterm fertility after multiple doses are not known. Therefore, we sought to evaluate the impact of 3, weekly doses of 5FU treatment on the ovary. Using a mouse model enabled accurate histomorphometric analysis of follicle numbers and ovarian structure and function, to accurately assess cumulative impact of 5FU on the ovary. This study clearly demonstrated that multidose 5FU treatment resulted in dramatic and progressive atresia of growing follicles and a profound decrease in ovarian volume due to reduced corpus luteum counts. However, primordial follicle numbers were unaffected. Thus, 5FU is unlikely to cause permanent infertility when administered to women of pre or reproductive age. Furthermore, this study suggests that depletion of the growing follicle population is insufficient to stimulate follicle activation and primordial follicle depletion.