Premature ovarian failure and infertility are major side effects of chemotherapy treatments in young cancer patients. A more thorough understanding of the mechanism behind chemotherapy-induced follicle loss is necessary in order to develop new methods to preserve fertility in these patients. This study shows that the alkylating agent cyclophosphamide (Cy) activates the growth of the quiescent primordial follicle (PMF) population in mice, resulting in loss of ovarian reserve. Despite the initial massive apoptosis observed in growing, though not in resting, follicles of Cy-treated mice, differential follicle counts demonstrated both a decrease in PMFs and an increase in early growing follicles. Immunohistochemistry showed that granulosa cells were undergoing proliferation. Analysis of the PI3K signaling pathway in the oocytes and granulosa cells demonstrated that Cy increased phosphorylation of proteins that trigger follicle activation.
The immunomodulator AS101 was explored as a novel means of preventing chemotherapy-induced ovarian damage in mice. Co-administration of AS101 reduced follicle activation of PMFs as well as reducing apoptosis in growing follicles, thereby increasing follicle reserve. Mating studies showed that AS101 also rescued fertility after Cy, increasing pregnancy incidence and litter size. Moreover, AS101 increased the efficacy of Cy against human breast cancer cell lines, and has synergistic and additive anti-cancer activity.
These findings suggest that the mechanism behind Cy-induced loss of ovarian reserve is accelerated PMFs activation, which results in a 'burn-out' effect and follicle depletion. AS101 co-administration protects the ovarian reserve, via inhibition of the PI3K pathway responsible for accelerated PMFs activation. By restoring the inhibitory influence on PMFs, and by attenuating PMFs activation, AS101 returns the ovary to a state of equilibrium, the PMFs are maintained in a dormant state, and the ovarian reserve is preserved. AS101 shows potential as an ovarian-protective agent to preserve fertility in female cancer patients.
