Cyclophosphamide Triggers Follicle Activation and “Burnout”; AS101 Prevents Follicle Loss and Preserves Fertility

Cyclophosphamide activates dormant follicle growth, leading to depletion of ovarian reserve, and AS101 prevents this activation, rescuing fertility in mice. Of Mice and Women: Protecting Cancer Patients from Treatment-Induced Infertility Cancer, especially in advanced stages, is a multisystem disease that can affect a patient in a myriad ways. Unfortunately, cancer treatments such as chemotherapy can also wreak havoc on the body, and some of their side effects can be felt for the rest of the patient’s lifetime. One notable consequence of chemotherapy is infertility, which is particularly problematic in young cancer patients who receive their treatments before they’ve had an opportunity to have children. Alkylating agents such as cyclophosphamide (Cy) carry a high risk of ovarian toxicity and are among the worst offenders with regard to risk of future infertility. Now, Kalich-Philosoph et al. present findings that show how Cy exerts its toxic effects on ovarian cells, as well as a potential method of protecting the ovaries and preserving fertility. In a mouse model of Cy treatment, the authors demonstrated that this chemotherapy drug attacks the ovaries by a twofold mechanism. It is toxic to dividing cells and kills actively growing ovarian follicles. At the same time, it also activates the quiescent follicles, inducing them to grow and proliferate, which makes them susceptible to the effects of the drug as well. In this way, Cy treatment depletes the ovarian reserve, leading to early ovarian failure and infertility. The authors also showed that an experimental drug called AS101 may provide protection against this adverse effect of cancer treatment. Mice treated with AS101 in conjunction with Cy fared much better than their counterparts receiving chemotherapy alone. Their primordial ovarian follicles remained dormant, did not start proliferating prematurely, and survived through the entire treatment. Subsequently, the mice that received AS101 along with Cy had normal fertility, whereas the ones treated with Cy alone had a lower rate of pregnancy and fewer total offspring. Future experiments will be needed to translate this work from mice into human patients and confirm the effectiveness of AS101 for preserving fertility in the clinical setting. Promisingly, AS101 is already in phase 2 clinical trials and appears to be safe for human use. Moreover, AS101 itself appears to have anticancer effects and may be able to reinforce for the therapeutic action of Cy while counteracting its reproductive toxicity. 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 to develop new methods to preserve fertility in these patients. We show that the alkylating agent cyclophosphamide (Cy) activates the growth of the quiescent primordial follicle 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 primordial follicles and an increase in early growing follicles. Immunohistochemistry showed that granulosa cells were undergoing proliferation. Analysis of the phosphatidylinositol 3-kinase signaling pathway demonstrated that Cy increased phosphorylation of proteins that stimulate follicle activation in the oocytes and granulosa cells. Coadministration of an immunomodulator, AS101, reduced follicle activation, thereby increasing follicle reserve and rescuing fertility after Cy, and also increased the efficacy of Cy against breast cancer cell lines. These findings suggest that the mechanism in Cy-induced loss of ovarian reserve is accelerated primordial follicle activation, which results in a “burnout” effect and follicle depletion. By preventing this activation, AS101 shows potential as an ovarian-protective agent, which may be able to preserve fertility in female cancer patients.