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.

Definition and IncidenceEclampsia is one of the most serious acute complications of pregnancy, and it carries high morbidity and mortality for both the mother and baby. 1 Eclampsia is defined as the occurrence of 1 or more generalized, tonic-clonic convulsions unrelated to other medical conditions in women with hypertensive disorder of pregnancy. Although 10% of pregnancies are complicated by hypertensive disorders, eclampsia continues to occur in 0.8% of women with hypertensive disorders. 2 During the past 50 years, there has been a reduction in the rate of eclampsia in developed countries with a reported incidence ranging from 1.6 per 10,000 deliveries to 10 per 10,000 deliveries. 3e13 In some low-resource or developing countries, the reported rate of eclampsia ranges from 50 to 151 per 10,000 deliveries (Figure 1). 14e18 Although the rate of eclampsia and the number of maternal deaths from hypertension in pregnancy have fallen steadily over recent years in developing countries, hypertensive disorders still feature among the top 6 causes of maternal mortality in the United States and are responsible for up to 14% of all maternal deaths worldwide. 1,19e21 Our impression is that differences in the incidence and complication rates between developed and developing countries result from gaps in access to care, appropriate and early prenatal care, surveillance and management protocols for timely hospitalization and delivery, antihypertensive therapy for prevention of stroke, pulmonary edema, congestive heart failure and magnesium sulfate prophylaxis during the peripartum period in women with severe preeclampsia. 22,23

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