Destruction of primordial ovarian follicles in adult cynomolgus macaques after exposure to 4-vinylcyclohexene diepoxide: a nonhuman primate model of the menopausal transition

Objective: To determine whether the 4-vinylcyclohexene diepoxide (VCD)-treated mouse menopause model, which involves accelerated atresia of primordial follicles and induces gradual ovarian failure (while sparing the ovarian stroma), can be adapted to nonhuman primates. Design: Controlled periclinical trial (nonhuman primates). Setting: Comparative Medicine Clinical Research Center. Animal(s): Four adult female cynomolgus monkeys. Intervention(s): Once-daily IM injections for 15 days as follows: vehicle or VCD doses of 80 mg/kg, 160 mg/kg, 250 mg/kg. Ovaries were removed 27 days after treatment, and pathological determinations were made at necropsy. Main Outcome Measure(s): Baseline and interim hematologic and biochemical measures, physical exams, and body weights. Follicle counts and organ evaluation at necropsy. Result(s): A nearly complete elimination of primordial, intermediate, primary and secondary follicles was achieved with 250 mg/kg VCD. A 50% reduction in primordial and primary follicles was observed with 160 mg/kg VCD. No effect of 80 mg/kg VCD per day was observed. Clinical health measures remained within normal range except for transient, mild increases in liver enzymes and an inflammatory response at the injection site with 250 mg/kg. Postmortem evaluations (9 months) revealed no gross or histological lesions in the organs studied. Conclusion(s): These results demonstrate that the monkey ovary is susceptible to VCD and that as in rodents, primordial and primary follicles are targeted selectively.