The 4-Vinylcyclohexene Diepoxide (VCD)-Treated Rat Provides A Unique Preclinical Model to Study Peri-Menopausal Hot Flushes

Objectives: Ovariectomy of young rodents is the most frequently used animal model of the menopause. However, the assumption that ovariectomy, causing a rapid loss of ovarian hormones is a general model of menopause in not well supported. Several animal models have been developed with the aim of mitigating the human conditions of the menopause. Among these, the ovotoxin 4-vinylcyclohexene diepoxide (VCD) has gained popularity as chronic exposure to low dosing VCD causes apoptosis and subsequent ovarian follicle loss in rats and mice. The objective of these studies was to evaluate the VCD-treated female rat as a model of menopausal hot flush. Methods: Fisher 344 rats were dosed daily with VCD (160 mg/kg, i.p.) or vehicle (sesame oil) for 20 days. By three months after the completion of VCD dosing all the animals showed vaginal cytology characteristic for constant diestrus indicating ovarian failure while control animals showed regular estrous cycles. At this point, control animals were ovariectomized. Four weeks later, all the animals were utilized in the morphineaddicted hot flush model. Results: VCD-treated rats responded similarly to untreated ovariectomized rats, i.e., a 5-6C increase in their tail skin temperature (representing hot flush) was observed following morphine withdrawal. The tail skin temperature of ovariectomized, estrogentreated rats increased only 2C following morphine withdrawal. Conclusions: VCD-treated rats provide a more physiologically relevant model than young ovariectomized rats for studying menopausal symptoms, including hot flushes, since the gradual decrease in estrogen levels better mimics the human perimenopausal situation than ovariectomized animals (abrupt decline in estrogens).