ABSTRACT
OBJECTIVE: Repeated daily dosing with 4-vinylcyclohexene diepoxide (VCD) causes gradual ovarian failure in mice. As a result, the animal undergoes ovarian failure, but retains residual ovarian tissue. The purpose of this study was to use a mouse model to regulate the induction of a period analogous to perimenopause in women. DESIGN: Female B6C3F1 mice (28 days old; n = 8) were dosed daily for 10 or 20 days with VCD (160 mg/kg/d) or sesame oil. The animals were evaluated for reproductive function on days 10, 20, 35 after the onset of dosing, and on the day of follicle depletion. Each animal was killed at the specified time points, and ovaries, uteri, and plasma were collected. RESULTS: VCD reduced (P < 0.05) the number of primordial (by 93.2%) and primary (by 85.1%) follicles after 10 days of dosing, whereas essentially all primordial and primary follicles were lost (P < 0.05) after 20 days of dosing. The average time to ovarian failure was on day 135 for 10-day-dosed mice and on day 52 for 20-day-dosed mice. Follicle-depleted mice in both groups had decreased (P < 0.05) ovarian and uterine weights. Circulating follicle-stimulating hormone levels were increased (P < 0.05) on day 44 after the onset of dosing in 10-day-dosed mice and on day 35 in 20-day-dosed mice. CONCLUSION: These results demonstrate that ovarian failure can be caused by VCD more rapidly if repeated daily dosing occurs for a longer period. Thus, the length of time leading up to ovarian failure (model for perimenopause) can be adjusted by varying the length of exposure.
Subject(s)
Disease Models, Animal , Follicular Atresia/physiology , Perimenopause/physiology , Animals , Cyclohexanes , Cyclohexenes , Estrus/drug effects , Female , Follicle Stimulating Hormone/blood , Follicular Atresia/blood , Mice , Mice, Inbred Strains , Ovarian Follicle/drug effects , Perimenopause/blood , Sesame Oil , Uterus/drug effects , Vinyl CompoundsABSTRACT
4-Vinylcyclohexene diepoxide (VCD) causes early, gradual ovarian failure in mice because it specifically targets small pre-antral ovarian follicles. The period between loss of these follicles and ovarian failure is analogous to perimenopause in women. We sought to characterize the period of onset of ovarian failure in VCD-treated mice in regard to estrous cycle length and hormonal changes. Female C57Bl/6 mice (age, 28 days) were dosed daily for 15 days with VCD (160 mg/kg intraperitoneally) to cause early ovarian failure or with vehicle only (control animals). Cycle length was monitored by vaginal cytology. Plasma levels of 17beta-estradiol (E2), progesterone (P4), and follicle-stimulating hormone (FSH) in control and VCD-treated animals were measured during proestrus of cycles 1 through 12. Cycle length (mean, 5.8 days) did not differ between groups for cycles 1 through 4. In contrast, cycle length during cycles 5 through 12 was increased (mean length, 10.9 days; P < 0.05 versus control) in VCD-treated animals, which also showed an apparent increase in plasma FSH levels. Plasma E2 and P4 at proestrus did not differ between groups during any cycle. Ovarian failure in VCD-treated mice was confirmed by histological evaluation on day 156 after onset of dosing, whereas control animals were still cycling. Therefore, despite compromised cycle length in VCD-treated mice, peak ovarian steroid production in preovulatory follicles at proestrus is adequate. These results demonstrate that the VCD-treated mouse can serve as an appropriate model to mimic hormonal changes during the perimenopausal transition in women.
