White spotting variant mouse as an experimental model for ovarian aging and menopausal biology

Objective: Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell-containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies. Methods: Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography. Results: The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. Conclusions: The reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in newborn mice and premature depletion of follicles in young mice, although mutant females have a normal life span after cessation of ovarian function. The Wv female mice exhibit consistent physiological changes that resemble common features of postmenopausal women. These alterations include follicle depletion, morphological aging of the ovary, altered serum levels of cholesterol, gonadotropins and steroid hormones, decreased bone density, and reduced cardiac function. These changes were not observed in male mice, either age-matched male Wv/Wv or wildtype mice, and are improbably caused by global loss of c-kit function. The Wv mouse may be a genetic, intact-ovary model that mimics closely the phenotypes of human menopause to be used for further studies to understand the mechanisms of menopausal biology.