Most women experience menopause between 47 and 51 years (normal menopause). However, 10-13 percent of women undergo menopause between 40 and 47 years (early menopause). Early menopause poses a serious health concern because it is associated with an increase risk of developing vaginal infections, hot flashes, incontinence, cardiovascular disease, and osteoporosis. The reasons for early menopause are not known. Several studies indicate that it results from an accelerated loss of ovarian follicles. This accelerated loss is proposed to result from excessive levels of luteinizing hormone (LH) and follicle- stimulating hormone (FSH). Excessive levels of both LH and FSH precede the onset of menopause and excessive LH levels have been shown to deplete primordial ovarian follicles. The mechanism by which LH depletes primordial follicles is unknown. Further, the effect of excessive FSH on the age at menopause is not understood. We propose that LH destroys primordial follicles by an indirect mechanism involving ovarian steroids (e.g., estrogens and androgens). We also hypothesize that FSH, like LH depletes primordial ovarian follicles. To test these hypotheses, we will neutralize steroid levels in transgenic mice that overexpress LH and determine if this treatment spares primordial follicles. We also will generate transgenic mice that chronically overexpress FSH and determine if this treatment depletes primordial follicles. This study will provide information about the neuroendocrine and steroid factors involved in regulation of the size of the primordial follicle pool and the timing of menopause. The results also will validate animal models to be used in future studies on the molecular processes underlying early menopause. Such studies are required to develop effective preventive strategies for the morbidities and chronic diseases associated with the menopausal transition.
