Our group has previously reported striking increases in estrogen secretin and excretion in women in the early stage of the menopause transition. The causes of he shortened follicular phases, increased whole cycle estrogen, and decreased progesterone in perimenopause, as well as the consequences of this altered reproductive hormonal environment on the hypothalamic-pituitary and endometrial axes are the focus of this continuing renewal. We propose 3 Specific Aims:
Aims 1 will determine the association of elevated FSH in the perimenopause with decreased inhibin A and B, and with increases in circulating activin A.
In Aim 2, we will test the hypothesis that increased estrogen secretion in perimenopausal cycles will caused increased menstrual bleeding. We will also determine whether increased estradiol exposure causes increased endometrial angiogenesis and proliferation as assessed immunohistochemically. We will test the hypothesis that abundance and location of ER alpha and beta subtypes differ between perimenopausal and mid-productive aged women's endometrium.
Aim 3 will test the hypothesis that perimenopausal anovulation is caused by LH surge failure secondary to supraphysiologic estradiol stimulation. We will administer physiologic and supraphysiologic estradiol by infusion and test the resulting LH surge. We will also test directly pituitary sensitivity to exogenous LH in estradiol primed perimenopausal women to determine if there id reduced positive feedback sensitivity in perimenopausal women to determine if there is reduced positive feedback sensitivity in perimenopausal women. In this manner, we hope to elucidate the critical mechanisms that may cause or be the consequence of the hormonal dynamics of the early stages of the menopausal transition.
