Menopause and Hypothalamic-Pituitary Sensitivity to Estrogen

CONTEXT The onset of human menopause is thought to be caused solely by ovarian failure and oocyte depletion. However, clinical symptoms and certain recent data in perimenopausal women suggest central nervous system involvement. OBJECTIVE To determine if modifications of hypothalamic-pituitary response to estrogen feedback mechanisms occur in older reproductive-age women as a mechanism of the onset of menopause. DESIGN, SETTING, AND PARTICIPANTS The Study of Women’s Health Across the Nation (SWAN) is a multiethnic observational cohort study of the menopausal transition in 3302 women at 7 US sites. Of the subcohort of 840 women who participated in the Daily Hormone Study between 1997 and 1999, 680 women had evidence of luteal activity. The remaining 160 women (19%) did not have luteal activity and are the subject of this report. MAIN OUTCOME MEASURES Daily urinary hormone levels of estrogen and progesterone metabolites, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). RESULTS Three groups of women were studied: those with estrogen increases with an LH surge, those with estrogen increases without an LH surge, and those with neither. There were no differences in age or ethnicity among the 3 groups of women. Women in the third group (no increases) experienced more menopausal symptoms (hot flashes) than did women in the other groups with estrogen increases. In older reproductive-age women, the frequent existence of anovulatory cycles with estrogen peaks, equivalent to those that result in LH surges in younger women, yet in which no LH surges occur, indicates failure of estrogen-positive feedback on LH secretion. In other anovulatory cycles, follicular-phase estrogen levels did not lower LH secretion as occurs in cycles of younger women, indicating decreased estrogen-negative feedback on LH secretion. CONCLUSION Our findings are compatible with hypothalamic-pituitary insensitivity to estrogen in aging perimenopausal women.