The etiology of menopause: not just ovarian dysfunction but also a role for the central nervous system

Background: The hormonal changes which occur leading up to menopause have been described in multiple cross-sectional and longitudinal studies. Results from these studies document the occurrence of marked alterations in pituitary-hypothalamic function, along with the changes in the ovary, which play a role in the etiology of menopause. However, the role of pituitary-hypothalamic function in the menopausal transition (MT) has been generally overlooked. Methods: Literature searches were performed using PubMed, Scopus, and Medline, for articles with content related to menopause and the MT. The searches were restricted to English language observational studies and reviews of human studies and clinical trials. Results: During the MT, in addition to a reduction in the number of ovarian follicles, there is a marked reduction in the sensitivity of the central nervous system to both the positive and negative feedback effects of estrogen. These changes in sensitivity explain menstrual irregularities and systemic systems which are present in the time before the final menstrual period. Although the timing of menopause is difficult to predict, broad patterns in hormonal changes are seen, including a slow drop in inhibin B levels, followed by a monotropic rise in follicle-stimulating hormone during the late reproductive period. The MT is marked by irregular cycles with unpredictable luteinizing hormone levels and unpredictable ovulation. The levels of estrogen remain stable, or are even elevated through most of the MT, and levels of estrogen do not begin to decrease until late in the MT. The Stages of Reproductive Aging Workshop guidelines have improved the homogeneity of classifications in studies. Conclusions: On the basis of longitudinal hormone studies, it is clear that desensitization of the hypothalamic-pituitary-ovarian feedback loop plays an important role, in addition to a decrease in follicle number and insensitivity of remaining follicles to the positive feedback of estrogen, to trigger ovulation. Further studies in humans are needed to elucidate the mechanisms responsible for these perimenopausal changes if proper therapeutic modalities for the symptoms associated with menopause can be developed.