Premature menopause and risk of neurological disease: basic mechanisms and clinical implications

Abstract

Since basic scientific studies in the 1990s revealed dramatic gender differences in neurological damage from cerebral ischemia, significant evidence has accumulated for a neuroprotective role of ovarian-derived 17β-Estradiol (E2). Intriguingly, observational studies have further suggested that early and prolonged loss of ovarian E2 (premature menopause) leads to a doubled lifetime risk for dementia and a fivefold increased risk of mortality from neurological disorders, but some controversy remains. Here, we briefly summarize and analyze clinical cohort studies assessing the detrimental neurological outcomes of premature menopause. Furthermore, we discuss current basic science studies elucidating the molecular mechanisms underlying the enhanced risk of neurological disease in prematurely menopausal women and the "window of opportunity" for estrogen benefit. Finally, we highlight four critical issues in the field that require collaboration between basic scientists and clinicians for successful resolution, with the ultimate goal of maintaining optimal neurological health in prematurely menopausal women.

Keywords: Dementia; Estradiol; Estrogen; Menopause; Neurological disease.

Figure 1. Molecular Mechanisms Underlying Enhanced Risk of Neurological Disease Following Premature Menopause

See text for further details. CNS, Central Nervous System; Dkk1, Dickkopf-1, E2, 17β-Estradiol, Wnt, Wingless.

Figure 2. Bridging the Gap

These four crucial areas need to be addressed by both scientists and clinicians in order to optimize postmenopausal ET and better protect the neurological health of prematurely menopausal women. E2, 17β-Estradiol; ET, Estrogen Therapy; RCT, Randomized Controlled Clinical Trials.