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

• Premature loss of ovarian estradiol enhances the risk of neurological disease.
• Premature menopause may cause brain hypersensitivity to pathologic stressors.
• Timely estrogen therapy may avert these negative neurological sequelae.
• Basic scientists and clinicians should collaborate to address these crucial issues.

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.