GREATER lifetime estrogen exposure and hormone therapy preserve neurovascular health while reducing cerebral small vessel disease. In a population-based longitudinal investigation of 352 cognitively unimpaired 70-year-old women from the Gothenburg H70 Birth Cohort, researchers assessed how estrogen exposure and brain health are connected across the lifespan. Participants underwent comprehensive 3.0-Tesla brain MRI assessments at age 70, with a subset completing five-year follow-up scans. Women who had a longer reproductive lifespan, defined as age at menopause minus age at menarche, demonstrated significantly lower odds of high cerebral small vessel disease burden. When evaluating reproductive milestones, later age at natural menopause independently drove this vascular protection, whereas age at menarche showed no significant association.
Exogenous hormonal therapies provided distinct, additive cerebrovascular benefits across different life stages. Both oral contraceptive use during reproductive years and menopausal hormone therapy during the menopausal transition correlated with significantly higher fractional anisotropy, reflecting superior white matter integrity across forty-eight major cerebral tracts. Furthermore, menopausal hormone therapy was independently associated with a lower total burden of cerebral small vessel disease, specifically reducing the odds of enlarged basal ganglia perivascular spaces and cerebral microbleeds. In joint exposure analyses, women who utilized both oral contraceptives and menopausal hormone therapy exhibited the greatest white matter preservation and the lowest odds of severe vascular burden compared to nonusers, supporting a cumulative life-course hormonal benefit. These combined therapies deliver notable neuroprotective and vasoprotective effects.
Investigating genetic susceptibility revealed an intriguing divergence between vascular and neurodegenerative markers. Although lifelong estrogen exposure did not correlate with global Alzheimer disease cortical thickness across the entire cohort, menopausal hormone therapy was associated with preserved cortical thickness in Alzheimer-vulnerable regions exclusively among apolipoprotein-ε4 carriers. Conversely, favorable cerebrovascular associations with small vessel disease and white matter integrity were most pronounced among noncarriers. Longitudinal analyses over five years indicated stable cortical thickness trajectories, alongside a trend toward attenuated white matter hyperintensity accumulation in hormone therapy users. For practicing physicians, understanding how estrogen exposure and brain health intersect provides vital clinical rationale for evaluating lifetime hormonal history when assessing cerebrovascular vulnerability and individualized dementia risk.
Reference
Lorenzon G et al. Reproductive Lifespan and Hormonal Therapy in Relation to Later-Life Neurovascular Health in Community-Dwelling Older Women. Neurology. 2026;107(11):e218706.
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