Could cumulative estrogen exposure influence cerebrovascular health?

Clinical takeaway: The study links lifetime endogenous and exogenous estrogen exposure to favorable MRI markers but cannot establish causation or preventive benefit.

Women are disproportionately affected by Alzheimer disease, and estrogen changes may contribute to that vulnerability. Estrogen’s effects on blood vessels could help explain how reproductive history relates to brain aging.

Researchers analyzed 352 cognitively unimpaired Swedish women from the Gothenburg H70–1944 Birth Cohort, using reproductive histories and brain MRI at age 70. Findings showed 28.6% had one marker of cerebral small vessel disease and 12% had two or more.

Each additional reproductive year was associated with 8% lower adjusted odds of having at least two small vessel disease markers versus none. Use of menopausal hormone therapy was associated with 59% lower odds compared with never using it, along with greater white matter integrity.

Women who had used both oral contraceptives and menopausal hormone therapy had 69% lower odds of having at least two disease markers compared with women who used neither. They also had the most favorable white matter integrity.

The menopausal hormone therapy associations with overall disease burden and white matter integrity persisted after correction for multiple comparisons, though the reproductive lifespan association did not. Greater cortical thickness in Alzheimer-vulnerable regions was associated with menopausal hormone therapy only among APOE ε4 carriers in exploratory analyses.

Among 205 women with repeat MRI five years later, estrogen exposures were not significantly associated with rates of cortical thinning or white matter lesion accumulation. Self-reported hormone use and missing treatment details, including timing, dose, and formulation, limit interpretation.

“Our results suggest that hormonal exposure across different periods of a woman’s life may have cumulative effects also on the cerebrovascular health in later life. The findings suggest that the brain’s blood vessels may play an important role in the link between oestrogen and brain ageing,” said senior author Anna Marseglia, PhD, of Karolinska Institutet in Stockholm, Sweden.

Source: Lorenzon G, et al. (2026 Nov 4) Neurology. Reproductive Lifespan and Hormonal Therapy in Relation to Later-Life Neurovascular Health in Community-Dwelling Older Women