Age at natural menopause and stroke: A U-shaped association in the health and retirement study

The association between age at natural menopause and cerebrovascular risk is unclear. This study investigates non-linear relationships, effect modification, mediation, and long-term stroke-free survival in postmenopausal women.

We analyzed 9,159 postmenopausal women from the Health and Retirement Study. Menopause age was categorized (<40, 40-44, 45-49, 50-55, >55) and modeled continuously. Stroke outcomes were derived from self-reports and linked Medicare claims. We used multivariable logistic regression with restricted cubic splines, interaction terms among hypertension, diabetes, and hypercholesterolemia, structural equation modeling for mediation, and Kaplan-Meier/Cox models for survival analysis.

Each additional year of later menopause was linked to lower stroke odds (OR 0.935, 95 % CI 0.922-0.948). Compared to the 50-55 age group, those with menopause <45 years (OR 2.76, 95 % CI 2.09-3.47) and 45-49 years (OR 2.08, 95 % CI 1.72-2.62) had higher risks. Spline analysis indicated a U-shaped curve, with the lowest risk at ages 50-52. Stroke-free survival differed significantly across groups (log-rank p = 0.0017), particularly worse with premature menopause.

Age at natural menopause exhibits a U-shaped association with stroke risk, emphasizing the importance of timing in individualized prevention strategies.