Early menopause and cardiovascular disease risk: triangulating the evidence with a combined analysis

Objective The relationship between early menopause and the risk of cardiovascular disease (CVD) is understudied in Asian women. This study aimed to investigate this association and its potential causality among East Asian women.Method A seven-year observational study involving 1929 postmenopausal women from the China Health and Retirement Longitudinal Study was combined with two-sample Mendelian randomization (MR) analyses utilizing genetic data from the China Kadoorie Biobank and Biobank Japan. Time-varying Cox proportional hazards models were employed for observational analysis. For MR analyses, the inverse variance-weighted method was used as the primary approach to investigate potential causality between genetically proxied age at natural menopause and CVD.Results In the multivariable-adjusted Cox regression model, early menopause was significantly associated with an increased CVD risk (hazard ratio 1.43, 95% confidence interval 1.05–1.97). However, MR analyses did not yield significant associations. Additionally, a dose–response relationship was observed between menopausal age and incident CVD risk (p-value for non-linearity = 0.022).Conclusions Early menopause was associated with a higher risk of incident CVD in the observational study, while MR findings suggested this association may not be causal. This study unravels the importance of early menopause in CVD risk assessment and informs CVD primary prevention for Asian women.