Insights into the relationship between menopausal timing and risk of cardiovascular disease: a systematic review and meta-analysis of Mendelian randomization analyses

Abstract

Cardiovascular disease (CVD) is the leading cause of death and imposes a substantial burden on women’s health. Early onset of menopause, as a unique trait of reproductive aging, has been associated with a higher risk of adverse cardiovascular events in traditional observational studies. However, the findings yielded from Mendelian randomization (MR) studies were inconsistent. This systematic review aimed to (1) synthesize existing evidence on the relationship between genetically determined menopausal timing and CVD risk and (2) assess the methodological quality of the included MR studies. A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from their inception to June 2025, supplemented by manual searches of the reference lists from retrieved studies and other sources. MR studies using genetic variants as instrumental variables to infer causality between menopausal timing and the risk of cardiovascular-related outcomes were included. The risk of bias of included studies was assessed based on three core MR assumptions and other potential sources of bias. Meta-analyses pooled the inverse-variance weighted-derived odds ratios (ORs) from individual studies using random-effects (RE) models. Seventeen articles were included in the systematic review, with study populations predominantly of European ancestry. Cardiovascular outcomes of interest included coronary artery disease, ischemic and hemorrhagic stroke, atrial fibrillation, heart failure, hypertension, ventricular structure and function, and cardiometabolic traits. Meta-analyses showed that genetically determined menopausal timing was not significantly associated with the risk of coronary heart disease (OR = 0.97; 95% CI, 0.87–1.07; P = 0.52; I 2 = 48.08%) or stroke (OR = 1.00; 95% CI, 0.95–1.05; P = 0.93; I 2 = 0.01%). Most of the included studies explicitly described the methods used to validate the core assumptions of the MR design. However, more than half of the studies were judged to have an unclear or even high risk of bias from other sources. The findings from our study do not support a causal relationship between menopausal timing and CVD risk. It is recommended that future Mendelian randomization studies incorporate participants from diverse ancestries, explore gene-environment interactions, and rigorously address potential sources of bias. The study protocol was prospectively registered with PROSPERO (CRD420251058908).