Abstract Body: Background:
Cardiovascular disease remains the leading cause of death among women, and risk accelerates after menopause. The menopausal transition involves marked metabolic changes driven by estrogen decline, yet longitudinal metabolomic data in population-based cohorts remain limited. Identifying metabolic pathways underlying this transition may clarify mechanisms linking menopause to increased cardiometabolic risk.
Objective:
To investigate longitudinal changes in plasma metabolites across the menopausal transition and their associations with incident metabolic syndrome (MetS).
Methods:
We analyzed 953 premenopausal women from the Tsuruoka Metabolomics Cohort Study in Japan. Menopausal status was classified into premenopause, menopausal transition (MT), or postmenopause, according to the Stages of Reproductive Aging Workshop (STRAW+10) criteria. Fasting plasma concentrations of 31 metabolites were quantified using capillary electrophoresis time-of-flight mass spectrometry. Linear mixed-effects models evaluated metabolic trajectories across menopausal stages. Among 695 women free of MetS at baseline, logistic regression estimated odds ratios (ORs) for incident MetS at follow-up, adjusting for age, lifestyle factors, and follow up duration.
Results:
The mean (SD) age was 43.8 (5.4) years and BMI 21.9 (3.6) kg/m²; 82.4% were premenopausal and 17.6% were in MT. During a mean (SD) follow up of 5.0 (1.1) years, 33.2% transitioned to postmenopause and 9.4% of MetS-free women at baseline developed MetS. Glutamate, branched-chain amino acids (valine, leucine, isoleucine), and pyruvate increased progressively from pre- to postmenopause, while glutamine, glycine, and betaine declined. Higher baseline glutamate was associated with greater odds of incident MetS (per SD: OR 1.45, 95% confidence interval 1.20–1.75), independent of adiposity. Conversely, higher betaine and glycine levels were inversely associated with MetS onset. These associations persisted after adjustment for lifestyle and follow-up duration.
Conclusions:
Distinct metabolic trajectories accompany the menopausal transition, reflecting alterations in amino acid and one-carbon metabolism that may contribute to cardiometabolic risk acceleration in midlife women. These findings highlight potential metabolic pathways linking estrogen decline to adverse cardiometabolic remodeling and underscore the importance of menopause-specific strategies for cardiovascular disease prevention.