Abstract
BACKGROUND: Women who experience menopause are at higher cardiometabolic risk and often display adverse changes in metabolic biomarkers compared with pre-menopausal women. It remains elusive whether the changes in cardiometabolic biomarkers during the menopausal transition are due to ovarian aging or chronological aging. Well-conducted longitudinal studies are required to determine this. The aim of this study was to explore the cross-sectional and longitudinal associations of reproductive status, defined according to the 2012 Stages of Reproductive Aging Workshop criteria, with 74 metabolic biomarkers, and establish whether any associations are independent of age-related changes. METHODS: We determined cross-sectional associations of reproductive status with metabolic profiling in 3,312 UK midlife women. In a subgroup of 1,492 women who had repeat assessments after 2.5 years, we assessed how the change in reproductive status was associated with the changes in metabolic biomarkers. Metabolic profiles were measured by high-throughput quantitative nuclear magnetic resonance metabolomics. In longitudinal analyses, we compared the change in metabolic biomarkers for each reproductive-status category change to that of the reference of being pre-menopausal at both time points. As all women aged by a similar amount during follow-up, these analyses contribute to distinguishing age-related changes from those related to change in reproductive status. RESULTS: Consistent cross-sectional and longitudinal associations of menopause with a wide range of metabolic biomarkers were observed, suggesting the transition to menopause induces multiple metabolic changes independent of chronological aging. The metabolic changes included increased concentrations of very small very low-density lipoproteins, intermediate-density lipoproteins, low-density lipoproteins (LDLs), remnant, and LDL cholesterol, and reduced LDL particle size, all toward an atherogenic lipoprotein profile. Increased inflammation was suggested via an inflammatory biomarker, glycoprotein acetyls, but not via C-reactive protein. Also, levels of glutamine and albumin increased during the transition. Most of these metabolic changes seen at the time of becoming post-menopausal remained or became slightly stronger during the post-menopausal years. CONCLUSIONS: The transition to post-menopause has effects on multiple circulating metabolic biomarkers, over and above the underlying age trajectory. The adverse changes in multiple apolipoprotein-B-containing lipoprotein subclasses and increased inflammation may underlie women's increased cardiometabolic risk in their post-menopausal years.