Menopause modulates the circulating metabolome: evidence from a prospective cohort study

Aims: We studied the changes in the circulating metabolome and their relation to the menopausal hormonal shift in 17β-oestradiol and follicle-stimulating hormone levels among women transitioning from perimenopause to early postmenopause.

Methods and results: We analysed longitudinal data from 218 Finnish women, 35 of whom started menopausal hormone therapy during the study. The menopausal transition was monitored with menstrual diaries and serum hormone measurements. The median follow-up was 14 months (interquartile range: 8-20). Serum metabolites were quantified with targeted nuclear magnetic resonance metabolomics. The model results were adjusted for age, follow-up duration, education, lifestyle, and multiple comparisons. Menopause was associated with 85 metabolite measures. The concentration of apoB (0.17 standard deviation [SD], 99.5% confidence interval [CI] 0.03-0.31), very-low-density lipoprotein triglycerides (0.25 SD, CI 0.05-0.45) and particles (0.21 SD, CI 0.05-0.36), low-density lipoprotein (LDL) cholesterol (0.17 SD, CI 0.01-0.34) and particles (0.17 SD, CI 0.03-0.31), high-density lipoprotein (HDL) triglycerides (0.24 SD, CI 0.02-0.46), glycerol (0.32 SD, CI 0.07-0.58) and leucine increased (0.25 SD, CI 0.02-0.49). Citrate (-0.36 SD, CI -0.57 to -0.14) and 3-hydroxybutyrate concentrations decreased (-0.46 SD, CI -0.75 to -0.17). Most metabolite changes were associated with the menopausal hormonal shift. This explained 11% and 9% of the LDL cholesterol and particle concentration increase, respectively. Menopausal hormone therapy was associated with increased medium-to-large HDL particle count and decreased small-to-medium LDL particle and glycine concentration.

Conclusions: Menopause is associated with proatherogenic circulating metabolome alterations. Female sex hormones levels are connected to the alterations, highlighting their impact on women's cardiovascular health.