Trimethylamine N-oxide is elevated in postmenopausal women relative to age-matched men and premenopausal women among individuals with obesity.

Trimethylamine N-oxide (TMAO) is linked to arterial stiffness and atherosclerosis. Cardiovascular disease (CVD) risk increases following menopause in women. Whether menopause influences plasma TMAO metabolism to mediate CVD risk is unknown. Women with obesity were classified as premenopausal (n = 13; 40.3 ± 2.7 years; 39.4 ± 2.0 kg/m²) or postmenopausal (n = 22; 56.5 ± 1.1 years; 35.6 ± 0.9 kg/m²) via self-reported presence/absence of menses (last 12 months). Men were age- and body mass index-matched to postmenopausal women (n = 16; 55.9 ± 2.1 years; 34.3 ± 1.2 kg/m²) as controls to discern potential menopause-driven TMAO differences. Carotid-femoral pulse wave velocity (cfPWV) and pulse wave analysis (applanation tonometry) were analysed to assess arterial stiffness, aortic waveforms and blood pressure. Fasting plasma TMAO and precursors (carnitine, choline, betaine and trimethylamine (TMA)) were assessed (mass spectroscopy). A 180 min 75 g oral glucose tolerance test was performed to approximate insulin sensitivity and quantify vascular cell (vascular cell adhesion molecule 1 (VCAM-1)) and intercellular adhesion molecules (intercellular adhesion molecule 1 (ICAM-1)). Body composition (DXA/BodPod) and fitness ( ${\dot{V}}_{O_2\mathrm{peak}}$ ) were measured. Premenopausal women were younger than men and postmenopausal women (P < 0.0001, η² = 2.29). Men had lower body fat (P = 0.001, η² = 0.80) and higher fat-free mass (P = 0.004, η² = 0.42) compared to both pre- and postmenopausal women. There were no differences among groups in fitness, insulin sensitivity, ICAM-1 or blood pressure (P > 0.05), but men had higher cfPWV (P = 0.040, η² = 0.27) and VCAM-1 (P = 0.041, η² = 0.32). Postmenopausal women had elevated TMAO (P = 0.040, η² = 0.29), compared with men and premenopausal women, yet men had elevated TMA (P = 0.041, η² = 0.17), carnitine (P = 0.003, η² = 0.27), choline (P = 0.022, η² = 0.35) and betaine (P < 0.0001, η² = 0.59). Thus when taken together, menopause may raise TMAO in women, while older men appear to have unique TMAO precursor metabolism linked to CVD risk.