Sex-Specific Determinants of the Ketone Body β-Hydroxybutyrate in the General Population

Being in a state of ketosis has been associated with numerous positive health outcomes and is currently studied in various medical fields. However, the influence of factors other than diet on ketone body levels in the general population has not yet been investigated.

This study aimed to investigate factors that are associated with plasma levels of the ketone body β-hydroxybutyrate (BHB) levels in a general population cohort.

We included 6102 participants with available plasma BHB data from the Prevention of Renal and Vascular End-stage Disease (PREVEND) population-based cohort study. Fasting plasma BHB was measured using nuclear magnetic resonance spectroscopy. Determinants of BHB concentrations were identified using univariable and stepwise backward regression analyses.

Women had significantly higher BHB levels than men (123 [interquartile range (IQR) 94-175] vs 119 [IQR 92-164] µmol/L, respectively; P < .001). In women, hormonal status was the most significant determinant of BHB levels. In a multivariable-adjusted model, oral contraceptive (OC) use was associated with a 45% increase in BHB concentration, whereas postmenopausal status was associated with an 11% decrease compared to premenopausal women without OC use. In men, age was the most significant determinant, with a 1% increase in BHB levels per year. In both sexes, other determinants of higher BHB levels were lower protein intake, habitual alcohol use, higher N-terminal pro-B-type natriuretic peptide, and a higher free thyroxine level.

A complex interplay of metabolic, hormonal, and lifestyle factors are associated with BHB levels in the general population, with distinct sex differences. In women, hormonal status was the most important factor, while in men increasing age was the most significant factor affecting BHB levels.