Increased levels of long-chain acylcarnitines and polyunsaturated fatty acids in girls with premature adrenarche: an exploratory longitudinal metabolomics study.

Premature adrenarche (PA) has been associated with accelerated growth, increased adiposity, and reduced insulin sensitivity traceable to early life, yet the mechanisms underlying these metabolic traits remain unclear. This study investigated whether PA is associated with distinct circulating metabolite signatures. Untargeted metabolomics was used to analyze fasting serum samples from a community-based cohort. Sixteen girls with PA at age 7 were compared with 27 age-matched controls before adrenarche at the same age ("age-matched" comparison) and again when controls developed adrenarche at age 9 ("event-matched" comparison). The groups were comparable in body composition, dietary intake, and standard biomarkers, including insulin and lipids. PA associated with significant differences in 93 and 128 metabolite features in the age- and event-matched comparisons, respectively. Twenty-three identified metabolites were consistently altered in both comparisons, with 22 elevated and one reduced in PA girls. Elevated metabolites included long-chain acylcarnitines, polyunsaturated fatty acids, and sulfated steroid derivatives, whereas the microbiota-derived p-cresol-sulfate was reduced. In PA girls, acylcarnitines were inversely associated with leptin and triglycerides, whereas polyunsaturated fatty acids correlated negatively with birth size and body fat percentage, and positively with lean mass, tumor necrosis factor alpha, and dietary intake of protein, fat, and sodium. PA is associated with metabolic alterations that extend beyond androgen excess, raising hypotheses regarding fatty acid oxidation and gut microbiota-derived metabolism. While these findings provide insights into the pathophysiology of PA and may inform future research on biomarkers relevant to long-term outcomes, they warrant confirmation in larger studies.