Work

Mapping sex-specific hormone–metabolite coupling in the adolescent brain: a longitudinal whole-brain spectroscopic imaging study

Year: 2026

Type: preprint

Abstract: Adolescence is marked by coordinated endocrine and brain maturation, yet how blood circulating steroid hormones relate to neurochemical change in the brain remains largely unknown. We combined longitudinal data from a novel fast whole-brain, high-resolution three-dimensional proton magnetic resonance spectroscopic imaging technique with repeated measurements of sexual hormones and adrenal steroids in the serum of 42 healthy adolescents (13–15 years; 24 females) totalizing 100 scan-visits. Longitudinal voxel-wise models separated within-individual changes from stable between-individual differences and controlled the false discovery rate across whole-brain tests. In the whole sample, increasing age was associated with higher N-acetylaspartate plus N-acetylaspartylglutamate within individuals, whereas age was positively associated with higher glutamate plus glutamine between individuals. We then observed a hormone–metabolite coupling that differed by sex and steroids. In males, within-individual increases in testosterone tracked frontal increases in glutamate plus glutamine and disseminated increases in total N-acetylaspartate. In females, higher mean estradiol between individuals was associated with higher frontal choline-containing compounds. Within-individual changes in cortisone were associated with myo-inositol and choline-containing compounds in a widespread sex-interaction effect, with positive coupling in males and negative in females. The cortisone/cortisol ratio showed a similar sex-interaction for choline-containing compounds. These findings reveal spatially distributed, sex-dependent links between steroid maturation and adolescent brain neurochemical composition and underscore the importance of differentiating within- and between-individual associations. These observational data extend predominantly structural descriptions of pubertal brain development by identifying distinct coupling of gonadal hormones with neuronal-metabolic markers and glucocorticoid interconversion with glia-weighted metabolites.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.07.749851