Cortical and metabolic brain development during pubertal hormone suppression

Suppression of pubertal hormonal signaling may alter trajectories of cortical development. However, the neurobiological effects of gonadotropin-releasing hormone agonists (GnRHa), including triptorelin, which are used in adolescents with gender dysphoria, remain largely unresolved. Here, we investigated how pubertal endocrine suppression influences brain development using a longitudinal in vivo translational model in which animals received long-acting triptorelin from pubertal onset and were followed with structural magnetic resonance imaging, diffusion imaging, and ex vivo 1 H HR-MAS spectroscopy. Triptorelin maintained testosterone at prepubertal levels and was associated with attenuated bilateral neocortical volume growth despite unchanged total brain volume. Diffusion imaging showed increased diffusivity indices consistent with altered microstructural maturation. In triptorelin-treated animals, long-term treatment produced coordinated metabolic changes, including reduced creatine and glutamine levels; multivariate analyses further identified creatine, glutamine, glutamate, and myoinositol as key contributors to group differentiation. Together, these findings provide multimodal evidence that pubertal endocrine suppression reshapes cortical developmental trajectories and offers a translational framework for interpreting structural and functional neuroimaging findings in adolescents undergoing GnRHa treatment.