Structural MRI assessment of hypothalamic alterations and cognitive implications in adolescents with rapid pubertal progression

BACKGROUND: Rapid pubertal progression involves hormonal and hypothalamic adaptations, yet its neurocognitive implications remain unclear. Insulin-like growth factor 1 (IGF-1), a key mediator of growth and neurodevelopment, is closely linked to pubertal processes. This study aims to investigate IGF-1-associated hypothalamic structural changes and their cognitive consequences in adolescents with rapid pubertal progression (Tanner stage advancement ≥ 1 within 3–6 months). METHODS: In this retrospective, cross-sectional cohort, 124 adolescents (8 to 13 years old) underwent a single session of structural MRI, cognitive assessments (The Wechsler Intelligence Scale for Children, Fourth Edition-Chinese Version), and gonadotropin-releasing hormone (GnRH) stimulation tests at baseline. The GnRH stimulation test was performed to assess hypothalamic-pituitary-gonadal (HPG) axis (HPG) axis activation, which was used to classify participants as HPG axis-activated (HPG+, n = 73) or non-activated (HPG−, n = 51) based on peak luteinizing hormone responses. Hypothalamic subunit volumes were quantified via high-resolution T1-weighted imaging. Stepwise forward regression identified structural predictors of HPG activation; mediation models tested IGF-1’s role in linking hypothalamic morphology to cognition. Covariates included sex, age, body mass index, and total intracranial volume. RESULTS: HPG+ adolescents exhibited elevated IGF-1 (p < 0.05), poorer cognitive performance (p < 0.05), and volumetric alterations in inferior tuberal and posterior hypothalamic subunits (p < 0.01). A model integrating right and total inferior tuberal volumes predicted HPG+ status with 83.9% accuracy. Mediation analysis demonstrated that total inferior tuberal enlargement fully mediated the inverse relationship between IGF-1 elevation and poorer cognitive performances. CONCLUSIONS: IGF-1-driven remodeling of the inferior tuberal hypothalamus contributes to cognitive deficits during rapid pubertal progression, revealing a neuroendocrine pathway linking hormonal activation, structural plasticity, and neurodevelopment. These findings position the hypothalamus as a biomarker candidate for early intervention in adolescents with atypical pubertal trajectories. TRIAL REGISTRATION: Not applicable.