Pubertal neuroendocrine network characteristics and sex differences: A hair-based hormone network study

Puberty is a critical developmental stage involving profound remodeling of neuroendocrine and neuromodulatory systems. While hormonal changes from a single system have been well studied, the systemic coordination across multiple systems and its sex-specific pattern remain unclear.

We recruited 449 healthy adolescents (226 males, 223 females) and constructed the network that encompasses nine hormones representative of the HPA and HPG axes, ECS, and melatonin system. The hormones were measured from hair with LC-MS/MS. Hormonal networks were estimated via Spearman correlations. Expected influence (EI), bridge expected influence (bridge EI), and global strength were calculated. Sex differences were examined in global strength, edge weight, EI and bridge EI using the Network Comparison Test.

The pubertal network showed the strongest coupling between metabolically related hormone pairs (i.e., F - E, MEL - NAS and T - P) and antagonistic pairs with cross-system associations (i.e., DHEA - NAS and DHEA - AEA). Cortisol, testosterone and melatonin with the highest EI were identified as hubs where testosterone emerged as a puberty-specific central node, but 1-AG exerted negative influence as an inhibitor. The pubertal network exhibited high global strength. Males showed significantly stronger global strength than females, but weaker edgeweight at the F - DHEA, E - NAS and T - NAS edges. Significant sex differences also appeared in both EI and bridge EI at nodes NAS and 1-AG.

Puberty is marked by intensified neuroendocrine integration and sex-specific reorganization. Cortisol and melatonin consistently act as central hubs, testosterone and progesterone show sex-differentiated roles, and 1-AG emerges as a potential inhibitory hormone. These findings highlight systemic bases of pubertal sexual differentiation and demonstrate the value of network analysis for mapping complex hormonal interactions.