Adrenal Biomarkers of Stress in Transgender and Gender-Diverse Adolescents

Transgender and gender diverse (TGD) adolescents are frequently exposed to minority stress, which may influence the hypothalamic-pituitary-adrenal (HPA) axis during critical developmental windows. Altered cortisol dynamics have been described in populations facing chronic stress, yet evidence in TGD youth is limited. Understanding adrenal function in this context is essential for clarifying potential biological pathways linking social stressors to developmental and health outcomes. In the present study, identifying as TGD serves as an indirect proxy of exposure to minority stressors, which were not directly measured. We conducted a retrospective, case-control study at a tertiary pediatric center, including 48 TGD adolescents and 298 controls referred for evaluation of premature pubarche with nonclassical congenital adrenal hyperplasia excluded. All participants underwent a standard dose synacthen test (SDST; 250 µg tetracosactide iv, sampling at baseline and 60 min, 8:00 a.m.), which assesses adrenal responsiveness to pharmacological ACTH stimulation. Serum cortisol, DHEAS, ACTH, and 17-hydroxyprogesterone were assayed. Statistical analyses included nonparametric group comparisons, correlations, and multivariable regression adjusting for age and sex assigned at birth. TGD individuals demonstrated significantly higher baseline cortisol levels (293 vs. 214 nmol/L; p < 0.001) and a reduced cortisol response to SDST (Δcortisol: 354 vs. 446 nmol/L; p < 0.001). In the full sample, basal DHEAS levels were higher in TGD youth (231 vs. 142 nmol/L; p = 0.362), whereas the DHEAS-to-cortisol ratio did not differ significantly between groups. In an age-matched subsample (1:2 matching), the DHEAS-to-cortisol ratio was significantly lower in TGD adolescents (0.72 vs. 1.03; p = 0.004). Multivariate analysis confirmed an independent association between TGD status and higher basal cortisol, lower Δcortisol, and a reduced DHEAS-to-cortisol ratio after adjustment for covariates (all p < 0.001). Our findings provide preliminary evidence of altered adrenal responsiveness in TGD adolescents, potentially reflecting the biological embedding of minority stress during development. Although exploratory, these results highlight the need for prospective, longitudinal studies integrating psychosocial and neuroendocrine measures to clarify mechanisms linking stress, HPA axis function, and developmental outcomes in gender-diverse youth.