Urinary steroid metabolome shows adrenal, gonadal, and neuroactive steroid dysregulation in adolescents with depressive symptoms

BACKGROUND: Steroid hormone profiles in affective disorders suggest hypothalamic-pituitary-adrenal (HPA) axis dysregulation and may reveal novel therapeutic targets. However, most existing studies focus narrowly on glucocorticoids. This study aims to comprehensively characterize alterations in the steroid metabolome of adolescents with depressive symptoms. METHODS: This cross-sectional study analyzed the urinary excretion of 39 steroid metabolites (via gas chromatography-mass spectrometry) from 75 adolescent psychiatric patients with depressive symptoms (63 females, age 15.6 ± 1.3 years) and 75 healthy controls (64 females, age 15.3 ± 1.3 years), matched for age, sex, and pubertal status. RESULTS: Patients exhibited significantly elevated excretion rates (μg/24h) of corticosterone metabolites (median = 608.4, interquartile range (IQR): 342.4 - 1208.2 vs. controls: median = 321.0, IQR: 243.9 - 443.8), dehydroepiandrosterone (DHEA) metabolites (median = 1253.8, IQR: 569.8 - 2796.2 vs. median = 519.5, IQR: 254.0 - 1028.7), androgen metabolites (median = 6721.0, IQR: 4185.6 - 9395.8 vs. median = 3680.4, IQR: 2510.8 - 5419.0), and individual progesterone and glucocorticoid metabolites, while estradiol excretion was lower (median = 4.0, IQR: 2.9 - 5.8 vs. median = 5.8, IQR: 4.3 - 7.7). Analyses of enzyme activities via multivariate machine learning identified the tetrahydrated urinary metabolite ratio of 11-deoxycorticosterone (TH-DOC) to corticosterone metabolites as a biomarker to distinguish patients from controls (AUC = 0.800, 95%-CI [0.702 - 0.882]). CONCLUSIONS: Elevated excretion rates of ACTH-dependent hormones indicate chronic stress in adolescents with depressive symptoms. The TH-DOC-to-corticosterone metabolite ratio may help identify at-risk patients or guide personalized therapies.