Thyroid function and depression among adolescents: a cross-sectional study exploring sex-based differences

The role of thyroid hormones and their interaction with sex hormones in adolescent major depressive disorder (MDD), particularly regarding sex differences, remains poorly understood.

This cross-sectional study included first-episode adolescent depression outpatients. All patients were stratified by depression severity into non-major depression disorder (non-MDD) and MDD groups. Serum levels of thyroid and sex hormones (testosterone, estradiol, progesterone) were measured. Group comparisons, correlation analyses, multivariate logistic regression, and moderation analysis were performed.

The study included 837 patients (597 females and 240 males), comprising 359 non-MDD and 478 MDD cases. The mean age was 15 years (IQR 14-16). Compared to males, females exhibited higher SDS (Z = -7.34, P < 0.001), higher SAS scores (Z = -5.73, P < 0.001), alongside lower T3 (Z = -3.81, P < 0.001), FT4 (Z = -3.54, P < 0.001), and FT3 levels (Z = -6.38, P < 0.001), while sex hormones differed as anticipated: testosterone was higher in males (Z = -21.00, P < 0.001), whereas estradiol and progesterone were higher in females (Z = -13.02, P < 0.001; Z = -5.74, P < 0.001, respectively). SDS scores correlated negatively with T4 (ρ = -0.080, P = 0.021), T3 (ρ = -0.099, P = 0.004), and testosterone (ρ = -0.207, P < 0.001), and positively with estradiol (ρ = 0.144, P < 0.001) and progesterone (ρ = 0.104, P = 0.003). Three multivariate regression models were established, among which Model 3-including age, sex, T3, and testosterone-achieved the highest AUC of 0.80 (95% CI = [0.77-0.83]). Moderation analysis demonstrated that testosterone significantly moderated the T3-depression relationship (interaction β = -0.09, P = 0.04). Furthermore, higher T3 was associated with lower depression severity in high-testosterone subgroups (simple slope = -1.39, P = 0.003).

Thyroid dysfunction is associated with adolescent MDD in a sex-specific manner. A logistic regression model incorporating both thyroid and sex hormones showed improved classification accuracy. Importantly, testosterone was found to moderate the relationship between T3 and depression severity. These findings suggest that assessing thyroid function alongside sex hormone levels may enhance risk stratification in adolescent MDD.