Decreased serum DHEAS to cortisol ratio in adolescents evaluated for gender dysphoria

Background: DHEAS is the most abundant adrenal steroid and it is also a neurosteroid, produced at the cerebral level from pregnenolone and 17OH-pregnenolone. It antagonizes the effects of cortisol at the level of glucocorticoid receptors, modulating biological energy output, inflammatory status, action of other steroidal hormones, and different brain functions, hypothalamus being rich in corticosteroid receptors. DHEAS secretion is usually synchronized with cortisol and a normal DHEAS to cortisol ratio is considered a marker of the biological activity of cortisol at the level of glucocorticoid receptor. This hypothesis is proven by the decrease of DHEAS to cortisol ratio in many pathological conditions, such as depression and anorexia nervosa. Methods: We recruited consecutively 41 children and adolescents evaluated for gender dysphoria (GD) (cases) and 235 controls among individuals who underwent a standard dose Synacthen test. All participants underwent a medical visit and fasting blood sampling. Results: Among the 235 controls, serum DHEAS to cortisol ratio resulted as correlated with age (Spearman’s rank correlation, ρ=0.524, p<0.001), BMI SDS (ρ=0.245, p<0.001), but not with assigned sex at birth, height SDS, ACTH, peak cortisol, basal 17-hydroxyprogesterone, peak 17-hydroxyprogesterone, total testosterone (all p-values >0.05). Since the median age in GD was significantly higher than controls (Kruskal Wallis test, 16.0 vs. 9.5 years, p<0.001), we compared the 41 individuals with GD with 82 age-matched control subjects (ratio 1:2): those with GD showed a significantly lower DHEAS to cortisol ratio compared to controls (0.182 vs. 0.271, p=0.016), with no significant differences for BMI SDS (p=0.396). The association between GD and DHEAS to cortisol ratio was confirmed at multivariate analysis in the entire cohort (n=276) after correction for assigned sex at birth, age, and BMI SDS (β of linear regression for GD=-0.08, p=0.009). Conclusions: To our knowledge, this is the first study that evaluated DHEAS to cortisol ratio in adolescents with suspected GD. This ratio was correlated with age and BMI SDS, but not with assigned sex at birth. Our results suggest that the dysphoria due to the incongruence between gender identity and sex assigned at birth might be reflected by lower DHEAS/cortisol ratios, indicating dysregulation of the stress response system. While it was already known that GD leads to distress and adaptation difficulties, this is the first biological proof.