Endocrine Abstracts

JOINT1467

Introduction: Thyroid hormones (THs) play an essential role in the development, cellular differentiation and metabolism of the human body. Although TH action on various tissues has been well-described, the effect on the adrenal glands remains less understood. Recent studies have indicated a regulatory role for THs in adrenal cortex development and function. However, the regulation of adrenal androgen production by THs has yet to be clarified.

Aim: To investigate the regulatory role of THs on androgen synthesis in human adrenocortical carcinoma H295R cells and to correlate TH levels to circulatory androgens in pediatric patients with congenital adrenal hyperplasia (CAH).

Methods: H295R cells were incubated with triiodothyronine (T3) [10⁻⁹ M] in serum-free media for either 48 h or 72 h. Gene expression was assessed by mRNA-sequencing (cutoff value for padj < 0.001), and steroid profiling of cell supernatants was examined via liquid chromatography–mass spectrometry (LC–MS). In addition, serum samples of pediatric CAH patients with 21-hydroxylase deficiency were analyzed, obtained from a prospective, observational multi-center cohort study. At 1 or 2 consecutive visits, a targeted and untargeted panel of conventional adrenal and additional peripheral steroids were measured by LC–MS. Data of 83 visits from 70 children (39 boys, 31 girls; 33 prepubertal, 37 postpubertal) were available. Mean age was 11.0 [1.2; 18.9] years and BMI z-score was 0.51 [−1.84; 2.91]. Free thyroxine (fT4) was measured via chemiluminescence immunoassays. Regression analyses were adjusted for age, sex, BMI-z-score, pubertal status (pre- and postpubertal), CAH subtype (salt-wasting, simple-virilizing, late-onset) and treatment quality (under-, over- and well-treated).

Results: T3 downregulated dehydroepiandrosterone (DHEA) and DHEA-sulfate production in H295R cells (fold changes 0.71 and 0.63 respectively; P<0.01), reflecting changes in the transcriptome profile of upregulated HSD3B2 (log2FC= 1.24) and downregulated CYP17A1 (log2FC =−0.42) and PAPSS2 (log2FC= −0.49) gene expression. Likewise, in our CAH patients, we found a weak negative correlation for fT4 and serum DHEA (R² =0.251; P=0.014), androstenedione (R² =0.368; P=0.018) and androsterone (R² =0.323; P=0.036).

Discussion: We show that T3 downregulates adrenal androgen secretion in H295R cells, mediated by changes in the expression of key steroidogenic enzymes. Furthermore, we found weak negative correlations between fT4 levels and serum androgens in pediatric patients with CAH. Together, these results indicate that THs may play a role in adrenal androgen production.