Introduction: Congenital adrenal hyperplasia (CAH) is most often caused by 21-hydroxylase deficiency (21OHD: 95%) or by 11-hydroxylase deficiency (11OHD). Classic CAH results in impaired cortisol production and consequently elevated ACTH concentrations leading to chronic adrenal stimulation with strongly elevated adrenal steroid precursors before the enzymatic defect. In contrast to other forms of adrenal insufficiency, some untreated classic CAH patients seem to have less clinical signs of cortisol deficiency.
Hypothesis: Elevated adrenal steroid precursors have agonistic glucocorticoid receptor (GR) activity, thereby compensating for the cortisol deficiency in CAH patients.
Methods: Clinical data of untreated classic CAH patients (age 346 years) from Indonesia (n=22) were collected. Adrenal steroids and precursors were measured by LC-MS/MS before and after ACTH stimulation. In vitro GR transactivation studies were performed using a dual luciferase assay in HEK293 cells transfected with the GR, that were incubated for 24 hours with increasing concentrations of steroids.
Results: Thirteen untreated classic CAH patients (59%) reported severe stress situations in the past: genital surgery (n=6), vomiting and/or seizures (n=5) or dengue or typhoid fever (n=3). All patients improved without application of glucocorticoid medication. Serum morning cortisol concentrations (before 9.00 am) were low without any increase after ACTH stimulation (median 73 (21OHD) and 180 (11OHD) nmol/l). Adrenal steroid precursors were strongly elevated (in 21OHD: 17-hydroxyprogesterone, 21-deoxycortisol, progesterone and in 11OHD: 11-deoxycortisol, deoxycorticosterone) without increase after ACTH stimulation. In vitro exposure of HEK293 cells showed that the GR was activated with similar potency to cortisol by corticosterone and 21-deoxycortisol. 11β-hydroxyprogesterone, 11-deoxycortisol, aldosterone, deoxycorticosterone, progesterone and 17-hydroxyprogesterone also led to GR transactivation, with a 4-100x lower potency than cortisol.
Conclusion: Untreated classic CAH patients may survive in severe stress situations even without application of stress-dosing of glucocorticoids. The elevated concentrations of adrenal steroid precursors, which are able to activate the GR, might compensate for the cortisol deficiency. Further studies have to be performed to study the clinical consequences of these findings.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology