Immunophenotypic Implications of Reverse-Circadian Glucocorticoid Treatment in Congenital Adrenal Hyperplasia

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) requires lifelong glucocorticoid replacement to manage cortisol deficiency and excessive androgen production. Conventional circadian treatment (CT) tries to mimic natural cortisol rhythms, whereas reverse-circadian treatment (RC) prioritizes the suppression of adrenal androgen excess overnight through evening dosing. Limited data exist on the immunological impact of these regimens. A bi-centric study was conducted, including 41 pediatric and adolescent CAH patients. Peripheral blood samples were collected from patients on conventional treatment (n = 38) or RC (n = 16), with 11 RC patients switching to conventional treatment. Immune cell phenotypes, cytokine profiles, and natural killer (NK) cell cytotoxicity were assessed. Patients receiving RC showed lower percentages of CD4+CD25+ T cells (p = 0.0139). After the switch, patients with RC presented with a higher percentage of non-classical monocytes (p = 0.0255) and a lower percentage of Th17 cells (p = 0.0195). A lower expression of CD107 was observed with RC (p < 0.0001), as well as a higher percentage of NKp30 (p = 0.0189). Comparing patients after the switch from RC to HC, patients with RC presented with a lower NKG2D expression (p = 0.0420). Both conventional treatment and RC exhibited distinct immunological impacts, with CT showing modest advantages in normalizing immune phenotypes. These findings suggest that CT may offer immunological benefits for managing young patients with congenital adrenal hyperplasia.