ESPE Yearbook of Paediatric Endocrinology

Int J Mol Sci. 2025;26(4):1479. PMID: 40003944 doi: 10.3390/ijms26041479. https://pubmed.ncbi.nlm.nih.gov/40003944/

Brief summary: This study investigated the immunological effects of reverse-circadian glucocorticoid treatment compared to conventional circadian glucocorticoid regimens in patients with Congenital Adrenal Hyperplasia (CAH).

Comment: Management of classic CAH requires lifelong glucocorticoid and mineralocorticoid replacement to prevent adrenal crises and to control androgen excess. Standard treatment involves hydrocortisone (HC) given in 3 daily doses, with the highest in the morning to mimic the natural diurnal circadian rhythm (circadian treatment, CT). This approach aims to align with peak hypothalamic-pituitary-adrenal axis activity and minimize side effects. Alternatively, some centers prefer reverse-circadian treatment (RC), which sets higher evening doses to suppress the early morning hypothalamic-pituitary-adrenal surge. While much attention has been given to optimizing biochemical control, the broader physiological consequences of glucocorticoid replacement treatment remain insufficiently studied, particularly their effects on immune function. Glucocorticoids are critical regulators of immune activity, and disruptions in their circadian rhythm, whether endogenous or treatment-induced, can significantly alter immune phenotypes.

These authors investigated the immunological effects of RC therapy (n=16) compared to conventional circadian glucocorticoid regimens, including standard HC and modified-release HC (n=38), in a cohort of pediatric and adolescent patients with CAH. Immune cell phenotypes, cytokine profiles, and natural killer cell cytotoxicity were assessed.

Patients receiving RC therapy showed a lower percentage of CD4⁺CD25⁺ T cells. Following the transition to CT, there was a notable increase in non-classical monocytes and a decrease in Th17 cells. Additionally, RC therapy was associated with reduced CD107 expression and an elevated proportion of NKp30⁺ natural killer cells. When comparing immune profiles before and after switching from RC to conventional CT therapy, patients previously on RC showed lower NKG2D expression. Both conventional and RC glucocorticoid regimens exerted distinct effects on immune function, with conventional treatment demonstrating modest advantages in normalizing immune phenotypes. Given that only 3 subjects received modified-release hydrocortisone (MRHC) treatment, no comparisons could be made between HC and MRHC groups.

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