The evolution of new approaches to the treatment of congenital adrenal hyperplasia.

Authors

Deborah P Merke, Richard J Auchus

Published in

Endocrine reviews. Aug 25, 2026. Epub Aug 25, 2026.

Abstract

Conventional management of classic congenital adrenal hyperplasia (CAH) relies on glucocorticoid (GC) therapy, both to replace the cortisol deficiency and to reduce the production of upstream cortisol precursors and subsequent metabolites. To attenuate the disinhibited hypothalamic-pituitary-adrenal (HPA) axis under endogenous cortisol deficiency, GCs are often administered at supraphysiological doses and at non-physiological timings, particularly to blunt the HPA axis activation in the early morning before awakening. Long-term studies of adults with CAH show increased risk of co-morbidities, which are often associated with chronic excessive GC exposures. To maintain disease control and to mitigate the adverse effects of conventional therapy, alternative approaches have been trialed. Circadian delivery of hydrocortisone with modified-release preparations or continuous subcutaneous infusion achieves better control at the same or lower daily dose than hydrocortisone tablets. GC-sparing therapies, the first being the corticotropin-releasing factor type 1 receptor antagonist crinecerfont, offer a block-and-replace approach, with near-physiologic dosing of GCs and a second agent to reduce precursor accumulation. The melanocortin type 2 (ACTH) receptor antagonist atumelnant and the anti-ACTH antibody asedebart are in trials. This article reviews the historical background, genetics, pharmacology, and data supporting the use of alternative strategies, as well as the practical implications and limitations of these approaches in routine patient care. A new era of CAH management has arrived, and we provide a perspective on the path forward using new tools to address the remaining unsolved challenges.

PMID:
42639844
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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