Future Directions in the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract

Context: The traditional management of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is difficult and often suboptimal.

Objective: To review improvements in the diagnosis and management of 21OHD.

Design: Literature review, synthesis, and authors' experience.

Setting: United States (2 centers).

Participants: Not applicable.

Interventions: Not applicable.

Main outcomes: Not applicable.

Results: The 11-oxygenated androgens are abundant in 21OHD, and their measurement might improve diagnosis and medication titration. Several new treatments are under development.

Conclusion: Circadian delivery of hydrocortisone improves disease management of 21OHD compared to conventional glucocorticoids. Glucocorticoid-sparing therapies such as crinecerfont and atumelnant offer the potential for a block-and-replace strategy, with physiologic replacement dosing of hydrocortisone.

Clinical trial registration: None.

Keywords: 11-ketotestosterone; 21-hydroxylase deficiency; congenital adrenal hyperplasia; crinecerfont; drug therapy; hydrocortisone.

Figure 1.

Wide variability of adrenal steroid concentrations within a 2-hour time frame after the morning hydrocortisone dose in a representative child with 21OHD. Reproduced with permission from Sarafoglou 2023 J Clin Endocrinol Metab. Observed cortisol, 17OHP, and A4 concentrations over 6 hours. Shaded area depicts a 2-hour time window, 1 to 3 hours post-morning 6 mg hydrocortisone dose. Concentration levels of each adrenal steroid showed a > 60% change within the 2-hour time frame. Child's regular total daily hydrocortisone dose was 12 mg/m²/day. Abbreviations: 17OHP, 17-hydroxyprogesterone; 21OHD, 21-hydroxylase deficiency; A4, androstenedione.

Figure 2.

Investigational treatment approaches in development for 21OHD. *As announced in December 2024. Adapted with permission from Mallappa and Merke 2022 Nat Rev Endocrinol. Underlined compounds are currently under development for 21OHD. Italicized compounds are approved in ≥1 country for 21OHD. Abbreviations: 21OHD, 21-hydroxylase deficiency; ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor; CRF₁, corticotropin-releasing factor type 1 receptor; HC, hydrocortisone; MC2R, melanocortin receptor type 2.