Therapeutic advances in congenital adrenal hyperplasia due to 21-hydroxylase deficiency


Read here to find out more about this group of rare autosomal recessive conditions affecting the adrenal cortex named Congenital Adrenal Hyperplasia (CAH). 

Congenital adrenal hyperplasia (CAH) is a group of rare autosomal recessive conditions affecting the adrenal cortex. In CAH, adrenal steroid biosynthesis is affected by an enzymatic defect, most commonly caused by 21-hydroxylase deficiency. The clinical symptoms of CAH are caused by a lack of cortisol, leading to hypoglycaemia, weight loss, and shock already in the first weeks of life. Additionally, accumulation of adrenal precursors and adrenal androgens lead to virilisation of the female external genitalia, already in utero. Nowadays, CAH screening is implemented in many neonatal screening programmes facilitating early start of treatment and preventing life threatening events.

Conventional glucocorticoid (GC) substitution therapy for patients with CAH strives to replace the lacking GCs and suppress adrenal androgen production by inhibiting hypothalamic secretion of corticotropic-releasing hormone (CRH) and pituitary secretion of adrenocorticotropic hormone (ACTH). Immediate-release GC fails to mimic the circadian rhythm of cortisol and does not effectively suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in excess GC levels following each dose, potentially followed by a period of low GC levels with elevated androgen levels until the next dose. Long-term complications can be attributed to supraphysiological GC dosages, longstanding exposure to elevated adrenal androgens, and chronically elevated ACTH levels [1]. Novel therapeutic strategies are necessary to prevent long-term complications.

Modified-release GC treatment (Efmody; Diurnal Ltd, Cardiff, UK) is a hard capsule hydrocortisone preparation with a formulation that better mimics the physiological GC levels and aims to more effectively suppress the overnight rise in ACTH and adrenal androgens. The modified-release treatment has been able to improve biochemical disease control while lowering the total daily GC dose [2, 3]. Differences in diurnal ACTH levels between modified-release and conventional treatment have not been significant [2]. A 1-year phase 3 clinical trial comparing the safety and efficacy of modified-release versus immediate-release hydrocortisone treatment in CAH patients aged 16 years and older is ongoing. Pending the results of this trial, expected in 2024, prolonged follow-up of CAH patients treated with modified-release treatment is needed to evaluate its effectiveness in the prevention of long-term complications.

Additionally, complementation of GC treatment with substances that block the HPA axis, a principle referred to as “block and replace”, may allow for more effective reduction of ACTH and adrenal androgen levels and/or for a further reduction in GC dose. Substances blocking CRH, ACTH, adrenal function, or androgens are currently being developed and clinically tested.

Crinecerfont, a potent CRH1 receptor antagonist, is well tolerated and has demonstrated effective reduction in ACTH, 17-hydroxyprogesterone and androstenedione levels in two 14-day phase 2 clinical trials including young adolescents [4] or adults [5]. The extent to which daily GC dose could be reduced in children and adults by co-administration of crinecerfont is currently being evaluated in two phase 3 clinical trials.

Another CRH1 receptor antagonist named tildacerfont has also demonstrated to be well tolerated and effective in the reduction of ACTH and androstenedione, albeit predominantly effective in poorly controlled patients. Importantly, tildacerfont should not be administered together with dexamethasone because of drug–drug interactions (both metabolized by CYP3A4) [6].

The effects of excessive ACTH could potentially also be diminished by targeting ACTH or its receptor directly. Results of a phase 1 clinical study assessing the safety and efficacy of an oral ACTH nonpeptide antagonist CRN04894 in healthy individuals has not yet been published.

Inhibition of adrenal steroidogenesis could allow for lower androgen levels and may potentially allow for GC dose reduction. Abiraterone acetate, a CYP17A1 inhibitor, is commonly used to treat prostate cancer and effectively decreases androgen production. Hence, the involvement of CYP17A1 in both adrenal as well as gonadal steroidogenesis hampers use of abiraterone acetate in (post-)pubertal patients. Mitotane, an adrenotoxic drug inhibiting adrenal steroidogenesis, has been used in adults to restore fertility in males with CAH and GC-irresponsive Testicular Adrenal Rest Tumours (TART). Also, inhibitors of androgen function (aromatase inhibitors together with anti-androgens) have been used in a clinical trial setting. Notably, while abiraterone acetate and anti-androgens may allow for GC dose reduction, they could potentially increase the risk of TART development due to elevated ACTH levels [1].   

Above-mentioned therapies do not restore the physiological stress response and patients will still suffer from periods of inadequate substitution. Gene-based therapy aims to restore HPA-regulated GC and mineralocorticoid production. Given the fast renewal of the adrenal cortex, durability of gene therapy is questioned and currently tested (aside from safety and efficacy) in a phase 1/2 clinical trial, including up to 25 poorly controlled males with 21-hydroxylase deficiency. Primary completion is expected in 2024.

Radboudumc Amalia Children’s Hospital, The Netherlands
  1. Schroder, M.A.M. and Claahsen-van der Grinten, H.L. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disord 2022; 23(3): p. 631-645. Link:
  2. Mallappa, A., et al. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2015; 100(3): p. 1137-1145. Link:
  3. Merke, D.P., et al. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2021; 106(5): p. e2063-e2077. Link:
  4. Newfield, R.S., et al. Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2023; 108(11): p. 2871-2878. Link:
  5. Auchus, R.J., et al. Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2022; 107(3): p. 801-812. Link:
  6. Sarafoglou, K., et al. Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies. J Clin Endocrinol Metab 2021; 106(11): p. e4666-e4679. Link:
Martin Savage
Programme Director
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