Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051.


Context: Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes.

Objective: We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.

Methods: A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study.

Results: The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).

Conclusion: MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

Trial registration: NCT02716818 NCT03062280.

Keywords: 21-hydroxylase deficiency; adrenal insufficiency; congenital adrenal hyperplasia; glucocorticoid; hydrocortisone.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Hyperplasia, Congenital / drug therapy*
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adrenal Hyperplasia, Congenital / pathology
  • Adult
  • Aged
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / metabolism
  • Female
  • Follow-Up Studies
  • Humans
  • Hydrocortisone / administration & dosage*
  • Hydrocortisone / chemistry*
  • Hydrocortisone / metabolism
  • Male
  • Middle Aged
  • Prognosis
  • Young Adult


  • Anti-Inflammatory Agents
  • Hydrocortisone

Associated data

  • EudraCT/2015-000711-40
  • EudraCT/2015-005448-32