Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia

Abstract

Background Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. Methods Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. Summary Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. Conclusions CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Long-Term Outcomes of Congenital Adrenal Hyperplasia

“…Neonatal screening for CAH with close collaboration between the screening laboratory and clinicians may improve the long-term outcome [ 125 ]. New treatments and improved monitoring during follow-up may further improve the long-term health [ 14 , 126 ]. Regular monitoring of various risk factors and complications are thus essential to identify problems and institute support and treatment at an early stage.…”

Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up‐to‐date comprehensive review

“…While potential has been seen in animal trials, implementation of human therapy has yet to occur 62 . Surgical adrenalectomy reduces the risk of virilization in women and the need for high doses of glucocorticoids 62,63 and would effectively diminish the symptoms of CAH. However, loss of adrenal function, particularly in utero, can disrupt normal fetal development as glucocorticoids play an essential role in the development of organs such as lungs, kidneys, heart, and vasculature 64 …”

Metabolic syndrome and cardiovascular morbidity in patients with congenital adrenal hyperplasia

“…Similar results were found in another study, with only half of the whole cohort having androgens level within normal range ( 4 ). New treatment approaches targeting the CRF type 1 receptor at pituitary levels (crinecerfont and tildacerfont) showed promise in reducing androgen biomarkers; ongoing studies are needed to demonstrate long-term improvement in metabolic profile ( 63 ).…”