Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia

Abstract

We know that conventional glucocorticoid therapies fail to mimic the normal diurnal profile of cortisol secretion, which should show an early morning surge in circulating levels, followed by a gradual daytime reduction, and night-time suppression. The early morning surge in ACTH also drives adrenal androgen production, which is excessive in congenital adrenal hyperplasia (CAH). Chronocort is a modified-release hydrocortisone preparation, which produces peak circulating cortisol concentrations 6-8 hours after ingestion. This study shows that treatment of CAH with Chronocort reduced combined excretion of markers of impaired 21-hydroxylase activity (sum of 17OHP metabolites 17HP, pregnanetriol, and the 21-deoxycortisol metabolite PTONE) more than any other glucocorticoid preparation (hydrocortisone, prednisolone, or dexamethasone), and in particular it reduced the early morning surge in these metabolites. The authors also showed that alternative pathway androgen synthesis, from its substrate 17OHP, contributes significantly to DHT production in CAH patients on standard glucocorticoid therapy, rather than the classic pathway via DHEA, androstenedione, and testosterone. The large phase 3 trial of Chronocort in CAH patients recently completed patient enrolment and we look forward to its findings, which are expected in Q3 2018.