Endocrine Abstracts

Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adrenal insufficiency. Cortisol has a diurnal rhythm regulated by the central body clock and this rhythm is a metabolic signal for peripheral tissue clocks. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance. A general principle in endocrinology is to replace hormones to replicate physiological concentrations; however the pharmacokinetics of oral immediate release hydrocortisone make it impossible to fully mimic the cortisol rhythm and patients still have an increased morbidity and mortality despite replacement. Traditionally physicians have replaced hydrocortisone with a total daily dose based on the diurnal 24 h cortisol production rate with hydrocortisone given twice or thrice daily with the highest dose first thing in the morning. Monitoring treatment and dose titration has been much debated with some clinicians using cortisol day curves and others relying on clinical symptoms. The main challenge being there is no established biomarker of cortisol activity. We have taken the view that an understanding of the cortisol circadian rhythm and hydrocortisone pharmacokinetics is essential when tailoring hydrocortisone dose. Using this approach we have developed a thrice daily, weight-related, dosing regimen and a pharmacokinetic and clinical method to monitoring treatment. However, this regimen still does not replicate the early morning rise in cortisol levels. To address this we have undertaken hydrocortisone infusion studies and developed a modified release formulation of hydrocortisone, Chronocort, that delivers the early morning rise in cortisol levels. We have undertaken pilot studies in patients with congenital adrenal hyperplasia to investigate the benefits of circadian cortisol therapy. Our argument for replicating the cortisol circadian rhythm is based on the observation that disruption of the rhythm is associated with ill health and preliminary data that circadian cortisol delivery improves disease control.

Declaration of interest

I am a Director of and hold equity in Diurnal Ltd.