Endocrine Abstracts

Cortisol secretion follows a distinct circadian rhythm, with circulating levels low at sleep onset, beginning to rise between 0200 and 0400 h, peaking within an hour of waking and then declining through the day. This circadian rhythm is determined by the central endogenous clock (pacemaker) of the hypothalamic–pituitary–adrenal (HPA) axis, located in the hypothalamic supra-chiasmatic nucleus. The HPA axis plays an important role in maintaining alertness and modulating sleep. Conditions associated with insomnia including depression, sleep apnoea and chronic fatigue disrupt the circadian rhythm of cortisol leading to metabolic abnormalities and increased cardiovascular risk. Patients with adrenal insufficiency have lost the normal circadian rhythm of cortisol and increased morbidity due to fatigue and excess mortality mainly from cardiovascular events and infections. Patients with congenital adrenal hyperplasia (CAH), have an even greater problem because of the challenge of both replacing glucocorticoid and controlling androgen excess. A recent large cohort study in the UK, CaHASE, has revealed evidence of greatly impaired health status in adult patients with CAH. Thus, there is a need for physiological circadian cortisol replacement to address some of these issues. Chronocort is a new approach to delivering hydrocortisone therapy. This modified release formulation replaces the overnight circadian rhythm of cortisol. Pilot formulations have demonstrated the ability to mimic the circadian cortisol rhythm in normal volunteers and studies in patients with CAH have confirmed the ability to control morning androgen levels. In conclusion, there is a need to develop new formulations of glucocorticoid replacement and chronocort provides one option for addressing this challenge.