Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy

Abstract

Cortisol has one of the most distinct and fascinating circadian rhythms in human physiology. This is regulated by the central clock located in the suprachiasmatic nucleus of the hypothalamus. It has been suggested that cortisol acts as a secondary messenger between central and peripheral clocks, hence its importance in the synchronization of body circadian rhythms. Conventional immediate-release hydrocortisone, either at twice- or thrice-daily doses, is not capable of replicating physiological cortisol circadian rhythm and patients with adrenal insufficiency or congenital adrenal hyperplasia still suffer from a poor quality of life and increased mortality. Novel treatments for replacement therapy are therefore essential. Proof-of-concept studies using hydrocortisone infusions suggest that the circadian delivery of hydrocortisone may improve biochemical control and life quality in patients lacking cortisol with an impaired cortisol rhythm. Recently oral formulations of modified-release hydrocortisone are being developed and it has been shown that it is possible to replicate cortisol circadian rhythm and also achieve better control of morning androgen levels. These new drug therapies are promising and potentially offer a more effective treatment with less adverse effects. Definite improvements clearly need to be established in future clinical trials.

Keywords: central clock; circadian rhythm; cortisol; hypothalamo—pituitary—adrenal axis; modified release hydrocortisone.

Figure 1.

Circadian rhythm of cortisol in 33 individuals with 20-minute cortisol profiling. Peak cortisol levels are reached at around 08:30 and nadir cortisol levels at around midnight. The peaks of cortisol at noon and around 18:00 represent meal-induced cortisol stimulation. (Reproduced with permission from The Endocrine Society and Debono et al. [2009]).

Figure 2.

Simulated cortisol profile for a patient (broken line) following thrice-daily hydrocortisone administration (10 mg at 06:00, 5 mg at 12:00 and 2.5 mg at 18:00, shown as solid arrows). (Reproduced with permission from John Wiley & Sons Ltd. and Mah et al. [2004]).

Figure 3.

Comparison of mean serum ACTH levels in Addison's and congenital adrenal hyperplasia patients during conventional replacement therapy and during circadian infusion of hydrocortisone (to convert values from ng/l to pmol/l × 0.22). (Reproduced with permission from John Wiley & Sons Ltd. and Merza et al. [2006]).

Figure 4.

Concentration-time profiles for modified-release hydrocortisone (MR-HC) 5 mg, 10 mg, 15 mg and 30 mg compared with immediate-release hydrocortisone (IRHC). Graph showing delayed and sustained release characteristics of MR-HC (to convert values from mcg/dl to nmol/l × 27.59). (Reproduced with permission from The Endocrine Society and Debono et al. [2009]).