Glucocorticoid Replacement Improves Circadian Rhythm in Adrenal Insufficiency

An extended-release dose of glucocorticoid replacement can improve circadian clock gene expression in patients with adrenal insufficiency, according to a report recently published in The Journal of Clinical Endocrinology & Metabolism.

Conventional glucocorticoid replacement has long been associated with a number of negative side effects. The single-blind DREAM trial reported significant effects of glucocorticoid replacement on immune function. An examination of patients’ peripheral blood mononuclear cells showed higher levels of pro-inflammatory monocytes, as well as lower levels of CD16+CD14- and CD16+ natural killer cells. However, after switching to physiological, oral-release hydrocortisone once per day, the rate of infections dropped, suggesting that this method is a safer alternative to conventional glucocorticoid replacement.

Glucocorticoid secretion, which is controlled by the suprachiasmatic nucleus, is highly tuned to circadian rhythmicity. Combined with the large number of glucocorticoid receptors on peripheral cells/tissues and their absence on suprachiasmatic nucleus neurons, this makes glucocorticoid secretion a likely contender for a peripheral circadian oscillator. It directly regulates the circadian clock gene expression and performs intact cellular glucocorticoid signaling to entrain circadian oscillators in peripheral tissue.

Glucocorticoid plays an important role in regulating immune response. Administering glucocorticoid leads to entrainment of molecular clocks in human peripheral blood mononuclear cells by regulating BMAL-1 and PER2-3.

The researchers conclude that “pharmacological strategies designed to consider 1) circadian timing of drug delivery, 2) circadian regulation of drug transport and metabolism and 3) circadian regulation of target gene/protein expression may be particularly beneficial for the prevention and treatment of many chronic diseases afflicting today’s society.”

Reference

Brown MR, Matveyenko AV. Physiological glucocorticoid replacement in adrenal insufficiency: Does it fix the broken clock? [published online July 2, 2018]. J Clin Endocrinol Metab. doi: 10.1210/jc.2018-01245