Rhythms within rhythms: The importance of oscillations for glucocorticoid hormones

Abstract

The circadian activity of the hypothalamic-pituitary-adrenal (HPA) axis is made up from an underlying oscillatory rhythm of ACTH and glucocorticoid pulses that vary in amplitude but not frequency over the 24 h. This oscillatory activity is not the result of a hypothalamic oscillator but emerges as a natural consequence of the feedforward:feedback interaction between the pituitary corticotropes and the glucocorticoid-secreting cells of the adrenal cortex. This oscillatory activity has resulted in adaptations in the way tissues read their ‘digital’ ligand signal. The adrenal cortex is relatively insensitive to constant signals of ACTH but responds briskly to the equivalent amount of ACTH administered in a pulsatile manner. Similarly glucocorticoid-responsive tissues such as the brain and the liver are able to read the oscillating signals of cortisol or corticosterone secretion, with differential biochemical and functional responses to different patterns of ligand presentation. During a prolonged acute stress there is a major change in the pituitary-adrenal relationship, with a marked increase in the sensitivity of the adrenal to small changes in ACTH, so that following cardiac surgery small oscillations in ACTH result in massive swings in cortisol. This response appears to be due to a change both in the ACTH signalling pathway and in the endogenous activators and inhibitors of glucocorticoid synthesis.