The circadian variation of hypothalamo-pituitary-adrenal (HPA) activity is well recognised, with levels of glucocorticoid rising in anticipation of the activity of the coming day (in humans) or night (in rodents). Less well recognised however, is that in common with many other hormones, both ACTH and corticosteroids are released in a pulsatile pattern with the largest pulses occurring in the morning in man explaining the large range of normal morning cortisol levels. Although this pulsatility was always assumed to be a result of an undefined pacemaker in the hypothalamus, there is no good experimental data to support this. We have mathematically modelled this system and find that the feedforward:feedback relationship between pituitary corticotrophs and adrenal fasciculata cells obviates the need for an external pacemaker and that the system should oscillate irrespective of the pattern of CRH input. We have now tested this in vivo in the rat and have shown that a constant infusion of CRH is sufficient to activate normal ultradian rhythmicity of both ACTH and corticosterone, occurring with the same frequency as that found under normal physiological conditions.
Since pulsatile release of glucocorticoids emerges as fundamental property of the pituitary adrenal system, it would be expected that tissue responses to glucocorticoids have also adapted to make use of this oscillating signal. We have shown that glucocorticoid receptor signalling is indeed able to respond to pulses of corticosterone with pulses of gene transcription (gene pulsing) and that this provides scope for a system that is very responsive to rapid changes in hormone levels a very important factor for a stress-responding homeostatic system like the HPA axis.
Declaration of funding
The Wellcome Trust, MRC and BBSRC
Generously supported by Clinical Endocrinology Trust