Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis

The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modeling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been successfully identified. We demonstrate that the combination of delay and feedforward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an external ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone (CRH) levels, with results that parallel our experimental in vivo data. Since the vast majority of hormones are secreted in ultradian patterns, and most endocrine systems involve excitatory/inhibitory pathways and delays, our theoretical approach could provide a basis for understanding the origin and reg- ulation of the ultradian rhythmicity seen in many other endocrine systems