Fig. 1.

The principal regulatory mechanisms that underlie hypothalamic-pituitary-adrenal (HPA) activity. Corticotrophin-releasing hormone (CRH) released from the paraventricular nucleus (PVN) of the hypothalamus reaches the anterior pituitary through the hypophyseal portal circulation, and stimulates corticotrophs to release corticotrophin (ACTH), which in turn reaches the adrenal gland through the systemic circulation and promotes the cortical synthesis and secretion of glucocorticoids (CORT). CORT, in turn, exerts an auto-inhibitory effect on their production by acting on at least three different levels: anterior pituitary, hypothalamus and hippocampus (displayed as part of corticolimbic system). CORT also affects extensive corticolimbic regions of the brain, which in turn modulate, primarily via indirect projections, the mode of HPA axis activity. (1) CORT pulsatility emerges as a consequence of the feedforward–feedback with a built-in delays relationship between the actions of ACTH on the adrenal cortex and endogenous CORT on the pituitary corticotrophs. (2) Physiological CRH drive creates the variability in the amplitude and duration of each CORT pulse throughout the day, which enables the gradual increase of CORT levels during the most active parts of the day (darker parts of the blue arrow) and their gradual fall during the less active parts of the day (lighter parts of the blue arrow). (3) An acute stressor, leading to a substantial raise in the hypothalamic CRH secretion, results in increased CORT levels characterised by a dampened oscillatory profile, and eventually resets the phase of the ultradian rhythm. Green arrows, stimulatory effect; red arrows, inhibitory effect; grey arrows, mixed effect.