Diurnal Rhythm of ACTH Release

Upon stimulation with ACTH, the adrenal cortex secretes cortisol, which inhibits further secretion of ACTH in a typical negative feedback pattern. Cortisol exerts its inhibitory effects on CRH neurons in the hypothalamus and corticotropes (see top figure). Superimposed on this system is a diurnal rhythm in the release of ACTH and hence oscillation in plasma levels of cortisol. Hormone levels are highest in the early morning hours. Rising in anticipation of arousal and becoming lowest in the evening (see bottom figure). The rhythmic secretion can be explained in terms of the negative feedback model by considering a set-point element within the feedback system that monitors existing levels of plasma cortisol (see top figure). The set-point oscillates throughout the day (the diurnal rhythm). In this negative feedback system, the set-point element matches its set-point with the existing plasma concentration of cortisol. If the concentration is below the set-point a positive signal is sent to the CRH hypothalamic neurons which, in turn, release CRH into the portal capillaries and stimulate release of ACTH. ACTH then reaches the adrenal cortex in the circulation and stimulates cortisol synthesis. Plasma cortisol rises and when it reaches a concentration equal to the set-point, no signal is sent to the CRH neurons and stimulation for further release of cortisol is withdrawn. As plasma cortisol levels gradually fall below the set-point, the cycle repeats. The anatomy and biochemical equivalent of the "set-point" element is not known. However, it has been suggested that changes in sensitivity of CRH-secreting cells to cortisol may account for this behavior. Decreased sensitivity to inhibitory effects of cortisol in the early morning results in increased output of CRH, ACTH, and cortisol. As the day progresses, sensitivity to cortisol increases, and there is a decrease in the output of CRH and hence ACTH and cortisol. The exact mechanisms regulating these changes are not understood. However, the important points are: (1) Secretion of ACTH is driven by changes in CRH secretion; and (2) although cortisol concentrations change with time of day, they are precisely controlled.