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FIGURE 18 Variations in plasma concentrations of ACTH and cortisol at different times of day. (From Matsukura S, West CD, Ichikawa Y, Jubiz W, Harada G, Tyler FH. A new phenomenon of usefulness in the radioimmunoassay of plasma adrenocortico-tropic hormone. J Lab Clin Med 1971;77:490-500.)

and their corticotropes express normal levels of mRNA for POMC. In normal mice, disruption of negative feedback by surgical removal of the adrenal glands results in a prompt increase both in POMC gene expression and ACTH secretion. Adrenalectomy of CRH knockout mice produces no increase in ACTH secretion, although POMC mRNA increases normally. These animals also suffer a severe impairment, but not total lack of ACTH secretion in response to stress. Thus it seems that basal function of the pituitary/adrenal negative feedback system does not require CRH, but that CRH is crucial for increasing ACTH secretion above basal levels. Further, it appears that transcription of the POMC gene is inhibited by glucocorticoids even under basal conditions.

It was pointed out earlier that negative feedback systems ensure constancy of the controlled variable. However, even in the absence of stress, ACTH and cortisol concentrations in blood plasma are not constant but oscillate with a 24-hr periodicity. This so-called circadian rhythm is sensitive to the daily pattern of physical activity. For all but those who work the night shift, hormone levels are highest in the early morning hours just before arousal and lowest in the evening (Fig. 18). This rhythmic pattern of ACTH secretion is consistent with the negative feedback model shown in Fig. 17 and is sensitive to glucocorticoid input throughout the day. In the negative feedback system, the positive limb (CRH and ACTH secretion) is inhibited when the negative limb (cortisol concentration in blood) reaches some set point. For basal ACTH secretion, the set point of the corticotropes and the CRH-secreting cells is thought to vary in its sensitivity to cortisol at different times of day. 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 consequently of ACTH and cortisol. The cellular mechanisms underlying the periodic changes in set point are not understood, however, although they vary with time of day, cortisol concentrations in blood are precisely controlled throughout the day.

Negative feedback also governs the response of the pituitary-adrenal axis to most stressful stimuli. Different mechanisms appear to apply at different stages of the response. With the imposition of a stressful stimulus, a sharp increase in ACTH secretion occurs that is driven by CRH and AVP. The rate of ACTH secretion is determined by both the intensity of the stimulus to CRH-secreting neurons and the negative feedback influence of cortisol. In the initial moments of the stress response, pituitary corticotropes and CRH neurons monitor the rate of change rather than the absolute concentration of cortisol and decrease their output accordingly. After about 2 hr, negative feedback seems to be proportional to the total amount of cortisol secreted during the stressful episode. With chronic stress a new steady state is reached, and the negative feedback system again seems to monitor the concentration of cortisol in blood but with the set point readjusted at a higher level.

Each phase of negative feedback involves different cellular mechanisms. During the first few minutes, the inhibitory effects of cortisol occur without a lag period and are expressed too rapidly to be mediated by altered gene expression. Indeed the rapid inhibitory action of cortisol is unaffected by inhibitors of protein synthesis. Its molecular basis is unknown, but it may be mediated by nongenomic responses of receptors in neuronal membranes. The negative feedback effect of cortisol in the subsequent interval occurs after a lag period and seems to require RNA and protein synthesis typical of the steroid actions discussed earlier. In this phase cortisol restrains secretion of CRH and ACTH but not their synthesis. At this time, corticotropes are less sensitive to CRH. With chronic administration of glucocorticoids or with chronic stress, negative feedback is also exerted at the level of POMC gene transcription and translation.

Major features of the regulation of ACTH secretion include the following:

1. Basal secretion of ACTH follows a diurnal rhythm driven by CRH and perhaps by intrinsic rhythmicity of the corticotropes.

2. Stress increases CRH and AVP secretion through neural pathways.

3. ACTH secretion is subject to negative feedback control under basal conditions and during the response to most stressful stimuli.

4. Cortisol inhibits secretion of both CRH and ACTH.

Some observations suggest that cytokines produced by cells of the immune system may directly affect secretion by the hypothalamic-pituitary-adrenal axis. In particular,

IL-1, IL-2, and IL-6 stimulate CRH secretion, and may also act directly on the pituitary to increase ACTH secretion. IL-2 and IL-6 may also stimulate cortisol secretion by a direct action on the adrenal gland. In addition, lymphocytes express ACTH and related products of the POMC gene and are responsive to the stimulatory effects of CRH and the inhibitory effects of glucocorticoids. Because glucocorticoids inhibit cytokine production, there is another negative feedback relationship between the immune system and the adrenals (Fig. 19). It has been suggested that this communication between the endocrine and immune systems provides a mechanism to alert the body to the presence of invading organisms or antigens.

In our discussion of the regulation of cortisol and ACTH secretion, we have ignored other members of the ACTH family that reside in the same secretory granule and are released along with ACTH. Endocri-nologists have focused their attention on the physiologic implications of increased secretion of ACTH and gluco-corticoids in response to stress. Recent observations suggest that other peptides such as ^-endorphin and a-MSH, whose concentration in blood increases in parallel with ACTH may exert anti-inflammatory actions.

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