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Hypothalamic‐Pituitary‐Adrenal Axis—Feedback Control

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The hypothalamo‐pituitary‐adrenal axis (HPA) is responsible for stimulation of adrenal corticosteroids in response to stress. Negative feedback control by corticosteroids limits pituitary secretion of corticotropin, ACTH, and hypothalamic secretion of corticotropin‐releasing hormone, CRH, and vasopressin, AVP, resulting in regulation of both basal and stress‐induced ACTH secretion. The negative feedback effect of corticosteroids occurs by action of corticosteroids at mineralocorticoid receptors (MR) and/or glucocorticoid receptors (GRs) located in multiple sites in the brain and in the pituitary. The mechanisms of negative feedback vary according to the receptor type and location within the brain‐hypothalmo‐pituitary axis. A very rapid nongenomic action has been demonstrated for GR action on CRH neurons in the hypothalamus, and somewhat slower nongenomic effects are observed in the pituitary or other brain sites mediated by GR and/or MR. Corticosteroids also have genomic actions, including repression of the pro‐opiomelanocortin (POMC) gene in the pituitary and CRH and AVP genes in the hypothalamus. The rapid effect inhibits stimulated secretion, but requires a rapidly rising corticosteroid concentration. The more delayed inhibitory effect on stimulated secretion is dependent on the intensity of the stimulus and the magnitude of the corticosteroid feedback signal, but also the neuroanatomical pathways responsible for activating the HPA. The pathways for activation of some stressors may partially bypass hypothalamic feedback sites at the CRH neuron, whereas others may not involve forebrain sites; therefore, some physiological stressors may override or bypass negative feedback, and other psychological stressors may facilitate responses to subsequent stress. © 2015 American Physiological Society. Compr Physiol 5:1161‐1182, 2015.

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Figure 1. Figure 1. Feedback effects of corticosteroids operate in several time domains. The most rapid effects are nongenomic, GR‐mediated effects in the hypothalamus, which appear within 3 to 5 min. Slightly slower effects of corticosteroids are observed within 10 min in the hippocampus; these are nongenomic MR‐mediated effects. Effects in the pituitary are observed by 10 to 20 min and inhibit CRH stimulated ACTH release. More delayed effects of corticosteroids in the pituitary have been shown that inhibit CRH stimulation of cAMP, cAMP‐stimulated CRH release, and CRH receptors on corticotropes. Inhibition of POMC and CRH transcription can begin as early as 30 min, but would be evident more slowly due to mRNA and protein turnover.
Figure 2. Figure 2. Location of mineralocorticoid receptors (MR, yellow) and glucocorticoid receptors (GR, red and green) in areas known to influence HPA activity. Direct inhibition of the HPA can occur through GR effects on corticotropes and GR effects on the CRH neurons. Corticosteroids also act in the hippocampus through MR and GR, to increase CA1 firing. Hippocampal excitation may inhibit PVN neurons through an inhibitory circuit involving GABAergic projection from the bed nucleus of the stria terminalis (BNST) to CRH neurons. Other potential inhibitory sites for GR action are in the prefrontal cortex and in the basolateral amygdala (BLA); projections from these nuclei is also relayed to PVN through the BNST. GR, and possibly MR, localized in the nucleus of the tractus solitaries may also exert inhibitory effects on CRH neuron activity. In contrast, GR in the central nucleus of the amygdala (CeA; shown in green) have a stimulatory effect on HPA activity.

Figure 1. Feedback effects of corticosteroids operate in several time domains. The most rapid effects are nongenomic, GR‐mediated effects in the hypothalamus, which appear within 3 to 5 min. Slightly slower effects of corticosteroids are observed within 10 min in the hippocampus; these are nongenomic MR‐mediated effects. Effects in the pituitary are observed by 10 to 20 min and inhibit CRH stimulated ACTH release. More delayed effects of corticosteroids in the pituitary have been shown that inhibit CRH stimulation of cAMP, cAMP‐stimulated CRH release, and CRH receptors on corticotropes. Inhibition of POMC and CRH transcription can begin as early as 30 min, but would be evident more slowly due to mRNA and protein turnover.

Figure 2. Location of mineralocorticoid receptors (MR, yellow) and glucocorticoid receptors (GR, red and green) in areas known to influence HPA activity. Direct inhibition of the HPA can occur through GR effects on corticotropes and GR effects on the CRH neurons. Corticosteroids also act in the hippocampus through MR and GR, to increase CA1 firing. Hippocampal excitation may inhibit PVN neurons through an inhibitory circuit involving GABAergic projection from the bed nucleus of the stria terminalis (BNST) to CRH neurons. Other potential inhibitory sites for GR action are in the prefrontal cortex and in the basolateral amygdala (BLA); projections from these nuclei is also relayed to PVN through the BNST. GR, and possibly MR, localized in the nucleus of the tractus solitaries may also exert inhibitory effects on CRH neuron activity. In contrast, GR in the central nucleus of the amygdala (CeA; shown in green) have a stimulatory effect on HPA activity.
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Maureen Keller‐Wood. Hypothalamic‐Pituitary‐Adrenal Axis—Feedback Control. Compr Physiol 2015, 5: 1161-1182. doi: 10.1002/cphy.c140065