Hypothalamicpituitaryadrenal Axis

The HPA axis transforms stressful stimuli into hormonal messages that enable the organism to adapt to environmental change and to maintain the body's homeostasis. Corticotropin-releasing hormone (CRH) is synthesized in the hypothalamus and is stimulated by stressors, which can be either "physical" (e.g., exercise, starvation) or "psychological" (e.g., perceived danger, stressful life events). The HPA axis is closely linked to the autonomic nervous system, and brain stem catecholamine systems can also "activate" CRH release (Herman et al. 1990; Plotsky 1987; Plotsky et al. 1989). CRH stimulates secretion of pituitary adrenocorticotropic hormone (ACTH), resulting in the secretion of glucocorticoids by the adrenal cortex in a feedforward cascade. Cortisol is the main glucocorticoid, and its secretion is tightly controlled by negative feedback effects of glucocorticoids at both pituitary and brain sites. These comprise very rapid real-time inhibition of the stress response that prevents oversecretion of glucocorticoids (Keller-Wood and Dallman 1984) and results in a slower effect on messenger ribonucleic acid (mRNA) and subsequent protein stores for both CRH and the ACTH precursor, pro-opiomelanocortin (Roberts et al. 1979) (Figure 7-1).

FIGURE 7-1. The hypothalamic-pituitary-adrenal axis.

Cortisol Estrogen

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend, All rights reserved.

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.

Stressful stimuli activate all levels of the HPA axis, causing increases in CRH, ACTH, and cortisol secretion. However, these increases are superimposed on an intrinsic circadian pattern of HPA activity driven by the suprachiasmatic nucleus (SCN) (Krieger 1979). HPA axis hormone secretion is pulsatile in nature, with the trough of integrated secretion occurring in the evening and early night and the peak of secretion occurring just before awakening; active secretion continues throughout the morning and early afternoon. This rhythm persists even in the absence of corticosteroid feedback (e.g., adrenalectomy [Jacobson et al. 1989]), and there is evidence that there are intrinsic neural elements responsible for both initiation and inhibition of the CRH/ACTH/cortisol circadian rhythm and that glucocorticoids merely act to dampen the overall amount of secretion (Kwak et al. 1993).

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