Physiology and Pathophysiology of the HPA Axis

Abstract

The corticotrophin releasing hormone (CRH), the main hypothalamic regulator of adrenocorticotropic hormone (ACTH) secretion, is mainly synthesized in the parvocellular, but also in the magnocellular neurons, of the paraventricular nucleus (PVN). CRH neurons of the PVN receive adrenergic afferent from nucleus tractus solitarius, locus coeruleus, and ventro-lateral medulla. CRH is secreted into the hypophyseal portal blood and binds to high affinity membrane type I CRH receptors (CRH-R1) in the anterior pituitary corticotrophs to stimulate pro-opiomelanocortin (POMC) gene transcription through a process that includes the activation of adenylyl cyclase. The CRH stimulates POMC gene transcription in vivo and in vitro and also in response to stress and adrenalectomy. ACTH, synthesized within the anterior pituitary as part of a large POMC 241-amino-acid precursor, is the principal hormone stimulating adrenal glucocorticoid biosynthesis and secretion. Angiotensin II, activin, inhibin, and cytokines (TNF-beta and leptin) synergize with or inhibit the effects of ACTH on the adrenal cortex. The hypothalamic pituitary adrenal (HPA) axis is also regulated by biological rhythms resulting from a complex interaction of genetic output of the endogenous circadian pacemaker and environmental synchronizers. ACTH is secreted in a pulsatile pattern with a circadian rhythm so that levels are the highest on waking and decline throughout the day, reaching the nadir values in the evening. Other regulator of the HPA axis is the stress system, which has main components the CRH and locus coeruleus-norepinephrine autonomic systems and their peripheral effectors. Basal and stress induced activity of the HPA axis is constrained by glucocorticoid negative feedback. Glucocorticoids and catecholamines affect major immune functions such as antigen presentation, leukocyte proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper (Th) 1 versus Th2 responses. The proinflammatory cytokines, notably interleukin-1, interleukin-6, tumor necrosis factor beta, and leukemia inhibitory factor also increase ACTH secretion either directly or by augmenting the effect of CRF. Glucocorticoids exert an immunoregulatory feedback by several mechanisms, involving the blockade of lymphocyte activation, the production and action of IL-2, IL-1, gamma-interferon, TNF, and prostaglandins. Another important aspect of the regulation of the HPA axis is the negative feedback control exerted by glucocorticoid, which inhibits the basal expression of CRH and AVP mRNA synthesis and secretion in the hypothalamus and also inhibits POMC gene transcription in the anterior pituitary. Glucocorticoid exerts its effects by activation of cytosolic receptors that belong to the nuclear receptor superfamily, the corticosteroid type I, or mineralocorticoid, and corticosteroid type II, or glucocorticoid, receptors. Several molecular mechanisms underlying glucocorticoid actions have been elucidated, most of which involve transcriptional regulation of gene expression. One of the most important factors regulating the access of endogenous glucocorticoid to its receptor is local metabolism of the steroids within the target cells by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzymes, a phenomenon sometimes termed prereceptor metabolism. Cortisol/corticosterone are responsible for the salt and water homeostasis and blood pressure control and influence carbohydrate, protein, lipid, and bone metabolism. They are also important regulators of immune and inflammatory proceses and are required for numerous processes associated with host defense. On the other hand, prolonged or high dose glucocorticoid therapy as well as an excess of endogenous production of glucocorticoids exert a large spectrum of deleterious actions in the whole body. Our understanding on the HPA axis biology has given significant insight into the critical role of glucocorticoids in the maintenance of homeostasis and, when dysregulated, in the pathogenesis of diseases.