CRH is a 41-amino-acid peptide that plays a central role in organizing the HPA axis and the systemic response to stress (4). It shows significant interspecies homology at the amino terminal region and acts as the main physiologic ACTH stimulator (5, 6). CRH is a member of a family of peptides, such as sauvagine, urotensin Ι, and urocortin that show similar activity (7, 8, 9). The single CRH and urocortin genes are located on human chromosomes 8 and 2, respectively. At first, CRH is synthesized as a larger precursor molecule (191 amino acid in humans) from which it is cleaved at flanking basic amino acid pairs (10). CRH is synthesized by parvocellular neurons of the paraventricular nucleus of the hypothalamus and is secreted in the hypophysial portal blood via projecting axons to the median eminence (10). These neurons also secrete other hormones that are potent stimulators of ACTH secretion, such as arginine vasopressin (AVP) which acts synergistically with CRH and is also secreted by magnocellular neuron terminals of the posterior pituitary (11). The magnocellular paraventricular nuclei also contain CRH-synthesizing neurons that project to the posterior pituitary (12). In addition, CRH is distributed in the brain and the spinal cord. The plasma half-life of CRH in humans is four minutes (13). ACTH released by CRH leads to secretion of cortisol (F) and other adrenal steroids such as DHEA and, transiently, aldosterone (14). There have not been noted any sex or age differences in plasma ACTH or F responses to CRH (15). Moreover, although ACTH response to CRH is not influenced by the hour of the day, the corresponding F response is maximized late in the afternoon (16). Inputs from higher centers regulate the HPA axis activity. The effects of the circadian pacemaker, stress and glucocorticoid negative feedback are superimposed. This negative feedback acts at pituitary, hypothalamic and higher levels, such as the hippocampus (1).

Peripheral CRH has also been found in the adrenal medulla, the testes, the ovaries, the cardiovascular system, the gastrointestinal tract, the pancreas, the lung, the spinal cord, the endometrium and the placenta (16-21), as well as in diverse inflammatory sites (1, 22, 23). Peripheral sensory afferent type C fibers and postganglionic sympathetic nerves also express CRH (24) and have been suggested as one more source of immune CRH. Another peripheral organ where CRH is locally produced is the skin where CRH receptor type 1 (CRH-R1) isoforms are expressed in keratinocytes (25). Peripheral CRH has the same electrophoretic profile as hypophysial CRH and the same expression pattern during acute inflammation, as the acute phase reactants, substance P and TNF-a, including their down-regulation by glucocorticoids (26).

The majority of the plasma CRH is of non-hypothalamic origin. That is because hypothalamic CRH is rapidly enzymatically decomposed at the pituitary level. However, under certain circumstances, such as insulin-induced hypoglycemia and pregnancy, hypothalamic CRH release leads to increments in plasma CRH concentration. Uniquely to humans, CRH in plasma is bound to a high-affinity binding protein (37 kilodaltons) (CRH-BP) (27). This protein has been characterized and is expressed in the brain, the pituitary and the peripheral tissues (liver, kidney, spleen). It plays a major role in limiting the distribution or activity duration of CRH (28).