CRH and ACTH
CRH, polypeptide of 41 amino acids, is secreted by the hypothalamus, carried by the portal system to the pituitary gland where it stimulates ACTH secretion and indirectly that of cortisol, without modifying that of prolactin nor that of growth hormone.
CRH is also present in brain, spinal cord, placenta, lymphoid tissue, fibroblasts. Its concentration increases in tissues, for example synovial fluid, during inflammation. There are specific CRH receptors called CRH-R1 and CRH-R2, whose presence is induced by inflammation. CRH has an analgesic activity, perhaps by release of opioids, and anti-edematous effect. Analogues of CRH could have an interest as anti-inflammatory drugs.
ACTH is a polypeptide of 39 amino acids released by the basophilic cells of the anterior pituitary after proteolytic cleavages of pro-opiomelanocortin.
Regulation of cortisol secretion
The secretion of CRH, ACTH and cortisol follows a circadian cycle and is at a maximum in the morning, around 6 a .m. Their secretion is increased during stress, particularly via IL-1, IL-2, IL-6 and TNF-alpha. It is also increased during withdrawal syndromes with alcohol, morphine, cannabis and in the majority of depressive states. In this last case, one does not know if the increase in CRF secretion is due to the depressive state or takes part in its development but antagonists of the CRF could have antidepressant effects. Vasopressin reinforces the ACTH secretion induced by CRH.
ACTH acts on the adrenal cortex to increase the synthesis and the secretion of cortisol and, to a lesser degree, of aldosterone. It acts by increasing the concentration of intracellular cyclic AMP responsible for the stimulation of enzymes implicated in the synthesis of the adrenocortical hormones. It induces in particular the conversion of cholesterol into pregnenolone. The rise in plasma cortisol or the administration of synthetic glucocorticoid, by negative pituitary feedback, decreases the release of CRH and ACTH.
The principal effects of ACTH are indirect, resulting from cortisol secretion. Its direct effects are not well known but it could be involved in the regulation of mood and anxiety.
ACTH used in therapeutics, is a tetracosactide, also called cosyntropin, a 24 amino acid polypeptide; it is used:
- for diagnostic purposes: exploration of adrenal cortex reactivity.
- for therapeutic uses:in a few diseases where its advantages over synthetic corticoids are not obvious, so that it is little used in practice. ACTH is not very effective in normalizing the cortisol secretion reduced by a long-term administration of corticosteroids.
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