Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency

Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitar y-adrenal (HPA) axis. Despite several manifestations of chronic glucocortic oid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenoc orticotrophic hormone (ACTH) peptide content within the pituitary, and plas ma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRN A content in KO mice is dependent upon residual glucocorticoid secretion, a s it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residua l. glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POM C mRNA content. Administration of CRH restores ACTH secretion to its expect ed high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficien cy, loss of glucocorticoid feedback by itself can increase POMC gene expres sion in the pituitary; but CRH action is essential for this to result in in creased secretion ofACTH, This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary pre requisite for recovery from suppression of the HPA axis.