Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency
Louis J. Muglia, … , Toshihiro Suda, Joseph A. Majzoub
Louis J. Muglia, … , Toshihiro Suda, Joseph A. Majzoub
Published May 1, 2000
Citation Information: J Clin Invest. 2000;105(9):1269-1277. https://doi.org/10.1172/JCI5250.
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Article

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

Abstract

Corticotropin-releasing hormone (CRH)–deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as 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 residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.

Authors

Louis J. Muglia, Lauren Jacobson, Christina Luedke, Sherri K. Vogt, Michele L. Schaefer, Pieter Dikkes, Shoko Fukuda, Yoko Sakai, Toshihiro Suda, Joseph A. Majzoub

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Effect of adrenalectomy (ADX) and low-dose corticosterone replacement on...
Effect of adrenalectomy (ADX) and low-dose corticosterone replacement on AP POMC mRNA in WT and CRH KO mice. (a) In situ hybridization of the pituitary with a radiolabeled POMC antisense riboprobe (representative of n = 3 per genotype and treatment group). The neurointermediate lobe is oriented at the left side of each panel. Basal levels of POMC mRNA are equivalent in WT and KO mice, and increase after adrenalectomy in AP corticotrophs. The neurointermediate lobe of the pituitary demonstrated unchanged hybridization intensity before and after adrenalectomy. (b) Quantitative analysis of POMC mRNA hybridization signal intensity in the AP. AP = 0.01 vs. WT Sham and WT ADX+B; BP < 0.05 vs. WT Sham and WT ADX + B.