jci.org
J Clin Invest, May 2000, Volume 105, Number 9, 1269-1277
Copyright ¸2000 by the American Society for Clinical Investigation
Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency
Louis J. Muglia1,2,3, Lauren Jacobson4, Christina Luedke4, Sherri K. Vogt1, Michele L. Schaefer4, Pieter Dikkes5, Shoko Fukuda6, Yoko Sakai6, Toshihiro Suda6 and Joseph A. Majzoub4
1 Department of Pediatrics, 2 Department of Molecular Biology and Pharmacology, and 3 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA 4 Division of Endocrinology, and 5 Department of Neurology, Children?s Hospital, Boston, Massachusetts, USA 6 Third Department of Medicine, Hirosaki University School of Medicine, Hirosaki, Japan
Address correspondence to: Joseph A. Majzoub, Division of Endocrinology, Children?s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. Phone: (617) 355-6421; Fax: (617) 355-3741; E-mail: majzoub@a1.tch.harvard.edu.
Received for publication September 16, 1998, and accepted in revised form March 14, 2000.
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. |
