Muglia L J, Jacobson L, Luedke C, Vogt S K, Schaefer M L, Dikkes P, Fukuda S, Sakai Y, Suda T, Majzoub J A
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
J Clin Invest. 2000 May;105(9):1269-77. doi: 10.1172/JCI5250.
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.
促肾上腺皮质激素释放激素（CRH）缺陷（KO）小鼠提供了一个独特的系统，用于确定CRH在下丘脑-垂体-肾上腺（HPA）轴调节中的作用。尽管存在慢性糖皮质激素不足的多种表现，但CRH基因敲除小鼠的垂体前阿黑皮素原（POMC）mRNA基础水平、垂体中促肾上腺皮质激素（ACTH）肽含量以及血浆ACTH浓度并未升高。基因敲除小鼠中正常的POMC mRNA含量依赖于残余的糖皮质激素分泌，因为在肾上腺切除术后，基因敲除小鼠和野生型小鼠中的POMC mRNA含量均增加；这种增加可被糖皮质激素而非醛固酮替代所逆转。然而，CRH基因敲除小鼠中正常的血浆ACTH水平并不依赖于残余的糖皮质激素分泌，因为肾上腺切除术后，尽管POMC mRNA含量增加，但这些小鼠的ACTH水平并未出现基因敲除小鼠中常见的正常升高。给予CRH可使肾上腺切除的CRH基因敲除小鼠的ACTH分泌恢复到预期的高水平。因此，在肾上腺功能不全时，糖皮质激素反馈缺失本身可增加垂体中POMC基因的表达；但CRH的作用对于这一过程导致ACTH分泌增加至关重要。这可能解释了为什么在慢性糖皮质激素治疗停药后，CRH分泌的重新激活是HPA轴从抑制状态恢复的必要前提条件。
