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

Abstract

IntroductionAdrenal glucocorticoid production is regulated by the complex integration of stimulatory and inhibitory signals that maintain homeostasis during stress (1-3). Secretion of adrenocorticotrophic hormone (ACTH) by the pituitary -the primary stimulus for glucocorticoid release -is modulated by the hypothalamic neuropeptides corticotropin-releasing hormone (CRH) and vasopressin (VP); the release of these neuropeptides is in turn influenced by inputs from other regions of the central nervous system (CNS) (4-6). The degree of feedback inhibition by glucocorticoid in the CNS and at pituitary sites, in combination with hypothalamic neuropeptide release, thus defines the set point for plasma glucocorticoid levels (7-10). Dysregulated glucocorticoid production by the hypothalamic-pituitary-adrenal (HPA) axis frequently results in clinical pathology. For instance, autonomous ACTH production with excess glucocorticoid output, as occurs in Cushing's disease, results in obesity, hyperglycemia, hypertension, and osteoporosis (3). Alternatively, prolonged supraphysiologic glucocorticoid administration impairs the ability of the hypothalamus and pituitary to respond to acute glucocorticoid withdrawal, resulting in iatrogenic adrenal insufficiency. Recovery from this type of adrenal insufficiency can be prolonged. More subtle derangement of adrenal modulation in psychiatric illness (11, 12) is suggested by elevated plasma glucocorticoid levels in the setting of inappropriately elevated CNS concentration of CRH.Despite many physiologic and pharmacologic studies designed to dissect the contribution of glucocorticoidmediated negative feedback to CRH, VP, and proopiomelanocortin (POMC) gene expression and ACTH release, the threshold and mechanisms by which glucocorticoid insufficiency exerts its impact on the HPA axis remain uncertain. We have generated mice with com- 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 fo...

60 YEARS OF POMC: N-terminal POMC peptides and adrenal growth

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