CORTICOTROPIN-RELEASING FACTOR--HUMAN PHYSIOLOGY

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The overall objective of this research project is to define further the normal and abnormal physiology of corticotropin-releasing factor (CRF) in man. An established ovine CRF (oCRF) radioimmunoassay (RIA) will be applied to define the plasma disappearance half-time and metabolic clearance rate of synthetic of oCRF administered iv to normal male volunteer subjects. Established RIAs for ACTH, other ACTH-related peptides and cortisol will be used to measure the responses to synthetic oCRF in normal subjects and patients with hypothalamic-pituitary-adrenal dysfunction. It will be determined if normal women exhibit similar responses to oCRF as do normal men, and if the plasma ACTH or cortisol response depends upon the phase of the ACTH circadian rhythm during which oCRF is administered. This information will be used to design a reliable clinical test of hypothalamic-pituitary function using oCRF. The effect of preexisting ACTH and cortisol levels on the response to oCRF will be examined in normal subjects in whom hypoglycemia, hypocortisolemia or hypercortisolemia has been induced. The effect of endogenous cortisol in modulating the ACTH response to oCRF will be investigated indirectly by studying patients with primary adrenocortical insufficiency. For possible therapeutics use of CRF, such as preventing or hastening recovery from pituitary-adrenal suppression due to chronic exposure to excess glucocorticoid, the relative effectiveness of intravenous, subcutaneous and intranasal oCRF will be defined. Glucocorticoid effects on the ACTH response will be examined quantitatively and temporally, as will the effect of one dose of oCRF on the response to a subsequent dose, providing additional information required to design a rational therapeutic regimen. The interactions between oCRF and other ACTH release-stimulating or release-inhibiting agents, such as vasopressin and somatostatin, will be explored. The usefulness of CRF, given alone and in combination with GnRH and TRH, as a clinical test of hypothalamic-pituitary function will be evaluated. Patients with Cushing's syndrome will be tested before and at intervals after treatment to define whether CRF might be useful in differentiating between the three causes of Cushing's syndrome or assessing the likelihood of recurrent pituitary Cushing's disease. An N-terminal CRF RIA will be developed for measuring human CRF concentrations in fluids and tissue extracts from normal subjects and patients with hypothalamic-pituitary-adrenal dysfunction. These studies will provide new information on the normal regulation of human ACTH secretion and its derangements in human disease and will define the possible usefulness of synthetic oCRF as a diagnostic and therapeutic agent in man.