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. 1985 Jun;75(6):1781–1785. doi: 10.1172/JCI111890

Continuous administration of synthetic ovine corticotropin-releasing factor in man. Physiological and pathophysiological implications.

H M Schulte, G P Chrousos, P W Gold, J D Booth, E H Oldfield, G B Cutler Jr, D L Loriaux
PMCID: PMC425532  PMID: 2989331

Abstract

The continuous 24-h infusion of a maximally stimulating dose (1 micrograms/kg per h) of ovine corticotropin-releasing factor (CRF) in man caused a modest elevation of plasma cortisol (17.2 +/- 1.4 micrograms/dl) and urinary-free cortisol (173 +/- 43 micrograms/24 h) concentrations, which was far less than that seen with a maximally stimulating dose of ACTH (50.4 +/- 2.2 micrograms/dl and 1,200 +/- 94 micrograms/24 h, respectively). The circadian rhythms of plasma ACTH and cortisol were preserved during CRF administration. An intravenous bolus injection of 1 microgram/kg of ovine CRF given to normal volunteers under basal conditions resulted in elevated plasma ACTH and cortisol peak levels (28 +/- 6 pg/ml and 15.0 +/- 1.0 micrograms/dl, respectively). However, no plasma ACTH and cortisol responses were observed when an identical CRF stimulation test was given at the end of the continuous infusion. These findings suggest that the stimulatory activity of exogenous CRF on the ACTH-secreting cells of the pituitary gland is restrained by the negative feedback of cortisol. The persistent circadian rhythm of ACTH, despite a constant level of plasma CRF during the infusion, suggests that the circadian variation in the activity of the hypothalamic-pituitary-adrenal axis cannot be explained solely by circadian periodicity of the endogenous CRF stimulus.

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Selected References

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  1. Boyar R. M., Witkin M., Carruth A., Ramsey J. Circadian cortisol secretory rhythms in Cushing's disease. J Clin Endocrinol Metab. 1979 May;48(5):760–765. doi: 10.1210/jcem-48-5-760. [DOI] [PubMed] [Google Scholar]
  2. Carroll, Curtis G. C., Mendels J. Neuroendocrine regulation in depression. I. Limbic system-adrenocortical dysfunction. Arch Gen Psychiatry. 1976 Sep;33(9):1039–1044. doi: 10.1001/archpsyc.1976.01770090029002. [DOI] [PubMed] [Google Scholar]
  3. Chrousos G. P., Schulte H. M., Oldfield E. H., Gold P. W., Cutler G. B., Jr, Loriaux D. L. The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome. N Engl J Med. 1984 Mar 8;310(10):622–626. doi: 10.1056/NEJM198403083101004. [DOI] [PubMed] [Google Scholar]
  4. Cooper C. E., Nelson D. H. ACTH LEVELS IN PLASMA IN PREOPERATIVE AND SURGICALLY STRESSED PATIENTS. J Clin Invest. 1962 Aug;41(8):1599–1605. doi: 10.1172/JCI104618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. DeBold C. R., Sheldon W. R., DeCherney G. S., Jackson R. V., Alexander A. N., Vale W., Rivier J., Orth D. N. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest. 1984 Feb;73(2):533–538. doi: 10.1172/JCI111240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gibbs D. M., Vale W. Presence of corticotropin releasing factor-like immunoreactivity in hypophysial portal blood. Endocrinology. 1982 Oct;111(4):1418–1420. doi: 10.1210/endo-111-4-1418. [DOI] [PubMed] [Google Scholar]
  7. Gillies G. E., Linton E. A., Lowry P. J. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature. 1982 Sep 23;299(5881):355–357. doi: 10.1038/299355a0. [DOI] [PubMed] [Google Scholar]
  8. Gold P. W., Chrousos G., Kellner C., Post R., Roy A., Augerinos P., Schulte H., Oldfield E., Loriaux D. L. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry. 1984 May;141(5):619–627. doi: 10.1176/ajp.141.5.619. [DOI] [PubMed] [Google Scholar]
  9. HUME D. M., BELL C. C., BARTTER F. Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery. 1962 Jul;52:174–187. [PubMed] [Google Scholar]
  10. Kao M., Voina S., Nichols A., Horton R. Parallel radioimmunoassay for plasma cortisol and 11-deoxycortisol. Clin Chem. 1975 Oct;21(11):1644–1647. [PubMed] [Google Scholar]
  11. LIDDLE G. W. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab. 1960 Dec;20:1539–1560. doi: 10.1210/jcem-20-12-1539. [DOI] [PubMed] [Google Scholar]
  12. Lamberts S. W., Verleun T., Oosterom R., de Jong F., Hackeng W. H. Corticotropin-releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release in man. J Clin Endocrinol Metab. 1984 Feb;58(2):298–303. doi: 10.1210/jcem-58-2-298. [DOI] [PubMed] [Google Scholar]
  13. Legros J. J., Chiodera P., Demey-Ponsart E. Inhibitory influence of exogenous oxytocin on adrenocorticotropin secretion in normal human subjects. J Clin Endocrinol Metab. 1982 Dec;55(6):1035–1039. doi: 10.1210/jcem-55-6-1035. [DOI] [PubMed] [Google Scholar]
  14. Nicholson W. E., DeCherney G. S., Jackson R. V., DeBold C. R., Uderman H., Alexander A. N., Rivier J., Vale W., Orth D. N. Plasma distribution, disappearance half-time, metabolic clearance rate, and degradation of synthetic ovine corticotropin-releasing factor in man. J Clin Endocrinol Metab. 1983 Dec;57(6):1263–1269. doi: 10.1210/jcem-57-6-1263. [DOI] [PubMed] [Google Scholar]
  15. Orth D. N., Jackson R. V., DeCherney G. S., DeBold C. R., Alexander A. N., Island D. P., Rivier J., Rivier C., Spiess J., Vale W. Effect of synthetic ovine corticotropin-releasing factor. Dose response of plasma adrenocorticotropin and cortisol. J Clin Invest. 1983 Mar;71(3):587–595. doi: 10.1172/JCI110804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Plumpton F. S., Besser G. M. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg. 1969 Mar;56(3):216–219. doi: 10.1002/bjs.1800560315. [DOI] [PubMed] [Google Scholar]
  17. Rivier C., Vale W. Influence of the frequency of ovine corticotropin-releasing factor administration on adrenocorticotropin and corticosterone secretion in the rat. Endocrinology. 1983 Oct;113(4):1422–1426. doi: 10.1210/endo-113-4-1422. [DOI] [PubMed] [Google Scholar]
  18. Rivier C., Vale W. Interaction of corticotropin-releasing factor and arginine vasopressin on adrenocorticotropin secretion in vivo. Endocrinology. 1983 Sep;113(3):939–942. doi: 10.1210/endo-113-3-939. [DOI] [PubMed] [Google Scholar]
  19. Rivier C., Vale W. Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature. 1983 Sep 22;305(5932):325–327. doi: 10.1038/305325a0. [DOI] [PubMed] [Google Scholar]
  20. Rodbard D. Statistical quality control and routine data processing for radioimmunoassays and immunoradiometric assays. Clin Chem. 1974 Oct;20(10):1255–1270. [PubMed] [Google Scholar]
  21. Ruder H. J., Guy R. L., Lipsett M. B. A radioimmunoassay for cortisol in plasma and urine. J Clin Endocrinol Metab. 1972 Aug;35(2):219–224. doi: 10.1210/jcem-35-2-219. [DOI] [PubMed] [Google Scholar]
  22. Sachar E. J., Hellman L., Roffwarg H. P., Halpern F. S., Fukushima D. K., Gallagher T. F. Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry. 1973 Jan;28(1):19–24. doi: 10.1001/archpsyc.1973.01750310011002. [DOI] [PubMed] [Google Scholar]
  23. Sachar E. J. Twenty-four-hour cortisol secretory patterns in depressed and manic patients. Prog Brain Res. 1975;42:81–91. doi: 10.1016/S0079-6123(08)63647-X. [DOI] [PubMed] [Google Scholar]
  24. Schulte H. M., Chrousos G. P., Booth J. D., Oldfield E. H., Gold P. W., Cutler G. B., Jr, Loriaux D. L. Corticotropin-releasing factor: pharmacokinetics in man. J Clin Endocrinol Metab. 1984 Jan;58(1):192–196. doi: 10.1210/jcem-58-1-192. [DOI] [PubMed] [Google Scholar]
  25. Schulte H. M., Chrousos G. P., Oldfield E. H., Gold P. W., Cutler G. B., Jr, Loriaux D. L. The effects of corticotropin releasing factor on the anterior pituitary function of stalk-sectioned cynomolgus macaques: dose response of cortisol secretion. J Clin Endocrinol Metab. 1982 Oct;55(4):810–812. doi: 10.1210/jcem-55-4-810. [DOI] [PubMed] [Google Scholar]
  26. Schulte H. M., Chrousos G. P., Oldfield E. H., Gold P. W., Cutler G. B., Loriaux D. L. Ovine corticotropin-releasing factor administration in normal men. Pituitary and adrenal responses in the morning and evening. Horm Res. 1985;21(2):69–74. doi: 10.1159/000180028. [DOI] [PubMed] [Google Scholar]
  27. Schürmeyer T. H., Avgerinos P. C., Gold P. W., Gallucci W. T., Tomai T. P., Cutler G. B., Jr, Loriaux D. L., Chrousos G. P. Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion. J Clin Endocrinol Metab. 1984 Dec;59(6):1103–1108. doi: 10.1210/jcem-59-6-1103. [DOI] [PubMed] [Google Scholar]
  28. Vale W., Rivier C., Brown M. R., Spiess J., Koob G., Swanson L., Bilezikjian L., Bloom F., Rivier J. Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res. 1983;39:245–270. doi: 10.1016/b978-0-12-571139-5.50010-0. [DOI] [PubMed] [Google Scholar]
  29. Vale W., Spiess J., Rivier C., Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981 Sep 18;213(4514):1394–1397. doi: 10.1126/science.6267699. [DOI] [PubMed] [Google Scholar]
  30. Vale W., Vaughan J., Smith M., Yamamoto G., Rivier J., Rivier C. Effects of synthetic ovine corticotropin-releasing factor, glucocorticoids, catecholamines, neurohypophysial peptides, and other substances on cultured corticotropic cells. Endocrinology. 1983 Sep;113(3):1121–1131. doi: 10.1210/endo-113-3-1121. [DOI] [PubMed] [Google Scholar]
  31. Wynn P. C., Aguilera G., Morell J., Catt K. J. Properties and regulation of high-affinity pituitary receptors for corticotropin-releasing factor. Biochem Biophys Res Commun. 1983 Jan 27;110(2):602–608. doi: 10.1016/0006-291x(83)91192-0. [DOI] [PubMed] [Google Scholar]

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