Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1979 Jul;64(1):102–108. doi: 10.1172/JCI109428

Positive Rate-Sensitive Corticosteroid Feedback Mechanism of ACTH Secretion in Cushing's Disease

H L Fehm 1,2, K H Voigt 1,2, G Kummer 1,2, E F Pfeiffer 1,2
PMCID: PMC372095  PMID: 221540

Abstract

To define the nature of the disturbance of the corticosteroid feedback mechanism in Cushing's disease, the dynamic aspects of the ACTH response to corticosteroid administration have been studied in patients with Cushing's disease after total adrenalectomy (C.d. post adx.). The results were compared with those obtained in patients with Addison's disease (control group). Different experimental designs for administration of cortisol were chosen to provide extreme variations in the input signal. The response of the system was evaluated by measuring plasma ACTH concentrations (radioimmunoassay) at short time intervals.

Infusion of cortisol at constant rate (50 mg/h for 2 h) resulted in a transient, paradoxical rise in ACTH levels with a maximum at 15 min. (315±65%, mean±SEM). In contrast, in the control group there was an immediate and rapid decrease in ACTH levels with a significant inhibition after 15 min (80±6%, mean±SEM). Infusion of 50 mg cortisol for 5 and 15 min, respectively, produced an increase in ACTH levels, which was confined to the time when cortisol levels were rising (maximum: 137±30% and 139±10% at 5 and 15 min, respectively, mean±SEM). This increase corresponded in time to the first decrease in ACTH levels in the Addisonian patients. With bolus injections of 25 mg cortisol, ACTH levels remained unchanged during the first 15 min. The time-course in the patients with C.d. post adx. was essentially the same as in the Addisonian patients.

From these results it is concluded that in the patients with C.d. post adx. the rapid, rate-sensitive feedback mechanism was converted into a positive one, whereas the delayed, dose-sensitive mechanism was completely undisturbed. The capacity of dexamethasone to activate rate-sensitive feedback elements was markedly diminished. Accordingly, there were only minor positive feedback effects upon ACTH secretion in the patients with C.d. post adx.

Full text

PDF
102

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe K., Critchlow V. Effects of corticosterone, dexamethasone and surgical isolation of the medial basal hypothalamus on rapid feedback control of stress-induced corticotropin secretion in female rats. Endocrinology. 1977 Aug;101(2):498–505. doi: 10.1210/endo-101-2-498. [DOI] [PubMed] [Google Scholar]
  2. Brooks R. V., Jeffcoate S. L., London D. R., Prunty F. T., Smith P. M. Intermittent Cushing's syndrome with anomalous response to dexamethasone. J Endocrinol. 1966 Sep;36(1):53–61. doi: 10.1677/joe.0.0360053. [DOI] [PubMed] [Google Scholar]
  3. Bucher B., Koch B., Mialhe C. Sur l'existence d'un mécanisme de "feedback rapide" ACTH-corticostérone. J Physiol (Paris) 1973;66(2):199–209. [PubMed] [Google Scholar]
  4. Dallman M. F., Yates F. E. Dynamic asymmetries in the corticosteroid feedback path and distribution-metabolism-binding elements of the adrenocortical system. Ann N Y Acad Sci. 1969 Apr 21;156(2):696–721. doi: 10.1111/j.1749-6632.1969.tb14008.x. [DOI] [PubMed] [Google Scholar]
  5. De Kloet R., Wallach G., McEwen B. S. Differences in corticosterone and dexamethasone binding to rat brain and pituitary. Endocrinology. 1975 Mar;96(3):598–609. doi: 10.1210/endo-96-3-598. [DOI] [PubMed] [Google Scholar]
  6. Engeland W. C., Shinsako J., Winget C. M., Vernikos-Danellis J., Dallman M. F. Circadian patterns of stress-induced ACTH secretion are modified by corticosterone responses. Endocrinology. 1977 Jan;100(1):138–147. doi: 10.1210/endo-100-1-138. [DOI] [PubMed] [Google Scholar]
  7. Fehm H. L., Voight K. H., Lang R. E., Beinert K. E., Kummer G. W., Pfeiffer E. F. Paradoxical ACTH response to glucocorticoids in Cushing's disease. N Engl J Med. 1977 Oct 27;297(17):904–907. doi: 10.1056/NEJM197710272971703. [DOI] [PubMed] [Google Scholar]
  8. Fehm H. L., Voigt K. H., Kummer G., Lang R., Pfeiffer E. F. Differential and integral corticosteroid feedback effects on ACTH secretion in hypoadrenocorticism. J Clin Invest. 1979 Feb;63(2):247–253. doi: 10.1172/JCI109296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fehm H. L., Voigt K. H., Pfeiffer E. F. Problems and artefacts in ACTH assay. Horm Metab Res. 1972 Nov;4(6):477–481. doi: 10.1055/s-0028-1094009. [DOI] [PubMed] [Google Scholar]
  10. French F. S., Macfie J. A., Baggett B., Williams T. F., Van Wyk J. J. Cushing's syndrome with a paradoxical response to dexamethasone. Am J Med. 1969 Oct;47(4):619–624. doi: 10.1016/0002-9343(69)90191-0. [DOI] [PubMed] [Google Scholar]
  11. James V. H., Landon J., Wynn V. Oral and intravenous suppression tests in the diagnosis of Cushing's syndrome. J Endocrinol. 1965 Nov;33(3):515–524. doi: 10.1677/joe.0.0330515. [DOI] [PubMed] [Google Scholar]
  12. Jones M. T., Brush F. R., Neame R. L. Characteristics of fast feedback control of corticotrophin release by corticosteroids. J Endocrinol. 1972 Dec;55(3):489–497. doi: 10.1677/joe.0.0550489. [DOI] [PubMed] [Google Scholar]
  13. Jones M. T., Hillhouse E. W., Burden J. L. Structure-activity relationships of corticosteroid feedback at the hypothalamic level. J Endocrinol. 1977 Sep;74(3):415–424. doi: 10.1677/joe.0.0740415. [DOI] [PubMed] [Google Scholar]
  14. Jones M. T., Hillhouse E. W. Structure-activity relationship and the mode of action of corticosteroid feedback on the secretion of corticotrophin-releasing factor (corticoliberin). J Steroid Biochem. 1976 Nov-Dec;7(11-12):1189–1202. doi: 10.1016/0022-4731(76)90054-6. [DOI] [PubMed] [Google Scholar]
  15. Jones M. T., Tiptaft E. M., Brush F. R., Fergusson D. A., Neame R. L. Evidence for dual corticosteroid-receptor mechanisms in the feedback control of adrenocorticotrophin secretion. J Endocrinol. 1974 Feb;60(2):223–233. doi: 10.1677/joe.0.0600223. [DOI] [PubMed] [Google Scholar]
  16. Kaneko M., Hiroshige T. Fast, rate-sensitive corticosteroid negative feedback during stress. Am J Physiol. 1978 Jan;234(1):R39–R45. doi: 10.1152/ajpregu.1978.234.1.R39. [DOI] [PubMed] [Google Scholar]
  17. Kaneko M., Hiroshige T. Site of fast, rate-sensitive feedback inhibition of adrenocorticotropin secretion during stress. Am J Physiol. 1978 Jan;234(1):R46–R51. doi: 10.1152/ajpregu.1978.234.1.R46. [DOI] [PubMed] [Google Scholar]
  18. Krieger D. T., Amorosa L., Linick F. Cyproheptadine-induced remission of Cushing's disease. N Engl J Med. 1975 Oct 30;293(18):893–896. doi: 10.1056/NEJM197510302931802. [DOI] [PubMed] [Google Scholar]
  19. Krieger D. T., Glick S. M. Sleep EEG stages and plasma growth hormone concentration in states of endogenous and exogenous hypercortisolemia or ACTH elevation. J Clin Endocrinol Metab. 1974 Dec;39(6):986–1000. doi: 10.1210/jcem-39-6-986. [DOI] [PubMed] [Google Scholar]
  20. Krieger D. T., Howanitz P. J., Frantz A. G. Absence of nocturnal elevation of plasma prolactin concentrations in Cushing's disease. J Clin Endocrinol Metab. 1976 Feb;42(2):260–272. doi: 10.1210/jcem-42-2-260. [DOI] [PubMed] [Google Scholar]
  21. Krieger D. T. The central nervous system and Cushing's disease. Med Clin North Am. 1978 Mar;62(2):261–268. doi: 10.1016/s0025-7125(16)31803-x. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Murphy B. E. Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding radioassay. J Clin Endocrinol Metab. 1967 Jul;27(7):973–990. doi: 10.1210/jcem-27-7-973. [DOI] [PubMed] [Google Scholar]
  24. Rose L. I., Williams G. H., Jagger P. I., Lauler D. P., Thorn G. W. The paradoxical dexamethasone reponse phenomenon. Metabolism. 1969 May;18(5):369–375. doi: 10.1016/0026-0495(69)90065-1. [DOI] [PubMed] [Google Scholar]
  25. Rotsztejn W. H., Normand M., Lalonde J., Fortier C. Relationship between ACTH release and corticosterone binding by the receptor sites of the adenohypophysis and dorsal hippocampus following infusion of corticosterone at a constant rate in the adrenalectomized rat. Endocrinology. 1975 Jul;97(1):223–230. doi: 10.1210/endo-97-1-223. [DOI] [PubMed] [Google Scholar]
  26. Sakakura M., Saito Y., Takebe K., Ishii K. Studies on fast feedback mechanisms by endogenous glucocorticoids. Endocrinology. 1976 Apr;98(4):954–957. doi: 10.1210/endo-98-4-954. [DOI] [PubMed] [Google Scholar]
  27. Salassa R. M., Laws E. R., Jr, Carpenter P. C., Northcutt R. C. Transsphenoidal removal of pituitary microadenoma in Cushing's disease. Mayo Clin Proc. 1978 Jan;53(1):24–28. [PubMed] [Google Scholar]
  28. Sirett N. E., Purves H. D. Plasma corticotrophin estimations in Addison's disease and following adrenalectomy for Cushing's disease. J Clin Endocrinol Metab. 1968 Sep;28(9):1367–1369. doi: 10.1210/jcem-28-9-1367. [DOI] [PubMed] [Google Scholar]
  29. Tyrrell J. B., Brooks R. M., Fitzgerald P. A., Cofoid P. B., Forsham P. H., Wilson C. B. Cushing's disease. Selective trans-sphenoidal resection of pituitary microadenomas. N Engl J Med. 1978 Apr 6;298(14):753–758. doi: 10.1056/NEJM197804062981401. [DOI] [PubMed] [Google Scholar]
  30. Voigt K. H., Fehm H. L., Reck R., Pfeiffer E. F. Spontaneous and stimulated secretion of QUSO-extractable immunoassayable ACTH in man. Klin Wochenschr. 1974 Jun 1;52(11):516–521. doi: 10.1007/BF01468721. [DOI] [PubMed] [Google Scholar]
  31. WILLIAMS W. C., Jr, ISLAND D., OLDFIELD R. A., Jr, LIDDLE G. W. Blood corticotropin (ACTH) levels in Cushing's disease. J Clin Endocrinol Metab. 1961 Apr;21:426–432. doi: 10.1210/jcem-21-4-426. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES