Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Aug;92(2):695–701. doi: 10.1172/JCI116639

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

C A Jaffe 1, R D Friberg 1, A L Barkan 1
PMCID: PMC294903  PMID: 8349808

Abstract

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.

Full text

PDF
696

Selected References

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

  1. Asplin C. M., Faria A. C., Carlsen E. C., Vaccaro V. A., Barr R. E., Iranmanesh A., Lee M. M., Veldhuis J. D., Evans W. S. Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1989 Aug;69(2):239–245. doi: 10.1210/jcem-69-2-239. [DOI] [PubMed] [Google Scholar]
  2. Barkan A. L., Stred S. E., Reno K., Markovs M., Hopwood N. J., Kelch R. P., Beitins I. Z. Increased growth hormone pulse frequency in acromegaly. J Clin Endocrinol Metab. 1989 Dec;69(6):1225–1233. doi: 10.1210/jcem-69-6-1225. [DOI] [PubMed] [Google Scholar]
  3. Bowers C. Y., Momany F. A., Reynolds G. A., Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984 May;114(5):1537–1545. doi: 10.1210/endo-114-5-1537. [DOI] [PubMed] [Google Scholar]
  4. Cheng K., Chan W. W., Barreto A., Jr, Convey E. M., Smith R. G. The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3',5'-monophosphate accumulation in rat primary pituitary cell culture. Endocrinology. 1989 Jun;124(6):2791–2798. doi: 10.1210/endo-124-6-2791. [DOI] [PubMed] [Google Scholar]
  5. Clark R. G., Carlsson L. M., Rafferty B., Robinson I. C. The rebound release of growth hormone (GH) following somatostatin infusion in rats involves hypothalamic GH-releasing factor release. J Endocrinol. 1988 Dec;119(3):397–404. doi: 10.1677/joe.0.1190397. [DOI] [PubMed] [Google Scholar]
  6. Clark R. G., Robinson I. C. Paradoxical growth-promoting effects induced by patterned infusions of somatostatin in female rats. Endocrinology. 1988 Jun;122(6):2675–2682. doi: 10.1210/endo-122-6-2675. [DOI] [PubMed] [Google Scholar]
  7. Cowan J. S., Moor B., Chow A., Kraicer J. Characteristics of the post-somatostatin rebound in growth hormone secretion from perifused somatotrophs. Endocrinology. 1983 Sep;113(3):1056–1061. doi: 10.1210/endo-113-3-1056. [DOI] [PubMed] [Google Scholar]
  8. Davies R. R., Turner S. J., Orskov H., Johnston D. G. The interaction of human pancreatic growth hormone releasing factor 1-44 with somatostatin in vivo in normal man. Clin Endocrinol (Oxf) 1985 Sep;23(3):271–276. doi: 10.1111/j.1365-2265.1985.tb00223.x. [DOI] [PubMed] [Google Scholar]
  9. Davis T. M., Burrin J. M., Bloom S. R. Growth hormone (GH) release in response to GH-releasing hormone in man is 3-fold enhanced by galanin. J Clin Endocrinol Metab. 1987 Dec;65(6):1248–1252. doi: 10.1210/jcem-65-6-1248. [DOI] [PubMed] [Google Scholar]
  10. Faria A. C., Bekenstein L. W., Booth R. A., Jr, Vaccaro V. A., Asplin C. M., Veldhuis J. D., Thorner M. O., Evans W. S. Pulsatile growth hormone release in normal women during the menstrual cycle. Clin Endocrinol (Oxf) 1992 Jun;36(6):591–596. doi: 10.1111/j.1365-2265.1992.tb02270.x. [DOI] [PubMed] [Google Scholar]
  11. Ferland L., Labrie F., Jobin M., Arimura A., Schally A. V. Physiological role of somatostatin in the control of growth hormone and thyrotropin secretion. Biochem Biophys Res Commun. 1976 Jan 12;68(1):149–156. doi: 10.1016/0006-291x(76)90022-x. [DOI] [PubMed] [Google Scholar]
  12. Foster D. L., Ebling F. J., Micka A. F., Vannerson L. A., Bucholtz D. C., Wood R. I., Suttie J. M., Fenner D. E. Metabolic interfaces between growth and reproduction. I. Nutritional modulation of gonadotropin, prolactin, and growth hormone secretion in the growth-limited female lamb. Endocrinology. 1989 Jul;125(1):342–350. doi: 10.1210/endo-125-1-342. [DOI] [PubMed] [Google Scholar]
  13. Frohman L. A., Downs T. R., Clarke I. J., Thomas G. B. Measurement of growth hormone-releasing hormone and somatostatin in hypothalamic-portal plasma of unanesthetized sheep. Spontaneous secretion and response to insulin-induced hypoglycemia. J Clin Invest. 1990 Jul;86(1):17–24. doi: 10.1172/JCI114681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fukata J., Diamond D. J., Martin J. B. Effects of rat growth hormone (rGH)-releasing factor and somatostatin on the release and synthesis of rGH in dispersed pituitary cells. Endocrinology. 1985 Aug;117(2):457–467. doi: 10.1210/endo-117-2-457. [DOI] [PubMed] [Google Scholar]
  15. Gaylinn B. D., Harrison J. K., Zysk J. R., Lyons C. E., Lynch K. R., Thorner M. O. Molecular cloning and expression of a human anterior pituitary receptor for growth hormone-releasing hormone. Mol Endocrinol. 1993 Jan;7(1):77–84. doi: 10.1210/mend.7.1.7680413. [DOI] [PubMed] [Google Scholar]
  16. Gelato M. C., Pescovitz O. H., Cassorla F., Loriaux D. L., Merriam G. R. Dose-response relationships for the effects of growth hormone-releasing factor-(1-44)-NH2 in young adult men and women. J Clin Endocrinol Metab. 1984 Aug;59(2):197–201. doi: 10.1210/jcem-59-2-197. [DOI] [PubMed] [Google Scholar]
  17. Hartman M. L., Veldhuis J. D., Johnson M. L., Lee M. M., Alberti K. G., Samojlik E., Thorner M. O. Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men. J Clin Endocrinol Metab. 1992 Apr;74(4):757–765. doi: 10.1210/jcem.74.4.1548337. [DOI] [PubMed] [Google Scholar]
  18. Hartman M. L., Veldhuis J. D., Vance M. L., Faria A. C., Furlanetto R. W., Thorner M. O. Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab. 1990 May;70(5):1375–1384. doi: 10.1210/jcem-70-5-1375. [DOI] [PubMed] [Google Scholar]
  19. Hindmarsh P. C., Brain C. E., Robinson I. C., Matthews D. R., Brook C. G. The interaction of growth hormone releasing hormone and somatostatin in the generation of a GH pulse in man. Clin Endocrinol (Oxf) 1991 Oct;35(4):353–360. doi: 10.1111/j.1365-2265.1991.tb03548.x. [DOI] [PubMed] [Google Scholar]
  20. Hizuka N., Takano K., Shizume K., Tanaka I., Honda N., Ling N. C. Plasma growth hormone (GH) and somatomedin C response to continuous growth hormone-releasing factor (GRF) infusion in patients with GH deficiency. Acta Endocrinol (Copenh) 1985 Sep;110(1):17–23. doi: 10.1530/acta.0.1100017. [DOI] [PubMed] [Google Scholar]
  21. Ho K. Y., Evans W. S., Blizzard R. M., Veldhuis J. D., Merriam G. R., Samojlik E., Furlanetto R., Rogol A. D., Kaiser D. L., Thorner M. O. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987 Jan;64(1):51–58. doi: 10.1210/jcem-64-1-51. [DOI] [PubMed] [Google Scholar]
  22. Katakami H., Downs T. R., Frohman L. A. Inhibitory effect of hypothalamic medial preoptic area somatostatin on growth hormone-releasing factor in the rat. Endocrinology. 1988 Aug;123(2):1103–1109. doi: 10.1210/endo-123-2-1103. [DOI] [PubMed] [Google Scholar]
  23. Kraicer J., Cowan J. S., Sheppard M. S., Lussier B., Moor B. C. Effect of somatostatin withdrawal and growth hormone (GH)-releasing factor on GH release in vitro: amount available for release after disinhibition. Endocrinology. 1986 Nov;119(5):2047–2051. doi: 10.1210/endo-119-5-2047. [DOI] [PubMed] [Google Scholar]
  24. Kraicer J., Sheppard M. S., Luke J., Lussier B., Moor B. C., Cowan J. S. Effect of withdrawal of somatostatin and growth hormone (GH)-releasing factor on GH release in vitro. Endocrinology. 1988 May;122(5):1810–1815. doi: 10.1210/endo-122-5-1810. [DOI] [PubMed] [Google Scholar]
  25. Liposits Z., Merchenthaler I., Paull W. K., Flerkó B. Synaptic communication between somatostatinergic axons and growth hormone-releasing factor (GRF) synthesizing neurons in the arcuate nucleus of the rat. Histochemistry. 1988;89(3):247–252. doi: 10.1007/BF00493148. [DOI] [PubMed] [Google Scholar]
  26. Lumpkin M. D., McDonald J. K. Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology. 1989 Mar;124(3):1522–1531. doi: 10.1210/endo-124-3-1522. [DOI] [PubMed] [Google Scholar]
  27. Lumpkin M. D., Mulroney S. E., Haramati A. Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist. Endocrinology. 1989 Mar;124(3):1154–1159. doi: 10.1210/endo-124-3-1154. [DOI] [PubMed] [Google Scholar]
  28. Maiter D., Underwood L. E., Martin J. B., Koenig J. I. Neonatal treatment with monosodium glutamate: effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats. Endocrinology. 1991 Feb;128(2):1100–1106. doi: 10.1210/endo-128-2-1100. [DOI] [PubMed] [Google Scholar]
  29. Martha P. M., Jr, Rogol A. D., Veldhuis J. D., Kerrigan J. R., Goodman D. W., Blizzard R. M. Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys. J Clin Endocrinol Metab. 1989 Sep;69(3):563–570. doi: 10.1210/jcem-69-3-563. [DOI] [PubMed] [Google Scholar]
  30. Miki N., Ono M., Shizume K. Withdrawal of endogenous somatostatin induces secretion of growth hormone-releasing factor in rats. J Endocrinol. 1988 May;117(2):245–252. doi: 10.1677/joe.0.1170245. [DOI] [PubMed] [Google Scholar]
  31. Millard W. J., Martin J. B., Jr, Audet J., Sagar S. M., Martin J. B. Evidence that reduced growth hormone secretion observed in monosodium glutamate-treated rats is the result of a deficiency in growth hormone-releasing factor. Endocrinology. 1982 Feb;110(2):540–550. doi: 10.1210/endo-110-2-540. [DOI] [PubMed] [Google Scholar]
  32. Ohtsuka M., Hisano S., Daikoku S. Electronmicroscopic study of somatostatin-containing neurons in rat arcuate nucleus with special reference to neuronal regulation. Brain Res. 1983 Mar 21;263(2):191–199. doi: 10.1016/0006-8993(83)90312-8. [DOI] [PubMed] [Google Scholar]
  33. Ono M., Miki N., Demura H. Effect of antiserum to rat growth hormone (GH)-releasing factor on physiological GH secretion in the female rat. Endocrinology. 1991 Oct;129(4):1791–1796. doi: 10.1210/endo-129-4-1791. [DOI] [PubMed] [Google Scholar]
  34. Painson J. C., Tannenbaum G. S. Sexual dimorphism of somatostatin and growth hormone-releasing factor signaling in the control of pulsatile growth hormone secretion in the rat. Endocrinology. 1991 Jun;128(6):2858–2866. doi: 10.1210/endo-128-6-2858. [DOI] [PubMed] [Google Scholar]
  35. Patel Y. C., Srikant C. B. Somatostatin mediation of adenohypophysial secretion. Annu Rev Physiol. 1986;48:551–567. doi: 10.1146/annurev.ph.48.030186.003003. [DOI] [PubMed] [Google Scholar]
  36. Plotsky P. M., Vale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science. 1985 Oct 25;230(4724):461–463. doi: 10.1126/science.2864742. [DOI] [PubMed] [Google Scholar]
  37. ROTH J., GLICK S. M., YALOW R. S., BERSONSA Hypoglycemia: a potent stimulus to secretion of growth hormone. Science. 1963 May 31;140(3570):987–988. doi: 10.1126/science.140.3570.987. [DOI] [PubMed] [Google Scholar]
  38. Robberecht P., Coy D. H., Waelbroeck M., Heiman M. L., de Neef P., Camus J. C., Christophe J. Structural requirements for the activation of rat anterior pituitary adenylate cyclase by growth hormone-releasing factor (GRF): discovery of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as a GRF antagonist on membranes. Endocrinology. 1985 Nov;117(5):1759–1764. doi: 10.1210/endo-117-5-1759. [DOI] [PubMed] [Google Scholar]
  39. Rochiccioli P. E., Tauber M. T., Uboldi F., Coude F. X., Morre M. Effect of overnight constant infusion of human growth hormone (GH)-releasing hormone-(1-44) on 24-hour GH secretion in children with partial GH deficiency. J Clin Endocrinol Metab. 1986 Nov;63(5):1100–1105. doi: 10.1210/jcem-63-5-1100. [DOI] [PubMed] [Google Scholar]
  40. SCHALCH D. S., PARKER M. L. A SENSITIVE DOUBLE ANTIBODY IMMUNOASSAY FOR HUMAN GROWTH HORMONE IN PLASMA. Nature. 1964 Sep 12;203:1141–1142. doi: 10.1038/2031141a0. [DOI] [PubMed] [Google Scholar]
  41. Sato M., Takahara J., Niimi M., Tagawa R., Irino S. Characterization of the stimulatory effect of galanin on growth hormone release from the rat anterior pituitary. Life Sci. 1991;48(17):1639–1644. doi: 10.1016/0024-3205(91)90124-t. [DOI] [PubMed] [Google Scholar]
  42. Tannenbaum G. S., Eikelboom R., Ling N. Human pancreas GH-releasing factor analog restores high-amplitude GH pulses in CNS lesion-induced GH deficiency. Endocrinology. 1983 Sep;113(3):1173–1175. doi: 10.1210/endo-113-3-1173. [DOI] [PubMed] [Google Scholar]
  43. Tannenbaum G. S., Martin J. B., Colle E. Ultradian growth hormone rhythm in the rat: effects of feeding, hyperglycemia, and insulin-induced hypoglycemia. Endocrinology. 1976 Sep;99(3):720–727. doi: 10.1210/endo-99-3-720. [DOI] [PubMed] [Google Scholar]
  44. Tannenbaum G. S., McCarthy G. F., Zeitler P., Beaudet A. Cysteamine-induced enhancement of growth hormone-releasing factor (GRF) immunoreactivity in arcuate neurons: morphological evidence for putative somatostatin/GRF interactions within hypothalamus. Endocrinology. 1990 Nov;127(5):2551–2560. doi: 10.1210/endo-127-5-2551. [DOI] [PubMed] [Google Scholar]
  45. Tannenbaum G. S., Rorstad O., Brazeau P. Effects of prolonged food deprivation on the ultradian growth hormone rhythm and immunoreactive somatostatin tissue levels in the rat. Endocrinology. 1979 Jun;104(6):1733–1738. doi: 10.1210/endo-104-6-1733. [DOI] [PubMed] [Google Scholar]
  46. Thomas G. B., Cummins J. T., Francis H., Sudbury A. W., McCloud P. I., Clarke I. J. Effect of restricted feeding on the relationship between hypophysial portal concentrations of growth hormone (GH)-releasing factor and somatostatin, and jugular concentrations of GH in ovariectomized ewes. Endocrinology. 1991 Feb;128(2):1151–1158. doi: 10.1210/endo-128-2-1151. [DOI] [PubMed] [Google Scholar]
  47. Van Cauter E., Caufriez A., Kerkhofs M., Van Onderbergen A., Thorner M. O., Copinschi G. Sleep, awakenings, and insulin-like growth factor-I modulate the growth hormone (GH) secretory response to GH-releasing hormone. J Clin Endocrinol Metab. 1992 Jun;74(6):1451–1459. doi: 10.1210/jcem.74.6.1592893. [DOI] [PubMed] [Google Scholar]
  48. Vance M. L., Borges J. L., Kaiser D. L., Evans W. S., Furlanetto R., Thominet J. L., Frohman L. A., Rogol A. D., MacLeod R. M., Bloom S. Human pancreatic tumor growth hormone-releasing factor: dose-response relationships in normal man. J Clin Endocrinol Metab. 1984 May;58(5):838–844. doi: 10.1210/jcem-58-5-838. [DOI] [PubMed] [Google Scholar]
  49. Vance M. L., Kaiser D. L., Evans W. S., Furlanetto R., Vale W., Rivier J., Thorner M. O. Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1-40). Evidence for intermittent somatostatin secretion. J Clin Invest. 1985 May;75(5):1584–1590. doi: 10.1172/JCI111864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vance M. L., Kaiser D. L., Rivier J., Vale W., Thorner M. O. Dual effects of growth hormone (GH)-releasing hormone infusion in normal men: somatotroph desensitization and increase in releasable GH. J Clin Endocrinol Metab. 1986 Mar;62(3):591–594. doi: 10.1210/jcem-62-3-591. [DOI] [PubMed] [Google Scholar]
  51. Veldhuis J. D., Iranmanesh A., Ho K. K., Waters M. J., Johnson M. L., Lizarralde G. Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab. 1991 Jan;72(1):51–59. doi: 10.1210/jcem-72-1-51. [DOI] [PubMed] [Google Scholar]
  52. Veldhuis J. D., Johnson M. L. Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol. 1986 Apr;250(4 Pt 1):E486–E493. doi: 10.1152/ajpendo.1986.250.4.E486. [DOI] [PubMed] [Google Scholar]
  53. Wehrenberg W. B., Brazeau P., Luben R., Böhlen P., Guillemin R. Inhibition of the pulsatile secretion of growth hormone by monoclonal antibodies to the hypothalamic growth hormone releasing factor (GRF). Endocrinology. 1982 Dec;111(6):2147–2148. doi: 10.1210/endo-111-6-2147. [DOI] [PubMed] [Google Scholar]
  54. Weiss J., Cronin M. J., Thorner M. O. Periodic interactions of GH-releasing factor and somatostatin can augment GH release in vitro. Am J Physiol. 1987 Nov;253(5 Pt 1):E508–E514. doi: 10.1152/ajpendo.1987.253.5.E508. [DOI] [PubMed] [Google Scholar]
  55. Willoughby J. O., Brogan M., Kapoor R. Hypothalamic interconnections of somatostatin and growth hormone releasing factor neurons. Neuroendocrinology. 1989 Nov;50(5):584–591. doi: 10.1159/000125285. [DOI] [PubMed] [Google Scholar]
  56. Winer L. M., Shaw M. A., Baumann G. Basal plasma growth hormone levels in man: new evidence for rhythmicity of growth hormone secretion. J Clin Endocrinol Metab. 1990 Jun;70(6):1678–1686. doi: 10.1210/jcem-70-6-1678. [DOI] [PubMed] [Google Scholar]
  57. Zadik Z., Chalew S. A., Kowarski A. The definition of a spontaneous growth hormone (GH) peak: studies in normally growing and GH-deficient children. J Clin Endocrinol Metab. 1992 Apr;74(4):801–805. doi: 10.1210/jcem.74.4.1548344. [DOI] [PubMed] [Google Scholar]

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

RESOURCES