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. 1996 Feb 15;97(4):934–940. doi: 10.1172/JCI118516

Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

C A Jaffe 1, R DeMott-Friberg 1, A L Barkan 1
PMCID: PMC507138  PMID: 8613546

Abstract

The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.

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Selected References

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  1. Alba-Roth J., Losa M., Spiess Y., Schopohl J., Müller O. A., von Werder K. Interaction of clonidine and GHRH on GH secretion in vivo and in vitro. Clin Endocrinol (Oxf) 1989 May;30(5):485–491. doi: 10.1111/j.1365-2265.1989.tb01419.x. [DOI] [PubMed] [Google Scholar]
  2. Alba-Roth J., Müller O. A., Schopohl J., von Werder K. Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab. 1988 Dec;67(6):1186–1189. doi: 10.1210/jcem-67-6-1186. [DOI] [PubMed] [Google Scholar]
  3. Alba-Roth J., von Creytz C., Mehltretter G., Schopohl J., Müller O. A., von Werder K. Interaction of L-dopa and GHRH on GH secretion in normal men. J Endocrinol Invest. 1989 Dec;12(11):783–787. doi: 10.1007/BF03350059. [DOI] [PubMed] [Google Scholar]
  4. Cataldi M., Magnan E., Guillaume V., Dutour A., Conte-Devolx B., Lombardi G., Oliver C. Relationship between hypophyseal portal GHRH and somatostatin and peripheral GH levels in the conscious sheep. J Endocrinol Invest. 1994 Oct;17(9):717–722. doi: 10.1007/BF03347767. [DOI] [PubMed] [Google Scholar]
  5. Chihara K., Kashio Y., Kita T., Okimura Y., Kaji H., Abe H., Fujita T. L-dopa stimulates release of hypothalamic growth hormone-releasing hormone in humans. J Clin Endocrinol Metab. 1986 Mar;62(3):466–473. doi: 10.1210/jcem-62-3-466. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Conway S., Richardson L., Speciale S., Moherek R., Mauceri H., Krulich L. Interaction between norepinephrine and serotonin in the neuroendocrine control of growth hormone release in the rat. Endocrinology. 1990 Feb;126(2):1022–1030. doi: 10.1210/endo-126-2-1022. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Delitala G., Tomasi P., Virdis R. Neuroendocrine regulation of human growth hormone secretion. Diagnostic and clinical applications. J Endocrinol Invest. 1988 Jun;11(6):441–462. doi: 10.1007/BF03349081. [DOI] [PubMed] [Google Scholar]
  10. Devesa J., Diaz M. J., Tresguerres J. A., Arce V., Lima L. Evidence that alpha 2-adrenergic pathways play a major role in growth hormone (GH) neuroregulation: alpha 2-adrenergic agonism counteracts the inhibitory effect of muscarinic cholinergic receptor blockade on the GH response to GH-releasing hormone, while alpha 2-adrenergic blockade diminishes the potentiating effect of increased cholinergic tone on such stimulation in normal men. J Clin Endocrinol Metab. 1991 Aug;73(2):251–256. doi: 10.1210/jcem-73-2-251. [DOI] [PubMed] [Google Scholar]
  11. Donnadieu M., Evain-Brion D., Tonon M. C., Vaudry H., Job J. C. Variations of plasma growth hormone (GH)-releasing factor levels during GH stimulation tests in children. J Clin Endocrinol Metab. 1985 Jun;60(6):1132–1134. doi: 10.1210/jcem-60-6-1132. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Gil-Ad I., Leibowitch N., Josefsberg Z., Wasserman M., Laron Z. Effect of oral clonidine, insulin-induced hypoglycemia and exercise on plasma GHRH levels in short-stature children. Acta Endocrinol (Copenh) 1990 Jan;122(1):89–95. doi: 10.1530/acta.0.1220089. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Ho P. J., Kletter G. B., Hopwood N. J., DeMott Friberg R., Barkan A. L. Somatostatin withdrawal alone is an ineffective generator of pulsatile growth hormone release in man. Acta Endocrinol (Copenh) 1993 Nov;129(5):414–418. doi: 10.1530/acta.0.1290414. [DOI] [PubMed] [Google Scholar]
  16. Jaffe C. A., Friberg R. D., Barkan A. L. 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. J Clin Invest. 1993 Aug;92(2):695–701. doi: 10.1172/JCI116639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jaffe C. A., Ho P. J., Demott-Friberg R., Bowers C. Y., Barkan A. L. Effects of a prolonged growth hormone (GH)-releasing peptide infusion on pulsatile GH secretion in normal men. J Clin Endocrinol Metab. 1993 Dec;77(6):1641–1647. doi: 10.1210/jcem.77.6.7903313. [DOI] [PubMed] [Google Scholar]
  18. Kashio Y., Chihara K., Kita T., Okimura Y., Sato M., Kadowaki S., Fujita T. Effect of oral glucose administration on plasma growth hormone-releasing hormone (GHRH)-like immunoreactivity levels in normal subjects and patients with idiopathic GH deficiency: evidence that GHRH is released not only from the hypothalamus but also from extrahypothalamic tissue. J Clin Endocrinol Metab. 1987 Jan;64(1):92–97. doi: 10.1210/jcem-64-1-92. [DOI] [PubMed] [Google Scholar]
  19. Kelijman M., Frohman L. A. Discordant effects of insulin-hypoglycemia on growth hormone (GH)-releasing hormone-stimulated GH and thyrotropin (TSH)-releasing hormone-stimulated TSH secretion. J Clin Endocrinol Metab. 1988 Apr;66(4):872–875. doi: 10.1210/jcem-66-4-872. [DOI] [PubMed] [Google Scholar]
  20. Kraicer J. Acetylcholine does not stimulate the release of growth hormone from perifused rat adenohypophyses. Can J Physiol Pharmacol. 1979 Jul;57(7):748–750. doi: 10.1139/y79-113. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Loche S., Balzano S., Bozzola M., Moretta A., Pintus S., Faedda A., Muntoni A., Carta D., Pintor C. Secretion of growth hormone releasing hormone in obese children. J Endocrinol Invest. 1992 Jun;15(6):453–457. doi: 10.1007/BF03348770. [DOI] [PubMed] [Google Scholar]
  23. Magnan E., Cataldi M., Guillaume V., Conte-Devolx B., Graziani N., Figaroli J. C., Thomas F., Chihara K., Oliver C. Acute changes in growth hormone-releasing hormone secretion after injection of BIM 23014, a long acting somatostatin analog, in rams. Life Sci. 1992;51(11):831–838. doi: 10.1016/0024-3205(92)90610-2. [DOI] [PubMed] [Google Scholar]
  24. Magnan E., Cataldi M., Guillaume V., Mazzocchi L., Dutour A., Conte-Devolx B., Giraud P., Oliver C. Neostigmine stimulates growth hormone-releasing hormone release into hypophysial portal blood of conscious sheep. Endocrinology. 1993 Mar;132(3):1247–1251. doi: 10.1210/endo.132.3.8095014. [DOI] [PubMed] [Google Scholar]
  25. Magnan E., Cataldi M., Guillaume V., Mazzocchi L., Dutour A., Razafindraibe H., Sauze N., Renard M., Oliver C. Role of growth hormone (GH)-releasing hormone and somatostatin in the mediation of clonidine-induced GH release in sheep. Endocrinology. 1994 Feb;134(2):562–567. doi: 10.1210/endo.134.2.7905408. [DOI] [PubMed] [Google Scholar]
  26. Massara F., Ghigo E., Molinatti P., Mazza E., Locatelli V., Müller E. E., Camanni F. Potentiation of cholinergic tone by pyridostigmine bromide re-instates and potentiates the growth hormone responsiveness to intermittent administration of growth hormone-releasing factor in man. Acta Endocrinol (Copenh) 1986 Sep;113(1):12–16. doi: 10.1530/acta.0.1130012. [DOI] [PubMed] [Google Scholar]
  27. Masuda A., Shibasaki T., Hotta M., Yamauchi N., Ling N., Demura H., Shizume K. Insulin-induced hypoglycemia, L-dopa and arginine stimulate GH secretion through different mechanisms in man. Regul Pept. 1990 Oct 29;31(1):53–64. doi: 10.1016/0167-0115(90)90195-3. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Müller E. E., Locatelli V., Ghigo E., Cella S. G., Loche S., Pintor C., Camanni F. Involvement of brain catecholamines and acetylcholine in growth hormone deficiency states. Pathophysiological, diagnostic and therapeutic implications. Drugs. 1991 Feb;41(2):161–177. doi: 10.2165/00003495-199141020-00002. [DOI] [PubMed] [Google Scholar]
  30. Page M. D., Dieguez C., Valcavi R., Koppeschaar H. P., Scanlon M. F. Growth hormone releasing hormone 1-44 NH2 and 1-40 OH levels in normal subjects during growth hormone stimulation tests. Clin Endocrinol (Oxf) 1994 Jan;40(1):97–102. doi: 10.1111/j.1365-2265.1994.tb02450.x. [DOI] [PubMed] [Google Scholar]
  31. Page M. D., Koppeschaar H. P., Edwards C. A., Dieguez C., Scanlon M. F. Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man. Clin Endocrinol (Oxf) 1987 May;26(5):589–595. doi: 10.1111/j.1365-2265.1987.tb00814.x. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. Richardson S. B., Hollander C. S., D'Eletto R., Greenleaf P. W., Thaw C. Acetylcholine inhibits the release of somatostatin from rat hypothalamus in vitro. Endocrinology. 1980 Jul;107(1):122–129. doi: 10.1210/endo-107-1-122. [DOI] [PubMed] [Google Scholar]
  35. Robinson B. M., Friberg R. D., Bowers C. Y., Barkan A. L. Acute growth hormone (GH) response to GH-releasing hexapeptide in humans is independent of endogenous GH-releasing hormone. J Clin Endocrinol Metab. 1992 Oct;75(4):1121–1124. doi: 10.1210/jcem.75.4.1400881. [DOI] [PubMed] [Google Scholar]
  36. Rosskamp R., Schmid G., Klumpp J., Tegeler A. Insulinhypoglycemia but not arginine infusion stimulates circulating plasma growth hormone-releasing hormone (GHRH) concentrations in children. Horm Metab Res. 1987 Sep;19(9):434–436. doi: 10.1055/s-2007-1011845. [DOI] [PubMed] [Google Scholar]
  37. Sopwith A. M., Penny E. S., Besser G. M., Rees L. H. Stimulation by food of peripheral plasma immunoreactive growth hormone releasing factor. Clin Endocrinol (Oxf) 1985 Mar;22(3):337–340. doi: 10.1111/j.1365-2265.1985.tb03245.x. [DOI] [PubMed] [Google Scholar]
  38. Strobl J. S., Thomas M. J. Human growth hormone. Pharmacol Rev. 1994 Mar;46(1):1–34. [PubMed] [Google Scholar]
  39. Tapanainen P., Knip M., Lautala P., Leppäluoto J. Variable plasma growth hormone (GH)-releasing hormone and GH responses to clonidine, L-dopa, and insulin in normal men. J Clin Endocrinol Metab. 1988 Oct;67(4):845–849. doi: 10.1210/jcem-67-4-845. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. 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]
  42. 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]
  43. Vinik A. I., Levitt N. S., Pimstone B. L., Wagner L. Peripheral plasma somatostatin-like immunoreactive responses to insulin hypoglycemia and a mixed meal in healthy subjects and in noninsulin-dependent maturity-onset diabetics. J Clin Endocrinol Metab. 1981 Feb;52(2):330–337. doi: 10.1210/jcem-52-2-330. [DOI] [PubMed] [Google Scholar]
  44. 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]

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