Effects of Growth Hormone Releasing Peptides on Stimulated Growth Hormone Secretion in Old Rats

  • Richard F. Walker
  • Sei-Won Yang
  • Ryuji Masuda
  • Cheng-Shih Hu
  • Barry B. Bercu
Part of the Serono Symposia USA Norwell, Massachusetts book series (SERONOSYMP)


Degenerative changes in body composition characterized by reduced muscle and bone mass decrease physical performance in the elderly. These decremental somatic changes correlate with reduced serum growth hormone (GH) concentrations. Limited availability of cadaver-derived hormone before the advent of recombinant gene technology precluded testing the functional relationship between GH deficiency and senescence. However, when bioengineered GH became available for experimentation, its administration to old men significantly increased serum IGF-I concentrations, urinary nitrogen retention, body weight gain, lean body mass, bone density, renal function, and improved quality of life (1–3). Thus, aberrant patterns of spontaneous GH secretion and low serum GH concentrations during aging (4–7) did not necessarily represent loss of GH efficacy. Furthermore, the experimental observations suggested a causal relationship between anatomical senescence and GH insufficiency (3, 4, 8, 9).


Growth Hormone Growth Hormone Release Hormone Growth Hormone Concentration Growth Hormone Secretagogue Exogenous Growth Hormone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kaiser FE, Silver AJ, Morley JE. The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 1991;39:235–40.PubMedGoogle Scholar
  2. 2.
    Marcus R, Butterfield G, Holloway L, et al. Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 1990;70:519–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Rudman D, Feller AG, Hoskote SN, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population. J Clin Invest 1981;67:1361–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972;35:665–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Ho KY, Evans WS, Blizzard RM, et al. 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;64:51–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Sonntag WE, Meites J. Decline in growth hormone secretion in aging animals and man. In: Everett AV, Walton JR, eds. Regulation of neuroendocrine aging. Basel: Karger AG, 1988:111–24.Google Scholar
  8. 8.
    Root AW, Oski FA. Effects of human growth hormone in elderly males. J Gerontol 1969;24:97–104.PubMedGoogle Scholar
  9. 9.
    Walker RF, Yang S-W, Bereu BB. Robust growth hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH). Life Sci 1991;49:1499–504.PubMedCrossRefGoogle Scholar
  10. 10.
    Kay MMB. Effect of age on T-cell differentiation. Federation Proc 1978; 37:1241–4.Google Scholar
  11. 11.
    Denckla WD. Systems analysis of possible mechanisms of mammalian aging. Mech Ageing Dev 1977;6:143–53.PubMedCrossRefGoogle Scholar
  12. 12.
    Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972;35:665–70.PubMedCrossRefGoogle Scholar
  13. 13.
    Weksler ME. The immune system and the aging process in man. Proc Soc Exp Biol Med 1980;165:200–35.PubMedGoogle Scholar
  14. 14.
    Shrewsbury MM, Reinhardt WO. Effect of pituitary growth hormone on lymphatic tissues, thoracic duct lymph flow, lymph protein and lymphocyte output in the rat. Endocrinology 1959;65:858–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Takemoto H, Yokoro K, Fürth J, Cohen AI. Adrenotropic activity of mammo-somatotropic tumors in rats and mice. Cancer Res 1962;22:917–24.PubMedGoogle Scholar
  16. 16.
    Pierpaoli W, Baroni C, Fabris N, Sorkin E. Immunology 1969;16:217–30.PubMedGoogle Scholar
  17. 17.
    Kelley KW, Brief S, Westly JH, et al. GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci 1986;83:5663–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Davila DR, Brief S, Simon J, Hammer RE, Brinster RL, Kelly KW. Role of growth hormone in regulating T-dependent immune events in aged, nude, and transgenic rodents. J Neurosci Res 1987;18:108–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Davila DR, Edwards CK, Arkins S, Simon J, Kelly K. Interferon-gamma-induced priming for secretion of superoxide anion and tumor necrosis factor/ alpha declines in macrophages from aged rats. FASEB J 1990;4:2906–11.PubMedGoogle Scholar
  20. 20.
    Kay M. Immunological aspects of aging: early changes in thymic activity. Mech Ageing Dev 1984;28:193–218.PubMedCrossRefGoogle Scholar
  21. 21.
    Fabris N, Pierpaoli W, Sorkin E. Lymphocytes, hormones and ageing. Nature 1972;240:557–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Price GB, Makinodan T. Immunologic deficiencies in senescence, II. Characterization of extrinsic deficiencies. J Immunol 1972;198:413–7.Google Scholar
  23. 23.
    Johanson AJ, Blizzard RM. Low somatomedin-C levels in older men rise in response to growth hormone administration. Johns Hopkins Med J 1981; 149:115–9.PubMedGoogle Scholar
  24. 24.
    Pavlov EP, Harman SM, Merriam GR, Gelato MC, Blackman MR. Responses of growth hormone (GH) and somatomedin-C to GH releasing hormone in healthy aging men. J Clin Endocrinol Metab 1986;62:595–600.PubMedCrossRefGoogle Scholar
  25. 25.
    Wehrenberg WB, Ling N. The absence of an age-related change in the pituitary response to growth hormone-releasing factor in rats. Neuroen-docrinology 1983;37:463–6.Google Scholar
  26. 26.
    Ceda GP, Valenti G, Butturini U, Hoffman AR. Diminished pituitary responsiveness to growth hormone-releasing factor in aging male rats. Endocrinology 1986;118:2109–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Ghigo E, Goffi S, Arvat E, et al. Pyridostigmine partially restores the GH responsiveness to GHRH in normal aging. Acta Endocrinol (Copenh) 1990;123:169–74.Google Scholar
  28. 28.
    Iovino M, Monteleone P, Steardo L. Repetitive growth hormone-releasing hormone administration restores the attenuated growth hormone (GH) response to GH-releasing hormone testing in normal aging. J Clin Endocrinol Metab 1989;69:910–3.PubMedCrossRefGoogle Scholar
  29. 29.
    Lang I, Kruz R, Geyer G, Tragi KH. The influence of age on human pancreatic growth hormone releasing hormone stimulated growth hormone secretion. Horm Metab Res 1988;20:574–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Lang I, Schernthaner G, Pietschmann P, Kurz R, Stephenson JM, Tempi H. Effects of sex and age on growth hormone response to growth hormone-releasing hormone in healthy individuals. J Clin Endocrinol Metab 1987; 65:535–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Shibasaki T, Shizume K, Nakahara M, et al. Age-related changes in plasma growth hormone response to growth hormone-releasing factor in man. J Clin Endocrinol Metab 1984;58:212–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Sonntag WE, Gough MA. Growth hormone releasing hormone induced release of growth hormone in aging male rats: dependence on pharmacological manipulation of endogenous somatostatin release. Neuroendocrinology 1988; 47:482–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Sonntag WE, Steger RW, Forman LJ, Meites J. Decreased pulsatile release of growth hormone in old male rats. Endocrinology 1980;107:1875–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Gershberg H. Growth hormone content and metabolic actions of human pituitary glands. Endocrinology 1957;61:160–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Bereu BB, Yang S-W, Masuda R, Hu C-S, Walker RF. Structural and functional responses of aged female rats to chronic co-administration of growth hormone releasing hormone (GHRH) and GH releasing hexapeptide (GHRP-6) [Abstract]. Endocr Soc annu meet, San Antonio, 1992.Google Scholar
  36. 36.
    De Gennaro Colonna V, Zoli M, Cocchi D, et al. Reduced growth hormone releasing factor (GHRF)-like immunoreactivity and GHRF gene expression in the hypothalamus of aged rats. Peptides 1989;10:705–8.CrossRefGoogle Scholar
  37. 37.
    Sonntag WE, Hylka VW, Meites J. Impaired ability of old male rats to secrete growth hormone in vivo but not in vitro in response to hpGRF(1–44). Endocrinology 1983;113:2305–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Morimoto N, Kawakami F, Makino S, Chihara K, Hasegawa M, Ibata Y. Age-related changes in growth hormone releasing factor and somatostatin in the rat hypothalamus. Neuroendocrinology 1988;47:459–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Ono M, Miki N, Shizume D. Release of immunoreactive growth hormone-releasing factor (GRF) and somatostatin from incubated hypothalamus in young and old male rats. Neuroendocrinology 1986;43:111.Google Scholar
  40. 40.
    Goth MI, Lyons CE, Canny BJ, Thorner MO. Pituitary adenylate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors. Endocrinology 1992;130:939–44.PubMedCrossRefGoogle Scholar
  41. 41.
    Abribat T, Boulanger L, Gaudreau P. Characterization of [125I-Tyr10] human growth hormone-releasing factor (1–44) amide binding to rat pituitary: evidence for high and low affinity classes of sites. Brain Res 1990;528:291–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Abribat T, Desiauriers N, Brazeau P, Gaudreau P. Alterations of pituitary growth hormone-releasing factor binding sites in aging rats. Endocrinology 1991;128:633–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Codd EE, Shu AYL, Walker RF. Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites. Neuropharmacology 1989;28:1139–44.PubMedCrossRefGoogle Scholar
  44. 44.
    Jansson J-O, Downs TR, Beamer WG, Frohman LA. The dwarf “little” (LIT/LIT) mouse is resistant to growth hormone releasing peptide (GHRP-6) as well as to GH-releasing hormone (GRH) [Abstract]. Endocr Soc, 1986.Google Scholar
  45. 45.
    Cheng K, Chan WW-S, Barreta A, Convey DM, Smith RG. 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;124:2791–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Bowers CY, Reynolds GA, Durham D, Barrera CM, Pezzoli SS, Thorner MO. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab 1990;70:975–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Bereu BB, Yang S-W, Masuda R, Walker RF. Role of selected endogenous peptides in growth hormone-releasing hexapeptide activity: analysis of growth hormone releasing hormone, thyroid hormone-releasing and gonadotropin-releasing hormone. Endocrinology 1992:2579–96.Google Scholar
  48. 48.
    Parenti M, Dall’ara A, Rusconi L, Coochi D, Muller EE. Different regulation of growth hormone-releasing factor-sensitive adenylate cyclase in the anterior pituitary of young and aged rats. Endocrinology 1987;121:1649–53.PubMedCrossRefGoogle Scholar
  49. 49.
    Sonntag WE, Forman LJ, Miki N, et al. Effects of CNS active drugs and somatostatin antiserum on growth hormone release in young and old male rats. Neuroendocrinology 1981;33:73–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Takahashi S, Gottshall PE, Quigley KL, Goya RG, Meites J. Growth hormone secretory patterns in young, middle-aged and old female rats. Neuroendocrinology 1987;46:137–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Ge F, Tsagarakis S, Rees LH, Besser GM, Grossman A. Relationship between growth hormone-releasing hormone and somatostatin in the rat: effects of age and sex on content and in-vitro release from hypothalamic explants. J Endocrinol 1989;123:53–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Jaffe CA, Ho PJ, DeMott Friberg R, Bowers CY, Barkan AL. Effect of prolonged growth hormone releasing peptide infusion on GH secretion in normal men. Endocr Soc annu meet, San Antonio, 1992.Google Scholar
  53. 53.
    Bereu BB, Weideman CA, Walker RF. Sex differences in growth hormone secretion by rats administered growth hormone releasing hexapeptide. Endocrinology 1991;129:2592–8.CrossRefGoogle Scholar
  54. 54.
    Blake AD, Smith RG. Desensitization studies using perifused pituitary cells show that growth hormone-releasing hormone and His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 stimulate growth hormone release through distinct receptor sites. J Endocrinol 1991;129:11–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Chihara K, Arimura A, Schally V. Immunoreaetive somatostatin in rat hypophyseal portal blood: effects of anesthetics. Endocrinology 1979;104:1434–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Shulman DI, Sweetland M, Duckett G, Root AW. Age-related differences in the growth hormone secretory response to hGHRH 1–44 in male rats from infancy through puberty. In vivo and in vitro studies. Acta Endocrinol (Copenh) 1987;116:138–44.Google Scholar
  57. 57.
    Bowers CY, Sartor AO, Reynolds GA, Badger TM. On the actions of growth hormone-releasing hexapeptide, GHRP. Endocrinology 1991;128:2027–35.PubMedCrossRefGoogle Scholar
  58. 58.
    Downs TR, Frohman LA. Evidence for a defect in growth hormone-releasing factor signal transduction in the dwarf (dw/dw) rat pituitary. Endocrinology 1991;129:58–67.PubMedCrossRefGoogle Scholar
  59. 59.
    Yalow RS, Berson SA. Immunoassay of plasma insulin. Methods Biochem Anal 1964;12:69–76.CrossRefGoogle Scholar
  60. 60.
    Cheng K, Chan WW-S, Butler B, Barreto A Jr, Smith RG. Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells. Endocrinology 1991;129:3337–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Thorner MO, Vance ML, Rogol AD, et al. Growth hormone releasing hormone and growth hormone releasing peptide as potential therapeutic modalities. Acta Paediatr Scand Suppl 1990;327:29–30.CrossRefGoogle Scholar
  62. 62.
    Berelowitz M, Szabo M, Frohman LH, Fireston S, Chu L. Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and pituitary. Science 1981;212:1279–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Frawley LS, Boockfor FR. Mammosomatotropes: presence and functions in normal and neoplastic pituitary tissue. Endocr Rev 1992;12:337–55.CrossRefGoogle Scholar
  64. 64.
    Meites J. Remembrance: neuroendocrinology and aging. A perspective. Endocrinology 1992;130:3107–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Walker RF. Impact of age-related changes in serotonin and norepinephrine metabolism on reproductive function in female rats. An analytical review. Neurobiol Aging 1984;5:121–39.PubMedCrossRefGoogle Scholar
  66. 66.
    Bevan JS, Webster J, Burke CW, Scanion MF. Dopamine agonists and pituitary tumor shrinkage. Endocr Rev 1992;13:220–40.PubMedGoogle Scholar
  67. 67.
    Li YM, Brunke DL, Dantzer R, Kelley KW. Pituitary epithelial cell implants reverse the accumulation of CD4-CD8- lymphocytes in thymus glands of aged rats. Endocrinology 1992;130:2703–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Goya RG, Castelletto L, Sosa YE. Plasma levels of growth hormone correlate with the severity of pathologic changes in the renal structure of aging rats. Lab Invest 1991;64:29–34.PubMedGoogle Scholar
  69. 69.
    Coleman GL, Barthold SW, Osbaldiston GW, Foster SJ, Jonas AM. Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol 1977;32:258–78.PubMedGoogle Scholar
  70. 70.
    Casad RC Jr, Adelman C. Aging enhances inhibitory action of somatostatin in rat pancreas. Endocrinology 1992;130:2420–2.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1994

Authors and Affiliations

  • Richard F. Walker
  • Sei-Won Yang
  • Ryuji Masuda
  • Cheng-Shih Hu
  • Barry B. Bercu

There are no affiliations available

Personalised recommendations