Skip to main content
SpringerLink
Log in

Hexarelin-induced growth hormone response in short stature. Comparison with growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Hexarelin (HEX) is a synthetic hexapeptide with strong GH-stimulating activity. We evaluated GH response (expressed as maximum value after stimulus [Cmax] and as area under the curve [AUC]) to HEX at the doses of 1 μg/kg iv (HEX 1) and 2 μg/kg iv (HEX 2), in comparison with the responses to GHRH (1 μg/kg iv) + pyridostigmine (PD, 60 mg po) and to arginine (ARG, 0.5 mg/kg iv) + ethinylestradiol (EE, 1 mg/day po for 3 days before the stimulation), in 5 subjects with familial short stature (FSS), 11 with constitutional growth delay (CGD), 6 with GH neurosecretory dysfunction (NSD), and 5 with isolated growth hormone deficiency (GHD). Cmax and AUC after HEX 1 were 26.8±10.5 ng/ml and 1448±514 ng/min x ml in FSS, 23.6±14.4 ng/ml and 1146±750 ng/min x ml in CGD, 36.9±21.5 ng/ml and 2048±1288 ng/min x ml in NSD, 9.4±5.8 ng/ml and 498±200 ng/min x ml in GHD (Cmax and AUC in FSS and CGD, p<0.05 vs GHD). Cmax and AUC after HEX 2 were 37.7±16 ng/ml and 1979±888 ng/min x ml in FSS, 32.5±16.2 ng/ml and 1613±237 ng/min x ml in CGD, 39.7±20.7 ng/ml and 2366±1569 ng/min xml in NSD, 13.4±4.2 ng/ml and 645±293 ng/min x ml in GHD (Cmax in FSS, CGD and NSD p<0.01 vs GHD; AUC in NSD, p<05 vs GHD). Cmax and AUC after GHRH±PD were 46.6±8.8 ng/ml and 3294±1031 ng/min x ml in FSS, 25.9±11.2 ng/ml and 1464±735 ng/min x ml in CGD, 38.8±21.7 ng/ml and 2428±1399 ng/min x ml in NSD, 8.4±6.2 ng/ml and 685±572 ng/min x ml in GHD (Cmax and AUC in FSS, p<0.001 vs CGD and GHD; Cmax in CGD and NSD, p<0.001 vs GHD). Cmax and AUC after ARG+EE were 21.3±4.2 ng/ml and 1432±514 ng/min x ml in FSS, 14.8±10 ng/ml and 805±489 ng/min x ml in CGD, 22.2±12.8 ng/ml and 1199±309 ng/min x ml in NSD, 4.6±2.5 ng/ml and 247±191 ng/min x ml in GHD (Cmax and AUC in FSS, CGD and NSD, p<0.01 vs GHD). Specificity was 62% for HEX 1 and 75% for HEX 2, GHRH+PD and ARG+EE. From a diagnostic point of view, HEX 1 + HEX 2 was the association with the largest percentage of false positives (20% in FSS, 27% in CGD and 33% in NSD), HEX 1+GHRH+PD resulted in 9% in CGD, while the combined use of HEX 1 or HEX 2 with GHRH+PD or ARG+EE and of GHRH+PD with ARG+EE did not show false positive responses. In conclusion: I) the most effective dose of HEX was 2 μg/kg iv; 2) HEX did not show more specificity than GHRH+PD and ARG+EE; 3) the association of GHRH+PD with ARG+EE could yield the best results at lower costs, confirming these tests as first-line tools in evaluating GH secretion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bowers C.Y. On a peptidomimetic growth hormone-releasing peptide (Editorial). J. Clin. Endocrinol. Metab. 1994, 79: 940–942.

    CAS  PubMed  Google Scholar 

  2. Camanni F., Ghigo E., Arvat E. Growth hormone-releasing peptides and their analogs. Frontiers in Neuroendocrinology 1998, 19: 47–72.

    Article  CAS  PubMed  Google Scholar 

  3. Deghenghi R., Cananzi M., Battisti C., Locatelli V., Muller E.E. Hexarelin (EP23905) — a superactive growth hormonereleasing peptide. J. Endocrinol. Invest. 1993, 5 (Suppl. 4): 45.

    Google Scholar 

  4. Wehrenberg W.B., Giustina A., Imbimbo B., Stagg L., Conley L., Deghenghi R. Biological potency of hexarelin (EP23905), a new growth hormone-releasing peptide. J. Endocrinol. Invest. 1992, 15 (Suppl. 4): 45.

    Google Scholar 

  5. Deghenghi R., Cananzi M.M., Torsello A., Battisti C., Muller E.E., Locatelli V. GH-releasing activities of hexarelin, a new growth hormone-releasing peptide, in infant and adult rats. Life Sci. 1994, 54: 1321–1328.

    Article  CAS  PubMed  Google Scholar 

  6. Deghenghi R., Bontignon F., Luoni M., Grilli R., Guidi M., Locatelli V. Small peptides as potent releasers of growth hormone. J. Ped. Endocrinol. Metab. 1995, 8: 311–313.

    Article  CAS  Google Scholar 

  7. Korbonits M., Grossman A.B. Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol. Metab. 1996, 6: 43–49.

    Article  Google Scholar 

  8. Arvat E., Camanni F., Ghigo E. Age-related growth hormone-releasing activity of growth hormone secretagogues in humans. Acta Paediatr. 1997, (Suppl. 423): 92–96.

    Google Scholar 

  9. Codd E.E., Shu A.Y., Walker R. Binding of a growth hormone-releasing hexapeptide to specific hypothalamic and pituitary binding sites. Neuropharmacology 1989, 28: 1139–1144.

    Article  CAS  PubMed  Google Scholar 

  10. Bowers C.Y., Sartor A.O., Reynolds G.A., Badger T.M. On the actions of the growth hormone-releasing hexapeptide, GHRP. Endocrinology 1991, 128: 2027–2035.

    Article  CAS  PubMed  Google Scholar 

  11. Blake A.D., Smith R.G. Desensitization studies using perifused rat 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: 11–19.

    Article  CAS  PubMed  Google Scholar 

  12. Goth M.I., Lyons C.E., Canny B.J., Thorner M.O. Pituitary adenylate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors. Endocrinology 1992, 130: 939–944.

    CAS  PubMed  Google Scholar 

  13. Akman M.S., Girard M., O’Brien L.F., Ho A.R., Chik C.L. Mechanism of action of a second generation growth hormone-releasing peptide (Ala-His-ßNal-Ala-Trp-D-Phe-Lys-NH2) in rat anterior pituitary cells. Endocrinology 1993, 182: 1286–1291.

    Google Scholar 

  14. Dickson S.L., Leng G., Robinson II C.A.F. Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience 1993, 53: 303–306.

    Article  CAS  PubMed  Google Scholar 

  15. Pong S.S., Chaung L., Dean D.C., Nargunt R.P., Patchett A.A., Smith RG. Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol. Endocrinol. 1996, 10: 57–61.

    CAS  PubMed  Google Scholar 

  16. Ong H., McNicoll N., Escher E., Collu R., Deghenghi R., Locatelli V., Ghigo E., Muccioli G., Boghen M., Nilsson M. Identification of a pituitary growth hormone-releasing peptide (GHRP) receptor subtype by photoaffinity labeling. Endocrinology 1998, 139: 432–435.

    Article  CAS  PubMed  Google Scholar 

  17. Fairhall K.M., Mynett A., Robinson I.C.A.F. Central effects of growth hormone-releasing peptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action. J. Endocrinol. 1995, 144: 555–560.

    Article  CAS  PubMed  Google Scholar 

  18. Bowers C.Y., Reynolds G.A., Durham D., Barrera C.M., Pezzoli S.S., Thorner M.O. Growth-hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J. Clin. Endocrinol. Metab. 1990, 70: 975–982.

    Article  CAS  PubMed  Google Scholar 

  19. Penalva A., Carballo A., Pombo A., Casanueva F., Dieguez C. Effect of growth hormone (GH)-releasing hormone (GHRH), atropine, pyridostigmine or hypoglycemia on GHRP-6 induced GH secretion in man. J. Clin. Endocrinol. Metab. 1993, 76: 168–171.

    CAS  PubMed  Google Scholar 

  20. Robinson B.M., DeMott Friberg R., Bowers C., 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, 75: 1121–1124.

    CAS  PubMed  Google Scholar 

  21. Popovich V., Micic D., Damjanovic S., Obradovic S., Djurovic M., Petakov M., Grudic D., Golubicic I., Nikitovic M., Mitrovic N., Dieguez C., Casanueva F.F. Growth hormone secretagogues in pathological states: diagnostic implications. Acta Paediatr. 1997, (Suppl. 423): 97–101.

    Google Scholar 

  22. Conley L.S., Teik J.A., Deghenghi R., Imbimbo B.P., Giustina A., Locatelli V., Weherenberg W.B. Mechanism of action of hexarelin and GHRP-6: analysis of the involvement of GHRH and somatostatin in the rat. Neuroendocrinology 1995, 61: 44–50.

    Article  CAS  PubMed  Google Scholar 

  23. Arvat E., Di Vito L., Ramunni J., Gianotti L., Giordano R., Deghenghi R., Camanni F., Ghigo E. Low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the GHRH-Induced GH response in man. Clin. Endocrinol. (Oxf.) 1997, 47: 495–500.

    Article  CAS  Google Scholar 

  24. Bercu B.B., Walker R.F. Growth hormone secretagogues in children with altered growth. Acta Paediatr. 1997, (Suppl. 423): 102–106.

    Google Scholar 

  25. Loche S., Cambiaso P., Carta D., Setzu S., Imbimbo B.P., Borrelli P., Pintor C., Cappa M. The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects. J. Clin. Endocrinol. Metab. 1995, 80: 674–678.

    CAS  PubMed  Google Scholar 

  26. Ghigo E., Arvat A., Gianotti L., Imbimbo B.P., Lenaerts V., Deghenghi R., Camanni F. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal and oral administration in man. J. Clin. Endocrinol. Metab. 1994, 78: 693–698.

    CAS  PubMed  Google Scholar 

  27. Bellone J., Aimaretti G., Bartolotta E., Benso L., Imbimbo B.P., Lenaerts V., Deghenghi R., Camanni F., Ghigo E. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty. J. Clin. Endocrinol. Metab. 1995, 80: 1090–1094.

    CAS  PubMed  Google Scholar 

  28. Loche S., Cambiaso P., Merola B., Colao A., Faedda A., lmbimbo B.P., Deghenghi R., Lombardi R., Cappa M. The effect of hexarelin on growth hormone (GH) secretion in patients with GH deficiency. J. Clin. Endocrinol. Metab. 1995, 80: 2692–2696.

    CAS  PubMed  Google Scholar 

  29. Arvat E., Gianotti L., Di Vito L., Imbimbo B.P., Lenaerts V., Deghenghi R., Camanni F., Ghigo E. Neuroendocrinological and metabolic modulation of the growth hormone-releasing activity of hexarelin in man. Neuroendocrinology 1995, 61: 51–56.

    Article  CAS  PubMed  Google Scholar 

  30. Bellone J., Ghizzoni L., Aimaretti G., Volta C., Boghen M.F., Bernasconi S., Ghigo E. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur. J. Endocrinol. 1995, 133: 425–429.

    Article  CAS  PubMed  Google Scholar 

  31. Arvat E., Gianotti L., Grottoli S., Imbimbo B.P., Lenaerts V., Deghenghi R., Camanni F., Ghigo E. Arginine and growth hormone-releasing hormone restore the blunted growth-hormone-releasing activity of hexarelin in elderly subjects. J. Clin. Endocrinol. Metab. 1994, 79: 1440–1443.

    CAS  PubMed  Google Scholar 

  32. Loche S., Colao A., Cappa M., Bellone J., Aimaretti G., Farello G., Faedda A., Lombardi G., Deghenghi R., Ghigo E. The growth hormone response to hexarelin in children: reproducibility and effect of sex steroids. J. Clin. Endocrinol. Metab. 1997, 82: 861–864.

    CAS  PubMed  Google Scholar 

  33. Cacciari E., Tassoni P., Parisi G., Pirazzoli P., Zucchini S., Mandini M., Cicognani A., Balsamo A. Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH-deficient. J. Clin. Endocrinol. Metab. 1992, 74: 1284–1289.

    CAS  PubMed  Google Scholar 

  34. Hindmarsh P.C., Swift P.G.F. An assessment of growth hormone provocation test. Arch. Dis. Child. 1995, 72: 362–368.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Ghigo E., Mazza E., Imperiale E., Rizzi G., Benso L., Muller E.E., Camanni F., Massara F. Enhancement of cholinergic tone by pyridostigmine promotes both basal and growth hormone (GH)-releasing hormone-induced GH secretion in children with short stature. J. Clin. Endocrinol. Metab. 1987, 65: 452–456.

    Article  CAS  PubMed  Google Scholar 

  36. Ghigo E., Imperiale E., Boffano G.M. A new test for diagnosis of GH deficiency due to a primary pituitary impairment: combined administration of pyridostigmine and GHRH. J. Endocrinol. Invest. 1990, 13: 307–316.

    CAS  PubMed  Google Scholar 

  37. Cappa M., Loche S., Salvatori R., Faedda A., Borrelli P., Cella S.G., Pintor C., Muller E.E. The growth hormone response to pyridostigmine plus growth hormone releasing hormone is not influenced by pubertal maturation. J. Endocrinol. Invest. 1991, 14: 41–45.

    CAS  PubMed  Google Scholar 

  38. Merimee T.J., Rabinowitz D., Fineberg S.E. Arginine-initiated release of human growth hormone. N. Engl. J. Med. 1969, 280: 1434–1438.

    Article  CAS  PubMed  Google Scholar 

  39. Raiti S., Davis W.T., Blizzard R.M. A comparison of the effects of insulin hypoglycemia and arginine infusion on release of human growth hormone. Lancet 1967, 2: 1182–1183.

    Article  CAS  PubMed  Google Scholar 

  40. Lippe B., Wong S.R., Kaplan S.A. Simultaneous assessment of growth hormone and ACTH reserve in children pretreated with diethylstilbestrol. J. Clin. Endocrinol. Metab. 1971, 33: 949–965.

    Article  CAS  PubMed  Google Scholar 

  41. Moll G., Rosenfield R., Fang V. Administration of low-dose estrogen rapidly and directly stimulates growth hormone production. Am. J. Dis. Child. 1986, 140: 124–127.

    PubMed  Google Scholar 

  42. Kerrigan J.R., Rogol A.D. The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. Endocr. Rev. 1992, 113: 281–298.

    Google Scholar 

  43. Marin G., Domené M., Barnes K.M., Blackwell B.J., Cassorla F.G., Cutler jr G.B. The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. J. Clin. Endocrinol. Metab. 1994, 79: 537–541.

    CAS  PubMed  Google Scholar 

  44. Deller Jr J.J., Boulis M.W., Harriss W.E., Hutsell T.C., Garcia J.F., Linfoot J.A. Growth hormone response patterns to sex hormone administration in growth ritardation. Am. J. Med. Sci. 1970, 259: 292–269.

    Article  PubMed  Google Scholar 

  45. Martin L.G., Clark J.W., Connor T.B. Growth hormone secretion enhanced by androgens. Clin. Endocrinol. 1968, 28: 425.

    Article  CAS  Google Scholar 

  46. Dammacco F., Boghen M.F., Camanni F., Cappa M., Ferrari C., Ghigo E., Giordano G., Loche S., Minuto F., Mucci M., Muller E.E. Somatotropic function in short stature: evaluation by integrated auxological and hormonal indices in 214 children. J. Clin. Endocrinol. Metab. 1993, 77 (1): 68–72.

    CAS  PubMed  Google Scholar 

  47. Spiliotis B.E., August G.P., Hung W., Sonis W., Mendelson W., Bercu B.B. Growth hormone neurosecretory dysfunction: a treatable cause of short stature. JAMA 1984, 251: 2223–2230.

    Article  CAS  PubMed  Google Scholar 

  48. Imbimbo P., Mont T., Edwards M., Amin D., Dalton N., Lenaerts V., Wuthrich P., Deghenghi R. The growth hormone releasing activity of hexarelin in humans: a dose response study. Eur. J. Clin. Pharmacol. 1994, 46 (5): 421–425.

    Article  CAS  PubMed  Google Scholar 

  49. Rosenfeld R.G., Albertsson-Wikland K., Cassorla F., Frasier S.D., Hasegawa Y., Hintz R.L., Lanfranchi S., Lippe B., Loriaux L., Melmed S., Preece M., Ranke M., Reiter E.O., Rogol A.D., Underwood L.E., Werther G.A. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J. Clin. Endocrinol. Metab. 1995, 80: 1532–1540.

    CAS  PubMed  Google Scholar 

  50. Ghigo E., Bellone J., Aimaretti G., Loche S., Cappa M., Bartolotta E., Dammacco F., Camanni F. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J. Clin. Endocrinol. Metab. 1996, 81: 3323–3327.

    CAS  PubMed  Google Scholar 

  51. Pombo M., Barreira J., Penalva A., Mallo F., Casanueva F.F., Dieguez C. Plasma growth hormone response to growth hormone-releasing hexapeptide (GH-RP-6) in children with short stature. Acta Paediatr. 1995, 84: 904–908.

    Article  CAS  PubMed  Google Scholar 

  52. Pihoker C., Middleton R., Reynolds G.A., Bowers C.Y., Badger T.M. Diagnostic studies with intravenous and intranasal growth hormone-releasing peptide-2 in children of short stature. J. Clin. Endocrinol. Metab. 1995, 80: 2987–2992.

    CAS  PubMed  Google Scholar 

  53. Laron Z. Growth hormone secretagogues. Drugs 1995, 50: 595–601.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisione di Auxologia, Ospedale San Giuseppe IRCCS, Istituto Auxologico Italiano, Casella Postale 1, 28044, Verbania Intra, Italy

    G. Guzzaloni, G. Grugni & F. Morabito

Authors
  1. G. Guzzaloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Grugni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Morabito
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guzzaloni, G., Grugni, G. & Morabito, F. Hexarelin-induced growth hormone response in short stature. Comparison with growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen. J Endocrinol Invest 22, 360–368 (1999). https://doi.org/10.1007/BF03343574

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03343574

Key-words

Search

Navigation