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Peripheral activities of growth hormone-releasing hormone

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Abstract

Growth hormone (GH)-releasing hormone (GHRH) is produced by the hypothalamus and stimulates GH synthesis and release in the anterior pituitary gland. In addition to its endocrine role, GHRH exerts a wide range of extrapituitary effects which include stimulation of cell proliferation, survival and differentiation, and inhibition of apoptosis. Accordingly, expression of GHRH, as well as the receptor GHRH-R and its splice variants, has been demonstrated in different peripheral tissues and cell types. Among the direct peripheral activities, GHRH regulates pancreatic islet and β-cell survival and function and endometrial cell proliferation, promotes cardioprotection and wound healing, influences the immune and reproductive systems, reduces inflammation, indirectly increases lifespan and adiposity and acts on skeletal muscle cells to inhibit cell death and atrophy. Therefore, it is becoming increasingly clear that GHRH exerts important extrapituitary functions, suggesting potential therapeutic use of the peptide and its analogs in a wide range of medical settings.

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References

  1. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB (1982) Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218(4572):585–587

    Article  CAS  PubMed  Google Scholar 

  2. Solloso A, Barreiro L, Seoane R, Nogueira E, Canibano C, Alvarez CV, Zalvide J, Dieguez C, Pombo CM (2008) GHRH proliferative action on somatotrophs is cell-type specific and dependent on Pit-1/GHF-1 expression. J Cell Physiol 215(1):140–150

    Article  CAS  PubMed  Google Scholar 

  3. Schally AV, Steelman SL, Bowers CY (1965) Effect of hypothalamic extracts on release of growth hormone in vitro. Proc Soc Exp Biol Med 119:208–212

    Article  CAS  PubMed  Google Scholar 

  4. Krulich L, Dhariwal AP, McCann SM (1968) Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 83(4):783–790

    Article  CAS  PubMed  Google Scholar 

  5. Frohman LA, Szabo M (1981) Ectopic production of growth hormone-releasing factor by carcinoid and pancreatic islet tumors associated with acromegaly. Prog Clin Biol Res 74:259–271

    CAS  PubMed  Google Scholar 

  6. Frohman LA, Kineman RD (2002) Growth hormone-releasing hormone and pituitary development, hyperplasia and tumorigenesis. Trends Endocrinol Metab 13(7):299–303

    Article  CAS  PubMed  Google Scholar 

  7. Kiaris H, Schally AV, Kalofoutis A (2005) Extrapituitary effects of the growth hormone-releasing hormone. Vitam Horm 70:1–24

    Article  CAS  PubMed  Google Scholar 

  8. Montero M, Yon L, Kikuyama S, Dufour S, Vaudry H (2000) Molecular evolution of the growth hormone-releasing hormone/pituitary adenylate cyclase-activating polypeptide gene family. Functional implication in the regulation of growth hormone secretion. J Mol Endocrinol 25(2):157–168

    Article  CAS  PubMed  Google Scholar 

  9. Barabutis N, Schally AV (2010) Growth hormone-releasing hormone: extrapituitary effects in physiology and pathology. Cell Cycle 9(20):4110–4116

    Article  CAS  PubMed  Google Scholar 

  10. Kiaris H, Chatzistamou I, Schally AV, Halmos G, Varga JL, Koutselini H, Kalofoutis A (2003) Ligand-dependent and -independent effects of splice variant 1 of growth hormone-releasing hormone receptor. Proc Natl Acad Sci USA 100(16):9512–9517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lin-Su K, Wajnrajch MP (2002) Growth hormone releasing hormone (GHRH) and the GHRH receptor. Rev Endocr Metab Disord 3(4):313–323

    Article  CAS  PubMed  Google Scholar 

  12. Baker LD, Barsness SM, Borson S, Merriam GR, Friedman SD, Craft S, Vitiello MV (2012) Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol 69(11):1420–1429

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jaszberenyi M, Rick FG, Szalontay L, Block NL, Zarandi M, Cai RZ, Schally AV (2012) Beneficial effects of novel antagonists of GHRH in different models of Alzheimer’s disease. Aging (Albany NY) 4(11):755–767

    Article  CAS  Google Scholar 

  14. Schally AV (2015) Endocrine approaches to treatment of Alzheimer’s disease and other neurological conditions: part I: some recollections of my association with Dr. Abba Kastin: a tale of successful collaboration. Peptides 72:154–163

    Article  CAS  PubMed  Google Scholar 

  15. Cai R, Schally AV, Cui T, Szalontay L, Halmos G, Sha W, Kovacs M, Jaszberenyi M, He J, Rick FG, Popovics P, Kanashiro-Takeuchi R, Hare JM, Block NL, Zarandi M (2014) Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities. Peptides 52:104–112

    Article  CAS  PubMed  Google Scholar 

  16. Granata R, Trovato L, Gallo MP, Destefanis S, Settanni F, Scarlatti F, Brero A, Ramella R, Volante M, Isgaard J, Levi R, Papotti M, Alloatti G, Ghigo E (2009) Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart. Cardiovasc Res 83(2):303–312

    Article  CAS  PubMed  Google Scholar 

  17. Kanashiro-Takeuchi RM, Szalontay L, Schally AV, Takeuchi LM, Popovics P, Jaszberenyi M, Vidaurre I, Zarandi M, Cai RZ, Block NL, Hare JM, Rick FG (2015) New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor. Oncotarget 6(12):9728–9739

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gallo D, Gesmundo I, Trovato L, Pera G, Gargantini E, Minetto MA, Ghigo E, Granata R (2015) GH-releasing hormone promotes survival and prevents TNF-alpha-induced apoptosis and atrophy in C2C12 myotubes. Endocrinology 156(9):3239–3252

    Article  CAS  PubMed  Google Scholar 

  19. Annunziata M, Grande C, Scarlatti F, Deltetto F, Delpiano E, Camanni M, Ghigo E, Granata R (2010) The growth hormone-releasing hormone (GHRH) antagonist JV-1–36 inhibits proliferation and survival of human ectopic endometriotic stromal cells (ESCs) and the T HESC cell line. Fertil Steril 94(3):841–849

    Article  CAS  PubMed  Google Scholar 

  20. Fu L, Osuga Y, Yano T, Takemura Y, Morimoto C, Hirota Y, Schally AV, Taketani Y (2008) Expression and possible implication of growth hormone-releasing hormone receptor splice variant 1 in endometriosis. Fertil Steril 92(1):47–53

  21. Schally AV, Varga JL, Engel JB (2008) Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer. Nat Clin Pract Endocrinol Metab 4(1):33–43

    Article  CAS  PubMed  Google Scholar 

  22. Kanashiro-Takeuchi RM, Tziomalos K, Takeuchi LM, Treuer AV, Lamirault G, Dulce R, Hurtado M, Song Y, Block NL, Rick F, Klukovits A, Hu Q, Varga JL, Schally AV, Hare JM (2010) Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction. Proc Natl Acad Sci USA 107(6):2604–2609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vetere A, Choudhary A, Burns SM, Wagner BK (2014) Targeting the pancreatic beta-cell to treat diabetes. Nat Rev Drug Discov 13(4):278–289

    Article  CAS  PubMed  Google Scholar 

  24. Potter KJ, Westwell-Roper CY, Klimek-Abercrombie AM, Warnock GL, Verchere CB (2014) Death and dysfunction of transplanted beta-cells: lessons learned from type 2 diabetes? Diabetes 63(1):12–19

    Article  CAS  PubMed  Google Scholar 

  25. Pagliuca FW, Melton DA (2013) How to make a functional beta-cell. Development 140(12):2472–2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Green IC, Southern C, Ray K (1990) Mechanism of action of growth-hormone-releasing hormone in stimulating insulin secretion in vitro from isolated rat islets and dispersed islet cells. Horm Res 33(5):199–204

    Article  CAS  PubMed  Google Scholar 

  27. Ludwig B, Ziegler CG, Schally AV, Richter C, Steffen A, Jabs N, Funk RH, Brendel MD, Block NL, Ehrhart-Bornstein M, Bornstein SR (2010) Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets. Proc Natl Acad Sci USA 107(28):12623–12628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ludwig B, Rotem A, Schmid J, Weir GC, Colton CK, Brendel MD, Neufeld T, Block NL, Yavriyants K, Steffen A, Ludwig S, Chavakis T, Reichel A, Azarov D, Zimermann B, Maimon S, Balyura M, Rozenshtein T, Shabtay N, Vardi P, Bloch K, de Vos P, Schally AV, Bornstein SR, Barkai U (2012) Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci USA 109(13):5022–5027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schubert U, Schmid J, Lehmann S, Zhang XY, Morawietz H, Block NL, Kanczkowski W, Schally AV, Bornstein SR, Ludwig B (2013) Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone. Proc Natl Acad Sci USA 110(6):2288–2293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang X, Cui T, He J, Wang H, Cai R, Popovics P, Vidaurre I, Sha W, Schmid J, Ludwig B, Block NL, Bornstein SR, Schally AV (2015) Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice. Proc Natl Acad Sci USA 112(44):13651–13656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cunha SR, Mayo KE (2002) Ghrelin and growth hormone (GH) secretagogues potentiate GH-releasing hormone (GHRH)-induced cyclic adenosine 3′,5′-monophosphate production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology 143(12):4570–4582

    Article  CAS  PubMed  Google Scholar 

  32. Giudice LC, Kao LC (2004) Endometriosis. Lancet 364(9447):1789–1799

    Article  PubMed  Google Scholar 

  33. Caruso S, Iraci M, Cianci S, Casella E, Fava V, Cianci A (2015) Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest. J Endocrinol Invest 38(11):1211–1218

    Article  CAS  PubMed  Google Scholar 

  34. Chatzistamou I, Schally AV, Pafiti A, Kiaris H, Koutselini H (2002) Expression of growth hormone-releasing hormone in human primary endometrial carcinomas. Eur J Endocrinol 147(3):381–386

    Article  CAS  PubMed  Google Scholar 

  35. Khorram O, Garthwaite M, Grosen E, Golos T (2001) Human uterine and ovarian expression of growth hormone-releasing hormone messenger RNA in benign and malignant gynecologic conditions. Fertil Steril 75(1):174–179

    Article  CAS  PubMed  Google Scholar 

  36. Wang Q, Wang Y, Fu X, Huang Y (2013) Comparison of expression of growth hormone-releasing hormone and its receptor splice variant 1 in different stages of endometriosis. Int J Fertil Steril 7(1):33–38

    PubMed  PubMed Central  Google Scholar 

  37. Kahan Z, Arencibia JM, Csernus VJ, Groot K, Kineman RD, Robinson WR, Schally AV (1999) Expression of growth hormone-releasing hormone (GHRH) messenger ribonucleic acid and the presence of biologically active GHRH in human breast, endometrial, and ovarian cancers. J Clin Endocrinol Metab 84(2):582–589

    CAS  PubMed  Google Scholar 

  38. Gallego R, Pintos E, Garcia-Caballero T, Raghay K, Boulanger L, Beiras A, Gaudreau P, Morel G (2005) Cellular distribution of growth hormone-releasing hormone receptor in human reproductive system and breast and prostate cancers. Histol Histopathol 20(3):697–706

    CAS  PubMed  Google Scholar 

  39. Hasegawa J, Saitoh M, Hirai S, Kinugawa T, Kotake H, Mashiba H (1988) Positive inotropic effect of growth hormone releasing factor in the guinea-pig cardiac muscles in vitro. Horm Metab Res 20(2):130–131

    Article  CAS  PubMed  Google Scholar 

  40. Fekete EM, Zorrilla EP (2007) Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 28(1):1–27

    Article  CAS  PubMed  Google Scholar 

  41. Granata R, Isgaard J, Alloatti G, Ghigo E (2011) Cardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone. Exp Biol Med (Maywood) 236(5):505–514

    Article  CAS  Google Scholar 

  42. Penna C, Granata R, Tocchetti CG, Gallo MP, Alloatti G, Pagliaro P (2015) Endogenous cardioprotective agents: role in pre and postconditioning. Curr Drug Targets 16(8):843–867

    Article  CAS  PubMed  Google Scholar 

  43. Penna C, Settanni F, Tullio F, Trovato L, Pagliaro P, Alloatti G, Ghigo E, Granata R (2013) GH-releasing hormone induces cardioprotection in isolated male rat heart via activation of RISK and SAFE pathways. Endocrinology 154(4):1624–1635

    Article  CAS  PubMed  Google Scholar 

  44. Kanashiro-Takeuchi RM, Takeuchi LM, Rick FG, Dulce R, Treuer AV, Florea V, Rodrigues CO, Paulino EC, Hatzistergos KE, Selem SM, Gonzalez DR, Block NL, Schally AV, Hare JM (2012) Activation of growth hormone releasing hormone (GHRH) receptor stimulates cardiac reverse remodeling after myocardial infarction (MI). Proc Natl Acad Sci USA 109(2):559–563

    Article  CAS  PubMed  Google Scholar 

  45. Bagno LL, Kanashiro-Takeuchi RM, Suncion VY, Golpanian S, Karantalis V, Wolf A, Wang B, Premer C, Balkan W, Rodriguez J, Valdes D, Rosado M, Block NL, Goldstein P, Morales A, Cai RZ, Sha W, Schally AV, Hare JM (2015) Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy. J Am Heart Assoc 4(4). doi:10.1161/JAHA.114.001464

  46. Florea V, Majid SS, Kanashiro-Takeuchi RM, Cai RZ, Block NL, Schally AV, Hare JM, Rodrigues CO (2014) Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival. Proc Natl Acad Sci USA 111(48):17260–17265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dioufa N, Schally AV, Chatzistamou I, Moustou E, Block NL, Owens GK, Papavassiliou AG, Kiaris H (2010) Acceleration of wound healing by growth hormone-releasing hormone and its agonists. Proc Natl Acad Sci USA 107(43):18611–18615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lucas R, Sridhar S, Rick FG, Gorshkov B, Umapathy NS, Yang G, Oseghale A, Verin AD, Chakraborty T, Matthay MA, Zemskov EA, White R, Block NL, Schally AV (2012) Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema. Proc Natl Acad Sci USA 109(6):2084–2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stepien T, Lawnicka H, Komorowski J, Stepien H, Siejka A (2010) Growth hormone-releasing hormone stimulates the secretion of interleukin 17 from human peripheral blood mononuclear cells in vitro. Neuro Endocrinol Lett 31(6):852–856

    CAS  PubMed  Google Scholar 

  50. Khorram O, Yeung M, Vu L, Yen SS (1997) Effects of [norleucine27]growth hormone-releasing hormone (GHRH) (1-29)-NH2 administration on the immune system of aging men and women. J Clin Endocrinol Metab 82(11):3590–3596

    CAS  PubMed  Google Scholar 

  51. Talhouk RS, Saade NE, Mouneimne G, Masaad CA, Safieh-Garabedian B (2004) Growth hormone releasing hormone reverses endotoxin-induced localized inflammatory hyperalgesia without reducing the upregulated cytokines, nerve growth factor and gelatinase activity. Prog Neuropsychopharmacol Biol Psychiatry 28(4):625–631

    Article  CAS  PubMed  Google Scholar 

  52. Qin YJ, Chan SO, Chong KK, Li BF, Ng TK, Yip YW, Chen H, Zhang M, Block NL, Cheung HS, Schally AV, Pang CP (2014) Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation. Proc Natl Acad Sci USA 111(51):18303–18308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Moretti C, Mencacci C, Frajese GV, Cerilli M, Frajese G (2002) Growth hormone-releasing hormone and pituitary adenylate cyclase-activating polypeptide in the reproductive system. Trends Endocrinol Metab 13(10):428–435

    Article  CAS  PubMed  Google Scholar 

  54. Iovino M, Triggiani V, Giagulli VA, Iovine N, Licchelli B, Resta F, Sabba C, Tafaro E, Solimando A, Tommasicchio A, Guastamacchia E (2011) Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects? Immunopharmacol Immunotoxicol 33(2):334–337

    Article  CAS  PubMed  Google Scholar 

  55. Frutos MG, Cacicedo L, Fernandez C, Vicent D, Velasco B, Zapatero H, Sanchez-Franco F (2007) Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis. Am J Physiol Endocrinol Metab 293(5):E1140–E1152

    Article  PubMed  Google Scholar 

  56. Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A (2013) Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife 2:e01098

    PubMed  PubMed Central  Google Scholar 

  57. Stanley TL, Grinspoon SK (2015) Effects of growth hormone-releasing hormone on visceral fat, metabolic, and cardiovascular indices in human studies. Growth Horm IGF Res 25(2):59–65

    Article  CAS  PubMed  Google Scholar 

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  1. Lab of Molecular and Cellular Endocrinology, Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Torino, Corso Dogliotti, 14, 10126, Turin, Italy

    R. Granata

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Granata, R. Peripheral activities of growth hormone-releasing hormone. J Endocrinol Invest 39, 721–727 (2016). https://doi.org/10.1007/s40618-016-0440-x

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