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Growth Hormone Physiology

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Book cover Growth Hormone Deficiency

Abstract

Human pituitary-derived growth hormone (GH), also known as somatotropin, is encoded by the GH1 gene, one of the five closely related genes in the 46.8 kb GH1 locus located on chromosome 17q24.2. The five exon-containing GH1 gene generates three transcript variants. The transcript variant 1 (NM_000515.4) encodes the largest of the putative GH isoforms, a protein containing 217 amino acid residues (isoform 1). The removal of the signal peptide (residues 1–26) generates a mature GH polypeptide of 191 residues, corresponding to a molecular mass of 22 kiloDalton (kDa). Although this 22 kDa is the predominant human GH found in the circulation (approximately 90 %), smaller GH isoforms have been described [1]. These include a 20 kDa variant from an alternative in-frame splicing event (NM_022559.3) that lacks 14 amino acid residues in the central coding region (residues 32–46) and a 17 kDa isoform lacking residues 1–66. In this section, we will summarize the known chemistry of the predominant 22 kDa GH isoform (amino acid residue numbering will be based on published nomenclature, which excludes the 26-amino-acid signal peptide). We describe how accumulated biochemical knowledge led to the development of human GH antagonists for GH excess in clinical conditions such as acromegaly as well as to the development of formulations of long-acting recombinant human GH (rhGH) for treatment of GH deficiency.

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References

  1. Lewis UJ, Sinha YN, Lewis GP. Structure and properties of members of the hGH family: a review. Endocr J. 2000;47(Suppl):S1–8.

    Article  CAS  PubMed  Google Scholar 

  2. Mott HR, Campbell ID. Four-helix bundle growth factors and their receptors: protein-protein interactions. Curr Opin Struct Biol. 1995;5:114–21.

    Article  CAS  PubMed  Google Scholar 

  3. de Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992;255:306–12.

    Article  PubMed  Google Scholar 

  4. Chantalat L, Jones ND, Korber F, Navaza J, Pavlovsky AG. The crystal-structure of wild-type growth-hormone at 2.5 Angstrom resolution. Protein Pept Lett. 1995;2:333–40.

    CAS  Google Scholar 

  5. Cunningham BC, Mulkerrin MG, Wells JA. Dimerization of human growth hormone by zinc. Science. 1991;253:545–8.

    Article  CAS  PubMed  Google Scholar 

  6. Brown RJ, Adams JJ, Pelekanos RA, Wan Y, Mckinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol. 2005;12:814–21.

    Article  CAS  PubMed  Google Scholar 

  7. Ultsch M, de Vos AM, Kossiakoff AA. Crystals of the complex between human growth hormone and the extracellular domain of its receptor. J Mol Biol. 1991;222:865–8.

    Article  CAS  PubMed  Google Scholar 

  8. Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR, Wells JA. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science. 1991;254:821–5.

    Article  CAS  PubMed  Google Scholar 

  9. Sundstrom M, Lundqvist T, Rodin J, Giebel LB, Milligan D, Norstedt G. Crystal structure of an antagonist mutant of human growth hormone, G120R, in complex with its receptor at 2.9 A resolution. J Biol Chem. 1996;271:32197–203.

    Article  CAS  PubMed  Google Scholar 

  10. Behncken SN, Waters MJ. Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone. J Mol Recognit. 1999;12:355–62.

    Article  CAS  PubMed  Google Scholar 

  11. Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA. Rational design of potent antagonists to the human growth hormone receptor. Science. 1992;256:1677–80.

    Article  CAS  PubMed  Google Scholar 

  12. Pearce Jr KH, Cunningham BC, Fuh G, Teeri T, Wells JA. Growth hormone binding affinity for its receptor surpasses the requirements for cellular activity. Biochemistry. 1999;38:81–9.

    Article  CAS  PubMed  Google Scholar 

  13. Baumann G, Lowman HB, Mercado M, Wells JA. The stoichiometry of growth hormone-binding protein complexes in human plasma: comparison with cell surface receptors. J Clin Endocrinol Metab. 1994;78:1113–8.

    CAS  PubMed  Google Scholar 

  14. Cunningham BC, Bass S, Fuh G, Wells JA. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science. 1990;250:1709–12.

    Article  CAS  PubMed  Google Scholar 

  15. Cunningham BC, Henner DJ, Wells JA. Engineering human prolactin to bind to the human growth hormone receptor. Science. 1990;247:1461–5.

    Article  CAS  PubMed  Google Scholar 

  16. Chen WY, Chen NY, Yun J, Wagner TE, Kopchick JJ. In vitro and in vivo studies of antagonistic effects of human growth hormone analogs. J Biol Chem. 1994;269:15892–7.

    CAS  PubMed  Google Scholar 

  17. Chen WY, Wight DC, Mehta BV, Wagner TE, Kopchick JJ. Glycine 119 of bovine growth hormone is critical for growth-promoting activity. Mol Endocrinol. 1991;5:1845–52.

    Article  CAS  PubMed  Google Scholar 

  18. Chen WY, Wight DC, Chen NY, Coleman TA, Wagner TE, Kopchick JJ. Mutations in the third alpha-helix of bovine growth hormone dramatically affect its intracellular distribution in vitro and growth enhancement in transgenic mice. J Biol Chem. 1991;266:2252–8.

    CAS  PubMed  Google Scholar 

  19. Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ. Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr Rev. 2002;23:623–46.

    Article  CAS  PubMed  Google Scholar 

  20. Kopchick JJ. Lessons learned from studies with the growth hormone receptor. 2015 Jun 3. pii: S1096-6374(15)30005-8. doi:10.1016/j.ghir. 2015.06.003 [epub ahead of print].

    Google Scholar 

  21. Ross RJ, Leung KC, Maamra M, Bennett W, Doyle N, Waters MJ, Ho KK. Binding and functional studies with the growth hormone receptor antagonist, B2036-PEG (pegvisomant), reveal effects of pegylation and evidence that it binds to a receptor dimer. J Clin Endocrinol Metab. 2001;86:1716–23.

    CAS  PubMed  Google Scholar 

  22. Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocr Pract. 2008;14:143–54.

    Article  PubMed  Google Scholar 

  23. Touraine P, D’Souza GA, Kourides I, Abs R, Barclay P, Xie R, Pico A, Torres-Vela E, Ekman B, Group GHLS. Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH. Eur J Endocrinol. 2009;161:533–40.

    Article  CAS  PubMed  Google Scholar 

  24. de Schepper J, Rasmussen MH, Gucev Z, Eliakim A, Battelino T. Long-acting pegylated human GH in children with GH deficiency: a single-dose, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics. Eur J Endocrinol. 2011;165:401–9.

    Article  PubMed  Google Scholar 

  25. Hoybye C, Cohen P, Hoffman AR, Ross R, Biller BM, Christiansin JS, Frowth Hormone Research Society. Status of long-acting growth hormone preparations - 2015. Growth Horm IGF Res 2015. Oct; 25(5): 201–206.

    Google Scholar 

  26. Rasmussen MH, Olsen MW, Alifrangis L, Klim S, Suntum M. A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile. J Clin Endocrinol Metab. 2014;99:E1819–29.

    Article  CAS  PubMed  Google Scholar 

  27. Osborn BL, Sekut L, Corcoran M, Poortman C, Sturm B, Chen G, Mather D, Lin HL, Parry TJ. Albutropin: a growth hormone-albumin fusion with improved pharmacokinetics and pharmacodynamics in rats and monkeys. Eur J Pharmacol. 2002;456:149–58.

    Article  CAS  PubMed  Google Scholar 

  28. Cleland JL, Geething NC, Moore JA, Rogers BC, Spink BJ, Wang CW, Alters SE, Stemmer WP, Schellenberger V. A novel long-acting human growth hormone fusion protein (VRS-317): enhanced in vivo potency and half-life. J Pharm Sci. 2012;101:2744–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fares F, Guy R, Bar-Ilan A, Felikman Y, Fima E. Designing a long-acting human growth hormone (hGH) by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of hGH. Endocrinology. 2010;151:4410–7.

    Article  CAS  PubMed  Google Scholar 

  30. Barinaga M, Yamonoto G, Rivier C, Vale W, Evans R, Rosenfeld MG. Transcriptional regulation of growth hormone gene expression by growth hormone-releasing factor. Nature. 1983;306:84–5.

    Article  CAS  PubMed  Google Scholar 

  31. Burgess R, Lunyak V, Rosenfeld M. Signaling and transcriptional control of pituitary development. Curr Opin Genet Dev. 2002;12:534–9.

    Article  CAS  PubMed  Google Scholar 

  32. Goldenberg N, Barkan A. Factors regulating growth hormone secretion in humans. Endocrinol Metab Clin North Am. 2007;36:37–55.

    Article  CAS  PubMed  Google Scholar 

  33. Mayo KE, Godfrey PA, Suhr ST, Kulik DJ, Rahal JO. Growth hormone-releasing hormone: synthesis and signaling. Recent Prog Horm Res. 1995;50:35–73.

    CAS  PubMed  Google Scholar 

  34. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6:1734–44.

    CAS  PubMed  Google Scholar 

  35. Vance ML, Kaiser DL, Martha Jr PM, Furlanetto R, Rivier J, Vale W, Thorner MO. Lack of in vivo somatotroph desensitization or depletion after 14 days of continuous growth hormone (GH)-releasing hormone administration in normal men and a GH-deficient boy. J Clin Endocrinol Metab. 1989;68:22–8.

    Article  CAS  PubMed  Google Scholar 

  36. Abrams RL, Parker ML, Blanco S, Reichlin S, Daughaday WH. Hypothalamic regulation of growth hormone secretion. Endocrinology. 1966;78:605–13.

    Article  CAS  PubMed  Google Scholar 

  37. Frohman LA, Bernardis LL. Growth hormone and insulin levels in weanling rats with ventromedial hypothalamic lesions. Endocrinology. 1968;82:1125–32.

    Article  CAS  PubMed  Google Scholar 

  38. Frohman LA, Nernardis LL, Kant KJ. Hypothalamic stimulation of growth hormone secretion. Science. 1968;162:580–2.

    Article  CAS  PubMed  Google Scholar 

  39. Thorner MO, Perryman RL, Cronin MJ, Rogol AD, Draznin M, Johanson A, Vale W, Horvath E, Kovacs K. Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. J Clin Invest. 1982;70:965–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jaffe CA, Friberg RD, Barkan AL. 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;92:695–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jaffe CA, Ho PJ, Demott-Friberg R, Bowers CY, Barkan AL. Effects of a prolonged growth hormone (GH)-releasing peptide infusion on pulsatile GH secretion in normal men. J Clin Endocrinol Metab. 1993;77:1641–7.

    CAS  PubMed  Google Scholar 

  42. Jaffe CA, DeMott-Friberg R, Barkan AL. Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest. 1996;97:934–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nakamura S, Mizuno M, Katakami H, Gore AC, Terasawa E. Aging-related changes in in vivo release of growth hormone-releasing hormone and somatostatin from the stalk-median eminence in female rhesus monkeys (Macaca mulatta). J Clin Endocrinol Metab. 2003;88:827–33.

    Article  CAS  PubMed  Google Scholar 

  44. Russell-Aulet M, Dimaraki EV, Jaffe CA, DeMott-Friberg R, Barkan AL. Aging-related growth hormone (GH) decrease is a selective hypothalamic GH-releasing hormone pulse amplitude mediated phenomenon. J Gerontol Ser A Biol Med Sci. 2001;56:M124–9.

    Article  CAS  Google Scholar 

  45. Turner JP, Tannenbaum GS. In vivo evidence of a positive role for somatostatin to optimize pulsatile growth hormone secretion. Am J Physiol. 1995;269:E683–90.

    CAS  PubMed  Google Scholar 

  46. Smith RG, Palyha OC, Feighner SD, Tan CP, McKee KK, Hreniuk DL, Yang L, Morriello G, Nargund R, Patchett AA, Howard AD. Growth hormone releasing substances: types and their receptors. Horm Res. 1999;51 Suppl 3:1–8.

    CAS  PubMed  Google Scholar 

  47. Bowers CY, Sartor AO, Reynolds GA, Badger TM. On the actions of the growth hormone-releasing hexapeptide, GHRP. Endocrinology. 1991;128:2027–35.

    Article  CAS  PubMed  Google Scholar 

  48. Smith RG, Van der Ploeg LH, Howard AD, Feighner SD, Cheng K, Hickey GJ, Wyvratt Jr MJ, Fisher MH, Nargund RP, Patchett AA. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997;18:621–45.

    Article  CAS  PubMed  Google Scholar 

  49. Muccioli G, Tschop M, Papotti M, Deghenghi R, Heiman M, Ghigo E. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol. 2002;440:235–54.

    Article  CAS  PubMed  Google Scholar 

  50. Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, le Bouc Y, Epelbaum J, Amselem S. Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J Clin Endocrinol Metab. 2009;94:4334–41.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science. 2005;310:996–9.

    Article  CAS  PubMed  Google Scholar 

  52. Dimaraki EV, Jaffe CA, Bowers CY, Marbach P, Barkan AL. Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Am J Physiol Endocrinol Metab. 2003;285:E163–70.

    Article  CAS  PubMed  Google Scholar 

  53. Ben-Shlomo A, Melmed S. Pituitary somatostatin receptor signaling. Trends Endocrinol Metab. 2010;21:123–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Korytnaya E, Barkan A. Pharmacological treatment of acromegaly: its place in the overall therapeutic approach. J Neuro-Oncol. 2014;117:415–20.

    Article  Google Scholar 

  55. Jessup SK, Malow BA, Symons KV, Barkan AL. Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep. Eur J Endocrinol. 2004;151:561–6.

    Article  CAS  PubMed  Google Scholar 

  56. Jaffe CA, Ocampo-Lim B, Guo W, Krueger K, Sugahara I, DeMott-Friberg R, Bermann M, Barkan AL. Regulatory mechanisms of growth hormone secretion are sexually dimorphic. J Clin Invest. 1998;102:153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML, Endocrine S. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1587–609.

    Article  CAS  PubMed  Google Scholar 

  58. Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly. J Clin Endocrinol Metab. 2009;94:523–7.

    Article  CAS  PubMed  Google Scholar 

  59. Clasey JL, Weltman A, Patrie J, Weltman JY, Pezzoli S, Bouchard C, Thorner MO, Hartman ML. Abdominal visceral fat and fasting insulin are important predictors of 24-hour GH release independent of age, gender, and other physiological factors. J Clin Endocrinol Metab. 2001;86:3845–52.

    Article  CAS  PubMed  Google Scholar 

  60. Ceda GP, Davis RG, Rosenfeld RG, Hoffman AR. The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology. 1987;120:1658–62.

    Article  CAS  PubMed  Google Scholar 

  61. Martha Jr PM, Rogol AD, Veldhuis JD, Kerrigan JR, Goodman DW, Blizzard RM. Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys. J Clin Endocrinol Metab. 1989;69:563–70.

    Article  CAS  PubMed  Google Scholar 

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Backeljauw, P., Hwa, V. (2016). Growth Hormone Physiology. In: Cohen, L. (eds) Growth Hormone Deficiency. Springer, Cham. https://doi.org/10.1007/978-3-319-28038-7_2

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