pp 1-20 | Cite as

GH and IGF-1 Replacement in Children

  • Roland PfäffleEmail author
  • Wieland Kiess
Part of the Handbook of Experimental Pharmacology book series


In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.


Growth hormone Growth hormone deficiency Idiopathic short stature Insulin-like growth factor I Long-acting growth hormone Noonan syndrome Prader-Willi syndrome Short stature Small for gestational age Turner syndrome 



Creutzfeldt-Jakob disease


European Medicines Agency


Food and Drug Administration


Growth hormone, somatropin


GH deficiency


Growth hormone insensitivity syndrome


Growth hormone receptor




Height velocity


Insulin-like growth factor binding protein 3


Insulin-like growth factor 1


Isolated growth hormone deficiency


Idiopathic short stature


Noonan syndrome


(Covalently) bound to polyethylene glycol


Primary insulin-like growth factor 1 deficiency


Protein tyrosine phosphatase, nonreceptor type 11


Prader-Willi syndrome


Recombinant human growth hormone


Standard deviation (SD) score


Small for gestational age


Short stature homeobox-containing gene


Standard incidence ratio


Standard mortality ratio


Turner syndrome


  1. Albertsson-Wikland K, Aronson SA, Gustafsson J, Hagenäs L, Ivarsson SA, Jonsson B et al (2008) Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metabol 93:4342–4350Google Scholar
  2. Albertsson-Wikland K, Mårtensson A, Sävendahl L, Niklasson A, Bang P, Dahlgren J et al (2016) Mortality is not increased in recombinant human growth hormone-treated patients when adjusting for birth characteristics. J Clin Endocrinol Metabol 101:2149–2159Google Scholar
  3. Backeljauw PF, Underwood LE (2001) Therapy for 6.5–7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study 1. J Clin Endocrinol Metabol 86:1504–1510Google Scholar
  4. Berglund A, Gravholt C, Olsen M, Christiansen J, Stochholm K (2015) Growth hormone replacement does not increase mortality in patients with childhood-onset growth hormone deficiency. Clin Endocrinol (Oxf) 83:677–683Google Scholar
  5. Binder G (2009) Response to growth hormone in short children with Noonan syndrome: correlation to genotype. Horm Res Paediatr 72:52–56Google Scholar
  6. Birnbacher R, Riedl S, Frisch H (1998) Long-term treatment in children with hypopituitarism: pubertal development and final height. Horm Res Paediatr 49:80–85Google Scholar
  7. Blethen S (1997) Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. J Clin Endocrinol Metabol 82:418–420Google Scholar
  8. Blethen S, Compton P, Lippe B, Rosenfeld R, August G, Johanson A (1993) Factors predicting the response to growth hormone (GH) therapy in prepubertal children with GH deficiency. J Clin Endocrinol Metabol 76:574–579Google Scholar
  9. Blum WF, Crowe BJ, Quigley CA, Jung H, Cao D, Ross JL et al (2007) Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metabol 92:219–228Google Scholar
  10. Blum WF, Ross JL, Zimmermann AG, Quigley CA, Child CJ, Kalifa G et al (2013) GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial. J Clin Endocrinol Metabol 98:E1383–E1392Google Scholar
  11. Bolar K, Hoffman AR, Maneatis T, Lippe B (2008) Long-term safety of recombinant human growth hormone in turner syndrome. J Clin Endocrinol Metabol 93:344–351Google Scholar
  12. Bryant J, Baxter L, Cave CB, Milne R (2007) Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Db Syst Rev:CD004440Google Scholar
  13. Carel J-C, Mathivon L, Gendrel C, Ducret J-P, Chaussain J-L (1998) Near normalization of final height with adapted doses of growth hormone in Turner’s syndrome. J Clin Endocrinol Metabol 83:1462–1466Google Scholar
  14. Carel J-C, Chatelain P, Rochiccioli P, Chaussain J-L (2003) Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. J Clin Endocrinol Metab 88:1587–1593. Scholar
  15. Carel J-C, Ecosse E, Landier F et al (2012) Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 97:416–425. Scholar
  16. Cave CB, Bryant J, Milne R (2003) Recombinant growth hormone in children and adolescents with Turner syndrome. Cochrane Database Syst Rev 2003(1). Art. No.: CD003887.
  17. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563–566Google Scholar
  18. Chatelain P, Malievsky O, Radziuk K, Senatorova G, Abdou MO, Vlachopapadopolou E et al (2017) A randomized phase 2 study of long-acting TransCon GH vs daily GH in childhood GH deficiency. J Clin Endocrinol Metabol 102:1673–1682Google Scholar
  19. Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J (2000) Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height 1. J Clin Endocrinol Metabol 85:2439–2445Google Scholar
  20. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, Group IG (2007) Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metabol 92:902–910Google Scholar
  21. Christiansen J, Backeljauw PF, Bidlingmaier M, Biller BM, Boguszewski MC, Casanueva FF et al (2016) Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations. Eur J Endocrinol 174:C1–C8Google Scholar
  22. Clayton P, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A (2007) Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metabol 92:804–810Google Scholar
  23. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard A-M, Rosenfeld RG et al (2007) Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. J Clin Endocrinol Metabol 92:2480–2486Google Scholar
  24. Cutfield WS, Derraik JG, Gunn AJ, Reid K, Delany T, Robinson E et al (2011) Non-compliance with growth hormone treatment in children is common and impairs linear growth. Plos One 6:e16223Google Scholar
  25. Dahlgren J, Wikland K, Swedish Study Group for Growth Hormone Treatment (2005) Final height in short children born small for gestational age treated with growth hormone. Pediatr Res 57:216–222Google Scholar
  26. Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY et al (2007) Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metabol 92:3406–3416Google Scholar
  27. de Zegher F, Hokken-Koelega A (2005) Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term. Pediatrics 115:e458–e462Google Scholar
  28. Ebbers HC, Crow SA, Vulto AG, Schellekens H (2012) Interchangeability, immunogenicity and biosimilars. Nat Biotechnol 30:1186Google Scholar
  29. Eiholzer U (2005) Deaths in children with Prader-Willi syndrome. Horm Res Paediatr 63:33–39Google Scholar
  30. Elder CJ, Barton JS, Brook CGD, Preece MA, Dattani MT, Hindmarsh PC (2008) A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature. Horm Res Paediatr 70:89–92Google Scholar
  31. Festen DA, van Wijngaarden R, Eekelen M, Otten BJ, Wit JM, Duivenvoorden HJ et al (2008) Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader–Willi syndrome. Clin Endocrinol (Oxf) 69:443–451Google Scholar
  32. Ghigo E, Bellone J, Aimaretti G, Bellone S, Loche S, Cappa M et al (1996) Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metabol 81:3323–3327Google Scholar
  33. Goeddel DV, Heyneker HL, Hozumi T, Arentzen R, Itakura K, Yansura DG et al (1979) Direct expression in Escherichia coli of a DNA sequence coding for human growth hormone. Nature 281:281544a0Google Scholar
  34. Growth Hormone Research Society (2001) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Pediatr Endocrinol Metabol 14:377–382Google Scholar
  35. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B et al (1998) Circulating concentrations of insulin-like growth factor I and risk of breast cancer. Lancet 351:1393–1396Google Scholar
  36. Hintz RL, Attie KM, Baptista J, Roche A (1999) Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 340:502–507Google Scholar
  37. Høybye C, Cohen P, Hoffman AR, Ross R, Biller B, Christiansen J et al (2015) Status of long-acting-growth hormone preparations – 2015. Growth Horm IGF Res 25:201–206Google Scholar
  38. Hwang J, Lee H, Chung W, Han H-S, Jin D-K, Kim H-S et al (2013) Efficacy and safety of LB03002, a once-weekly sustained-release human GH for 12-month treatment in Korean children with GH deficiency. Eur J Endocrinol 169:179–185Google Scholar
  39. Joss E, Zuppinger K, Schwarz H, Roten H (1983) Final height of patients with pituitary growth failure and changes in growth variables after long term hormonal therapy. Pediatr Res 17:pr1983158Google Scholar
  40. Klammt J, Kiess W, Pfäffle R (2011) IGF1R mutations as cause of SGA. Best Pract Res Clin Endocrinol Metabol 25:191–206Google Scholar
  41. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P, International Small for Gestational Age Advisory Board (2003) International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24–October 1, 2001. Pediatrics 111:1253–1261Google Scholar
  42. Leschek E, Rose SR, Yanovski JA, Troendle JF, Quigley CA, Chipman JJ et al (2004) Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metabol 89:3140–3148Google Scholar
  43. Lindgren AC (2006) Somatropin therapy for children with Prader-Willi syndrome. Treat Endocrinol 5:223–228Google Scholar
  44. Lindgren AC, Lindberg A (2008) Growth hormone treatment completely normalizes adult height and improves body composition in Prader-Willi syndrome: experience from KIGS (Pfizer International Growth Database). Horm Res Paediatr 70:182–187Google Scholar
  45. Luca DF, Maghnie M, Arrigo T, Lombardo F, Messina M, Bernasconi S (1996) Final height outcome of growth hormone-deficient patients treated since less than five years of age. Acta Paediatr 85:1167–1171Google Scholar
  46. Luo X, Hou L, Liang L, Dong G, Shen S, Zhao Z et al (2017) Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies. Eur J Endocrinol 177:195–205Google Scholar
  47. MacGillivray M, Blethen S, Buchlis J, Clopper R, Sandberg D, Conboy T (1998) Current dosing of growth hormone in children with growth hormone deficiency: how physiologic? Pediatrics 102:527–530Google Scholar
  48. Maghnie M, Ambrosini L, Cappa M, Pozzobon G, Ghizzoni L, Ubertini M et al (2006) Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies. J Clin Endocrinol Metabol 91:2900–2905Google Scholar
  49. Myers SE, Carrel AL, Whitman BY, Allen DB (2000) Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome. J Pediatr 137:42–49Google Scholar
  50. Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort J-M et al (2009) Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metabol 94:3913–3921Google Scholar
  51. Nicholls RD (1993) Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 46:16–25Google Scholar
  52. Noordam C, Peer P, Francois I, Schepper DJ, van den Burgt I, Otten B (2008) Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11. Eur J Endocrinol 159:203–208Google Scholar
  53. Osio D, Dahlgren J, Wikland K, Westphal O (2005) Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr 94:1232–1237Google Scholar
  54. Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A (2003) Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metabol 88:3584–3590Google Scholar
  55. Pasquino A, Pucarelli I, Segni M, Tarani L, Calcaterra V, Larizza D (2005) Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group. J Endocrinol Invest 28:350–356Google Scholar
  56. Poidvin A, Touzé E, Ecosse E, Landier F, Béjot Y, Giroud M et al (2014) Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology 83:780–786Google Scholar
  57. Quigley CA, Crowe BJ, Anglin GD, Chipman JJ (2002) Growth hormone and low dose estrogen in turner syndrome: results of a united states multi-center trial to near-final height. J Clin Endocrinol Metabol 87:2033–2041Google Scholar
  58. Raaijmakers R, Noordam C, Karagiannis G, Gregory JW, Hertel NT, Sipilä I et al (2008) Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database. J Pediatr Endocrinol Metabol 21:267–274Google Scholar
  59. Raben M (1957) Preparation of growth hormone from pituitaries of man and monkey. Science 125:883–884Google Scholar
  60. Ranke MB (2015) Treatment with recombinant human insulin-like growth factor-1 in severe primary IGF deficiency and beyond. Horm Res Paediatr 83:358–360Google Scholar
  61. Ranke MB, Wit JM (2018) Growth hormone – past, present and future. Nat Rev Endocrinol 14:285Google Scholar
  62. Ranke PC, Lindberg A, Dorr H, Bettendorf M, Hauffa B et al (2002) Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001. Eur J Endocrinol 147:625–633Google Scholar
  63. Ranke MB, Lindberg A, Board K (2010) Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metabol 95:1229–1237Google Scholar
  64. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A et al (1997) Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54–63Google Scholar
  65. Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA et al (2007) Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 44:306Google Scholar
  66. Richmond EJ, Rogol AD (2008) Recombinant human insulin-like growth factor-I therapy for children with growth disorders. Adv Ther 25:1276Google Scholar
  67. Richmond E, Rogol AD (2010) Current indications for growth hormone therapy for children and adolescents. Endocr Dev 18:92–108Google Scholar
  68. Romano AA, Dana K, Bakker B, Davis AD, Hunold J, Jacobs J et al (2009) Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone. J Clin Endocrinol Metabol 94:2338–2344Google Scholar
  69. Rosenfeld RG, Attie KM, Frane J, Brasel A, Burstein S, Cara JF et al (1998) Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr 132:319–324Google Scholar
  70. Saggese G, Fanos M, Simi F (2013) SGA children: auxological and metabolic outcomes – the role of GH treatment. J Matern Fetal Neonatal Med 26:64–67Google Scholar
  71. Samani A, Yakar S, LeRoith D, Brodt P (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20–47Google Scholar
  72. Sävendahl L, Maes M, Albertsson-Wikland K, Borgström B, Carel J-C, Henrard S et al (2012) Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. J Clin Endocrinol Metabol 97:E213–E217Google Scholar
  73. Soriano-Guillen L, Coste J, Ecosse E, Léger J, Tauber M, Cabrol S et al (2005) Adult height and pubertal growth in turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metabol 90:5197–5204Google Scholar
  74. Sprogøe K, Mortensen E, Karpf DB, Leff JA (2017) The rationale and design of TransCon growth hormone for the treatment of growth hormone deficiency. Endocr Connect 6:R171–R181Google Scholar
  75. Stephure DK, Committee C (2005) Impact of growth hormone supplementation on adult height in Turner syndrome: results of the canadian randomized controlled trial. J Clin Endocrinol Metabol 90:3360–3366Google Scholar
  76. Takeda A, Cooper K, Bird A, Baxter L, Frampton G, Gospodarevskaya E et al (2010) Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. Health Technol Assess (Winch Eng) 14:1–209. iii–ivGoogle Scholar
  77. Tillmann V, Buckler JM, Kibirige MS, Price DA, Shalet SM, Wales JK et al (1997) Biochemical tests in the diagnosis of childhood growth hormone deficiency 1. J Clin Endocrinol Metabol 82:531–535Google Scholar
  78. van Pareren YK, de Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ et al (2003) Final height in girls with Turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metabol 88:1119–1125Google Scholar
  79. Wilson TA, Rose SR, Cohen P, Rogol AD, Backeljauw P, Brown R et al (2003) Update of guidelines for the use of growth hormone in children: the Lawson Wilkins pediatric endocrinology society drug and therapeutics committee. J Pediatr 143:415–421Google Scholar
  80. Wit JM, Rekers-Mombarg L, Cutler GB, Crowe B, Beck TJ, Roberts K et al (2005) Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect. J Pediatr 146:45–53Google Scholar
  81. Yang Y, Bai X, Yuan X, Zhang Y, Chen S, Yang H et al (2019) Efficacy and safety of long-acting growth hormone in children with short stature: a systematic review and meta-analysis. Endocrine 65:25–34Google Scholar
  82. Yuen KC, Conway GS, Popovic V, Merriam GR, Bailey T, Hamrahian AH et al (2013) A long-acting human growth hormone with delayed clearance (VRS-317): results of a double-blind, placebo-controlled, single ascending dose study in growth hormone–deficient adults. J Clin Endocrinol Metabol 98:2595–2603Google Scholar
  83. Zelinska N, Iotova V, Skorodok J, Malievsky O, Peterkova V, Samsonova L et al (2017) Long-acting C-terminal peptide–modified hGH (MOD-4023): results of a safety and dose-finding study in GHD children. J Clin Endocrinol Metabol 102:1578–1587Google Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatric EndocrinologyUniversity Children’s Hospital LeipzigLeipzigGermany

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