Endocrinol Metab.  2020 Jun;35(2):272-287. 10.3803/EnM.2020.35.2.272.

Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology

• Kim JH
• Chae HW
• Chin SO
• Ku CR
• Park KH
• Lim DJ
• Kim KJ
• Lim JS
• Kim G
• Choi YM
• Ahn SH
• Jeon MJ
• Hwangbo Y
• Lee JH
• Kim BK
• Choi YJ
• Lee KA
• Moon SS
• Ahn HY
• Choi HS
• Hong SM
• Shin DY
• Seo JA
• Kim SH
• Oh S
• Yu SH
• Kim BJ
• Shin CH
• Kim SW
• Kim CH
• Lee EJ

• KMID: 2503257
• DOI: http://doi.org/10.3803/EnM.2020.35.2.272

Abstract

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

Keyword

Growth hormone; Dwarfism, pituitary; Hypopituitarism; Hormone replacement therapy

Figure

• 

  Fig. 1 Algorithm for growth hormone (GH) therapy in GH deficiency adults. IGF-1, insulin-like growth factor-1.

Reference

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

2. Melmed S. Pathogenesis and diagnosis of growth hormone deficiency in adults. N Engl J Med. 2019; 380:2551–62.

3. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008; 37:151–71.

4. Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab. 2000; 85:1789–93.

5. Webb SM, Rigla M, Wagner A, Oliver B, Bartumeus F. Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab. 1999; 84:3696–700.

6. Mulder RL, Kremer LC, van Santen HM, Ket JL, van Trotsenburg AS, Koning CC, et al. Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review. Cancer Treat Rev. 2009; 35:616–32.

7. Gleeson HK, Gattamaneni HR, Smethurst L, Brennan BM, Shalet SM. Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy. J Clin Endocrinol Metab. 2004; 89:662–6.

8. Agha A, Rogers B, Sherlock M, O’Kelly P, Tormey W, Phillips J, et al. Anterior pituitary dysfunction in survivors of traumatic brain injury. J Clin Endocrinol Metab. 2004; 89:4929–36.

9. Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA. 2007; 298:1429–38.

10. Hong JW, Kim JY, Kim YE, Lee EJ. Metabolic parameters and nonalcoholic fatty liver disease in hypopituitary men. Horm Metab Res. 2011; 43:48–54.

11. Yuen KC, Tritos NA, Samson SL, Hoffman AR, Katznelson L. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: update on growth hormone stimulation testing and proposed revised cut-point for the glucagon stimulation test in the diagnosis of adult growth hormone deficiency. Endocr Pract. 2016; 22:1235–44.

12. Aimaretti G, Corneli G, Razzore P, Bellone S, Baffoni C, Arvat E, et al. Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone+ arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab. 1998; 83:1615–8.

13. Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2002; 87:2067–79.

14. Corneli G, Di Somma C, Baldelli R, Rovere S, Gasco V, Croce CG, et al. The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol. 2005; 153:257–64.

15. Colao A, Di Somma C, Savastano S, Rota F, Savanelli MC, Aimaretti G, et al. A reappraisal of diagnosing GH deficiency in adults: role of gender, age, waist circumference, and body mass index. J Clin Endocrinol Metab. 2009; 94:4414–22.

16. Qu XD, Gaw Gonzalo IT, Al Sayed MY, Cohan P, Christenson PD, Swerdloff RS, et al. Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests. J Clin Endocrinol Metab. 2005; 90:1563–9.

17. Berg C, Meinel T, Lahner H, Yuece A, Mann K, Petersenn S. Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery. Eur J Endocrinol. 2010; 162:477–82.

18. Hamrahian AH, Yuen KC, Gordon MB, Pulaski-Liebert KJ, Bena J, Biller BM. Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study. Pituitary. 2016; 19:332–41.

19. Gomez JM, Espadero RM, Escobar-Jimenez F, Hawkins F, Pico A, Herrera-Pombo JL, et al. Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults. Clin Endocrinol (Oxf). 2002; 56:329–34.

20. Conceicao FL, da Costa e Silva A, Leal Costa AJ, Vaisman M. Glucagon stimulation test for the diagnosis of GH deficiency in adults. J Endocrinol Invest. 2003; 26:1065–70.

21. Dichtel LE, Yuen KC, Bredella MA, Gerweck AV, Russell BM, Riccio AD, et al. Overweight/obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency. J Clin Endocrinol Metab. 2014; 99:4712–9.

22. Wilson JR, Utz AL, Devin JK. Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease. Growth Horm IGF Res. 2016; 26:24–31.

23. Garcia JM, Biller BMK, Korbonits M, Popovic V, Luger A, Strasburger CJ, et al. Macimorelin as a diagnostic test for adult GH deficiency. J Clin Endocrinol Metab. 2018; 103:3083–93.

24. Clemmons DR. Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. Clin Chem. 2011; 57:555–9.

25. Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ, et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab. 2002; 87:477–85.

26. Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL, Thoren M. Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19–82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab. 1999; 84:2013–9.

27. Hoffman AR, Kuntze JE, Baptista J, Baum HB, Baumann GP, Biller BM, et al. Growth hormone (GH) replacement therapy in adult-onset GH deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004; 89:2048–56.

28. Brabant G, Krogh Rasmussen A, Biller BM, Buchfelder M, Feldt-Rasmussen U, Forssmann K, et al. Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency. J Clin Endocrinol Metab. 2007; 92:2604–9.

29. Yuen KCJ, Biller BMK, Radovick S, Carmichael JD, Jasim S, Pantalone KM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocr Pract. 2019; 25:1191–232.

30. Wacharasindhu S, Cotterill AM, Camacho-Hubner C, Besser GM, Savage MO. Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth. Clin Endocrinol (Oxf). 1996; 45:553–6.

31. Nicolson A, Toogood AA, Rahim A, Shalet SM. The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood [see comment]. Clin Endocrinol (Oxf). 1996; 44:311–6.

32. Melmed S. Idiopathic adult growth hormone deficiency. J Clin Endocrinol Metab. 2013; 98:2187–97.

33. Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf). 1995; 43:143–9.

34. Hoffman AR, Strasburger CJ, Zagar A, Blum WF, Kehely A, Hartman ML, et al. Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing. J Clin Endocrinol Metab. 2004; 89:3224–33.

35. Underwood LE, Attie KM, Baptista J. Genentech Collaborative Study Group. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a two-year, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab. 2003; 88:5273–80.

36. Johannsson G, Bjarnason R, Bramnert M, Carlsson LM, Degerblad M, Manhem P, et al. The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. J Clin Endocrinol Metab. 1996; 81:1575–81.

37. Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009; 10:145–56.

38. Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab. 1997; 82:550–5.

39. Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab. 1999; 84:3956–60.

40. Yang Y, Bai X, Yuan X, Zhang Y, Chen S, Yang H, et al. Efficacy and safety of long-acting growth hormone in children with short stature: a systematic review and meta-analysis. Endocrine. 2019; 65:25–34.

41. Miller BS, Velazquez E, Yuen KCJ. Long-acting growth hormone preparations: current status and future considerations. J Clin Endocrinol Metab. 2020; 105:dgz149.

42. Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes. 2012; 19:47–52.

43. Van Vught AJ, Nieuwenhuizen AG, Gerver WJ, Veldhorst MA, Brummer RJ, Westerterp-Plantenga MS. Pharmacological and physiological growth hormone stimulation tests to predict successful GH therapy in children. J Pediatr Endocrinol Metab. 2009; 22:679–94.

44. Ghigo E, Bellone J, Aimaretti G, Bellone S, Loche S, Cappa M, et al. Reliability of provocative tests to assess growth hormone secretory status: study in 472 normally growing children. J Clin Endocrinol Metab. 1996; 81:3323–7.

45. Muller A, Scholz M, Blankenstein O, Binder G, Pfaffle R, Korner A, et al. Harmonization of growth hormone measurements with different immunoassays by data adjustment. Clin Chem Lab Med. 2011; 49:1135–42.

46. Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016; 86:361–97.

47. Kalina MA, Kalina-Faska B, Gruszczynska K, Baron J, Malecka-Tendera E. Usefulness of magnetic resonance findings of the hypothalamic-pituitary region in the management of short children with growth hormone deficiency: evidence from a longitudinal study. Childs Nerv Syst. 2012; 28:121–7.

48. Tillmann V, Tang VW, Price DA, Hughes DG, Wright NB, Clayton PE. Magnetic resonance imaging of the hypothalamic-pituitary axis in the diagnosis of growth hormone deficiency. J Pediatr Endocrinol Metab. 2000; 13:1577–83.

49. Mullis PE. Genetics of isolated growth hormone deficiency. J Clin Res Pediatr Endocrinol. 2010; 2:52–62.

50. Boot AM, van der Sluis IM, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency. Horm Res. 2009; 71:364–71.

51. Aimaretti G, Corneli G, Rovere S, Croce CG, Ghigo E, Procopio M. Is GH therapy useful to preserve bone mass in transition-phase patients with GH deficiency? J Endocrinol Invest. 2005; 28(10 Suppl):28–32.

52. Bechtold S, Bachmann S, Putzker S, Dalla Pozza R, Schwarz HP. Early changes in body composition after cessation of growth hormone therapy in childhood-onset growth hormone deficiency. J Clin Densitom. 2011; 14:471–7.

53. Colao A, di Somma C, Pivonello R, Cuocolo A, Spinelli L, Bonaduce D, et al. The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective study. J Clin Endocrinol Metab. 2002; 87:1088–93.

54. Ahmid M, Ahmed SF, Shaikh MG. Childhood-onset growth hormone deficiency and the transition to adulthood: current perspective. Ther Clin Risk Manag. 2018; 14:2283–91.

55. Ahmid M, Fisher V, Graveling AJ, McGeoch S, McNeil E, Roach J, et al. An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland. Int J Pediatr Endocrinol. 2016; 2016:6.

56. Downing J, Gleeson HK, Clayton PE, Davis JR, Wales JK, Callery P. Transition in endocrinology: the challenge of maintaining continuity. Clin Endocrinol (Oxf). 2013; 78:29–35.

57. Roshan S, Nader S, Orlander P. Review: ageing and hormones. Eur J Clin Invest. 1999; 29:210–3.

58. Kim SY. Diagnosis and treatment of hypopituitarism. Endocrinol Metab (Seoul). 2015; 30:443–55.

59. Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans KA, et al. The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab. 1995; 80:153–9.

60. Beshyah SA, Johnston DG. Cardiovascular disease and risk factors in adults with hypopituitarism. Clin Endocrinol (Oxf). 1999; 50:1–15.

61. Khang AR, Ku EJ, Kim YA, Roh E, Bae JH, Oh TJ, et al. Sex differences in the prevalence of metabolic syndrome and its components in hypopituitary patients: comparison with an age- and sex-matched nationwide control group. Pituitary. 2016; 19:573–81.

62. Attanasio AF, Bates PC, Ho KK, Webb SM, Ross RJ, Strasburger CJ, et al. Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status: 3-year results from the HypoCCS Database. J Clin Endocrinol Metab. 2002; 87:1600–6.

63. Attanasio AF, Shavrikova E, Blum WF, Cromer M, Child CJ, Paskova M, et al. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. J Clin Endocrinol Metab. 2004; 89:4857–62.

64. Beauregard C, Utz AL, Schaub AE, Nachtigall L, Biller BM, Miller KK, et al. Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008; 93:2063–71.

65. Gotherstrom G, Elbornsson M, Stibrant-Sunnerhagen K, Bengtsson BA, Johannsson G, Svensson J. Ten years of growth hormone (GH) replacement normalizes muscle strength in GH-deficient adults. J Clin Endocrinol Metab. 2009; 94:809–16.

66. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P, et al. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab. 2004; 89:2192–9.

67. Kim KW, Nam SY, Kim DS, Ahn CW, Kim KR, Lim SK, et al. Effects of growth hormone treatment beyond the body fat changes in GH-deficient adults. Korean J Obes. 2013; 22:56–65.

68. Choi HS, Kim SS, Ko KJ, Lee EJ, Park IW, Park TW, et al. The effects of growth hormone administration on the markers of cardiovascular disease in growth hormone deficient adults. Korean J Med. 2005; 68:519–27.

69. Park JK, Hong JW, Kim CO, Kim SW, Lim CY, Chung YS, et al. Sustained-release recombinant human growth hormone improves body composition and quality of life in adults with somatopause. J Am Geriatr Soc. 2011; 59:944–7.

70. Hong JW, Park JK, Lim CY, Kim SW, Chung YS, Kim SW, et al. A weekly administered sustained-release growth hormone reduces visceral fat and waist circumference in abdominal obesity. Horm Metab Res. 2011; 43:956–61.

71. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab. 1994; 78:669–74.

72. Murray RD, Columb B, Adams JE, Shalet SM. Low bone mass is an infrequent feature of the adult growth hormone deficiency syndrome in middle-age adults and the elderly. J Clin Endocrinol Metab. 2004; 89:1124–30.

73. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA. Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 1993; 129:201–6.

74. Colao A, Di Somma C, Pivonello R, Loche S, Aimaretti G, Cerbone G, et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab. 1999; 84:1919–24.

75. Vestergaard P, Jorgensen JO, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, et al. Fracture risk is increased in patients with GH deficiency or untreated prolactinomas: a case-control study. Clin Endocrinol (Oxf). 2002; 56:159–67.

76. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol. 1997; 137:240–5.

77. Gotherstrom G, Bengtsson BA, Bosaeus I, Johannsson G, Svensson J. Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency. Eur J Endocrinol. 2007; 156:55–64.

78. Mo D, Fleseriu M, Qi R, Jia N, Child CJ, Bouillon R, et al. Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study. Lancet Diabetes Endocrinol. 2015; 3:331–8.

79. Giovannini L, Tirabassi G, Muscogiuri G, Di Somma C, Colao A, Balercia G. Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [review]. Endocr J. 2015; 62:1037–48.

80. Colao A, Cuocolo A, Di Somma C, Cerbone G, Della Morte AM, Nicolai E, et al. Impaired cardiac performance in elderly patients with growth hormone deficiency. J Clin Endocrinol Metab. 1999; 84:3950–5.

81. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990; 336:285–8.

82. Svensson J, Mattsson A, Rosen T, Wiren L, Johannsson G, Bengtsson BA, et al. Three-years of growth hormone (GH) replacement therapy in GH-deficient adults: effects on quality of life, patient-reported outcomes and healthcare consumption. Growth Horm IGF Res. 2004; 14:207–15.

83. van Bunderen CC, van Nieuwpoort IC, Arwert LI, Heymans MW, Franken AA, Koppeschaar HP, et al. Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency?: data from the Dutch National Registry of Growth Hormone Treatment in adults. J Clin Endocrinol Metab. 2011; 96:3151–9.

84. Pappachan JM, Raskauskiene D, Kutty VR, Clayton RN. Excess mortality associated with hypopituitarism in adults: a meta-analysis of observational studies. J Clin Endocrinol Metab. 2015; 100:1405–11.

85. Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101:3888–921.

86. Bjork S, Jonsson B, Westphal O, Levin JE. Quality of life of adults with growth hormone deficiency: a controlled study. Acta Paediatr Scand Suppl. 1989; 356(55–60):73–4.

87. Woo JT, Kim DY, Kim SW, Yang IM, Kim JW, Kim YS, et al. Effects of human growth hormone treatment in healthy older female. J Korean Soc Endocrinol. 1992; 7:352–7.

88. Kim Y, Hong JW, Chung YS, Kim SW, Cho YW, Kim JH, et al. Efficacy and safety of sustained-release recombinant human growth hormone in Korean adults with growth hormone deficiency. Yonsei Med J. 2014; 55:1042–8.

89. Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009; 30:152–77.

90. Chipman JJ, Attanasio AF, Birkett MA, Bates PC, Webb S, Lamberts SW. The safety profile of GH replacement therapy in adults. Clin Endocrinol (Oxf). 1997; 46:473–81.

91. Boguszewski CL, Boguszewski MC. Growth hormone’s links to cancer. Endocr Rev. 2019; 40:558–74.

92. Sheppard MC. Growth hormone therapy does not induce cancer. Nat Clin Pract Endocrinol Metab. 2006; 2:532–3.

93. Packer RJ, Boyett JM, Janss AJ, Stavrou T, Kun L, Wisoff J, et al. Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol. 2001; 19:480–7.

94. Sklar CA, Mertens AC, Mitby P, Occhiogrosso G, Qin J, Heller G, et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2002; 87:3136–41.

95. Ergun-Longmire B, Mertens AC, Mitby P, Qin J, Heller G, Shi W, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab. 2006; 91:3494–8.

96. Arnold JR, Arnold DF, Marland A, Karavitaki N, Wass JA. GH replacement in patients with non-functioning pituitary adenoma (NFA) treated solely by surgery is not associated with increased risk of tumour recurrence. Clin Endocrinol (Oxf). 2009; 70:435–8.

97. Buchfelder M, Kann PH, Wuster C, Tuschy U, Saller B, Brabant G, et al. Influence of GH substitution therapy in deficient adults on the recurrence rate of hormonally inactive pituitary adenomas: a case control study. Eur J Endocrinol. 2007; 157:149–56.

98. Chung TT, Drake WM, Evanson J, Walker D, Plowman PN, Chew SL, et al. Tumour surveillance imaging in patients with extrapituitary tumours receiving growth hormone replacement. Clin Endocrinol (Oxf). 2005; 63:274–9.

99. Frajese G, Drake WM, Loureiro RA, Evanson J, Coyte D, Wood DF, et al. Hypothalamo-pituitary surveillance imaging in hypopituitary patients receiving long-term GH replacement therapy. J Clin Endocrinol Metab. 2001; 86:5172–5.

100. Hatrick AG, Boghalo P, Bingham JB, Ayres AB, Sonksen PH, Russell-Jones DL. Does GH replacement therapy in adult GH-deficient patients result in recurrence or increase in size of pituitary tumours? Eur J Endocrinol. 2002; 146:807–11.

101. Jostel A, Mukherjee A, Hulse PA, Shalet SM. Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors. Clin Endocrinol (Oxf). 2005; 62:698–705.

102. Karavitaki N, Warner JT, Marland A, Shine B, Ryan F, Arnold J, et al. GH replacement does not increase the risk of recurrence in patients with craniopharyngioma. Clin Endocrinol (Oxf). 2006; 64:556–60.

103. Olsson DS, Buchfelder M, Schlaffer S, Bengtsson BA, Jakobsson KE, Johannsson G, et al. Comparing progression of non-functioning pituitary adenomas in hypopituitarism patients with and without long-term GH replacement therapy. Eur J Endocrinol. 2009; 161:663–9.

104. Sklar CA, Antal Z, Chemaitilly W, Cohen LE, Follin C, Meacham LR, et al. Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018; 103:2761–84.

105. Yuen KC, Dunger DB. Impact of treatment with recombinant human GH and IGF-I on visceral adipose tissue and glucose homeostasis in adults. Growth Horm IGF Res. 2006; 16(Suppl A):S55–61.

106. Al-Shoumer KA, Gray R, Anyaoku V, Hughes C, Beshyah S, Richmond W, et al. Effects of four years’ treatment with biosynthetic human growth hormone (GH) on glucose homeostasis, insulin secretion and lipid metabolism in GH-deficient adults. Clin Endocrinol (Oxf). 1998; 48:795–802.

107. Behan LA, Monson JP, Agha A. The interaction between growth hormone and the thyroid axis in hypopituitary patients. Clin Endocrinol (Oxf). 2011; 74:281–8.

108. Filipsson H, Johannsson G. GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies. Eur J Endocrinol. 2009; 161(Suppl 1):S85–95.

109. Jorgensen JO, Moller J, Laursen T, Orskov H, Christiansen JS, Weeke J. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults. Clin Endocrinol (Oxf). 1994; 41:609–14.

110. Agha A, Walker D, Perry L, Drake WM, Chew SL, Jenkins PJ, et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf). 2007; 66:72–7.

111. Losa M, Scavini M, Gatti E, Rossini A, Madaschi S, Formenti I, et al. Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency. Thyroid. 2008; 18:1249–54.

112. Mazziotti G, Giustina A. Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol. 2013; 9:265–76.

113. Stewart PM, Toogood AA, Tomlinson JW. Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. Horm Res. 2001; 56(Suppl 1):1–6.

114. Giavoli C, Libe R, Corbetta S, Ferrante E, Lania A, Arosio M, et al. Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients. J Clin Endocrinol Metab. 2004; 89:5397–401.