Growth hormone deficiency in childhood brain tumors and acute lymphoblastic leukemia survivors

Thanks to modern treatment protocols, childhood cancer survivors (CCS) are a very fast-growing population nowadays. Cancer therapy inevitably leads to different late adverse effects, where endocrine disorders are highly prevalent, including growth hormone deficiency (GHD) which is the most common endocrine outcome after cancer treatment in childhood and contributes to impaired growth. Short stature is a big issue, which leads to problems in psychological and social adaptation of patients and reduces their quality of life. Impact of GH treatment on various physiological processes and global outcome of CCS is of great interest. Several studies have demonstrated an influence of GH and IGF-1 on the development/tumour growth, cell proliferation. In this regard, the issue of increasing the risk of cancer recurrence and/or the development of secondary neoplasms in CCS, causes a lot of controversy and is the subject of continuous evaluation. In this review, we went through the available data on the prevalence and pathogenesis of GHD following chemo- and radiotherapy, in particular after treatment of brain tumors and acute lymphoblastic leukaemia in childhood. In addition, here we discuss the existing problems in the diagnosis of GHD, the safety of GH replacement therapy, as well as the treatment algorithm of the GHD in adults.

1. American Cancer Society. Cancer Facts & Figures, 2018. Cancer Statistics. 2018;2018:23.

2. Kaprin AD, Starinskii VV, Shakhzadova AO. Zlokachestvennye novoobrazovaniya v Rossii v 2019 godu (zabolevaemost’ i smertnost’). Moscow: MNIOI im. P.A. Gertsena — filial FGBU NMIRTs. Minzdrava Rossii; 2020. 252 p. (In Russ.).

3. Zheludkova OG, Polyakov VG, Rykov MYu, et al. Klinicheskie proyavleniya onkologicheskikh zabolevaniĭ u deteĭ: prakticheskie rekomendatsii. Ed. by Polyakova VG, Rykova MYu. — SPb.: Tipografiya Mikhaila Fursova; 2017. 52 p. (In Russ.).

4. Gurney JG, Kadan-Lottick NS, Packer RJ, et al. Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer. 2003;97:663-673. doi: https://doi.org/10.1002/cncr.11095

5. Bobrova EI, Pavlova MG, Sotnikov VM, et al. Hypopituitarism after radiotherapy for childhood malignant tumors. Clinical and experimental thyroidology. 2013;9(3):15-20. (In Russ.). doi: https://doi.org/10.14341/ket20139315-20

6. Uday S, Murray RD, Picton S, et al. Endocrine sequelae beyond 10 years in survivors of medulloblastoma. Clin Endocrinol (Oxf). 2015;83(5):663-670. doi: https://doi.org/10.1111/cen.12815

7. Mirouliaei M, Shabani M, Bakhshi F, Ordouei M. Radiation-induced hypopituitarism in children with acute lymphoblastic leukemia. Indian J Med Paediatr Oncol. 2013;34(1):8-10. doi: https://doi.org/10.4103/0971-5851.113396

8. Olshan JS, Gubernick J, Packer RJ, et al. The effects of adjuvant chemotherapy on growth in children with medulloblastoma. Cancer. 1992;70(7):2013-2017. doi: https://doi.org/10.1002/1097-0142(19921001)70:7<2013::AID-CNCR2820700734>3.0.CO;2-J

9. Pavlova MG, Sych YuP, Bobrova EI, et al. Endokrinnye posledstviya kompleksnogo lecheniya medulloblastom v detskom i molodom vozraste. In: Sbornik tezisov IV (XXVII) Natsional’nogo kongressa endokrinologov s mezhdunarodnym uchastiem. Moscow; 2021. 202 р. (In Russ.). doi: https://doi.org/10.14341/Conf22-25.09.21-202

10. Jarfelt M, Bjarnason R, Lannering B. Young adult survivors of childhood acute lymphoblastic leukemia: spontaneous GH secretion in relation to CNS radiation. Pediatr Blood Cancer. 2004;42:582-588. doi: https://doi.org/10.1002/pbc.20020

11. Brignardello E, Felicetti F, Castiglione A, et al. Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol. 2013;168(3):465-472. doi: https://doi.org/10.1530/EJE-12-1043

12. Darzy KH. Radiation-induced hypopituitarism. Curr Opin Endocrinol Diabetes Obes. 2013;20(4):342-353. doi: https://doi.org/10.1097/MED.0b013e3283631820

13. Darzy KH, Pezzoli SS, Thorner MO, Shalet SM. The dynamics of growth hormone (GH) secretion in adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretor. J Clin Endocrinol Metab. 2005;90(5):2794-2803. doi: https://doi.org/10.1210/jc.2004-2002

14. Brauner R, Czernichow P, Rappaport R. Greater susceptibility to hypothalamopituitary irradiation in younger children with acute lymphoblastic leukemia. J Pediatr. 1986;108(2):332. doi: https://doi.org/10.1016/s0022-3476(86)81027-7

15. Samaan NA, Schultz PN, Yang KPP, et al. Endocrine complications after radiotherapy for tumors of the head and neck. J Lab Clin Med. 1987;109:364-372. doi: https://doi.org/10.5555/uri:pii:002221438790059X

16. Shen Y, Zhang J, Zhao Y, et al. Diagnostic value of serum IGF-1 and IGFBP-3 in growth hormone deficiency: a systematic review with meta-analysis. Eur J Pediatr. 2015;174(4):419-427. doi: https://doi.org/10.1007/s00431-014-2406-3

17. Cattoni A, Clarke E, Albanese A. The Predictive Value of Insulin-Like Growth Factor 1 in Irradiation-Dependent Growth Hormone Deficiency in Childhood Cancer Survivors. Horm Res Paediatr. 2018;90(5):314-325. doi: https://doi.org/10.1159/000495760

18. Tavares ABW, Collett-Solberg PF. Growth hormone deficiency and the transition from pediatric to adult care. J Pediatr (Rio J). 2021;97(6):595-602. doi: https://doi.org/10.1016/j.jped.2021.02.007

19. Yuen KCJ, Biller BMK, Radovick S, et al. American association of clinical endocrinologists and American college of endocrinology guidelines for management of growth hormone defficiency in adults and patients transitioning from pediatric to adult care. Endocr Pract. 2019;25(11):1191-1232. doi: https://doi.org/10.4158/GL-2019-0405

20. Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(6):1587-1609. doi: https://doi.org/10.1210/jc.2011-0179

21. Cook DM, Yuen KC, Biller BM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients — 2009 update. Endocr Pract. 2009;15(S2):1-29. doi: https://doi.org/10.4158/EP.15.S2.1

22. Bidlingmaier M. Problems with GH assays and strategies toward standardization. Eur J Endocrinol. 2008;159(S1):S41-44. doi: https://doi.org/10.1530/EJE-08-0284

23. Hymer WC, Kennett MJ, Maji SK, et al. Bioactive growth hormone in humans: Controversies, complexities and concepts. Growth Horm IGF Res. 2020;50:9-22. doi: https://doi.org/10.1016/j.ghir.2019.11.003

24. Bidlingmaier M, Freda PU. Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res. 2010;20(1):19-25. doi: https://doi.org/10.1016/j.ghir.2009.09.005

25. Baumann G. Growth hormone binding protein 2001. J Pediatr Endocrinol Metab. 2001;14(4):355-375. doi: https://doi.org/10.1515/jpem.2001.14.4.355

26. Tanaka T, Tachibana K, Shimatsu A, et al. A nationwide attempt to standardize growth hormone assays. Horm Res. 2005;64(S2):6-11. doi: https://doi.org/10.1159/000087746

27. Binder G. Growth hormone deficiency: new approaches to the diagnosis. Pediatr Endocrinol Rev. 2011;9(S1):535-537.

28. Dall R, Longobardi S, Ehrnborg C, et al. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85(11):3990-3993. doi: https://doi.org/10.1210/jcem.85.11.6984

29. Trainer PJ. Consensus statement on the standardisation of GH assays. Eur J Endocrinol. 2006;155(1):1-2. doi: https://doi.org/10.1530/eje.1.02186

30. Hoeck HC, Vestergaard P, Jakobsen PE, et al. Diagnosis of growth hormone (GH) deficiency in adults with hypothalamic-pituitary disorders: comparison of test results using pyridostigmine plus GH-releasing hormone (GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia as GH secretagogues. J Clin Endocrinol Metab. 2000;85(4):1467-1472. doi: https://doi.org/10.1210/jcem.85.4.6538

31. Markkanen HM, Pekkarinen T, Välimäki MJ, et al. Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic. Growth Horm IGF Res. 2013;23(5):165-169. doi: https://doi.org/10.1016/j.ghir.2013.06.002

32. Poyrazoğlu Ş, Akçay T, Arslanoğlu İ, et al. Current Practice in Diagnosis and Treatment of Growth Hormone Deficiency in Childhood: A Survey from Turkey. J Clin Res Pediatr Endocrinol. 2015;7(1):37-44. doi: https://doi.org/10.4274/jcrpe.1794

33. Biller BMK, Samuels MH, Zagar A, et al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2002;87(5):2067-2079. doi: https://doi.org/10.1210/jcem.87.5.8509

34. Deutschbein T, Bidlingmaier M, Schopohl J, et al. Anthropometric factors have significant influence on the outcome of the GHRH-arginine test — establishment of normative data for an automated immunoassay specifically measuring 22kD human growth hormone. Eur J Endocrinol. 2017;176(3):273-281. doi: https://doi.org/10.1530/EJE-16-0668

35. Conceição 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(11):1065-1070. doi: https://doi.org/10.1007/BF03345251

36. Gómez JM, Espadero RM, Escobar-Jiménez F, et al. Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults. Clin Endocrinol (Oxf). 2002;56(3):329-334. doi: https://doi.org/10.1046/j.1365-2265.2002.01472.x

37. Aimaretti G, Corneli G, Razzore P, 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(5):1615-1618. doi: https://doi.org/10.1210/jcem.83.5.4837

38. Dedov II, Mel’nichenko GA. Endokrinologiya. Natsional’noe Rukovodstvo. 2-e Izd. Moscow: GEOTAR-Media, 2018. 832 p. (In Russ.).

39. Golounina OO, Pavlova MG, Belaya ZE, et al. Endocrine late-effects and bone mineral density after combined treatment of malignant brain tumors. Problems of Endocrinology. 2021;67(1):31-40. (In Russ.). doi: https://doi.org/10.14341/probl12680

40. Chae HW, Kim DH, Kim HS. Growth hormone treatment and risk of malignancy. Korean J Pediatr. 2015;58(2):41-46. doi: https://doi.org/10.3345/kjp.2015.58.2.41

41. Robison LL, Mertens AC, Boice JD, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: A multi-institutional collaborative project. Med Pediatr Oncol. 2002;38(4):229-239. doi: https://doi.org/10.1210/jcem.83.5.4837

42. Sklar CA, Mertens AC, Mitby P, 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(7):3136-3141. doi: https://doi.org/10.1210/jcem.87.7.8606

43. Arslanian SA, Becker DJ, Lee PA, et al. Growth hormone therapy and tumor recurrence. Findings in children with brain neoplasms and hypopituitarism. Am J Dis Child. 1985;139(4):347-350. doi: https://doi.org/10.1001/archpedi.1985.02140060029020

44. Chae HW, Park YS, Kim DS, et al. Final height and insulin-like growth factor-1 in children with medulloblastoma treated with growth hormone. Child’s Nerv Syst. 2013;29(10):1859-1863. doi: https://doi.org/10.1007/s00381-013-2124-6

45. Packer RJ, Boyett JM, Janssa J, et al. Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol. 2001;19(2):480-487. doi: https://doi.org/10.1200/JCO.2001.19.2.480

46. Leung W, Rose SR, Zhou Y, et al. Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2002;20(13):2959-2964. doi: https://doi.org/10.1200/JCO.2002.09.142

47. Carel J-C, Butler G. Safety of recombinant human growth hormone. Endocr Dev. 2010;18:40-54. doi: https://doi.org/10.1159/000316126

48. Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: The childhood cancer survivor study. J Natl Cancer Inst. 2010;102(14):1083-1095. doi: https://doi.org/10.1093/jnci/djq238

49. Ergun-Longmire B, Mertens AC, Mitby P, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab. 2006;91(9):3494-3498. doi: https://doi.org/10.1210/jc.2006-0656

50. Patterson BC, Chen Y, Sklar CA, et al. Growth Hormone Exposure as a Risk Factor for the Development of Subsequent Neoplasms of the Central Nervous System: A Report From the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2014;99(6):2030-2037. doi: https://doi.org/10.1210/jc.2013-4159

51. Mazerkina NA, Gorelyshev SK, Zheludkova OG, et al. Results of growth hormone substitution therapy in children with brain tumours. Problems of Endocrinology. 2013;59(2):19-25. (In Russ.). doi: https://doi.org/10.14341/probl201359219-25

52. Mackenzie S, Craven T, Gattamaneni HR, et al. Long-term safety of growth hormone replacement after CNS irradiation. J Clin Endocrinol Metab. 2011;96(9):2756-2761. doi: https://doi.org/10.1210/jc.2011-0112

53. Brignardello E, Felicetti F, Castiglione A, et al. GH replacement therapy and second neoplasms in adult survivors of childhood cancer: A retrospective study from a single institution. J Endocrinol Invest. 2015;38(2):171-176. doi: https://doi.org/10.1007/s40618-014-0179-1

54. 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(6):698-705. doi: https://doi.org/10.1111/j.1365-2265.2005.02282.x

55. Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr. 2003;143(4):415-421. doi: https://doi.org/10.1067/s0022-3476(03)00246-4

56. Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet (London, England). 2004;363(9418):1346-1353. doi: https://doi.org/10.1016/S0140-6736(04)16044-3

57. van den Heijkant S, Hoorweg-Nijman G, Huisman J, et al. Effects of growth hormone therapy on bone mass, metabolic balance, and well-being in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2011;33(6):e231-238. doi: https://doi.org/10.1097/MPH.0b013e31821bbe7a

58. Murray RD, Darzy KH, Gleeson HK, Shalet SM. GH-deficient survivors of childhood cancer: GH replacement during adult life. J Clin Endocrinol Metab. 2002;87(1):129-135. doi: https://doi.org/10.1210/jcem.87.1.8146

59. Höybye C, Beck-Peccoz P, Simsek S, et al. Safety of current recombinant human growth hormone treatments for adults with growth hormone deficiency and unmet needs. Expert Opin Drug Saf. 2020;19(12):1539-1548. doi: https://doi.org/10.1080/14740338.2020.1839410

60. Ahmid M, Perry CG, Ahmed SF, Shaikh MG. Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement. Endocr Connect. 2016;5(3):R1-R11. doi: https://doi.org/10.1530/EC-16-0024

61. Stochholm K, Johannsson G. Reviewing the safety of GH replacement therapy in adults. Growth Horm IGF Res. 2015;25(4):149-157. doi: https://doi.org/10.1016/j.ghir.2015.06.006

62. Schiffman JD, Geller JI, Mundt E, et al. Update on pediatric cancer predisposition syndromes. Pediatr Blood Cancer. 2013;60(8):1247-1252. doi: https://doi.org/10.1002/pbc.24555

63. Yuen KCJ, Heaney AP, Popovic V. Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician. Endocrine. 2016;52(2):194-205. doi: https://doi.org/10.1007/s12020-015-0840-2

64. Høybye C, Cohen P, Hoffman AR, et al. Christiansen JS. Status of long-acting-growth hormone preparations — 2015. Growth Hormone and IGF Research. 2015;25(5):201-206. doi: https://doi.org/10.1016/j.ghir.2015.07.004