DOI QR코드

DOI QR Code

Growth hormone treatment and risk of malig­nancy

  • Chae, Hyun-Wook (Department of Pediatrics, Endocrine Research Institute, Yonsei University College of Medicine) ;
  • Kim, Duk-Hee (Sowha Children's Hospital) ;
  • Kim, Ho-Seong (Department of Pediatrics, Endocrine Research Institute, Yonsei University College of Medicine)
  • Received : 2014.08.25
  • Accepted : 2014.11.06
  • Published : 2015.02.10

Abstract

Growth hormone (GH) treatment has been increasingly widely used for children with GH deficiencies as the survival rate of pediatric patients with malignancies has increased. Both GH and insulin-like growth factor-I have mitogenic and antiapoptotic activity, prompting concern that GH treatment may be associated with tumor development. In this review, the authors examined the relationship between GH treatment and cancer risk in terms of de novo malignancy, recurrence, and secondary neoplasm. Although the results from numerous studies were not entirely consistent, this review of various clinical and epidemiological studies demonstrated that there is no clear evidence of a causal relationship between GH treatment and tumor development. Nonetheless, a small number of studies reported that childhood cancer survivors who receive GH treatment have a small increased risk of developing de novo cancer and secondary malignant neoplasm. Therefore, regular follow-ups and careful examination for development of cancer should be required in children who receive GH treatment. Continued surveillance for an extended period is essential for monitoring long-term safety.

Keywords

References

  1. Blizzard RM. History of growth hormone therapy. Indian J Pediatr 2012;79:87-91. https://doi.org/10.1007/s12098-011-0609-4
  2. Laron Z. Growth hormone therapy: emerging dilemmas. Pediatr Endocrinol Rev 2011;8:364-73.
  3. Carel JC, Ecosse E, Landier F, Meguellati-Hakkas D, Kaguelidou F, Rey G, et al. 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 2012;97:416-25. https://doi.org/10.1210/jc.2011-1995
  4. Noorda EM, Somers R, van Leeuwen FE, Vulsma T, Behrendt H; Dutch Late Effects Study Group. Adult height and age at menarche in childhood cancer survivors. Eur J Cancer 2001;37:605-12. https://doi.org/10.1016/S0959-8049(00)00438-X
  5. Adan L, Sainte-Rose C, Souberbielle JC, Zucker JM, Kalifa C, Brauner R. Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation. Med Pediatr Oncol 2000;34:14-9. https://doi.org/10.1002/(SICI)1096-911X(200001)34:1<14::AID-MPO3>3.0.CO;2-W
  6. Wabitsch M, Braun S, Hauner H, Heinze E, Ilondo MM, Shymko R, et al. Mitogenic and antiadipogenic properties of human growth hormone in differentiating human adipocyte precursor cells in primary culture. Pediatr Res 1996;40:450-6. https://doi.org/10.1203/00006450-199609000-00014
  7. Ogilvy-Stuart AL, Gleeson H. Cancer risk following growth hormone use in childhood: implications for current practice. Drug Saf 2004;27:369-82. https://doi.org/10.2165/00002018-200427060-00002
  8. Banerjee I, Clayton PE. Growth hormone treatment and cancer risk. Endocrinol Metab Clin North Am 2007;36:247-63. https://doi.org/10.1016/j.ecl.2006.11.007
  9. Sklar CA. Growth hormone treatment: cancer risk. Horm Res 2004;62 Suppl 3:30-4.
  10. Pekic S, Popovic V. GH therapy and cancer risk in hypopituitarism: what we know from human studies. Eur J Endocrinol 2013;169:R89-97. https://doi.org/10.1530/EJE-13-0389
  11. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000;21:215-44. https://doi.org/10.1210/edrv.21.3.0399
  12. Furstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol 2002;3:298-302. https://doi.org/10.1016/S1470-2045(02)00731-3
  13. Mercola KE, Cline MJ, Golde DW. Growth hormone stimulation of normal and leukemic human T-lymphocyte proliferation in vitro. Blood 1981;58:337-40.
  14. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer 2003;107:873-7. https://doi.org/10.1002/ijc.11487
  15. Cohen P, Clemmons DR, Rosenfeld RG. Does the GH-IGF axis play a role in cancer pathogenesis? Growth Horm IGF Res 2000;10:297-305. https://doi.org/10.1054/ghir.2000.0171
  16. Watanabe S, Tsunematsu Y, Fujimoto J, Komiyama A. Leukemia in patients treated with growth-hormone. Lancet 1988;1:1159-60.
  17. Nishi Y, Tanaka T, Takano K, Fujieda K, Igarashi Y, Hanew K, et al. Recent status in the occurrence of leukemia in growth hormonetreated patients in Japan. GH Treatment Study Committee of the Foundation for Growth Science, Japan. J Clin Endocrinol Metab 1999;84:1961-5. https://doi.org/10.1210/jcem.84.6.5716
  18. Fradkin JE, Mills JL, Schonberger LB, Wysowski DK, Thomson R, Durako SJ, et al. Risk of leukemia after treatment with pituitary growth hormone. JAMA 1993;270:2829-32. https://doi.org/10.1001/jama.1993.03510230067037
  19. Allen DB, Rundle AC, Graves DA, Blethen SL. Risk of leukemia in children treated with human growth hormone: review and reanalysis. J Pediatr 1997;131(1 Pt 2):S32-6. https://doi.org/10.1016/S0022-3476(97)70008-8
  20. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab 2010;95:167-77. https://doi.org/10.1210/jc.2009-0178
  21. Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 2002;360:273-7. https://doi.org/10.1016/S0140-6736(02)09519-3
  22. Tyden G, Wernersson A, Sandberg J, Berg U. Development of renal cell carcinoma in living donor kidney grafts. Transplantation 2000;70:1650-6. https://doi.org/10.1097/00007890-200012150-00018
  23. Mehls O, Wilton P, Lilien M, Berg U, Broyer M, Rizzoni G, et al. Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr Nephrol 2002;17:984-9. https://doi.org/10.1007/s00467-002-0962-7
  24. Tuffli GA, Johanson A, Rundle AC, Allen DB. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab 1995;80:1416-22.
  25. Moshang T Jr, Rundle AC, Graves DA, Nickas J, Johanson A, Meadows A. Brain tumor recurrence in children treated with growth hormone: the National Cooperative Growth Study experience. J Pediatr 1996;128(5 Pt 2):S4-7. https://doi.org/10.1016/S0022-3476(96)70002-1
  26. Wilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr 2010;157:265-70. https://doi.org/10.1016/j.jpeds.2010.02.028
  27. Haddy TB, Mosher RB, Nunez SB, Reaman GH. Growth hormone deficiency after chemotherapy for acute lymphoblastic leukemia in children who have not received cranial radiation. Pediatr Blood Cancer 2006;46:258-61. https://doi.org/10.1002/pbc.20485
  28. Leung W, Rose SR, Zhou Y, Hancock ML, Burstein S, Schriock EA, et al. Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2002;20:2959-64. https://doi.org/10.1200/JCO.2002.09.142
  29. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab 1996;81:1704-10.
  30. Maneatis T, Baptista J, Connelly K, Blethen S. Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Endocrinol Metab 2000;13 Suppl 2:1035-44.
  31. Wyatt D. Lessons from the national cooperative growth study. Eur J Endocrinol 2004;151 Suppl 1:S55-9. https://doi.org/10.1530/eje.0.151S055
  32. 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. https://doi.org/10.1210/jcem.87.7.8606
  33. Bernier V. Technical aspects in cerebrospinal irradiation. Pediatr Blood Cancer 2004;42:447-51. https://doi.org/10.1002/pbc.10468
  34. Arslanian SA, Becker DJ, Lee PA, Drash AL, Foley TP Jr. Growth hormone therapy and tumor recurrence. Findings in children with brain neoplasms and hypopituitarism. Am J Dis Child 1985;139:347-50. https://doi.org/10.1001/archpedi.1985.02140060029020
  35. Clayton PE, Shalet SM, Gattamaneni HR, Price DA. Does growth hormone cause relapse of brain tumours? Lancet 1987;1:711-3.
  36. Ranke MB, Price DA, Lindberg A, Wilton P, Darendeliler F, Reiter EO. Final height in children with medulloblastoma treated with growth hormone. Horm Res 2005;64:28-34. https://doi.org/10.1159/000087325
  37. Chae HW, Park YS, Kim DS, Kwon AR, Kim HS, Kim DH. Final height and insulin-like growth factor-1 in children with medulloblastoma treated with growth hormone. Childs Nerv Syst 2013;29:1859-63. https://doi.org/10.1007/s00381-013-2124-6
  38. 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. https://doi.org/10.1200/JCO.2001.19.2.480
  39. Price DA, Jonsson P. Effect of growth hormone treatment in children with craniopharyngioma with reference to the KIGS (Kabi International Growth Study) database. Acta Paediatr Suppl 1996;417:83-5.
  40. Hogeveen M, Noordam C, Otten B, Wit JM, Massa G. Growth before and during growth hormone treatment in children operated for craniopharyngioma. Horm Res 1997;48:258-62. https://doi.org/10.1159/000185531
  41. Price DA, Wilton P, Jonsson P, Albertsson-Wikland K, Chatelain P, Cutfield W, et al. Efficacy and safety of growth hormone treatment in children with prior craniopharyngioma: an analysis of the Pharmacia and Upjohn International Growth Database (KIGS) from 1988 to 1996. Horm Res 1998;49:91-7. https://doi.org/10.1159/000023133
  42. Weiss M, Sutton L, Marcial V, Fowble B, Packer R, Zimmerman R, et al. The role of radiation therapy in the management of childhood craniopharyngioma. Int J Radiat Oncol Biol Phys 1989;17:1313-21. https://doi.org/10.1016/0360-3016(89)90543-9
  43. Swerdlow AJ, Reddingius RE, Higgins CD, Spoudeas HA, Phipps K, Qiao Z, et al. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J Clin Endocrinol Metab 2000;85:4444-9.
  44. 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. https://doi.org/10.1210/jcem.86.11.8018
  45. Henderson TO, Rajaraman P, Stovall M, Constine LS, Olive A, Smith SA, et al. Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 2012;84:224-30. https://doi.org/10.1016/j.ijrobp.2011.11.022
  46. Meadows AT, Friedman DL, Neglia JP, Mertens AC, Donaldson SS, Stovall M, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 2009;27:2356-62. https://doi.org/10.1200/JCO.2008.21.1920
  47. Henderson TO, Whitton J, Stovall M, Mertens AC, Mitby P, Friedman D, et al. Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2007;99:300-8. https://doi.org/10.1093/jnci/djk052
  48. 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. https://doi.org/10.1210/jc.2006-0656
  49. Carel JC, Butler G. Safety of recombinant human growth hormone. Endocr Dev 2010;18:40-54. https://doi.org/10.1159/000316126
  50. Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 2001;93:618-29. https://doi.org/10.1093/jnci/93.8.618
  51. Patterson BC, Chen Y, Sklar CA, Neglia J, Yasui Y, Mertens A, 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;99:2030-7. https://doi.org/10.1210/jc.2013-4159
  52. Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-53. https://doi.org/10.1016/S0140-6736(04)16044-3
  53. Kelnar CJ. Which children should receive growth hormone treatment. Cost-benefit analysis is the key. Arch Dis Child 2000;83:176-8. https://doi.org/10.1136/adc.83.2.176

Cited by

  1. The effect of a 10-week Nordic walking training program on the level of GH and LH in elderly women vol.18, pp.6, 2015, https://doi.org/10.3109/13697137.2015.1058354
  2. Mortality and cancer incidence among patients treated with recombinant growth hormone during childhood in Israel vol.85, pp.5, 2015, https://doi.org/10.1111/cen.13131
  3. Long-term safety and efficacy of Omnitrope®, a somatropin biosimilar, in children requiring growth hormone treatment: Italian interim analysis of the PATRO Children study vol.42, pp.1, 2015, https://doi.org/10.1186/s13052-016-0302-3
  4. The relationship between serum levels of prolactin and growth hormone in the early postnatal period vol.82, pp.5, 2015, https://doi.org/10.1038/pr.2017.164
  5. Advances in paediatrics in 2016: current practices and challenges in allergy, autoimmune diseases, cardiology, endocrinology, gastroenterology, infectious diseases, neonatology, nephrology, neurology, vol.43, pp.1, 2015, https://doi.org/10.1186/s13052-017-0401-9
  6. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects vol.9, pp.None, 2015, https://doi.org/10.3389/fendo.2018.00035
  7. Der Effekt von Wachstumshormon auf die menschlichen Alterungsprozesse. Teil 2 vol.21, pp.4, 2015, https://doi.org/10.1007/s41975-018-0064-y
  8. aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1 vol.8, pp.None, 2015, https://doi.org/10.1038/s41598-018-24678-4
  9. Der Effekt von Wachstumshormon auf die menschlichen Alterungsprozesse. Teil 2 vol.28, pp.4, 2015, https://doi.org/10.1007/s41974-018-0059-3
  10. DNA LIGASE IV SYNDROME: A RARE CAUSE OF GROWTH FAILURE & HYPOGONADISM vol.5, pp.2, 2015, https://doi.org/10.4158/accr-2018-0291