Skip to main content
SpringerLink
Log in

Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background: Recent studies have linked raised levels of IGF-I and/or reduced levels of its main binding protein, IGF binding protein (IGFBP)-3, with the risk of developing cancer. A GH dose-dependent increase in IGF-I/IGFBP-3 molar ratio has been reported in subjects treated with GH, raising concern about the long-term safety. Objective: The aim of this study was to evaluate changes in serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio over the first 12 months of replacement GH therapy in GH deficient (GHD) children. Methods: The study included 20 GHD children who had not previously received GH treatment, and 40 untreated non-GHD short children closely matched for age, gender, pubertal stage, and body mass index (BMI), as controls. Serum IGF-I, IGFBP-3 levels were measured before and after 12 months of GH treatment. Based on the molecular weight of IGF-I (7500) and IGFBP-3 (40,000, mean of glycosylated variants), we calculated the molar ratio of IGF-I/IGFBP-3. Results: IGF-I/IGFBP-3 molar ratio significantly increased during GH therapy (p=0.01). No significant difference in IGF-I/IGFBP-3 ratio was found between GHD children and controls at the different time points. In the multiple regression analysis, BMI (β=0.33) and age (β=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r2=0.53, p<0.0001). Conclusions: Our results suggest that at a conventional replacement dose GH does not alter the IGF-I/IGFBP-3 molar ratio. Potential fears related to long-term cancer risk are likely to be greatest in patients exposed to high-dose GH therapy and with genetic predisposition to high IGF-I and/or low IGFBP-3 concentrations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ogilvy-Stuart AL. Safety of growth hormone after treatment of a childhood malignancy. Horm Res 1995, 44 (Suppl 3): 73–9.

    Article  PubMed  CAS  Google Scholar 

  2. Ng ST, Zhou J, Adesanya OO, Wang J, Le Roith D, Bondy CA. Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nat Med 1997, 3: 1141–4.

    Article  PubMed  CAS  Google Scholar 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. Fürstenberger G, Senn H-J. Insulin-like growth factors and cancer. Lancet Oncol 2002, 3: 298–02.

    Article  PubMed  Google Scholar 

  5. LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett 2003, 195: 127–37.

    Article  PubMed  CAS  Google Scholar 

  6. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer 2003, 107: 873–7.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998, 279: 563–6.

    Article  PubMed  CAS  Google Scholar 

  9. Buckbinder L, Talbott R, Velasco-Miguel S, et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 1995, 377: 646–9.

    Article  PubMed  CAS  Google Scholar 

  10. Le Marchand L, Kolonel LN, Henderson BE, Wilkens LR. Association of an exon 1 polymorphism in the IGFBP3 gene with circulating IGFBP-3 levels and colorectal cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 2005, 14: 1319–21.

    Article  PubMed  Google Scholar 

  11. Cohen P. Insulin-like growth factor binding protein-3: insulin-like growth factor independence comes of age. Endocrinology 2006, 147: 2109–11.

    Article  PubMed  CAS  Google Scholar 

  12. Juul A, Pedersen SA, Sorensen S, et al. Growth hormone (GH) treatment increases serum insulin-like growth factor binding protein-3, bone isoenzyme alkaline phosphatase and forearm bone mineral content in adults with GH-deficiency of childhood onset. Eur J Endocrinol 1994, 131: 41–9.

    Article  PubMed  CAS  Google Scholar 

  13. Juul A, Main K, Blum WF, Lindholm J, Ranke MB, Skakkebaek NE. The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients. Clin Endocrinol 1994, 41: 85–93.

    Article  CAS  Google Scholar 

  14. Ghigo E, Aimaretti G, Maccario M, et al. Dose-response study of GH effects on circulating IGF-I and IGFBP-3 levels in healthy young men and women. Am J Physiol 1999, 276: E1009–13.

    PubMed  CAS  Google Scholar 

  15. Cameron N. The measurements of human growth. Sydney: Croom-Helm, 1984.

    Google Scholar 

  16. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976, 51: 170–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of hand and wrist. Stanford, CA: Stanford University Press, 1959.

    Google Scholar 

  18. Pietrobelli A, Faith MS, Allison DB, Gallanger D, Chiumello G, Heymsfield SB. Body mass index as a measure of adiposity among children and adolescents: a validation study. J Pediatr 1998, 132: 204–10.

    Article  PubMed  CAS  Google Scholar 

  19. Cianfarani S, Boemi S, Spagnoli A, et al. Is IGF binding protein-3 assessment helpful for the diagnosis of GH deficiency? Clin Endocrinol 1995, 43: 43–7.

    Article  CAS  Google Scholar 

  20. Cianfarani S, Liguori A, Boemi S, et al. Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3 assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment. J Clin Endocrinol Metab 2005, 90: 6028–34.

    Article  PubMed  CAS  Google Scholar 

  21. Gunnell D, Oliver SE, Donovan JL, et al.. Do height-related variations in insulin-like growth factors underlie the associations of stature with adult chronic disease? J Clin Endocrinol Metab 2004, 89: 213–8.

    Article  PubMed  CAS  Google Scholar 

  22. Tillmann V, Patel L, Gill MS, et al. Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth. Clin Endocrinol 2000, 53: 329–36.

    Article  CAS  Google Scholar 

  23. Milani D, Carmichael JD, Welkowitz J, et al. Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab 2004, 89: 2271–4.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Harrela M, Koistinen H, Kaprio J, et al. Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 1996, 98: 2612–5.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Deal C, Ma J, Wilkin F, et al. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab 2001, 86: 1274–80.

    PubMed  CAS  Google Scholar 

  26. Cohen, KL, Nissley SP. The serum half-life of somatomedin activity: evidence for growth hormone dependence. Acta Endocrinol (Copenh) 1976, 83: 243–58.

    CAS  Google Scholar 

  27. Davenport, ML, Clemmons DR, Miles MV, Camacho-Hubner C, D’Ercole AJ, Underwood LE. Regulation of serum insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat pregnancy. Endocrinology 1990, 127: 1278–86.

    Article  PubMed  CAS  Google Scholar 

  28. Jones JL, Clemmons DR. Insulin-like growth factors and their binding proteins. Endocr Rev 1995, 16: 3–34.

    PubMed  CAS  Google Scholar 

  29. Spagnoli A, Gargosky SE, Spadoni GL, et al. Characterization of a low molecular mass form of insulin-like growth factor binding protein-3 (17.7 kilodaltons) in urine and serum from healthy children and growth hormone (GH)-deficient patients: relationship with GH therapy. J Clin Endocrinol Metab 1995, 80: 3668–76.

    PubMed  CAS  Google Scholar 

  30. Lassarre C, Lalou C, Perin L, Binoux M. Protease-induced alteration of insulin-like growth factor binding protein-3 as detected by radioimmunoassay. Agreement with ligand blotting data. Growth Regul 1994, 4: 48–55.

    CAS  Google Scholar 

  31. Lassarre C, Binoux M. Measurement of intact insulin-like growth-factor binding protein-3 in human plasma using a ligand immunofunctional assay. J Clin Endocrinol Metab 2001, 86: 1260–6.

    PubMed  CAS  Google Scholar 

  32. Löfqvist C, Andersson E, Gelander L, et al. References values for insulin-like growth factor-binding protein-3 (IGFBP-3) and the ratio IGF-I/IGFBP-3 throughout childhood and adolescence. J Clin Endocrinol Metab 2005, 90: 1420–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. ‘Rina Balducci’ Center of Pediatric Endocrinology, Department of Public Health and Cell Biology, Room E-178, Tor Vergata University, Via Montpellier 1, IT-00133, Rome, Italy

    G. Scirè, C. Del Bianco, G. L. Spadoni & S. Cianfarani MD

Authors
  1. G. Scirè
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Del Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. L. Spadoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Cianfarani MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Cianfarani MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scirè, G., Del Bianco, C., Spadoni, G.L. et al. Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children. J Endocrinol Invest 31, 153–158 (2008). https://doi.org/10.1007/BF03345582

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345582

Key Words

Search

Navigation