Skip to main content
SpringerLink
Log in

The effect of GH therapy on the immunoreactive forms and distribution of IGFBP-3, IGF-I, the acid-labile subunit, and growth rate in GH-deficient children

  • Original Articles
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

We have previously shown that the major correlates of growth following growth hormone (GH) therapy in growth hormone-deficient (GHD) children are changes in circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), suggesting a synergistic interaction between IGF-I and IGFBP-3 (1). The first aim of this project was to examine the molecular forms of IGFBP-3 and the acid-labile subunit (ALS), and to assess the changes in these molecular forms during GH administration to GHD children. Plasma samples from prepubertal GHD patients, prior to therapy and during the first year of GH treatment, were subjected to Western ligand and immunoblot analysis. Densitometric analysis of Western ligand blotting (WLB) showed a 76% increase in IGFBP-3 (p=0.02), but a 56% decrease in 36-kDa IGFBP-2 (p=0.03) during GH therapy. Western immunoblot (WIB) analysis of IGFBP-3 revealed the presence of intact (40- to 45-kDa doublet) as well as a proteolyzed (28-kDa) form of IGFBP-3 in the serum of GHD and healthy children. Both immunoreactive forms of IGFBP-3 increased by 64% during GH therapy (intactp=0.003; proteolyzedp=0.0001). WIB analysis of the ALS showed an 84-to 86-kDa doublet, which increased by 41% with GH therapy (p=0.01). The response to GH therapy, as measured by the height velocity standard deviation score (SDS) adjusted for bone age, correlated with the percent change in total IGFBP-3 (r=0.772,p=0.002 by WIB), intact IGFBP-3 (r=0.845,p=0.0005 by WLB;r=0.541,p-0.05 by WIB), and proteolyzed IGFBP-3 (r=0.703,p=0.007), as well as with the percent change in ALS (r=0.813,p=0.014).

The second aim of this project was to assess the changes in distribution of the immunoreactive forms of IGFBP-3 and IGF-I among the ternary (ALS/IGFBP-3/IGF) complex, the binary (IGFBP-3/IGF) complex, and uncomplexed IGF during the first year of GH therapy, and to explore further the correlation with growth response to GH. Plasma samples, prior to therapy and after the first year of GH treatment, were separated by neutral size-exclusion chromatography and then subjected to IGFBP-3 immunoradiometric assay (IRMA), IGFBP-3 WIB, and IGF-I IRMA analysis. IGFBP-3 increased in both the ternary (p<0.0001) and binary (p=0.01) complexes, but there was a shift in the percentage of IGFBP-3 from the binary to the ternary complex during GH therapy. Both intact and proteolyzed forms of IGFBP-3 were found in both the ternary and binary complexes, but the shift occurred primarily for the proteolyzed (28-kDa) form (p=0.001). There was a significant increase in IGF-I in the ternary (p=0.001) and binary (p=0.005) complexes, but not in uncomplexed IGF-I. The percentage of IGF-I in the ternary complex increased (p=0.006), whereas the percentage of uncomplexed IGF-I decreased (p=0.02), during GH therapy. Growth rate, assessed by the height velocity SDS for bone age, correlated best with the changes in ternary complex IGFBP-3 (r=0.72,p=0.01) and ternary complex IGF-I (r=0.56,p=0.10).

In conclusion, GH treatment of GHD children results in significant increases of intact, proteolyzed, and total IGFBP-3, as well as an increase in ALS, which all correlate with the growth response to GH therapy. In addition, GH treatment results in increases in ternary complex IGFBP-3 and IGF-I, which also correlate with the response to therapy. We suggest that the formation of the ternary complex may be a determining factor in the somatic growth response.

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. Mandel, S., Moreland, E., Nichols, V., Hanna, C., and LaFranchi, S. (1995).J. Clin. Endocrinol. Metab. 80, 190–194.

    Article  PubMed  CAS  Google Scholar 

  2. Baxter, R. C. (1988).Comp. Biochem. Physiol. 91, 229–235.

    CAS  Google Scholar 

  3. Baxter, R. C. and Martin, J. L. (1989).Prog. Growth Factor Res. 1, 49–68.

    Article  PubMed  CAS  Google Scholar 

  4. Holly, J. M. P. and Wass, J. A. H. (1989).J. Endocrinol. 122, 611–618.

    Article  PubMed  CAS  Google Scholar 

  5. Rosenfeld, R. G., Lamson, G. L., Pham, H., Oh, Y., Conover, C., DeLeon, D. D., et al. (1991).Recent Prog. Hormone Res. 46, 99–159.

    Google Scholar 

  6. Shimasaki, S. and Ling, N. (1991).Prog. Growth Factor Res. 3, 243–266.

    Article  PubMed  CAS  Google Scholar 

  7. Kelly, K. M., Oh, Y., Gasgosky, S. E., Gucev, Z., Matsumoto, T., Hwa, V., et al. (1996).Int. J. Biochem. 28, 619–637.

    Article  Google Scholar 

  8. Jones, J. I. and Clemmons, D. R. (1995).Endocr. Rev. 16, 3–34.

    Article  PubMed  CAS  Google Scholar 

  9. Rosenbloom, A. L., Guevara-Aguirre, J., Martinez, A. L., Martinez, V., Vasconez, O., Rosenfeld, R. G., et al. (1995).Pediatr. Res. 37, 97A.

    Google Scholar 

  10. Blum, W. F., Ranke, M. B., Kietzmann, K., Gauggel, E., Zeisel, H. J., and Bierich, J. R. (1990).J. Clin. Endocrinol. Metab. 70, 1292–1298.

    PubMed  CAS  Google Scholar 

  11. Smith, W. J., Nam, T. J., Underwood, L. E., Busby, W. H., Celnicker, A., and Clemmons, D. R. (1993).J. Clin. Endocrinol. Metab. 77, 1294–1299.

    Article  PubMed  CAS  Google Scholar 

  12. Clemmons, D. R., Busby, W. H., and Snyder, D. K. (1991).J. Clin. Endocrinol. Metab. 73, 727–733.

    PubMed  CAS  Google Scholar 

  13. Cohick, W. S., McGuire, M. A., Clemmons, D. R., and Bauman, D. E. (1992).Endocrinology 130, 1508–1514.

    Article  PubMed  CAS  Google Scholar 

  14. Suikkari, A. M. and Baxter, R. C. (1991).J. Clin. Endocrinol. Metab. 73, 1377–1379.

    PubMed  CAS  Google Scholar 

  15. Hossenlopp, P., Segovia, B., Lassarre, C., Roghani, M., Bredon, M., and Binoux, M. (1990).J. Clin. Endocrinol. Metab. 71, 797–805.

    PubMed  CAS  Google Scholar 

  16. Giudice, L. C., Farrell, E. M., Pham, H., Lamson, G., and Rosenfeld, R. G. (1990).J. Clin. Endocrinol. Metab. 71, 806–817.

    PubMed  CAS  Google Scholar 

  17. Bang, P., Stangenberg, M., Westgren, M., and Rosenfeld, R. G. (1994).Growth Regul. 4(2), 68–76.

    PubMed  CAS  Google Scholar 

  18. Gargosky, S. E., Wilson, K. F., Fielder, P. J., Baxter, R. C., Vacarello, M. A., Diamond, F. B., et al. (1993).J. Clin. Endocrinol. Metab. 77, 1683–1689.

    Article  PubMed  CAS  Google Scholar 

  19. Spagnoli, A., Gargosky, S. E., Spadoni, G. L., MacGillivary, M., Oh, Y., Boscherini, B., et al. (1995).J. Clin. Endocrinol. Metab. 80, 3668–3676.

    Article  PubMed  CAS  Google Scholar 

  20. Gargosky, S. E., Pham, H. M., Wilson, K. F., Liu, F., Giudice, L. C., and Rosenfeld, R. G. (1992).Endocrinology 131, 3051–3060.

    Article  PubMed  CAS  Google Scholar 

  21. Liu, F., Baxter, R. C., and Hintz, R. L. (1992).J. Clin. Endocrinol. Metab. 75, 1261–1267.

    Article  PubMed  CAS  Google Scholar 

  22. Baxter, R. C. (1990).J. Clin. Endocrinol. Metab. 70, 1347–1353.

    Article  PubMed  CAS  Google Scholar 

  23. Labarta, J., Gargosky, S. E., Simpson, D., Aguirre, J. G., and Rosenfeld, R. G. (1997).Clin. Endocrinol. 47, 657–666.

    Article  CAS  Google Scholar 

  24. Conover, C. A. and Powell, D. R. (1991).Endocrinology 129, 710–716.

    PubMed  CAS  Google Scholar 

  25. Binoux, M., Roghani, M., Hossenlopp, P., Hardouin, S., and Gourmelen, M. (1991),Acta Endocrinol. 124(Suppl.2), 41–47.

    PubMed  CAS  Google Scholar 

  26. Greulich, W. W. and Pyle, S. I. (1950).Radiologic Atlas of Skeletal Development of the Hand and Wrist. Stanford University Press, Stanford, CA.

    Google Scholar 

  27. Mandel, S., Moreland, E., Rosenfeld, R. G., and Gargosky, S. E. (1996).Endocrine 5, 1–8.

    Article  CAS  Google Scholar 

  28. Van Obberghen-Schilling, E. and Pouyssegur, J. (1983).Exp. Cell Biol. 151, 207–214.

    Google Scholar 

  29. Gargosky, S. E., Pham, H. P., Wilson, K. F., Liu, F., Giudice, L. C., and Rosenfeld, R. G. (1992).Endocrinology 131, 3051–3060.

    Article  PubMed  CAS  Google Scholar 

  30. Hossenlopp, P., Seurin, D., Segovia-Quinson, B., Hardouin, S., and Binoux, M. (1986).Anal. Biochem. 154, 138–143.

    Article  PubMed  CAS  Google Scholar 

  31. Laemmli, U. K. (1970).Nature 227, 680–685.

    Article  PubMed  CAS  Google Scholar 

  32. Towbin, H., Staehlin, T., and Gordon, J. (1979).Proc. Natl. Acad. Sci. USA 76, 4350–4354.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Oregon Health Sciences University, 10043 S.W. Quail Post Rd., 97219, Portland, OR

    Scott H. Mandel, Erin Moreland, Ron G. Rosenfeld & Sharron E. Gargosky

Authors
  1. Scott H. Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erin Moreland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ron G. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sharron E. Gargosky
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mandel, S.H., Moreland, E., Rosenfeld, R.G. et al. The effect of GH therapy on the immunoreactive forms and distribution of IGFBP-3, IGF-I, the acid-labile subunit, and growth rate in GH-deficient children. Endocr 7, 351–360 (1997). https://doi.org/10.1007/BF02801330

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02801330

Key Words

Search

Navigation