Skip to main content
SpringerLink
Log in

Utility of Free IGF-I Measurements

  • Original Paper
  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

For nearly 30 years, the endogenous bioactivity of insulin-like growth factor I (IGF-I) has been estimated by its circulating concentrations of immunoreactive IGF-I, obtained after either removal or inactivation of the IGF-binding proteins (IGFBPs), and today serum/plasma total IGF-I serves as a useful parameter in the diagnosis and clinical control of growth hormone (GH) disorders. Different assays for the measurement of free, unbound IGF-I were introduced more than a decade ago. Nevertheless, this measurement remains controversial, and in daily clinical practice serum total IGF-I has retained its position as the most widely used IGF-related measurement in GH disorders. This review will provide a survey of data on free versus total IGF-I, with particular reference to GH disorders. As it will be clear, there is reasonable clinical evidence to conclude that both in the diagnosis of as well as during treatment of patients with GH disorders, serum/plasma total IGF-I should remain the primary IGF-related measurement. However, in certain patients the inclusion of free IGF-I may be useful and therefore, some guidelines for the inclusion of free IGF-I measurements will be given.

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. Van den Brande JL (1999) A personal view on the early history of the insulin-like growth factors. Horm Res 51(Suppl 3):149–175

    Article  PubMed  Google Scholar 

  2. Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518

    Article  PubMed  CAS  Google Scholar 

  3. Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17:328–336

    Article  PubMed  CAS  Google Scholar 

  4. Samani AA, Yakar S, LeRoith D, Brodt P (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20–47

    Article  PubMed  CAS  Google Scholar 

  5. Carro E, Torres-Aleman I (2006) Serum insulin-like growth factor I in brain function. Keio J Med 55:59–63

    Article  PubMed  CAS  Google Scholar 

  6. Frystyk J (2004) Free insulin-like growth factors–measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res 14:337–375

    Article  PubMed  CAS  Google Scholar 

  7. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jørgensen T (2002) Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106:939–944

    Article  PubMed  CAS  Google Scholar 

  8. Juul A (2003) Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res 13:113–170

    Article  PubMed  CAS  Google Scholar 

  9. LeRoith D, Bondy C, Yakar S, Liu JL, Butler A (2001) The somatomedin hypothesis: 2001. Endocr Rev 22:53–74

    Article  CAS  Google Scholar 

  10. Furlanetto RW, Underwood LE, Van Wyk JJ, D’Ercole AJ (1977) Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest 60:648–657

    Article  PubMed  CAS  Google Scholar 

  11. Clemmons DR (2001) Commercial assays available for insulin-like growth factor I and their use in diagnosing growth hormone deficiency. Horm Res 55(Suppl 2):73–79

    Article  PubMed  CAS  Google Scholar 

  12. Frystyk J, Skjærbæk C, Dinesen B, Ørskov H (1994) Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Lett 348:185–191

    Article  PubMed  CAS  Google Scholar 

  13. Frystyk J, Ivarsen P, Støving RK, Dall R, Bek T, Hagen C, Ørskov H (2001) Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay. Growth Horm IGF Res 11:117–127

    Article  PubMed  CAS  Google Scholar 

  14. Takada M, Nakanome H, Kishida M, Hirose S, Hasegawa T, Hasegawa Y (1994) Measurement of free insulin-like growth factor-I using immunoradiometric assay. J Immunoassay 15:263–276

    PubMed  CAS  Google Scholar 

  15. Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34

    Article  PubMed  CAS  Google Scholar 

  16. Silha JV, Murphy LJ (2002) Insights from insulin-like growth factor binding protein transgenic mice. Endocrinology 143:3711–3714

    Article  PubMed  CAS  Google Scholar 

  17. Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854

    Article  PubMed  CAS  Google Scholar 

  18. Rajaram S, Baylink DJ, Mohan S (1997) Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18:801–831

    Article  PubMed  CAS  Google Scholar 

  19. Ekins R (1990) Measurement of free hormone in blood. Endocr Rev 11:5–46

    PubMed  CAS  Google Scholar 

  20. Bang P, Ahlsen M, Berg U, Carlsson-Skwirut C (2001) Free insulin-like growth factor I: are we hunting a ghost? Horm Res 55(Suppl 2):84–93

    Article  PubMed  CAS  Google Scholar 

  21. Juul A, Flyvbjerg A, Frystyk J, Müller J, Skakkebæk NE (1996) Serum concentrations of free and total insulin-like growth factor-I, IGF binding proteins-1 and -3 and IGFBP-3 protease activity in boys with normal or precocious puberty. Clin Endocrinol (Oxf) 44:515–523

    Article  CAS  Google Scholar 

  22. Juul A, Holm K, Kastrup KW, Pedersen SA, Michaelsen KF, Scheike T, Rasmussen S, Müller J, Skakkebæk NE (1997) Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. J Clin Endocrinol Metab 82:2497–2502

    Article  PubMed  CAS  Google Scholar 

  23. Sadick MD (1999) Kinase receptor activation (KIRA): a rapid and accurate alternative to endpoint bioassays. Dev Biol Stand 97:121–133

    PubMed  CAS  Google Scholar 

  24. Chen JW, Ledet T, Ørskov H, Jessen N, Lund S, Whittaker J, De Meyts P, Larsen MB, Christiansen JS, Frystyk J (2003) A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum. Am J Physiol Endocrinol Metab 284:E1149–E1155

    PubMed  CAS  Google Scholar 

  25. Boni Schnetzler M, Schmid C, Meier PJ, Froesch ER (1991) Insulin regulates insulin-like growth factor I mRNA in rat hepatocytes. Am J Physiol 260:E846–E851

    PubMed  CAS  Google Scholar 

  26. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK (2000) Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 85:4712–4720

    Article  PubMed  CAS  Google Scholar 

  27. Wurzburger MI, Prelevic GM, Sonksen PH, Balint Peric LA, Wheeler M (1993) The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes. J Clin Endocrinol Metab 77:267–272

    Article  PubMed  CAS  Google Scholar 

  28. Chapman IM, Hartman ML, Pieper KS, Skiles EH, Pezzoli SS, Hintz RL, Thorner MO (1998) Recovery of growth hormone release from suppression by exogenous insulin-like growth factor-I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I. J Clin Endocrinol Metab 83:2836–2842

    Article  PubMed  CAS  Google Scholar 

  29. Chen JW, Højlund K, Beck-Nielsen H, Sandahl CJ, Ørskov H, Frystyk J (2005) Free rather than total circulating insulin-like growth factor-I determines the feedback on growth hormone release in normal subjects. J Clin Endocrinol Metab 90:366–371

    Article  PubMed  CAS  Google Scholar 

  30. Sizonenko PC, Clayton PE, Cohen P, Hintz RL, Tanaka T, Laron Z (2001) Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 1: diagnosis of growth hormone deficiency. Growth Horm IGF Res 11:137–165

    Article  PubMed  CAS  Google Scholar 

  31. Shalet SM, Toogood A, Rahim A, Brennan BM (1998) The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 19:203–223

    Article  PubMed  CAS  Google Scholar 

  32. Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KK (1994) Diagnosis of growth-hormone deficiency in adults. Lancet 343:1064–1068

    Article  PubMed  CAS  Google Scholar 

  33. Yu H, Mistry J, Nicar MJ, Khosravi MJ, Diamandis A, Van Doorn J, Juul A (1999) Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation. J Clin Lab Anal 13:166–172

    Article  PubMed  CAS  Google Scholar 

  34. Marzullo P, Di Somma C, Pratt KL, Khosravi J, Diamandis A, Lombardi G, Colao A, Rosenfeld RG (2001) Usefulness of different biochemical markers of the insulin-like growth factor (IGF) family in diagnosing growth hormone excess and deficiency in adults. J Clin Endocrinol Metab 86:3001–3008

    Article  PubMed  CAS  Google Scholar 

  35. Hilding A, Brismar K, Degerblad M, Thoren M, Hall K (1995) Altered relation between circulating levels of insulin-like growth factor-binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects. J Clin Endocrinol Metab 80:2646–2652

    Article  PubMed  CAS  Google Scholar 

  36. Smith WJ, Nam TJ, Underwood LE, Busby WH, Celnicker A, Clemmons DR (1993) Use of insulin-like growth factor-binding protein-2 (IGFBP-2), IGFBP-3, and IGF-I for assessing growth hormone status in short children. J Clin Endocrinol Metab 77:1294–1299

    Article  PubMed  CAS  Google Scholar 

  37. Skjærbæk C, Kaal A, Møller J, Vahl N, Weeke J, Ørskov H, Flyvbjerg A (1998) No effect of growth hormone on serum insulin-like growth factor binding protein-3 proteolysis. J Clin Endocrinol Metab 83:1206–1210

    Article  PubMed  Google Scholar 

  38. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ (2000) Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 342:1171–1177

    Article  PubMed  CAS  Google Scholar 

  39. Jørgensen JOL, Feldt-Rasmussen U, Frystyk J, Chen JW, Kristensen LØ, Hagen C, Ørskov H (2005) Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. J Clin Endocrinol Metab 90:5627–5631

    Article  PubMed  CAS  Google Scholar 

  40. van der Hoek J, van der Lelij A-J, Feelders RA, de Herder WW, Uitterlinden P, Poon KW, Boerlin V, Lewis I, Krahnke T, Hofland LJ, Lamberts SW (2005) The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients. Clin Endocrinol 63:176–184

    Article  CAS  Google Scholar 

  41. Kaal A, Frystyk J, Skjærbæk C, Nielsen S, Jørgensen JOL, Bruns C, Marbach P, Lancranjan I, Weeke J, Ørskov H (1995) Effects of intramuscular microsphere-encapsulated octreotide on serum growth hormone, insulin-like growth factors (IGFs), free IGFs, and IGF-binding proteins in acromegalic patients. Metabolism 44(suppl 1):6–14

    Article  CAS  Google Scholar 

  42. Iranmanesh A, Lizarralde G, Veldhuis JD (1991) Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 73:1081–1088

    Article  PubMed  CAS  Google Scholar 

  43. Scacchi M, Pincelli AI, Cavagnini F (1999) Growth hormone in obesity. Int J Obes Relat Metab Disord 23:260–271

    Article  PubMed  CAS  Google Scholar 

  44. Frystyk J, Vestbo E, Skjærbæk C, Mogensen CE, Ørskov H (1995) Free insulin-like growth factors in human obesity. Metabolism 44:37–44

    Article  PubMed  CAS  Google Scholar 

  45. Rasmussen MH, Juul A, Kjems LL, Hilsted J (2006) Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects. Eur J Endocrinol 155:575–581

    Article  PubMed  CAS  Google Scholar 

  46. Fisker S (2006) Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects. Growth Horm IGF Res 16:1–28

    Article  PubMed  CAS  Google Scholar 

  47. Maccario M, Tassone F, Gauna C, Oleandri SE, Aimaretti G, Procopio M, Grottoli S, Pflaum CD, Strasburger CJ, Ghigo E (2001) Effects of short-term administration of low-dose rhGH on IGF-I levels in obesity and Cushing’s syndrome: indirect evaluation of sensitivity to GH. Eur J Endocrinol 144:251–256

    Article  PubMed  CAS  Google Scholar 

  48. Jehle PM, Ostertag A, Schulten K, Schulz W, Jehle DR, Stracke S, Fiedler R, Deuber HJ, Keller F, Boehm BO, Baylink DJ, Mohan S (2000) Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy. Kidney Int 57:423–436

    Article  PubMed  CAS  Google Scholar 

  49. Frystyk J, Ivarsen P, Skjærbæk C, Flyvbjerg A, Pedersen EB, Ørskov H (1999) Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure. Kidney Int 56:2076–2084

    Article  PubMed  CAS  Google Scholar 

  50. Hasegawa Y, Hasegawa T, Takada M, Tsuchiya Y (1996) Plasma free insulin-like growth factor I concentrations in growth hormone deficiency in children and adolescents. Eur J Endocrinol 134:184–189

    Article  PubMed  CAS  Google Scholar 

  51. Skjærbæk C, Vahl N, Frystyk J, Hansen TB, Jørgensen JO, Hagen C, Christiansen JS, Ørskov H (1997) Serum free insulin-like growth factor-I in growth hormone-deficient adults before and after growth hormone replacement. Eur J Endocrinol 137:132–137

    Article  PubMed  Google Scholar 

  52. Kawai N, Kanzaki S, Takano-Watou S, Tada C, Yamanaka Y, Miyata T, Oka M, Seino Y (1999) Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF-binding protein-3 concentrations in normal children and children with growth hormone deficiency. J Clin Endocrinol Metab 84:82–89

    Article  PubMed  CAS  Google Scholar 

  53. Musolino NR, Cunha Neto MB, Marino JR, Giannella-Neto D, Bronstein MD (1999) Evaluation of free insulin-like growth factor-I measurement on the diagnosis and follow-up treatment of growth hormone-deficient adult patients. Clin Endocrinol (Oxf) 50:441–449

    Article  CAS  Google Scholar 

  54. Stoffel-Wagner B, Springer W, Bidlingmaier F, Klingmuller D (1997) A comparison of different methods for diagnosing acromegaly. Clin Endocrinol (Oxf) 46:531–537

    Article  CAS  Google Scholar 

  55. Sneppen SB, Lange M, Pedersen LM, Kristensen LL, Main KM, Juul A, Skakkebæk NE, Feldt-Rasmussen U (2001) Total and free insulin-like growth factor I, insulin-like growth factor binding protein 3 and acid-labile subunit reflect clinical activity in acromegaly. Growth Horm IGF Res 11:384–391

    Article  PubMed  CAS  Google Scholar 

  56. van der Lely AJ, de HW, Janssen JA, Lamberts SW (1997) Acromegaly: the significance of serum total and free IGF-I and IGF-binding protein-3 in diagnosis. J Endocrinol 155(Suppl 1):S9–S13

    PubMed  Google Scholar 

Download references

Acknowledgment

JF is supported by a grant from the Danish Medical Research Council.

Author information

Authors and Affiliations

  1. Medical Research Laboratories, Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Building No. 3, basement, Aarhus Sygehus, Nørrebrogade 44, 8000, Aarhus C, Denmark

    Jan Frystyk

Authors
  1. Jan Frystyk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan Frystyk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frystyk, J. Utility of Free IGF-I Measurements. Pituitary 10, 181–187 (2007). https://doi.org/10.1007/s11102-007-0025-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-007-0025-y

Keywords

Search

Navigation