In blood, circulating IGFs are bound to six high-affinity IGFBPs, which modulate IGF delivery to target cells. Serum IGFs and IGFBP-3, the main carrier of IGFs, are upregulated by GH. The functional role of serum IGFBP-3-bound IGFs is not well understood, but they constitute the main reservoir of IGFs in the circulation. We have used an equation derived from the law of mass action to estimate serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II, as well as serum free IGF-I and free IGF-II, in 129 control children and adolescents (48 girls and 81 boys) and in 13 patients with GHD. Levels of serum total IGF-I, total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined experimentally, while those of IGFBP-4, IGFBP-5 and IGFPB-6, as well as the 12 affinity constants of association of the two IGFs with the six IGFBPs, were taken from published values. A correction for in vivo proteolysis of serum IGFBP-3 was also considered. In controls, serum total IGF-I, total IGF-II, IGFBP-3, IGFBP-3-bound IGF-I, IGFBP-3-bound IGF-II and free IGF-I increased linearly with age, from less than 1 to 15 years, in the two sexes. The concentrations of serum free IGF-I and free IGF-II were approximately two orders of magnitude below published values, as well as below the affinity constant of association of IGF-I with the type-1 IGF receptor. Therefore, it is unlikely that these levels can interact with the receptor. In the 13 patients with GHD, mean (± SD) SDS of serum IGFBP-3-bound IGF-I was –2.89 ± 0.97. It was significantly lower than serum total IGF-I, free IGF-I or IGFBP-3 SDSs (–2.35 ± 0.83, –1.12 ± 0.78 and –2.55 ± 1.07, respectively, p = 0.0001). The mean SDS of serum total IGF-II, IGFBP-3-bound IGF-II and free IGF-II were –1.25 ± 0.68, –2.03 ± 0.87 and 0.59 ± 1.10, respectively, in GHD. In control subjects, 89.8 ± 4.47% of serum total IGF-I and 77.3 ± 9.4% of serum total IGF-II were bound to serum IGFBP-3. In patients with GHD, the mean serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II were 8.63 ± 8.53 and 19.1 ± 14.7% below the respective means of control subjects (p < 0.02). In conclusion, in GHD there was a relative change in the distribution of serum IGFs among IGFBPs, due to the combined effects of the decrease in both total IGF-I and IGFBP-3. As a result, serum IGFBP-3-bound IGF-I and IGFBP-3 bound IGF-II, the main reservoirs of serum IGFs, were severely affected. This suggests that the decrease in serum IGFPB-3-bound IGF-I and IGFBP-3-bound IGF-II might have a negative effect for growth promotion and other biological effects of IGF-I and IGF-II. Finally, the estimation of serum IGFBP-3-bound IGF-I, or the percentage of total IGF-I and IGF-II bound to IGFBP-3, might be useful markers in the diagnosis of GHD.

Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Reasier SD, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, Melmed S, Preece M, Ranke M, Reiter EO, Rogol AD, Underwood LE, Wherter GA: Diagnostic controversy: The diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 1995;80:1532–1540.
Rikken B, van Doorn J, Ringeling A, Van den Branden JL, Massa G, Wit JM: Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood growth hormone deficiency. Horm Res 1998;50:166–176.
Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev 1995;16:3–34.
Twigg SM, Baxter RC: Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit. J Biol Chem 1998;273:6074–6079.
Baxter RC, Martin JL, Beniac BA: High molecular weight insulin-like growth factor binding protein complex: Purification and properties of the acid-labile subunit from human serum. J Biol Chem 1989;264:11843–11848.
Guler H-P, Zapf J, Schmid C, Froesch ER: Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol (Copenh) 1989;121:753–758.
Lewitt MS, Saunders H, Phuyal JL, Baxter RC: Complex formation by human insulin-like growth factor binding protein-3 and human acid-labile subunit in growth hormone deficient rats. Endocrinology 1994;134:2404–2409.
Young SCJ, Miles MV, Clemmons DR: Determination of the pharmacokinetic profiles of insulin-like growth factor binding proteins-1 and -2 in rats. Endocrinology 1992;131:1867–1873.
Baxter RC: Circulating binding proteins for the insulin-like growth factors. Trends Endocrinol Metab 1993;4:91–96.
Rajaram S, Baylink DJ, Mohan S: Insulin-like growth factor-binding proteins in serum and other biological fluids: Regulation and functions. Endocr Rev 1997;18:801–831.
Oh Y, Muller HL, Lamson G, Rosenfeld RG: Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. J Biol Chem 1993;268:14964–14971.
Lalou C, Lasarre C, Binoux M: A proteolytic fragment of insulin like growth factor (IGF) binding protein-3 that fails to bind IGFs inhibits the mitogenic effects of IGF-I and insulin. Endocrinology 1996;137:3206–3212.
Ranke MB, Elmlinger M: Functional role of insulin-like growth factor binding proteins. Horm Res 1997;48(suppl 4):9–15.
Hasegawa Y: Clinical utility of free insulin-like growth factor-I levels during childhood. J Endocrinol Invest 1998;21:101–104.
Takada M, Nakanome H, Kishida M, Hirose S, Hasegawa T, Hasegawa Y: Measurement of free insulin-like growth factor-I using immunoradiometric assay. J Immunoassay 1994;15:263–276.
Frystyk J, Skjaerbaek C, Dinesen B, Orskov H: Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Lett 1994;348:185–191.
Juul A, Holm K, Kastrup KW, Pedersen SA, Michaelsen KF, Scheike T, Rasmussen S, Muller J, Skakkebaek EN: 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 1997;82:2497–2502.
Hasegawa Y, Takada M, Hasegawa T, Tsuchiya Y: Clinical utility of newly developed free insulin-like growth factor-I measurements in the diagnosis of growth hormone deficiency in children and adolescents. Eur J Endocrinol 1996;134:184–189
Holly JMP, Claffey DCP, Cwyfan-Hughes SC, Frost VT, Yateman ME: Protease acting on IGFBPs: Their occurrence and physiological significance. Growth Regul 1993;3:88–91.
Clemmons DR, Busby WH, Arai T, Clarke JB, Jones JI, Ankrapp DK: Role of growth factor binding protein in the control of IGF-I actions. Prog Growth Factor Res 1995;6:357–366.
Holly JMP, Maile LA, Whellams EJ: Insulin-like growth factor binding protein proteases in vivo. J Endocrinol Invest 1998;21:93–100.
Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, Muller J, Skakkebaek EN: Serum levels of insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: The relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 1995;80:2534–2542.
Ciaccio M, Rivarola MA, Belgorosky A: Differences in insulin-like growth factor-I and sex hormone binding globulin levels between late and early prepuberty in patients with idiopathic and organic growth hormone deficiency. Acta Endocrinol (Copenh) 1993;129:419–423.
Belgorosky A, Escobar ME, Rivarola MA: Validity of the calculation of nonsex hormone-binding globulin-bound estradiol from total testosterone, total estradiol and sex hormone binding globulin concentrations in human serum. J Steroid Biochem 1987;28:429–432.
Belgorosky A, Rivarola MA: Progressive increase in nonsex hormone-binding globulin-bound testosterone and estradiol from infancy to late prepuberty in girls. J Clin Endocrinol Metab 1988;67:234–237.
Belgorosky A, Rivarola MA: Determination of albumin-bound thyroxine in human serum. Clin Chem 1990;36:699.
Belgorosky A, Weller G, Chaler E, Iorcansky S, Rivarola MA: Evaluation of serum total thyroxine, and triiodothyronine, and their serum fractions, in nonthyroidal illness secondary to congenital heart disease. Studies before and after surgery. J Endocrinol Invest 1993;16:499–503.
Bach LA, Hsieh S, Sakano K, Fuyiwara H, Perdue J, Rechler M: Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1–6. J Biol Chem 1993;268:9246–9254.
Skjaerbaek C, Kaal A, Moller J, Vahl N, Weeke J, Orskov H, Flyvbjerg A: No effect of growth hormone on serum insulin-like growth factor binding protein-3 proteolysis. J Clin Endocrinol Metab 1998;83:1206–1210.
Honda Y, Landale EC, Strong DD, Baylink DJ, Mohan S: Recombinant synthesis of insulin-like growth factor binding protein-4 (IGFBP-4): Development, validation, and application of a radioimmunoassay for IGFBP-4 in human serum and other biological fluids. J Clin Endocrinol Metab 1996;81:1389–1396.
Baxter RC, Saunders H: Radioimmunoassay of insulin-like growth factor binding protein-6 in human serum and other body fluids. J Endocrinol 1992;134:133–139.
Mohan S, Libanati C, Dony C, Lang K, Srinivasan N, Baylink DJ: Development, validation, and application of a radioimmunoassay for insulin-like growth factor binding protein-5 in human serum and other biological fluids. J Clin Endocrinol Metabol 1995;80:2638–2645.
Kim H-S, Nagalla SR, Oh Y, Wilson E, Robert Jr CT, Rosenfeld RG: Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): Characterization of connective tissue growth factor as a member of IGFBP superfamily. Proc Natl Acad Sci USA 1997;94:12981–12986.
Holman SR, Baxter RC: Insulin-like growth factor binding protein-3: Factors affecting binary and ternary complex formation. Growth Regul 1996;6:42–47.
Rosenthal SM, Hsiao D, Silverman LA: An insulin-like growth factor-II (IGF-II) analog with highly selective affinity for IGF-II receptors stimulates differentiation, but not IGF-I receptor down-regulation, in muscle cells. Endocrinology 1994;135:38–44.
Powell DR, Durham SK, Liu F, Baker BK, Lee PDK, Watkins SL, Campbell PG, Brewer DE, Hintz RL, Hogg RJ: The insulin-like growth factor axis and growth in children with chronic renal failure: A report of the Southwest Pediatric Nephrology Study Group. J Clin Endocrinol Metab 1998;83:1654–1661.
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