Insulin-like growth factor binding protein (IGFBP)-3-Bound IGF-I and IGFBP-3-Bound IGF-II in growth hormone deficiency

In blood, circulating IGFs are bound to six high-affinity IGFBPs, which mod ulate IGF delivery to target cells. Serum IGFs and IGFBP-3, the main carrie r of IGFs, are upregulated by GH. The functional role of serum IGFBP- 3-bou nd IGFs is not well understood, but they constitute the main reservoir of I GFs in the circulation. We have used an equation derived from the law of ma ss action to estimate serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II, a s well as serum free IGF-I and free IGF-II, in 129 control children and ado lescents (48 girls and 81 boys) and in 13 patients with GHD. Levels of seru m total IGF-I, total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined e xperimentally, 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, w ere taken from published values. A correction for in vivo proteolysis of se rum 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 incre ased 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 c onstant 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 pa tients 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 I GFBP-3 SDSs (-2.35 +/- 0.83, -1.12 +/- 0.78 and -2.55 +/- 1.07, respectivel y, p = 0.0001). The mean SDS of serum total IGF-II, IGFBP-3-bound IGF-II an d free IGF-II were -1.25 +/- 0.68, -2.03 +/- 0.87 and 0.59 +/- 1.10, respec tively, in GHD. In control subjects, 89.8 +/- 4.47% of serum total IGF-I an d 77.3 +/- 9.4% of serum total IGF-II were bound to serum IGFBP-3. In patie nts with GHD, the mean serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II w ere 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 t he 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-bo und 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 prom otion and other biological effects of IGF-I and IGF-II. Finally, the estima tion 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. Copy right (C) 2000 S. Karger AG, Basel.