ONTOGENY OF INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-1, PROTEIN-2, AND PROTEIN-3 - QUANTITATIVE MEASUREMENTS BY RADIOIMMUNOASSAY IN HUMAN FETAL SERUM

There is evidence for a role for IGF-I in the endocrine control of human fetal growth despite the low serum IGF-I concentrations. The formation in serum of binary complexes between IGF-I or -II and either of six IGF binding proteins (IGFBP-1 to -6) and, in particular, of long-lived ternary complexes between IGF-I or -II, IGFBP-3, and acid-labile subunit is thought to regulate IGF-I bioavailability by increasing its serum half-life. The present study assesses the bioavailability of circulating IGF-I in 19- to 35-wk gestation human fetuses in utero 1) by quantitative RIA measurements of IGF and IGFBP in serum and 2) by examining whether serum proteolysis of IGFBP-3 may further increase IGF-I bioavailability. Fetal serum concentrations of IGFBP-3, IGF-I, and IGF-II were low with marked or only modest increases with gestational age (p < 0.001, p < 0.005, and p < 0.05, respectively). The mean molar ratio between IGF-I plus -II and IGFBP-3 demonstrated a molar excess of IGF (50%) similar to that in adolescents but in contrast to the 1:1 molar ratio in adults. The median IGFBP-2 concentration was 3-fold elevated to a molar concentration similar to that of IGFBP-3 (adult serum displays 10-fold higher IGFBP-3 concentrations). The median serum IGFBP-1 concentration was not elevated as previously reported in newborns. IGFBP-3 protease activity was not increased in fetal serum, in contrast to pregnancy serum and amniotic fluid. Nevertheless, IGFBP-3 protease activity did interfere with IGFBP-3 determinations by Western ligand blotting, and IGFBP-1 and IGFBP-2 levels obtained by this technique did not correlate with concentrations determined by RIA, stressing the importance of quantitative IGFBP measurements. In summary, increased IGF-I bioavailability in the human fetus is suggested by the molar excess of IGF over IGFBP-3 and the increase in IGFBP-2, which do not form a long-lived ternary complex. The lack of suppression of fetal serum IGFBP-1 may suggest that the delivery of IGF-I to the tissues is normal.