We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases of noninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glyce- mia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the anal- ysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substan- tially decreased in IUGR at 28 -30 weeks gestation (K28) and 36 -38 weeks gestation (K36). The mean concentration (6SEM) of total PGH increased significantly from K28 to K36 (30.0 6 2.2 to 50.7 6 6.2 ng/mL; n 5 40), as did the concentration of free PGH (23.4 6 2.3 to 43.7 6 6.0 ng/mL; n 5 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P , 0.01). Macrosomia was associated with an increase in these param- eters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-3 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGH at K28 and K36. Nonin- sulin-dependent diabetes mellitus patients had a lower mean per- centage of free PGH (65%; P , 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P , 0.01) than normal subjects. Mean postprandial glucose at K28 correlated posi- tively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r 52 0.52; P , .001), free PGH and total PGH correlated very closely (r 5 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth. (J Clin Endocrinol Metab 85: 1143- 1150, 2000)