GROWTH-RETARDATION IN CONSTITUTIONALLY SHORT CHILDREN IS RELATED BOTHTO LOW SERUM LEVELS OF INSULIN-LIKE GROWTH-FACTOR-I AND TO ITS REDUCED BIOAVAILABILITY

Measurements of serum levels of insulin-like growth factor (IGF)-I, IG F-II and IGF binding protein (IGFBP)-1 have been carried out in conjun ction with Western ligand blot analysis of serum IGFBPs in 39 constitu tionally short children and adolescents and compared with those of 27 age-matched normal subjects (and also with 23 hypopituitary patients), Estimated amounts of the two forms of IGFBP-3 (42 and 39 kDa) and of IGFBP-2 (34 kDa) were obtained by laser densitometry scanning. Mean se rum levels of ICE-I were decreased by 46% +/- 5% in short, compared to normal, prepubertal children (P<0.01) and reduced slightly, but not s ignificantly, in short pubertal children, IGFBP-1 levels decreased wit h age in short children, as they did in normals, but average values we re significantly higher in short children (P<0.001), There was also a tendency for higher IGFBP-2 levels in short prepubertal and pubertal c hildren, IGFBP-3 bands were of equal intensity in short and normal sub jects. Physiologically, IGFBP-3 undergoes limited proteolysis which re sults in facilitated dissociation of the IGFs, particularly IGF-I, and an increase in their turnover, Western immunoblotting detects proteol ytic fragments of IGFBP-3 (the major one being of 30 kDa) that are not detected by ligand blotting, The ratio of proteolysed to total IGFBP- 3 in short prepubertal children (36.8 +/- 2.6%) was significantly lowe r (P<0.01) than in normal prepubertal subjects (60.6 +/- 8.9%), This l esser proteolysis of IGFBP-3 would explain the excessive levels of IGF BP-3 (detected by ligand blotting) relative to IGF levels in short chi ldren, These results suggest that growth retardation in short children involves IGF-I deficiency resulting from both decreased ICE-I synthes is and lesser bioavailability of the circulating ICE-I bound to IGFBP- 3. High IGFBP-1 levels may also contribute towards limiting the availa bility of ICE-I to its target cells,