Growth retardation in constitutionally short children is related both to 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, IGF-II and IGF binding protein (IGFBP)-1 have been carried out in conjunction with Western ligand blot analysis of serum IGFBPs in 39 constitutionally 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 serum levels of IGF-I were decreased by 46% +/- 5% in short, compared to normal, prepubertal children (P < 0.01) and reduced slightly, but not significantly, in short pubertal children. IGFBP-1 levels decreased with age in short children, as they did in normals, but average values were significantly higher in short children (P < 0.001). There was also a tendency for higher IGFBP-2 levels in short prepubertal and pubertal children. IGFBP-3 bands were of equal intensity in short and normal subjects. Physiologically, IGFBP-3 undergoes limited proteolysis which results in facilitated dissociation of the IGFs, particularly IGF-I, and an increase in their turnover. Western immunoblotting detects proteolytic 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 lower (P < 0.01) than in normal prepubertal subjects (60.6% +/- 8.9%). This lesser proteolysis of IGFBP-3 would explain the excessive levels of IGFBP-3 (detected by ligand blotting) relative to IGF levels in short children. These results suggest that growth retardation in short children involves IGF-I deficiency resulting from both decreased IGF-I synthesis and lesser bioavailability of the circulating IGF-I bound to IGFBP-3. High IGFBP-1 levels may also contribute towards limiting the availability of IGF-I to its target cells.
Lindgren
B F
BF
Endocrinology and Diabetology Clinic, Karolinska Hospital, Stockholm, Sweden.
Segovia
B
B
Lassarre
C
C
Binoux
M
M
Gourmelen
M
M
D000293:Adolescent; D000704:Analysis of Variance; D001682:Biological Availability; D001827:Body Height; D002648:Child; D002675:Child, Preschool; D006130:Growth Disorders / Q000097:blood* / Q000503:physiopathology*; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D018579:Patient Selection; D011627:Puberty; D012016:Reference Values
D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II