Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation.
Circulating IGF-I and -II are bound to specific insulin-like growth factor (IGF)-binding proteins (IGFBPs), of which IGFBP-3 binds the majority of the IGFs. IGFBP-3 levels are regulated by GH and have been suggested to provide additional information on GH secretory capacity compared to IGF-I. However, the diagnostic value of IGFBP-3 is still controversial, perhaps because the quality of the available normative data for IGFBP-3 varies. It has recently been shown that a large number of individuals is required to establish reference ranges for IGF-I that take into account age, sex, body mass index (BMI), and pubertal stage. Therefore, we measured IGFBP-3, IGF-I, IGF-II, IGFBP-1, and IGFBP-2 levels by RIA in 907 healthy children to establish well characterized normative data on IGFBP-3 according to age, sex, and pubertal stage and to study the complex relationship between IGFs and their BPs in puberty. We found that IGFBP-3 levels increase with age in children, with maximal levels in puberty; girls experience peak values approximately 1 yr earlier than boys. Age, sex, height, BMI, and pubertal maturation were all important factors in determining the circulating levels of IGFBP-3, whereas IGF-I levels were unaffected by BMI. Comparison of IGFBP-3 with IGF-1 concentrations revealed that they did not exhibit the same developmental pattern in puberty. IGF-I levels increased to relatively higher levels than IGFBP-3, leading to an increasing molar ratio between IGF-I and IGFBP-3 in puberty, when growth velocity is high. Concomitantly, IGF-II and IGFBP-2 levels were unchanged throughout puberty, whereas IGFBP-1 levels declined with age in prepubertal children, with lowest values in puberty. There was a highly significant correlation between IGF-I and -II and IGFBP-3 on a molar basis (r = 0.84; P < 0.0001). Thus, we speculate that IGFBP-3 is pivotal for circulating IGF bioactivity and that the increase in the molar ratio between IGF-I and IGFBP-3 reflects an increase in free, biologically active IGF-I. In conclusion, we have provided normative data on a large group of healthy individuals and conclude that age, sex, height, BMI, and pubertal maturation have to be taken into account before a single IGFBP-3 value in a growth-retarded child can be evaluated properly.
Juul
A
A
University Department of Growth and Reproduction GR, Rigshospitalet, Denmark.
Dalgaard
P
P
Blum
W F
WF
Bang
P
P
Hall
K
K
Michaelsen
K F
KF
Müller
J
J
Skakkebaek
N E
NE
D000293:Adolescent; D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D015992:Body Mass Index; D002352:Carrier Proteins / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007223:Infant; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D011627:Puberty; D011863:Radioimmunoassay; D012016:Reference Values; D012044:Regression Analysis; D012727:Sex Characteristics
D002352:Carrier Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II