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Insulin-Like Growth Factor Binding Protein-3 Generation as a Measure of GH Sensitivity

Department of Genetics (C.K.B.), Stanford University, Stanford, California 94305; Department of Pediatrics (K.A.S., K.L.P., E.T., R.G.R.), Oregon Health & Science University, Portland, Oregon 97239; and Institute of Endocrinology, Metabolism, and Reproduction (J.G.-A.), Quito, Ecuador

Address all correspondence and requests for reprints to: Karin A. Selva, M.D., Department of Pediatrics, Oregon Health & Science University, 707 SW Gaines Road, Child Development and Rehabilitation Center-Pediatrics (CDRC-P), Portland, Oregon 97201. E-mail: selvak{at}ohsu.edu.

Abstract

A total of 198 subjects were randomized to either high-dose (0.05 mg/kg·d) or low-dose (0.025 mg/kg·d) GH for 7 d; the alternate dose was then received after a 2-wk washout period. Groups included in the study were: normal, GH-insensitive (GHI; homozygous for the E180 splice mutation); heterozygous GHI (carriers of the E180 splice mutation); GH-deficient; and idiopathic short stature.

Serum IGF binding protein-3 (IGFBP-3) concentrations (collected on d 1, 5, and 8 of treatment weeks) were GH-dependent, with significant elevation by d 5 of treatment, regardless of dose, in all normal subjects. GHI subjects had low baseline IGFBP-3 and poor or no response to either low- or high-dose GH. Heterozygous subjects, however, did not differ from age-matched normals with regard to IGFBP-3 generation. All GH-deficient subjects had subnormal baseline concentrations of IGFBP-3; most, but not all, were able to generate levels into normal ranges by 8 d of therapy. Children with idiopathic short stature showed a better response in IGFBP-3 generation compared with that previously observed with IGF-I, reaching concentrations in normal range with either dose of GH, suggesting that any GHI in this group is relatively limited to IGF-I production.

For the diagnosis of GHI, the highest sensitivity (100%) and specificity (92%) was found on d 8 of the high-dose GH-IGFBP-3 generation test. Failure to raise both IGF-I and IGFBP-3 lowered sensitivity to 82–86% with low-dose GH, and 86–91% with high-dose GH.

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