No abstract

IGF-I generation tests were developed over 20 yr ago and are currently used in differentiating GH insensitivity (GHI) from other disorders characterized by low serum IGF-I. Nevertheless, generation tests have never been adequately characterized, and insufficient normative data are available. One hundred and ninety-eight subjects [including normal subjects; subjects with GHI, GH deficiency (GHD), and idiopathic short stature (ISS); and heterozygotes for the E180 splice GH receptor mutation] were randomized to self-administration of either a high (0.05 mg/kg x d) or a low (0.025 mg/kg x d) dose of GH for 7 d. After a 2-wk washout period, they received the alternate dose. Samples were collected on d 1, 5, and 8 of each treatment period. In normal individuals, IGF-I generation was GH dependent at all ages, and little advantage was observed in using the higher dose of GH or extending beyond the d 5 sample. Some GHD patients had IGF-I levels, both baseline and stimulated, that overlapped levels in the verified GHI patients. Subjects heterozygous for the E180 GH receptor splice mutation did not show a decreased responsiveness to GH. ISS patients had low-normal IGF-I levels that did not stimulate beyond the baseline normative ranges for age. These data provide the first large scale effort to provide preliminary normative IGF generation data and evaluate the GH sensitivity of patients with GHI, GHD, and ISS.

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.

No abstract

Background/Aim: Insulin-like growth factor I (IGF-I) and insulin-lke growth factor binding protein 3 (IGFBP-3) generation tests are both sensitive and specific measures of growth hormone (GH) sensitivity. Recently, the question of reproducibility of IGF generation tests has been raised. We report our analysis of the correlation of low- and high-dose GH IGF-I and IGFBP-3 generation tests among patients with GH deficiency, GH insensitivity, and idiopathic short stature. Methods: A total of 198 subjects were randomized to either high- or low-dose GH for 7 days; the alternate dose was received after a 2-week washout period. Samples were collected at baseline and on days 5 and 8 of GH administration. Results: The serum concentrations of IGF-I and IGFBP-3 correlated significantly from one test to the other, regardless of the diagnosis. In normal subjects and patients with GH insensitivity and GH deficiency, the delta over baseline in IGF-I and IGFBP-3 in the low-dose test was highly predictive of the delta values in the high-dose test. The delta correlation was greatly diminished, however, in the patient population having idiopathic short stature. Conclusions: These observations support partial GH insensitivity effecting IGF-I generation specifically, as a possible etiology for idiopathic short stature, and thus such patients may warrant appropriate biochemical and/or molecular evaluation for partial GH insensitivity.