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High-Dose Growth Hormone (GH) Treatment in Non-GH-Deficient Children Born Small for Gestational Age Induces Growth Responses Related to Pretreatment GH Secretion and Associated with a Reversible Decrease in Insulin Sensitivity

Deparment of Paediatrics (F.d.z., M.v.H.), University of Leuven, 3000 Leuven, Belguim; Department of Paediatrics (K.O., K.W., D.D.), University of Cambridge, Cambridge CB1 7TF, United Kingdom; and Department of Paediatrics (A.M., K.W.), University of Oxford, Oxford OX3 4DU, United Kingdom

GH therapy variably reduces the height deficit of short children born small for gestational age (SGA) but is associated with hyperinsulinemia. Intermittent, higher-dose GH regimens may be alternatives to continuous, lower-dose treatment. We examined whether the growth response to GH therapy is related to pre-treatment indices of endogenous somatotropic activity, and studied the reversibility of the insulin resistant state induced by GH. 13 non-GH deficient short SGA children were randomised to high-dose GH (100 mcg/kg/day) by daily sc injection (n = 9), or no GH treatment (n = 4) for 2 years (2/4 controls subsequently received GH treatment). Overnight GH profiles were performed at baseline; intravenous glucose tolerance tests were performed at baseline, yearly on GH treatment, and 3 months post-GH treatment. Fasting glucose, insulin and proinsulin levels were measured, insulin sensitivity estimated using Bergman’s minimal model, and glucose tolerance calculated from rate of glucose disappearance. In all GH-treated children, gain in height SDS (mean gain yr 1 = +1.2 SDS) was inversely related to baseline peak overnight GH (r = -0.88, n = 10, p = 0.0008), IFG-I (r = -0.74, n = 11, p = 0.009), and fasting insulin levels (r = -0.71, n = 11, p = 0.014).

GH treatment increased fasting glucose (means: baseline vs. yr 2: 3.7 vs. 4.4 mmol/l, p = 0.005), insulin (3.8 vs. 13.9 mU/l, p = 0.0002), and proinsulin levels (1.7 vs. 4.5 pmol/l, p = 0.004), and decreased insulin sensitivity (26.9 vs. 4.0 per min/mU/1 x 10⁴, p = 0.002). Glucose tolerance initially decreased (baseline: 2.62 min^-1; yr 1: 2.18, p = 0.02; yr 2: 2.39, p = 0.12). However, by 3 months post-GH treatment significant improvements were seen in fasting insulin (post-GH: 5.2 mU/1, p = 0.0003 vs. yr 2), proinsulin (1.7 pmol/l, p = 0.002), and insulin sensitivity (17.6 per min/mU/1 x 10⁴, p = 0.0001). Post-GH treatment, fasting glucose levels (4.1 mmol/l, p = 0.04) and glucose tolerance (2.49 min^-1, p = 0.4) were similar to baseline, and the slight increase in fasting insulin levels (5.2 mU/1, p = 0.04) was similar to that observed in non-GH treated children over the 2 yr study period (baseline vs. 2 years: 3.9 vs. 5.9 mU/1, n = 4). In conclusion, in this study of 13 short non-GH-deficient SGA children, high-dose GH therapy induced growth responses that were associated with reversible decreases in insulin sensitivity, and that were predicted by pretreatment markers of endogenous, but not stimulated, somatotropic activity.

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