Variable degree of Growth Hormone (GH) and Insulin-like Growth Factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: Evidence from an IGF-based dosing study of short children

Context: We recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters. Objective: The objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy. Design: This was a 2-yr, open-label, randomized trial. Setting: The setting was multicenter and outpatient. Patients: Prepubertal short children [height SD score (SDS)<-2] with low IGF-I levels (≤-1 SDS), subclassified based on the peak stimulated serum GH concentration at baseline, into two subgroups: GHD (n = 63, GH < 7 ng/ml) and ISS (n = 102, GH ≥ 7 ng/ml). Interventions: Patients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 μg/kg • d (Conv). Main Outcome Measures: Change in (Δ) height SDS, IGF-I SDS, and GH dose was measured. Results: ISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 μg/kg • d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Δheight SDS of 2.04 ± 0.17 for GHD and 1.33 ± 0.09 for ISS groups in IGF2T, 1.41 ± 0.13 for children with GHD, and 0.84 ± 0.07 for those with ISS in IGF0T. Conclusion: IGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.