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Effects of Dose and Gender on the Growth and Growth Factor Response to GH in GH-Deficient Children: Implications for Efficacy and Safety

Department of Pediatrics (P.C.), University of California Los Angeles, Los Angeles, California 90095; Department of Pediatrics (A.D.R.), University of Virginia, Charlottesville, Virginia 22903; Department of Pediatrics (R.G.R.), Oregon Health & Sciences University, Portland, Oregon 97201; Novo Nordisk (G.M.B.), Princeton, New Jersey 08540; and Novo Nordisk (A.-M.K.), DK2830 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Director of Research and Training, Division of Endocrinology, Department of Pediatrics, Mattel Children’s Hospital at University of California Los Angeles, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy{at}mednet.ucla.edu

We evaluated the dose-response effects of GH on the growth and growth factor levels of GH-deficient patients. One hundred eleven short (-3.0 ± 0.9 height SD score), prepubertal GH-deficient children were randomized to receive low- (L; 0.025 mg/kg per day), medium- (M; 0.05 mg/kg per day), or high- (H; 0.1 mg/kg per day) dose GH. One hundred four children completed the 2-yr study. At 2 yr, the three groups displayed increases in height SD scores of 1.4 ± 0.1 for L, 2.2 ± 0.1 for M, and 2.3 ± 0.1 for H (P < 0.001 relative to L, P = NS relative to M). The serum levels of IGF-I and IGF binding protein-3 during treatment also demonstrated dependency on the GH dose and were independently correlated with the increase in height SD scores attained. Bone age advancement, the occurrence of puberty, fasting glucose, and hemoglobin A1c did not change during therapy, but fasting insulin levels rose in a dose-dependent manner. Surprisingly, the GH dose-response curve for both auxological and biochemical parameters differed between prepubertal females (n = 33) and males (n = 71). Males had a linear GH dose response, whereas females had an apparent plateau of both linear growth and IGF-I SD score responses at 0.05 mg/kg per day. In this large, randomized, 2-yr study, we observed a dose-response effect of GH on growth and serum growth factor levels and a prepubertal gender difference in GH sensitivity. These results suggest that the efficacy and theoretical safety of GH therapy can be optimized by modulating the GH dose in a gender-specific manner, based on the growth response and serum growth factor levels.

This study was supported by a research grant from Novo Nordisk. P.C., R.G.R., and A.D.R. served as nonequity consultants for Novo Nordisk. This work was presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, 2000.

Abbreviations: GHD, GH-deficient; H, high; HbA1c, hemoglobin A1c; IGFBP-3, IGF-binding protein 3; L, low; M, medium; rhGH, recombinant human GH.

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