Effects of Dose and Gender on the Growth and Growth Factor Response to GH in GH-Deficient Children: Implications for Efficacy and Safety
Pinchas Cohen,
George M. Bright,
Alan D. Rogol,
Anne-Marie Kappelgaard and
Ron G. Rosenfeld on behalf of the American Norditropin Clinical Trials Group
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 andgrowth factor levels of GH-deficient patients. One hundred elevenshort (-3.0 ± 0.9 height SD score), prepubertal GH-deficientchildren were randomized to receive low- (L; 0.025 mg/kg perday), medium- (M; 0.05 mg/kg per day), or high- (H; 0.1 mg/kgper day) dose GH. One hundred four children completed the 2-yrstudy. At 2 yr, the three groups displayed increases in heightSD 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 bindingprotein-3 during treatment also demonstrated dependency on theGH dose and were independently correlated with the increasein height SD scores attained. Bone age advancement, the occurrenceof puberty, fasting glucose, and hemoglobin A1c did not changeduring therapy, but fasting insulin levels rose in a dose-dependentmanner. Surprisingly, the GH dose-response curve for both auxologicaland 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 growthand IGF-I SD score responses at 0.05 mg/kg per day. In thislarge, randomized, 2-yr study, we observed a dose-response effectof GH on growth and serum growth factor levels and a prepubertalgender difference in GH sensitivity. These results suggest thatthe efficacy and theoretical safety of GH therapy can be optimizedby modulating the GH dose in a gender-specific manner, basedon 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 forNovo Nordisk. This work was presented in part at the 82nd AnnualMeeting of The Endocrine Society, Toronto, Canada, 2000.
Abbreviations: GHD, GH-deficient; H, high; HbA1c, hemoglobinA1c; IGFBP-3, IGF-binding protein 3; L, low; M, medium; rhGH,recombinant human GH.
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