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Effects of Recombinant Human Insulin-Like Growth Factor I (IGF-I) Therapy on the Growth Hormone-IGF System of a Patient with a Partial IGF-I Gene Deletion

Department of Endocrinology (C.C.-H., F.M.-M., A.J.C.), Pediatric Endocrinology Section (C.C.-H., K.A.W., M.O.S.), and Department of Clinical Pharmacology (A.J.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE; Cobbold Laboratories (P.C.H.), University College, London, United Kingdom; Pharmacia & Upjohn, Inc. (Y.H.), Stockholm, Sweden; and the Kolling Institute of Medical Research (R.B.), Sydney, Australia

Address all correspondence and requests for reprints to: Cecilia Camacho-Hübner, M.D., Department of Endocrinology and Chemical Endocrinology, 51–53 Bartholomew Close, London, United Kingdom EC1A 7BE.

We have previously reported a 17.2-yr-old boy with severe growth retardation and undetectable serum levels of insulin-like growth factor I (IGF-I) due to a partial deletion of the IGF-I gene. The aim of this study was to investigate the effects of recombinant human IGF-I (rhIGF-I) therapy on the GH-IGF system of this patient to gain further insights into its growth-promoting and metabolic actions. To assess the changes in GH, IGFs, IGF-binding proteins (IGFBPs), acid-labile subunit (ALS), and insulin levels, blood samples were obtained before therapy and during the first year of treatment. Hormones were analyzed by specific RIAs. Overnight GH profiles were performed before and at 1, 6, and 12 months of therapy. Fasting ALS, IGF-II, IGFBP-3, IGFBP-2, IGFBP-1, and insulin levels before rhIGF-I treatment were 46.3 mg/L, 1044 µg/L, 5.8 mg/L, 73 ng/mL, 4.7 ng/mL, and 27.3 mU/L, respectively. IGF-II, ALS, and insulin levels were elevated, whereas IGFBP-1 and IGFBP-2 levels were decreased compared to reference values. Twenty-four hours after a single sc injection of rhIGF-I (40 µg/kg), the concentrations were 46 mg/L, 888 µg/L, 6.9 mg/L, 112 ng/mL, 5.0 ng/mL, and 21.0 mU/L, respectively. After a single sc injection of rhIGF-I of 40 or 80 µg/kg·day and modelling the data using a two-compartment model, the half-lives of elimination were 15.7 and 14.3 h, with a maximum increase in IGF-I levels to 341 and 794 µg/L around 7 h, respectively. An increase in IGFBP-3 levels was observed with both doses of rhIGF-I, with a peak values of 9 mg/L. GH profiles showed a decrease in peak amplitude from 342 to 84 mU/L at 1 month, to 67 mU/L at 6 months, and to 40 mU/L at 1 yr of therapy, with no significant changes in peak number. A significant increase in IGFBP-1 levels was observed during treatment with 80 µg/kg·day IGF-I, reflecting the inhibitory effect of rhIGF-I on insulin secretion. The clinical response to rhIGF-I therapy was an increased height velocity from 3.8 cm/yr before treatment to 6.6 cm/yr. Increased lean body mass correlated with changes in the doses of rhIGF-I and, in turn, with the biochemical changes in the GH-IGF axis. Similar to healthy individuals, this patient had normal IGFBP-3 and ALS levels, which are the major regulators of the pharmacokinetics of rhIGF-I. In summary, rhIGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBP, and insulin levels.

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