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Stimulation of the 150-Kilodalton Insulin-Like Growth Factor-Binding Protein-3 Ternary Complex by Continuous and Pulsatile Patterns of Growth Hormone (GH) Administration in GH-Deficient Patients¹

Center for Clinical Pharmacology, Department of Pharmacology, Aarhus University (T.L.), and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Kommunehospitalet (A.F., J.O.L.J., J.S.C.), DK-8000 Aarhus C, Denmark; and Kolling Institute of Medical Research, Royal North Shore Hospital (R.C.B.), St. Leonards, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Dr. Torben Laursen, Ph.D., Center for Clinical Pharmacology, Department of Pharmacology, Aarhus University, Bartholin Building, DK-8000 Aarhus C, Denmark. E-mail: tl{at}farm.au.dk/torben.laursen@dadlnet.dk

In the circulation insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3), and the acid-labile subunit (ALS) form a 150-kDa ternary complex that is of importance for the regulation of IGF-I bioactivity. GH administration is known to increase each of the single components of the ternary complex, and in GH-deficient rats formation of the 150-kDa complex is induced more by continuous than by pulsatile GH patterns. The aim of the present studies was to study the effects of the GH administration pattern on the formation of the 150-kDa ternary complex in humans. A fixed total GH dose (2 IU/m²·24 h) was administered iv randomly as 1) continuous infusion or 2) eight bolus injections to five GH-deficient patients over a period of 24 h. GH administration significantly increased serum IGF-I and IGFBP-3 levels and the IGF-I/IGFBP-3 ratio. IGF-I levels increased most pronouncedly after continuous administration (P < 0.01). Serum ALS levels increased significantly (both P < 0.005) from 94 ± 21 to 180 ± 29 (infusion) and from 85 ± 17 to 155 ± 17 nmol/L (pulses). Employment of neutral size exclusion chromatography enabled separation of IGFBP-3 in ternary complex and noncomplex-bound fractions. IGFBP-3 in the ternary complex increased significantly after GH administration [by 44% (P = 0.048) during infusion and by 62% (P = 0.004) during bolus]. The noncomplex-associated IGFBP-3 fraction, however, did not increase significantly after GH administration (P = NS). Finally, formation of the ternary complex was unaffected by the pattern of GH delivery. In conclusion, short-term GH administration increased all components of the 150-kDa ternary complex. Higher levels of IGF-I after constant GH exposure could indicate an increased bound fraction. However, the GH pattern did not influence the induction of the ternary complex itself. Continuous and intermittent GH patterns may be clinically equally effective during long-term GH therapy, as judged by levels of the components of the ternary complex.

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