No Influence of Prednisolone on IGFBP-3 Proteolysis in Healthy Young Men

Abstract

Aims: The impact of growth hormone (GH) and prednisolone on the GH/insulin-like growth factor (IGF) axis with special emphasis on IGF binding protein-3 (IGFBP-3) proteolysis was studied in 8 healthy adults in a double-blind cross-over study with four periods: (1) placebo; (2) s.c. GH 0.1 IU/kg/day; (3) oral prednisolone 50 mg/day, and (4) co-administration of GH and prednisolone. Methods: Each treatment period lasted for 4 days followed by a washout period of 10 days. We measured IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 by immunoassays, IGFBP-3 by Western ligand blotting (WLB) and finally in vitro IGFBP-3 proteolysis by a ¹²⁵I-IGFBP-3 degradation assay. Results: IGF-I levels increased by 99% during GH administration and 67% during co-administration of GH and prednisolone (p < 0.0005), whereas no significant change was seen during prednisolone alone. IGFBP-1 levels decreased 55% during the prednisolone period (p < 0.002), but the between period changes were not significant (p < 0.1). IGFBP-2 decreased 33% during co-administration of GH and prednisolone (p < 0.002). IGFBP-3 increased 12% during GH and 7% during co-administration of GH and prednisolone (p < 0.003 and p < 0.03 compared to placebo, respectively), whereas prednisolone alone induced no significant changes. IGFBP-3 measured by WLB did not change significantly, neither did IGFBP-3 proteolysis. Conclusions: Prednisolone administration induces only minimal changes in circulating components of the IGF axis and is not accompanied by alterations in IGFBP-3 proteolysis. This indicates that the metabolic effects of glucocorticoids do not depend on serum IGF-I.

Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1

“…This is true for patients with anorexia nervosa (28,29), endstage renal failure (30), and poorly controlled type 1 diabetes (31), whereas GC treatment makes a notable exception. Despite its catabolic effects, GC excess is generally not accompanied by a suppression of the circulating IGF system (6,7,12,32). With the present data in mind, it appears that the ability of GC to inhibit serum IGF1 action is mediated through an inhibition of IGF1R phosphorylation rather than through changes in the circulating concentrations of free IGF1, total IGFs, or insulin.…”

“…In this context, Lalou et al (34) demonstrated that proteolysis of IGFBP3 may yield fragments that possess no IGF1 binding activity but nevertheless retain the ability to inhibit IGF1 action in vitro. Whether this mechanism is operational following prednisolone treatment is, however, uncertain as prednisolone failed to induce IGFBP3 proteolysis in healthy adults (32). However, it could be speculated that prednisolone is able to induce inhibitory fragments from other IGFBPs than IGFBP3.…”