The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Systemic administration of epidermal growth factor (EGF) in neonatal rats results in reduced body weight gain and decreased circulating levels of IGF-I, suggesting its involvement in EGF-induced growth retardation. We investigated the effect of EGF and/or IGF-I administration for 7 days on circulating IGF-I and IGFBP levels and hepatic and renal IGF-system mRNA expression profiles in adult female rats. EGF administration (30 microg/rat/day) did not influence body weight, liver or kidney weight. In contrast, IGF-I (400 microg/rat/day) and EGF/IGF-I administration increased both body weight and kidney weight. Also, serum IGF-I and the 30 kDa IGFBPs (IGFBP-1 and -2) were significantly increased in these groups. Serum IGFBP-3 levels increased in the IGF-I group along with increased hepatic IGFBP-1 and -3 mRNA levels. In contrast, in the EGF administration group serum IGFBP-3 levels were significantly decreased; however, the mRNA levels remained unchanged. In the EGF/IGF-I administration group, serum IGF-I and IGFBP-3 levels were significantly lowered when compared with the IGF-I administration group. This was in contrast to the effect on kidney weight increase that was identical for the IGF-I and EGF/IGF-I groups. The decrease in serum IGFBP-3 was not reflected at the hepatic IGFBP-3 mRNA level. IGFBP-3 expression might be regulated at a post-transcriptional level although EGF induced IGFBP-3 proteolysis could not be demonstrated in vitro. We conclude that EGF administration reduced serum IGFBP-3 whereas IGF-I administration increased the level of IGFBP-3 and IGF-I and resulted in an increased body and kidney weight in adult female rats.