Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Abstract

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.

A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice

“…After short-term dosing of male mice (seven days), the maximum level of reduction in serum IGF-I levels relative to the untreated control animals was 44%. This reduction is similar to results achieved using pegvisomant (Somavert) after a seven-day treatment schedule in normal female mice (van Neck et al 2000). This product is currently used in humans for treatment of acromegaly, where decreases in serum IGF-I of 30-70% may be required for normalisation (Trainer et al 2000).…”

Growth hormone receptor modulators

“…B2036-PEG (pegvisomant) binds to the GH receptor and induced receptor internalization [47]. It was introduced for human trials in the late 1990s and since then has been established as a safe and effective treatment for acromegaly [48].…”

Development of Pure Prolactin Receptor Antagonists

“…This result deserves further comments. First, the active doses of antagonists used in this study (0.25-1 mg/animal, which corresponds to ϳ6 -25 mg/kg) are not that much different from the doses of long acting formulation of hGH antagonist (B2036-PEG) required to down-regulate insulin-like growth factor-1 levels in mice (5-10 mg/kg/day) (61). Second, because in probasin-PRL transgenic mice, the local concentration of autocrine PRL cannot be quantified in the prostate (it is not detected in serum) (44), the actual molar excess of the antagonist versus local PRL cannot be determined.…”