Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) on GH and Insulin-Like Growth Factor I Levels in Transgenic Mice Overexpressing the Human GHRH Gene, an Animal Model of Acromegaly*

Abstract

Abstract Transgenic mice overexpressing the human GH-releasing hormone (hGHRH) gene, an animal model of acromegaly, were used to investigate the effects of potent GHRH antagonists MZ-4–71 and MZ-5–156 on the excessive GH and insulin-like growth factor I (IGF-I) secretion caused by overproduction of hGHRH. Because metallothionein (MT)-GHRH mice express the hGHRH transgene in various tissues, including the pituitary and hypothalamus, initial experiments focused on the effectiveness of the GHRH antagonists in blocking basal and stimulated GH secretion from pituitary cells in vitro. Both MZ-4–71 and MZ-5–156 suppressed basal release of GH from superfused MT-GHRH pituitary cells, apparently by blocking the action of endogenously produced hGHRH. In addition, these antagonists effectively eliminated the response to stimulatory action of exogenous hGHRH(1–29)NH2 (30 and 100 nm). To ascertain whether MZ-4–71 and MZ-5–156 could antagonize the effect of hGHRH hyperstimulation in vivo, each antagonist was administered to MT-GHRH transgenic mice in a single iv dose of 10–200 μg. Both compounds decreased serum GH levels in transgenic mice by 39–72% at 1 h after injection. The inhibitory effect of 50 μg MZ-5–156 was maintained for 5 h. Twice daily ip administration of 100 μg MZ-5–156 for 3 days suppressed the highly elevated serum GH and IGF-I concentrations in transgenic mice by 56.8% and 39.0%, respectively. This treatment also reduced IGF-I messenger RNA levels in the liver by 21.8% but did not affect the level of GH messenger RNA in the pituitary. Our results demonstrate that GHRH antagonists MZ-4–71 and MZ-5–156 can inhibit elevated GH levels caused by overproduction of hGHRH. The suppression of circulating GH concentrations induced by the antagonists seems to be physiologically relevant, because both IGF-I secretion and synthesis also were reduced. Our findings, showing the suppression of GH and IGF-I secretion with GHRH antagonists, suggest that this class of analogs could be used for the diagnosis and therapy of disorders characterized by excessive GHRH secretion.