Differential Effects of Estrogen and Growth Hormone on Uterine and Hepatic Insulin-Like Growth Factor I Gene Expression in the Ovariectomized Hypophysectomized Rat*

Abstract

The acute and chronic effects of 17.beta.-estradiol (E2) and GH on uterine and hepatic insulin-like growth factor I (IGF-I) gene expression in ovariectomized hypophysectomized (ovx-hypox) rats were examined. Six hours after a singl injection of E2 (5 .mu.g/100 g BW), uterine IGI-I gene expression was increased 22.5 .+-. 5.4-fold (P < 0.005) above that in untreated rats. In the same experiment E2 alone had no significant effect on hepatic IGF-I gene expression. Similarly, in chronic experiments uterine IGF-I in ovx-hypox rats receiving 0.1 or 1 .mu.g/rat .cntdot. day E2 for 10 days was significantly increased compared to that in ovx-hypox rats that did not receive E2 [5.38.+-.0.79 vs 1.10 .+-. 0.15 (P < 0.005) and 6.64 .+-. 0.28 vs 0.93 .+-. 0.06 (P < 0.005), respectively]. While administration of human GH alone significantly increased uterine IGF-I expression (3.76 .+-. 1.61-fold compared to that in untreated rats; P < 0.05), a significant and reproducible attenuation of E2-induced IGF-I expression was seen in two acute experiments where GH reduced the E2-induced response by 36 .+-. 3.7% and 53 .+-. 19.4%. While chronic administration of E2 to ovx-hypox rats resulted in uterine growth, a significant decrease in body weight was seen in rats treated with 1 .mu.g/day E2 compared to that in untreated ovx-hypox controls (-4.3 .+-. 1.5 vs 2.5 .+-. 0.6 g; P < 0.0005). E2 treatment also significantly decreased the GH-induced increase in weight gain at each GH dose by approximately 40%. GH-induced hepatic IGF-I gene expression and serum IGF-I concentration were similarly reduced by chronic E2 administration. In contrast, in acute experiments where E2 alone had no effect on hepatic IGF-I expression, it acted in a synergistic fashion with GH and resulted in significantly greater accumulation of IGF-I mRNA. From these observations we conclude that 1) both E2 and human GH are potent stimulators of IGF-I gene expression in appropriate target tissues; and 2) in addition to any effects E2 has on GH secretion and IGF-I action, the growth-retarding effect of estrogen in the rat involves inhibition of GH-dependent hepatic IGF-I expression.