The effects of experimental hyperinsulinemia on steroid secretion, ovarian [¹²⁵i]insulin binding, and ovarian [¹²⁵i]insulin-like growth-factor i binding in the rat*

We randomized 32 cycling female Sprague-Dawley rats (82 days old) into experimental and control groups (16 animals/group). Hyperinsulinemia was induced and maintained for 22 days in the experimental group with NPH human insulin (Novolin, Squibb-Novo, Princeton, NJ) as previously described. Controls received an identical volume of vehicle. Fifteen minutes before death, each rat received a sc injection of 100 ng synthetic GnRH (Factrel, Ayerst Laboratories, New York, NY). The mean serum insulin level was significantly higher in the insulin-treated group than in the control group (165 ± 57 vs. 49 ± 9 μU/ml; P < 0.05). The mean final weight also was significantly higher in the insulin-treated group (283 ± 4 vs. 242 ± 7 g; P < 0.001). There were no significant differences in mean final serum levels of testosterone, estradiol, estrone, or androstenedione or in GnRH-stimulated serum levels of LH or FSH. The androstenedione to estrone ratio, however, was significantly lower in the insulin-treated group (2.5 ± 0.3 vs. 3.4 ± 0.2; P < 0.01), suggesting that aromatase activity increased with hyperinsulinemia. Specific [¹²⁵I] insulin binding to ovarian tissue homogenates was lower in the insulin-treated group (1.7 ± 0.1% vs. 2.6 ± 0.6%/ 0.2 mg protein; P > 0.05), suggesting that ovarian insulin receptors tended to down-regulate with hyperinsulinemia. Specific [¹²⁵I]insulin-like growth factor I ([¹²⁵I]IGF-I) binding to ovarian tissue homogenates, in contrast, was significantly higher in the insulin-treated group (13.3 ± 1.4% vs. 7.2 ± 0.6%/0.2 mg protein; P < 0.05), suggesting that ovarian IGF receptors up-regulated with hyperinsulinemia. The affinity of neither [¹²⁵I] insulin binding nor that of [¹²⁵I]IGF-I binding changed significantly, with the 50% inhibition point remaining between 2.0 and 5.0 ng/ml for each peptide in both groups. We conclude that hyperinsulinemia increases ovarian [¹²⁵I]IGF-I binding and stimulates aromatase activity in the rat. These phenomena, if also true in women, could be important factors contributing to the ovarian hyperstimulation observed in various hyperinsulinemic states.