Synergistic effects of insulin-like growth factor-I and human chorionic gonadotropin in the rat ovary

Insulin and low doses of lutenizing hormone (LH) activity (human chorionic gonadotropin [hCG]) act synergistically in the rat to produce anovulation, large ovarian cysts, and elevated plasma androstenedione levels. Further, both insulin and insulin-like growth factor-I (IGF-I) affect the ability of gonadotropins to enhance both ovarian theca and granulosa cell function in vitro. The present series of experiments were performed to determine if recombinant human IGF-I (rhIGF-I) can act in a manner similar to insulin when combined with subovulatory doses of hCG in adult normally cycling rats. Fifty-four female Sprague-Dawley rats were randomly assigned to the following treatment groups at the age of 64 days: (A) vehicle alone (controls, phosphate-buffered saline containing 0.09% pig gelatin), (B) twice-daily subcutaneous injections of 0.5 to 3.0 U insulin, (C) twice-daily subcutaneous injections of 1.5 U hCG, (D) both insulin and hCG, (E) twice-daily subcutaneous injections of rhIGF-I (2.5 mg/kg/d), and (F) both hCG and rhIGF-I. After 22 days of treatment, the animals were killed on day 23, trunk blood was collected, and the ovaries were excised for histological study. Eight of 9 control rats and 5 or 6 of 9 rats treated with insulin, hCG, or rhIGF-I alone displayed normal estrus cycles throughout the in vivo treatment period as assessed by daily vaginal smears. In marked contrast, only 1 animal treated with hCG + insulin and 2 animals treated with hCG + rhIGF-I continued to display vaginal smears indicative of normal cycling. Multiple large ovarian follicular cysts were found only in these latter 2 groups (3 of 9 animals in each group). Mean serum testosterone levels were significantly elevated in animals receiving insulin + hCG (0.72 +/- 0.28 v 0.17 +/- 0.03 ng/mL in controls, P = .05). Mean serum androstenedione levels were significantly elevated in animals receiving hCG and animals receiving rhIGF-I + hCG (5.57 +/- 0.99 and 2.39 +/- 0.68 ng/mL, respectively, v0.14 +/- 0.14 ng/mL in controls, P< .01 and P< .05, respectively). We conclude that rhIGF-I and insulin act synergistically with subovulatory doses of hCG to disrupt normal reproductive cycling, elevate serum androgen concentrations, and induce large ovarian cysts in intact adult rats.