Insulin-like growth factor-I regulates aromatase activity in human granulosa and granulosa luteal cells

Abstract

The purpose of this research was to test the hypothesis that insulin-like growth factor-I (IGF-I) regulates estradiol (E2) synthesis in human granulosa and granulosa luteal cells. Cells from individual follicles from spontaneous and human menopausal gonadotropin/CG-stimulated cycles were cultured in serum-free medium containing androstenedione, IGF-I, FSH, and/or CG. At 2, 4, and 6 days, E2 in the medium was measured by RIA. In the granulosa experiments, control cells produced basal levels of E2 at 2 days, and the levels increased with increasing follicle size. Treatment with FSH stimulated E2 production (on the average, 5-fold), and the effect was dose dependent (ED50 = 5 ng/mL or 16 mlU/mL). Incubation with IGF-I alone caused increases in E2 production comparable to those caused by FSH, and the IGF-I effect was dose dependent (ED50 = 8 ng/mL). In most cases, coincubation with FSH and IGF-I augmented E2 levels more than either hormone alone, and at 4 and 6 days the interaction was synergistic. The data from dose-response experiments suggested that the basis of the synergy between FSH and IGF-I was a marked potentiation by either hormone (-10-fold) in the potency of the complementary hormone to stimulate E2 production. In the experiments with granulosa luteal cells from spontaneous and in vitro fertilization preovulatory follicles, the controls synthesized very high levels of E2 spontaneously at 2 days; however, E2 production declined 700% at 4 days, and no E2 was produced by control cells at 6 days. Treatment with FSH, CG, or IGF-I did not cause a significant increase in the high basal levels of E2 at 2 days. During subsequent culture, however, all three hormones stimulated E2 production at 4 and 6 days, but the increases were modest and not sustained. In contrast, coincubation of granulosa luteal cells with FSH plus IGF-I or CG plus IGF-I dramatically enhanced E2 production at 4 and 6 days (on the average, 4-fold), and the effects were sustained throughout the culture period. In summary, these in vitro results with human granulosa and granulosa luteal cells show that 1) physiological amounts of IGF-I are highly active in stimulating E2 production; 2) IGF-I is as effective or more effective than FSH (or CG) in stimulating E2 production; and 3) IGF-I acts synergistically with both FSH and CG to stimulate and maintain maximal levels of E2 synthesis by these cells types. These observations support the concept that IGF-I, in addition to FSH and LH, may play an important role in regulating E2 production in the human ovary. © 1990 by The Endocrine Society.