Interactions between FSH, estradiol-17β and transforming growth factor-β regulate growth and differentiation in the rat gonad

Abstract

Estradiol-17β (E 2) is a mitogen in vivo for the proliferation of granulosa cells in the rat ovary. E 2 is synthesized by the preovulatory follicle through a series of gonadotrophin-dependent events: LH stimulates thecal cells to synthesize androgens (androstenedione and testosterone) which are substrates for FSH-induced aromatization to estrogens in granulosa cells. More recently, we have found that transforming growth factor-β (TGF-β) stimulates DNA synthesis in rat granulosa cells in vitro and this effect is augmented by FSH. Since E 2 is a mitogen in vivo and TGF-β is the only known growth factor to stimulate proliferation in vitro, the possible link between the actions of E 2 and TGF-β were examined. E 2 stimulated the secretion of a TGF-β-like factor by rat granulosa cells in culture, and with time DNA synthesis was stimulated. The mitogenic action of E 2 was enhanced in the presence of FSH, and attenuated by a neutralizing antibody to TGF-β. The latter observations have identified TGF-β as the “missing-link” in the mitogenic actions of E 2 on rat granulosa cells. In addition to the growth-promoting actions of TGF-β plus FSH, TGF-β enhanced FSH-induced aromatase activity. Consequently, FSH plus TGF-β stimulates both the proliferation and aromatization capacity of rat granulosa cells. We propose that interactions between FSH, E 2 and TGF-β lead to the exponential increase in serum E 2 levels that occurs during the follicular phase of the cycle. Similarly, FSH stimulates the aromatization of exogenous androgens to estrogen by Sertoli cells isolated from immature rat testes, and there is a correlation between FSH-induced aromatization and mitotic activity. We have shown that FSH plus TGF-β stimulates DNA synthesis in Sertoli cells. Since E 2 increases the secretion of TGF-β by Sertoli cells, interactions between FSH, E 2 and TGF-β may provide the mitogenic stimulus for Sertoli cells during the prepubertal period. In summary, our findings suggest that the estrogen-induced growth of rat granulosa cells is mediated through the production of TGF-β, which acts as an autocrine regulator of proliferation. We also propose that the growth-promoting actions of FSH on Sertoli cells may depend upon a cascade series of events involving estrogens and TGF-β.