Epidermal growth factor influences growth and differentiation of rat granulosa cells

The interactions of epidermal growth factor (EGF) with transforming growth factor beta (TGF beta), insulin-like growth factor-I (IGF-I), and FSH in the modulation of DNA synthesis and differentiated functions were examined in cultures of granulosa cells isolated from the ovaries of immature rats primed with diethylstilbestrol. EGF alone or in the presence of FSH had no effect on [3H]thymidine incorporation into the DNA of granulosa cells; however, EGF inhibited FSH plus TGF beta-induced DNA synthesis. In contrast, when FSH was omitted from the culture medium, EGF acted in concert with TGF beta, and TGF beta plus IGF-I, to promote DNA synthesis. EGF therefore has opposing actions on DNA synthesis; it inhibits or stimulates depending upon the presence or absence of FSH and consequently upon the endocrine environment in the follicle. As shown previously EGF alone had no effect on basal aromatase activity. EGF however inhibited FSH-induced and FSH plus IGF-I-induced aromatase activity. In this paper we show that EGF also inhibited the FSH-induced aromatase activity in the presence of TGF beta, which augmented FSH action on this system. The action of EGF on 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was different from the effect of EGF on aromatase. In the absence of FSH, EGF induced 3 beta-HSD activity in the presence or absence of TGF beta. EGF augmented the action of FSH on 3 beta-HSD, and this interaction was further enhanced by TGF beta. These observations emphasize the multifunctional nature of EGF in influencing the growth and differentiation of immature rat granulosa cells. EGF can inhibit or stimulate growth and differentiated functions (aromatase and 3 beta-HSD), the response depending on the context of the signals that the cell receives from its endocrine and microenvironment.