Transforming growth factor‐α attenuates the acquisition of aromatase activity by cultured rat granulosa cells

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Abstract
The effect of transforming growth factor-α (TGFα) on granulosa cell differentiation, as assessed by the acquisition of aromatase activity, was evaluated in vitro by using a primary culture of rat granulosa cells. Harvested from immature, diethylstilbestrol-treated rats, granulosa cells were cultured under serum-free conditions for 72 hr in the presence of saturating concentrations (10−7M) of aromatase substrate androstenedione with or without the specified experimental agents. Basal aromatase activity, as assessed by the generation of radioimmunoassayable estrogen was negligible, remaining unaffected by treatment with TGFα; (10 ng/ml) by itself. Whereas treatment with follicle-stimulating hormone (FSH) resulted in a substantial increase in the extent of aromatization, concurrent treatment with TGFα: (10 ng/ml) resulted in significant (P50) of 0.33 ± 0.04 ng/ml, and a minimal time requirement of 48 hr. Capable of substantial inhibition of the forskolin-stimulated accumulation of extracellular adenosine 3′, 5′ cyclic monophosphate (cAMP) and estrogen, TGFα had a measurable albeit limited effect on N6, 2-′O-Dibutyryladensine 3′:5′-cyclic monophosphate-supported estrogen production. Relative potency comparison revealed epidermal growth factor (EGF; EC50 = 0.24 ± 0.03ng/ml) and TGFα to be virtually equipotent as regards the attenuation of FSH-stimulated estrogen biosynthesis. Taken together, our findings indicate that TGFα, like EGF, acting at subnanomolar concentrations, is capable of attenuating the FSH-stimulated (but not basal) accumulation of estrogen. This effect of TGFα proved time- and dose-dependent, involving virtually complete neutralization of FSH action at site(s) both proximal and distal to cAMP generation. As such, these findings provide yet another example of the remarkable qualitative and quantitative similarities between EGF and TGFα, thereby reaffirming the prospect that ligands of the EGF/TGFα receptor may play a modulatory role in the course of granulosa cell ontogeny.