Direct biphasic effects of danazol on gonadotropin-dependent differentiation of cultured rat granulosa cells.

The direct effects of danazol on granulosa cell differentiation were studied in vitro over a broad concentration range with a primary culture of rat granulosa cells. Whereas treatment with low-dose (defined herein as less than 10(-6) M) danazol by itself was without significant effect on basal steroid secretion, combined treatment with low-dose danazol (10(-7) M) and a minimally effective dose of follicle-stimulating hormone (FSH, 20 ng/ml) resulted in a substantial augmentation of the FSH effect. Although independent of the FSH dose employed, the effect of danazol proved dose- and time-dependent, with an apparent median effective dose of 3.6 +/- 0.3 X 10(-8) M. In contrast, high-dose danazol (defined herein as greater than 10(-6) M) produced dose-dependent inhibition of FSH (250 ng/ml)-supported steroid secretion. Taken together, our findings indicate that the effects of danazol on granulosa cell differentiation may be biphasic in nature, displaying a stimulatory low-dose component, followed by inhibition at higher dose levels.