Experimental therapy of fetuses affected with congenital adrenal hyperplasia (CAH) has been reported by administering dexamethasone (Dex) to pregnant women at risk for carrying a CAH fetus. Such prenatal therapy can almost wholly eliminate virilization of the external genitalia of affected female fetuses, but only when treatment is started before 9 weeks of gestation. As it is not known whether the hypothalamic–pituitary–adrenal axis is functional at this time, and as the minimal effective doses of Dex are substantially supraphysiologic for the fetus, the mechanism of action of prenatal Dex treatment has been unclear.

To assess the possibility that Dex might act directly on the adrenal, we used human adrenocortical NCIH295A cells, an established model of the human fetal adrenal. Short term (6h) incubation of these cells with Dex decreased synthesis of 11-deoxycortisol and 17α-hydroxyprogesterone and increased synthesis of deoxycorticosterone (DOC), but only at very high con-