Production of Congenital Adrenocortical Hyperplasia in Rats by Estradiol-17β and Inhibition of 3β-Hydroxysteroid Dehydrogenase

Abstract

Large doses of estradiol-17β were administered to pregnant rats in order to determine whether the paradoxical effects of this estrogen on fetal genital differentiation could be attributed to inhibition of activity of 3β-hydroxysteroid dehydrogenase (3β-ol dehydrogenase). Estradiol-17β produces a defect in activity of 3β-ol dehydrogenase in maternal adrenals and ovaries in vivo and in vitro. The ovarian enzymatic defect remains uncompensated, but adrenal hyperplasia tends to raise enzymatic activity to normal levels. Adrenal hyperplasia is much more noticeable when the estrogen is given on the 15th or 16th day. Estradiol-17β also inhibits activity of 3β-ol dehydrogenase in fetal Leydig and adrenal cells. It produces fetal adrenal hyperplasia and clitoral hypertrophy in female fetuses on the 19th and 20th days, when enzymatic activity is greatest in the fetal adrenal. It also produces hypospadias in male fetuses on the 15th and 16th days, when enzymatic activity is greatest in fetal Leydig cells. These effects may be due to the demonstrated inhibition of 3β-ol dehydrogenase by estradiol-17β, or to some other disturbance of steroid metabolism produced by the large doses of this estrogen. The fetal effects of estradiol-17β are similar to those occurring spontaneously in children born with a genetic defect of 3β-ol dehydrogenase. The same effects are also observed in experiments with offspring of pregnant rats treated with a relatively specific inhibitor of this enzyme. These similarities suggest that inhibition of 3β-ol dehydrogenase may account, at least in part, for the fetal effects of estradiol-17β.