INDUCED GENITAL ANOMALIES *

Summary The human female fetus has been reported to have varying degrees of virilization of the lower urogenital tract after maternal treatment with androgenic hormones with certain progestins, and rarely with estrogens. Paradoxically, three cases of feminization of male fetuses with varying degrees of hypospadias have been reported to occur after maternal treatment with large doses of either diethyl‐stilbestrol and progesterone, of progesterone alone, or of acetoxyprogesterone (Prodox). An analysis of the human reports and comparable experimental data suggest that the fetal effects of these agents are not analogous to their effects on the end organs in the postnatal animal. Rather, they appear to have some common dose‐dependent teratogenic action during critical periods of genital development in the two sexes. Genetic male infants born with a severe form of congenital adrenal hyperplasia due to a genetic deficiency in activity of 3β‐ hydroxysteroid dehydrogenase (3β‐enzyme) also have incomplete masculine development and hypospadias. Genetic females with this disease are born with a moderate degree of virilization, clitoral hypertrophy, and labial fusion. The 3β‐enzyme is essential in the early biosynthetic pathway of every biologically active steroid hormone. We have produced an experimental model of this disease by inhibiting rat fetal 3β‐enzyme with a synthetic derivative of testosterone, which differs from the usual product of the 3β‐enzyme primarily by a C‐2 α ‐cyano group on the androst‐5‐en nucleus. Unlike most enzyme inhibitors, this steroid is tightly and relatively irreversibly bound to the 3β‐enzyme. Evidence is presented that suggests that progestins or estrogens may affect human fetal genital development by inhibiting the activity of the fetal 3β‐enzyme, thereby mimicking the human genetic form and our experimental model of congenital adrenal hyperplasia.