Production of Congenital Adrenal Cortical Hyperplasia, Hypospadias, And Clitoral Hypertrophy (Adrenogenital Syndrome) in Rats by Inactivation of 3 -Hydroxysteroid Dehydrogenase.

Abstract

Summary Varying daily doses of a steroidal inhibitor of 3β-hydroxysteroid dehydrogenase (2α-cyano-4,4,17α-trimethylandrost-5-en-17β-ol-3-one), were administered to pregnant rats on the 15 th to 20th days of gestation to determine whether this inhibitor could produce the biological manifestations of the human disease associated with deficient activity of this enzyme. A single dose of the inhibitor was also administered to pregnant rats on various days to determine the critical periods for production of these manifestations. Infants with this disorder have hyperplastic adrenal cortices deficient in activity of the 3β-enzyme, incomplete masculine development in males resulting in hypospadias with shortening of the anogenital distance, and clitoral hypertrophy without urethral orificial displacement in females. The experimental fetuses had adrenal cortical hyperplasia (average of 5.9 ± 1.32 mg against 2.2 ± 0.26 mg controls), deficient histochemical activity of the 3β-enzyme in the adrenals and testes, increased activity of glucose-6-phosphate dehydrogenase in adrenals, testes, and liver and no change in histochemical activities of 3α- or 17β-enzymes in these tissues. The anogenital distance in gonadal males was reduced from the normal of 2.88 ± .12 mm to 1.26 ± .08 mm in proportion to dose. The gonadal females had clitoral hypertrophy but no change in anogenital distance from the normal of 1 mm. The optimal period for production of hypospadias by the inhibitor corresponds to the early appearance of strong activity of the 3β-enzyme in the fetal testis. The optimal day for the production of adrenal hyperplasia and of clitoral hypertrophy corresponds to the time of maximal adrenal activity of the enzyme. This study thus demonstrates an experimental model for production of the congenital manifestations of this inborn error of metabolism.