Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes

Mice lacking steroid 5 alpha -reductase 1 and 2 were produced by gene targe ting and breeding. Male mice without 5 alpha -reductase 2 or without both e nzymes had fully formed internal and external genitalia and were fertile, b ut had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administ ration increased seminal vesicle and coagulating gland weights in mice defi cient in 5 alpha -reductase 2 and increased the weights of the prostate, se minal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5 alpha -reductases (GI 208335X) decreased prostate an d coagulating gland weights of control mice, but had no effect in those lac king 5 alpha -reductase 1 and 2. Castration reduced the sizes of these tiss ues in animals of all genotypes. Androgen-dependent gene expression was dec reased in the seminal vesicles of mice lacking one or more 5 alpha -reducta ses and was restored by administration of T or DHT. Female mice missing bot h enzymes exhibited parturition arid fecundity defects similar to those of animals without 5 alpha -reductase 1. We conclude that T is the only androg en required for differentiation of the male urogenital tract in mice and th at the synthesis of DHT serves largely as a signal amplification mechanism.