Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes.
Mice lacking steroid 5 alpha-reductase 1 and 2 were produced by gene targeting and breeding. Male mice without 5 alpha-reductase 2 or without both enzymes had fully formed internal and external genitalia and were fertile, but had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administration increased seminal vesicle and coagulating gland weights in mice deficient in 5 alpha-reductase 2 and increased the weights of the prostate, seminal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5 alpha-reductases (GI 208335X) decreased prostate and coagulating gland weights of control mice, but had no effect in those lacking 5 alpha-reductase 1 and 2. Castration reduced the sizes of these tissues in animals of all genotypes. Androgen-dependent gene expression was decreased in the seminal vesicles of mice lacking one or more 5 alpha-reductases and was restored by administration of T or DHT. Female mice missing both enzymes exhibited parturition and fecundity defects similar to those of animals without 5 alpha-reductase 1. We conclude that T is the only androgen required for differentiation of the male urogenital tract in mice and that the synthesis of DHT serves largely as a signal amplification mechanism.
Mahendroo
M S
MS
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cala
K M
KM
Hess
D L
DL
Russell
D W
DW
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D058891:5-alpha Reductase Inhibitors; D000728:Androgens / Q000502:physiology; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005298:Fertility; D005837:Genitalia, Male / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D013739:Testosterone / Q000378:metabolism; D014770:Virilism / Q000201:enzymology* / Q000473:pathology
D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D000736:Androstenes; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C438725:N-(1-(4-trifluoromethylphenyl)cyclopentenyl)-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase