5 alpha-reduced androgens play a key role in murine parturition.
Two steroid 5 alpha-reductase isozymes designated type 1 and 2 synthesize 5 alpha-reduced androgens and other 5 alpha-reduced steroid hormones. Naturally occurring mutations in the gene encoding 5 alpha-reductase type 2 cause male pseudohermaphroditism, indicating that this isozyme is responsible for the synthesis of dihydrotestosterone required for virilization of the embryonic male urogenital tract. To determine the physiological role of 5 alpha-reductase type 1, homologous recombination in mouse embryonic stem cells was used to produce male and female mice with a disruption (null allele) in the type 1 gene (Srd5a1). Male mice lacking 5 alpha-reductase type 1 appear normal. Females exhibit a parturition defect that is maternal in origin. The parturition defect is reversed by administration of 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-Adiol), a 5 alpha-reduced androgen previously thought to be a breakdown product. Enzymes that synthesize 3 alpha-Adiol, including 5 alpha-reductase type 1 and 3 alpha-hydroxysteroid dehydrogenase, are induced in wild type uterus during late gestation. Induction leads to peak circulating levels of 3 alpha-Adiol on days 17/18 of gestation in wild type but not mutant mice. The results document a role for 5 alpha-reduced androgens synthesized by the type 1 isozyme in normal female physiology, and they suggest that 3 alpha-Adiol is a new hormone required for parturition in mice.
Mahendroo
M S
MS
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046, USA.
Cala
K M
KM
Russell
D W
DW
D000728:Androgens / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D001755:Blastocyst / Q000502:physiology; D042944:Cholestenone 5 alpha-Reductase; D003433:Crosses, Genetic; D012734:Disorders of Sex Development / Q000201:enzymology / Q000235:genetics; D005091:Exons; D005260:Female; D015870:Gene Expression; D005838:Genotype; D007743:Labor, Obstetric; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009154:Mutation; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D012733:Sex Differentiation; D013234:Stem Cells
D000728:Androgens; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase