5α-reduced androgens play a key role in murine parturition

Two steroid 5α-reductase isozymes designated type 1 and 2 synthesize 5α- reduced androgens and other 5α-reduced steroid hormones. Naturally occurring mutations in the gene encoding 5α-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 5α-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 5α-reductase type 1 appear normal. Females exhibit a parturition defect that is maternal in origin. The parturition defect is reversed by administration of 5α-androstan-3α,17β-diol (3α- Adiol), a 5α-reduced androgen previously thought to be a breakdown product. Enzymes that synthesize 3α-Adiol, including 5α-reductase type 1 and 3α- hydroxysteroid dehydrogenase, are induced in wild type uterus during late gestation. Induction leads to peak circulating levels of 3α-Adiol on days 17/18 of gestation in wild type but not mutant mice. The results document a role for 5α-reduced androgens synthesized by the type 1 isozyme in normal female physiology, and they suggest that 3α-Adiol is a new hormone required for parturition in mice.