Involvement of 20α-Hydroxysteroid Dehydrogenase in the Maintenance of Pregnancy in Mice

The enzyme 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) catabolizes progesterone into a biologically inactive steroid, 20 alpha-dihydroprogesterone (20 alpha-OHP). In the corpora lutea of rats and mice, 20 alpha-HSID is considered to be involved in functional luteolysis. It is also distributed in other tissues including the placenta, endometrial epithelia and fetal skin, although the roles it plays in these tissues remain to be elucidated. In the present Study, we investigated the role of 20 alpha-HSD in the maintenance of pregnancy using mice with targeted disruption of the 20 alpha-HSD gene. We first confirmed that the number of pups was significantly smaller in 20 alpha-HSD-/- pairs than in 20 alpha-HSD+/+ pairs. We then mated 20 alpha-HSD+/- males and females so that each pregnant female produced 20 alpha-HSD+/+, 20 alpha-HSD+/- and 20 alpha-HSD-/- offspring. The genotype ratio of the offspring did not match the Mendel's law of inheritance, and the numbers of 20 alpha-HSD+/- and 20 alpha-HSD-/- offspring were smaller than expected values. Although the genotype ratio of fetuses on days 13, 15 and 18 of pregnancy matched the Mendel's law, the total number of fetuses on day 18 was significantly smaller than that oil day 13, suggesting that fetal loss occurred during late pregnancy. Next, we transferred 20 alpha-HSD+/+ embryos to 20 alpha-HSD+/+ or 20 alpha-HSD-/- females and found that the number of offspring was significantly smaller in 20 alpha-HSD-/- dams than in 20 alpha-HSD+/+ dams. Expression of 20 alpha-HSD mRNA in the fetus, placenta and uterus progressively increased from day 11 to 18 of pregnancy. In addition, concentrations of progesterone were significantly higher in the 20 alpha-HSD-/- fetuses than in the 20 alpha-HSD+/+ fetuses, while those of 20 alpha-OHP were lower in the 20 alpha-HSD-/- fetuses than in the 20 alpha-HSD+/+ fetuses. These results suggest that both maternal and fetal 20 alpha-HSD play a role in maintaining normal pregnancy at least partially by reducing progesterone concentrations in fetuses.