Regulation of progesterone levels during pregnancy and parturition by signal transducer and activator of transcription 5 and 20α-hydroxysteroid dehydrogenase

The two highly related signal transducers and activators of transcription (Stats), Stat5a and Stat5b, are major mediators of prolactin signaling in both the mammary gland and in the ovary. Deficiencies in Stat5b, or in both Stat5a and Stat5b, result in loss of pregnancy during midgestation and are correlated with an increase in ovarian 20α-hydroxysteroid dehydrogenase (20α-HSD) and a decrease in serum progesterone, which normally declines only immediately before parturition. To determine the relative contribution of 20α-HSD to progesterone metabolism and Stat5 function during pregnancy and parturition, we created a 20α-HSD-deficient strain of mice by gene disruption. Mice deficient for 20α-HSD sustain high progesterone levels and display a delay in parturition of several days demonstrating that 20α-HSD regulates parturition downstream of the prostaglandin F _2α receptor in an essential and nonredundant manner. Moreover, 20α-HSD deficiency partially corrected the abortion of pregnancies associated with Stat5b deficiency, supporting the concept that prolactin activation of Stat5b is important in suppressing 20α-HSD gene expression and thereby allowing the maintenance of progesterone levels that are required to sustain pregnancy.