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Regulation of Progesterone Levels during Pregnancy and Parturition by Signal Transducer and Activator of Transcription 5 and 20-Hydroxysteroid Dehydrogenase

Howard Hughes Medical Institute (R.P.P., S.G., A.H., J.N.I.), Department of Biochemistry (R.P.P., S.G., A.H., J.N.I.), St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; and Faculty of Health Sciences (Y.W.), Department of Microbiology and Immunology, Ben Gurion University of the Negev, Beer Sheva, Israel 84105

Address all correspondence and requests for reprints to: James N. Ihle, Howard Hughes Medical Institute, Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105. E-mail: james.ihle{at}stjude.org.

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 20-hydroxysteroid dehydrogenase (20-HSD) and a decrease in serum progesterone, which normally declines only immediately before parturition. To determine the relative contribution of 20-HSD to progesterone metabolism and Stat5 function during pregnancy and parturition, we created a 20-HSD-deficient strain of mice by gene disruption. Mice deficient for 20-HSD sustain high progesterone levels and display a delay in parturition of several days demonstrating that 20-HSD regulates parturition downstream of the prostaglandin F₂ receptor in an essential and nonredundant manner. Moreover, 20-HSD deficiency partially corrected the abortion of pregnancies associated with Stat5b deficiency, supporting the concept that prolactin activation of Stat5b is important in suppressing 20-HSD gene expression and thereby allowing the maintenance of progesterone levels that are required to sustain pregnancy.

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Ligands:   Progesterone

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