Regulation of progesterone levels during pregnancy and parturition by signal transducer and activator of transcription 5 and 20alpha-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 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) and a decrease in serum progesterone, which normally declines only immediately before parturition. To determine the relative contribution of 20alpha-HSD to progesterone metabolism and Stat5 function during pregnancy and parturition, we created a 20alpha-HSD-deficient strain of mice by gene disruption. Mice deficient for 20alpha-HSD sustain high progesterone levels and display a delay in parturition of several days demonstrating that 20alpha-HSD regulates parturition downstream of the prostaglandin F2alpha receptor in an essential and nonredundant manner. Moreover, 20alpha-HSD deficiency partially corrected the abortion of pregnancies associated with Stat5b deficiency, supporting the concept that prolactin activation of Stat5b is important in suppressing 20alpha-HSD gene expression and thereby allowing the maintenance of progesterone levels that are required to sustain pregnancy.
Howard Hughes Medical Institute, Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Roland P
RP
Piekorz
Sébastien
S
Gingras
Angelika
A
Hoffmeyer
James N
JN
Ihle
Yacob
Y
Weinstein
D043607:20-alpha-Hydroxysteroid Dehydrogenase / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003008:Cloprostenol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005822:Genetic Vectors; D005838:Genotype; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007668:Kidney / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D008894:Milk Proteins / Q000378:metabolism*; D008957:Models, Genetic; D009154:Mutation; D010053:Ovary / Q000378:metabolism; D036801:Parturition; D011247:Pregnancy; D011270:Pregnancy, Animal; D011374:Progesterone / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D011863:Radioimmunoassay; D011982:Receptors, Prostaglandin / Q000378:metabolism; D050799:STAT5 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011982:Receptors, Prostaglandin; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; C034671:prostaglandin F2alpha receptor; D015735:Mifepristone; D003008:Cloprostenol; D011374:Progesterone; D043607:20-alpha-Hydroxysteroid Dehydrogenase