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Submitted on January 12, 2007
Accepted on February 27, 2007
Department of Reproductive Biology, Case Western Reserve University and Department of Obstetrics and Gynecology, University Hospitals of Cleveland, Cleveland OH; Department of Obstetrics and Gynecology, MetroHealth Medical Center, Cleveland OH; Department of Obstetrics and Gynecology, Northwestern University, Evanston, IL, 60201
* To whom correspondence should be addressed. E-mail: sam.mesiano{at}case.edu.
Context: We examined whether human parturition involves functional progesterone withdrawal mediated by changes in myometrial expression of progesterone receptors -A and -B (PR-A and PR-B).
Objective: Our objectives were: 1) measure PR-A and PR-B protein levels in human pregnancy myometrium and determine whether the PR-A/PR-B ratio changes with advancing gestation and labor onset; and 2) determine how changes in the PR-A/PR-B ratio affect myometrial cell progesterone responsiveness.
Design: PR protein levels and cellular localization were measured by western blotting and immunohistochemistry, respectively, in lower uterine segment uterine wall tissue from preterm (<37 weeks; not laboring; n = 5) and term (37-40 weeks; not in labor: n = 6; in labor: n = 5) cesarean delivery. The capacity for PR-A and PR-B, alone and in combination, to mediate genomic progesterone responsiveness measured by the activity of a progesterone-responsive reporter plasmid was examined by artificially modulating their levels the PHM1-31 myometrial cell line.
Results: PR-A and PR-B immunostaining was detected only in the nucleus of myometrial cells. The PR-A/PR-B protein ratio was 0.49 ± 0.082 (mean ± SEM) in preterm tissue; increased to 1.03 ± 0.071 (P < 0.001) in non-laboring term tissue, and increased further to 2.65 ± 0.344 (P<0.001) in laboring term tissue. Only PR-B mediated progesterone-induced transcriptional activity. PR-A had no effect alone, but markedly decreased PR-B-mediated progesterone responsiveness.
Conclusions: Functional progesterone withdrawal in human parturition may be mediated by an increase in the myometrial PR-A/PR-B ratio due to increased PR-A expression.
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