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Nuclear Progesterone Receptors in the Human Pregnancy Myometrium: Evidence that Parturition Involves Functional Progesterone Withdrawal Mediated by Increased Expression of Progesterone Receptor-A

Department of Reproductive Biology, Case Western Reserve University, and Department of Obstetrics and Gynecology (T.N.W., H.T., L.J.Y., S.M., V.C.), University Hospitals, Case Medical Center, Cleveland, Ohio 44106; and Department of Obstetrics and Gynecology (A.A.M., B.M.M.), MetroHealth Medical Center, Cleveland, Ohio 44109

Address all correspondence and requests for reprints to: Sam Mesiano, Ph.D., Department of Reproductive Biology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, Ohio 44106-5034. 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 (PRs)-A and -B.

Objective: Our objectives were to: 1) measure PR-A and PR-B protein levels in human pregnancy myometrium and determine whether the PR-A to PR-B ratio changes with advancing gestation and labor onset; and 2) determine how changes in the PR-A to 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 wk; not laboring; n = 5) and term (37–40 wk; 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 in 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 to PR-B protein ratio was 0.49 ± 0.082 (mean ± SEM) in preterm tissue; increased to 1.03 ± 0.071 (P < 0.001) in nonlaboring 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 to PR-B ratio due to increased PR-A expression.

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