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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2924-2930
Copyright © 2002 by The Endocrine Society

Other Original Articles

Progesterone Withdrawal and Estrogen Activation in Human Parturition Are Coordinated by Progesterone Receptor A Expression in the Myometrium

Sam Mesiano, Eng-Cheng Chan, John T. Fitter, Kenneth Kwek, George Yeo and Roger Smith

Mothers and Babies Research Center, University of Newcastle and John Hunter Hospital (S.M., E.-C.C., J.T.F., R.S.), Newcastle, New South Wales 2310, Australia; and Singapore KK Women’s and Children’s Hospital (K.K., G.Y.), Singapore 229899

Address all correspondence and requests for reprints to: Dr. Sam Mesiano, Mothers and Babies Research Center, John Hunter Hospital, Locked Bag 1 HRMC, New South Wales 2310, Australia. E-mail: . smesiano{at}mail.newcastle.edu.au

Abstract

In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ER{alpha} and/or ERß. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ER{alpha}, and ERß in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ER{alpha} mRNA were significantly increased in laboring myometrium, whereas ERß mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ER{alpha} mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ER{alpha} and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ER{alpha} mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ER{alpha} expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ER{alpha} and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.




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