Increased expression of estrogen receptor beta in human uterine smooth muscle at term.

Expression of the cx43 gene for the gap junction protein, connexin43 (Cx43), through activator protein (AP)-1 activity has been shown to be inhibited in human primary myometrial cultures pretreated with estrogen. In the present study, the primary myometrial cultures were shown to express predominantly ERbeta, a subtype of estrogen receptor that inhibits AP-1 activity when bound to agonists. ERbeta levels were decreased in the primary myometrial cultures after treatment with the phorbol ester, 12-O-tetradecanolyl-13 acetate, to stimulate AP-1 activity, and this effect is inhibited if cells were pretreated with estrogen. Two isoforms of ERbeta were found in primary myometrial and leiomyoma cultured cells. Immunoblot and RT-PCR analyses indicated that ERbeta expression was increased in human term myometrial tissue compared with non-pregnancy tissue. Immunohistochemistry localized ERbeta to the nucleus in cells of term myometrial tissue samples that had high ERbeta expression. ERbeta was increased in term tissue in which Cx43 protein levels were low. In myometrial tissue in which Cx43 protein levels are greatest (e.g. during active labor), ERbeta was barely detectable. Only low levels of ERbeta were detected in non-pregnancy myometrial and leiomyoma tissues, and the lowest levels were found in tissues from mid cycle. In contrast, ERalpha was highly detectable in the non-pregnancy myometrial and leiomyoma tissues, but not in term myometrial tissue samples. This work indicates there is a dramatic switch from ERalpha to ERbeta expression in the myometrium during pregnancy. The results suggest that, during gestation, myometrial ERbeta may inhibit AP-1 activity and thus block induction of the cx43 gene and other labor-associated genes. Labor may ensue after a loss of myometrial ERbeta expression.