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Estren Behaves as a Weak Estrogen Rather than a Nongenomic Selective Activator in the Mouse Uterus

Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology (S.C.H., K.H., K.S.K.), and Microarray Group (J.C., S.G.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Sylvia C. Hewitt, Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709. E-mail: curtiss{at}niehs.nih.gov.

A proposed membrane-mediated mechanism of rapid nongenomic response to estrogen has been the intense focus of recent research. Estren, a synthetic steroid, is reported to act selectively through a rapid membrane-mediated pathway, rather than through the classical nuclear estrogen receptor (ER)-mediated pathway, to maintain bone density in ovariectomized mice without uterotropic effects. To evaluate the mechanism and physiological effects of estren, we studied responses in adult ovariectomized mice. In a 3-d uterine bioassay, we found that 300 µg estren significantly increased uterine weight; in comparison, a more maximal response was seen with 1 µg estradiol (E2). The estren response was partly ER independent, because ER knockout (ERKO) uteri also exhibited a more moderate weight increase. Estren induced epithelial cell proliferation in wild-type, but not ERKO, mice, indicating ER dependence of the epithelial growth response. Examination of estren-regulated uterine genes by microarray indicated that early (2 h) changes in gene expression are similar to the early responses to E2. These gene responses are ER dependent, because they are not seen in ERKO mice. Later estren-induced changes in gene expression (24 h) are blunted compared with those seen 24 h after E2. In contrast to early genes, these later estren responses are independent of ER, because the ERKO shows a similar response to estren at 24 h. We found that E2 or estren treatments lead to depletion of ER in the uterine cytosol fraction and accumulation in the nuclear fraction within 30–60 min, consistent with the ability of estren to regulate genes through a nuclear ER rather than a nongenomic mechanism. Interestingly, estren, but not E2, induces accumulation of androgen receptor (AR) in the nuclear fraction of both wild-type and ERKO samples, suggesting that AR might be involved in the later ER-independent genomic responses to estren. In conclusion, our studies suggest that estren is weakly estrogenic in the mouse uterus and might induce nuclear ER- and AR-mediated responses. Given its activity in our uterine model, the use of estren as a bone-selective clinical compound needs to be reconsidered.

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