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BOR - Papers in Press, published online ahead of print December 1, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.034595
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Submitted September 13, 2004
Returned for revision October 11, 2004
Accepted November 10, 2004

Female Reproductive Tract


Differential Effects of Estrogen and Raloxifene on Messenger RNA and Matrix Metalloproteinase 2 Activity in Rat Uterus

L. M. Helvering *, M. D. Adrian , A. G. Geiser , S. T. Estrem , T. Wei , S. Huang , P. Chen , E. R. Dow , J. N. Calley , J. A. Dodge , T. A. Grese , S. A. Jones , D. L. Halladay , R. R. Miles , J. E. Onyia , Y. L. Ma , M. Sato , and H. U. Bryant

* To whom correspondence should be addressed. E-mail: l.helvering{at}lilly.com.

Abstract
A detailed analysis of the differential effects of estrogen (E) compared to raloxifene (Ral), a selective estrogen receptor modulator (SERM), following estrogen receptor binding in gynecological tissues was conducted using gene microarrays, northern analysis and MMP2 activity studies. We profiled gene expression in the uterus following acute (1 day) and prolonged daily treatment (5 weeks) of E and Ral in ovariectomized rats. E regulated twice as many genes as Ral, largely those associated with catalysis and metabolism, whereas Ral treatment induced genes associated with cell death and negative cell regulation. Follow-up studies confirmed that genes associated with matrix integrity were differentially regulated by Ral and E at various timepoints in uterine and vaginal tissues. Additional experiments were conducted to determine the levels of MMP2 activity in uterus explants from ovariectomized rats following 2 weeks of treatment with E, Ral, or one of two additional SERMs: lasofoxifene, and levormeloxifene. E and lasofoxifene stimulated uterine MMP2 activity to a level twice that of Ral while levormeloxifene elevated MMP2 activity to a level 12 times that of Ral. These data show that one of the significant differences between E and Ral signaling in the uterus is the regulation of genes and proteins associated with matrix integrity. This may be a potential key difference between the action of SERMs in the uterus of postmenopausal women.

Key words: Female Reproductive Tract • Mechanisms of Hormone Action • Estradiol receptor • Uterus • Vagina


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