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Simvastatin Protects against the Development of Endometriosis in a Nude Mouse Model

Women’s Reproductive Health Research Center (K.L.B.-T., K.G.O.), Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Division of Reproductive Endocrinology and Infertility (A.J.D.), Department of Obstetrics and Gynecology, University of California Davis, Sacramento, California 95817

Address all correspondence and requests for reprints to: Antoni J. Duleba, 4869 Y Street, Suite 2500, Sacramento, California 95817. E-mail: ajduleba{at}ucdavis.edu.

Context: Endometriosis is a common condition associated with infertility and pelvic pain in women. Recent in vitro studies have shown that statins decrease proliferation of endometrial stroma (ES) and inhibit angiogenesis.

Objective: The aim was to evaluate effects of simvastatin on development of endometriosis in a nude mouse model.

Methods: Proliferative phase human endometrial biopsies were obtained from healthy donors and established as organ cultures or used to isolate ES cells. To establish endometriosis in the nude mouse, endometrial tissues were maintained in 1 nM estradiol (E) for 24 h and subsequently injected into ovariectomized nude mice. Mice (n = 37) were treated with E (8 mg, SILASTIC capsule implants; made in author laboratory) alone or with E plus simvastatin (5 or 25 mg/kg · d) for 10 d beginning 1 d after tissue injection (from three donors). Mice were killed and examined for disease. Effects of simvastatin on matrix metalloproteinase-3 (MMP-3) were evaluated in cultures of ES cells.

Primary Outcome: The number and size of endometriotic implants were measured.

Results: Simvastatin induced a dose-dependent decrease of the number and size of endometrial implants in mice. At the highest dose of simvastatin, the number of endometrial implants decreased by 87%, and the volume by 98%. Simvastatin also induced a concentration-dependent decrease in MMP-3 in the absence and presence of inflammatory challenge (using IL-1).

Conclusions: Simvastatin exerted a potent inhibitory effect on the development of endometriosis in the nude mouse. Mechanisms of action of simvastatin may include inhibition of MMP-3. The present findings may lead to the development of novel treatments of endometriosis involving statins.