Simvastatin protects against the development of endometriosis in a nude mouse model.
BACKGROUND
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 x 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.


METHODS
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-1alpha).


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.
Bruner-Tran
Kaylon L
KL
Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Osteen
Kevin G
KG
Duleba
Antoni J
AJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004715:Endometriosis / Q000473:pathology / Q000517:prevention & control*; D004958:Estradiol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014591:Uterine Diseases / Q000473:pathology / Q000517:prevention & control*; D055815:Young Adult
D000924:Anticholesteremic Agents; D004958:Estradiol; D019821:Simvastatin; D019278:Matrix Metalloproteinase 3