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

Simvastatin Protects Against the Development of Endometriosis in a Nude Mouse Model - Kaylon L. Bruner-Tran - Kevin G. Osteen - Antoni J. Duleba Previous studies have demonstrated that proliferation of endometrial stroma (ES) in vitro is inhibited by a number of statins in a concentration-dependent manner. An in vitro model of endometriosis found that lovastatin also abolished angiogenesis. Another study using a rat autotransplantation model reported that the size of surgically induced experimental endometriosis was reduced by atorvastatin. These actions of statins in preventing the development of endometriosis may involve their anti-inflammatory properties. A number of studies have shown that inhibition of matrix metalloproteinase-3 (MMP-3) in mice and tissues results in a marked reduction in the establishment of experimental endometriosis. The present study investigated the effects of simvastatin on development of endometriosis using a nude mouse model. The effects of simvastatin on MMP-3 were also evaluated in the presence and absence of an inflammatory challenge induced by interleukin (IL)-1α. Normal endometrial tissues were obtained by biopsy from 11 healthy volunteers. The tissues were used to isolate ES cells or to establish organ cultures. All tissues were maintained in culture in the presence of 1 nM 17β-estradiol for 24 hour before injection into mice. Ovariectomized female nude mice were implanted with a SILASTIC capsule implant containing 8 mg 17β-estradiol for 24 hours before receiving subperitoneal injections of human endometrial tissues. Twenty-four hours after tissue injection, mice were randomly assigned to receive by gavage either 5 mg/kg or 25 mg/kg of simvastatin, or a placebo vehicle daily for 10 days. At various times after treatment, the mice were killed and examined for the presence, number, and size of lesions. To evaluate the in vitro effect of simvastatin on MMP-3, isolated human ES cells were cultured for 24 hours in medium containing 1 nM estradiol, in the absence (control) or the presence of simvastatin (1 and 10 μM). Some cells were exposed to an inflammatory challenge by addition of IL-1α (200 ng/mL) for the last 6 hour of culture. Simvastatin reduced both the number and the volume of endometriotic lesions in nude mice in a dose-dependent manner. About 85% of the mice receiving vehicle alone (control) developed lesions, whereas 58% of the mice receiving low-dose simvastatin (P = 0.2) and only 17% (P = 0.001) of those given high-dose simvastatin had lesions. In cultured ES cells, simvastatin induced a concentration-dependent decrease in MMP-3 expression, even after a challenge with IL-1α. These findings demonstrating a marked simvastatin-induced inhibition of both endometriosis development in the nude mouse model and reduced MMP-3 expression in cultures of ES cells suggest that the use of statins for the treatment of endometriosis is promising.