Simvastatin Induces Apoptosis and Alters Cytoskeleton in Endometrial Stromal Cells

Context: Statins are competitive inhibitors of 3-hydroxy-3methylglutaryl-coenzyme A reductase, with antimitotic, antioxidant, antiinflammatory, and immunomodulatory properties. Recent studies have shown that statins reduce the growth of human endometrial stromal (HES) cells and protect from the development of endometriosis in animal models. Objectives: The present study was conducted to evaluate the effects of simvastatin on apoptosis and cytoskeleton of HES cells. Design and Setting: In vitro experiments were performed in the university research laboratory. Patients: HES cells were obtained from endometrial biopsies collected from nine subjects in the proliferative phase of their menstrual cycle. Main Outcome Measures: The effect of simvastatin (10 and 30 mu M) and/or geranylgeranyl pyrophosphate (GGPP, 30 mu M) on caspase 3 and 7 activity, DNA fragmentation, and HES cell morphology was evaluated. Results: Simvastatin induced significant time-and concentration-dependent apoptotic effects on HES cells as determined by increased activity of executioner caspases and DNA fragmentation. Simvastatin also caused profound alterations in HES cell morphology and F-actin cytoskeleton. This effect was abrogated by geranylgeranyl pyrophosphate, an important product of the mevalonate pathway. Conclusions: Simvastatin induces apoptosis and disruption of the cytoskeleton of HES cells by reducing isoprenylation in cultures of human endometrial stroma. The present findings may lead to the development of novel treatments for endometriosis involving statins. (J Clin Endocrinol Metab 95:3453-3459, 2010)