Statins Inhibit Growth of Human Theca-Interstitial Cells in PCOS and Non-PCOS Tissues Independently of Cholesterol Availability

摘要

Context: Polycystic ovary syndrome (PCOS) is associated with ovarian enlargement, prominent theca-interstitial hyperplasia, and excessive androgen production. Recent clinical trials have demonstrated that statins, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, decrease androgen levels in women with PCOS.Objective: The present study evaluated the effect of statins on proliferation of human ovarian theca-interstitial cells.Design and Settings: In vitro experiments were performed in the university research laboratory.Patients: Human theca-interstitial cells were isolated from ovaries of PCOS (n = 4) and non-PCOS (n = 4) patients.Main Outcome Measures: The cells were incubated for 48 h without additives (control) or with simvastatin (3–30 μm), mevastatin (3–30 μm), and/or the cell- and mitochondrion-permeable form of cholesterol (22-hydroxycholesterol; 10 μm). To determine whether the effects of statins could be affected by leukocytes, the experiment was carried out on cells not purified of leukocytes and cells purified using anti-CD-45 immunomagnetic beads. The effect of statins on proliferation was evaluated by determination of DNA synthesis using radiolabeled thymidine-incorporation assay and by quantification of viable cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2 H -tetrazolium assay.Results: Statins induced an inhibition of DNA synthesis in both the absence and the presence of 22-hydroxycholesterol; furthermore, 22-hydroxycholesterol alone also inhibited DNA synthesis. These effects of statins and 22-hydroxycholesterol were confirmed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2 H -tetrazolium assay. Comparable inhibition of proliferation was observed in cells obtained from women with and without PCOS and in cell preparations treated and not treated with anti-CD-45 immunomagnetic beads.Conclusions: Statins inhibit proliferation of human theca-interstitial cells irrespective of the availability of cholesterol and independently of leukocytes both in normal and PCOS ovaries.