The estrogen metabolites 2-methoxyestradiol and 2-hydroxyestradiol inhibit endometriotic cell proliferation in estrogen-receptor-independent manner

Abstract

Endometriosis, a painful disorder associated with infertility, is estimated to occur in approximately 7–10% of reproductive age women. Although endometriosis is considered as an estrogen-dependent disease, the role of estrogen metabolites via receptor-independent mechanisms has not yet been comprehensively clarified. In the present study, growth studies were performed comparing the effect of estradiol (E2), estrogen metabolites, that is, 2-hydroxyestradiol (2-OHE2) and 2-methoxyestradiol (2-ME), as well as estrogen-receptor-independent mechanisms using the estrogen receptor antagonist fulvestrant, on cell proliferation of endometriotic cells. The estrogen metabolites 2-OHE2 and 2-ME inhibited cell growth in a dose-dependent manner in pharmacological doses. Lower concentrations of 2-OHE2 had a stimulating effect on cell proliferation while pharmacologic doses exerted an antimitogenic effect. The effects on cell growth were at least partially receptor-independent, as demonstrated by simultaneous receptor antagonization with fulvestrant. In conclusion, our results demonstrate that in pharmacological doses the estrogen metabolites 2-ME and 2-OHE2 show inhibiting effects on the proliferation of endometriotic cells and may be promising substances for the treatment of endometriosis.

Chinese abstract

子宫内膜异位症（简称内异症）是一种疼痛伴随不孕的疾病，在育龄期女性中的发生率为7-10%。尽管内异症被认为是一种雌激素依赖性疾病，但不依赖受体的雌激素代谢产物的作用机制尚未被全面阐明。本研究比较了雌二醇(E2)代谢产物2-羟基雌二醇(2-OHE2)和2-甲羟雌二醇(2-ME)的作用，并采用雌激素受体拮抗剂氟维司群对异位内膜细胞不依赖于雌激素受体增殖的机制进行了研究。雌激素代谢产物2-OHE2和2-ME对细胞生长的抑制呈剂量依赖性。低浓度的2-OHE2对细胞增殖有刺激效应，而当达到药理学剂量时则表现出抑制有丝分裂的效应。通过氟维司群的同步受体拮抗作用说明，这种细胞生长至少呈部分地受体非依赖性。因此，我们的结果证实，药理学剂量的雌激素代谢产物2-ME和2-OHE2显示了抑制异位内膜细胞增殖的作用，这有可能用于开发内异症的治疗药物。

• Endometriosis
• estrogen metabolites
• fulvestrant (ICI 182780)
• 2-hydroxyestradiol
• 2-methoxyestradiol

Acknowledgements

This work was supported by the Hartmann Müller and the EMDO foundation (grants to Brigitte Leeners and Raghvendra Dubey) and by the Swiss National Science Foundation Grant # IZERO-142213/1 and Grant # 31003A-138067 (to Raghvendra Dubey). We thank Prof. Dr. Starzinski-Powitz for giving us the opportunity to realize our research project by providing her endometriotic cell line (12Z).