エストロゲンの効果の臨床的再評価と選択的エストロゲン受容体調節薬の次世代HRTとしての基礎的検討 : 心血管系および乳腺細胞における検討(<特集>第57回学術講演会シンポジウム: ホルモン補充療法-その基礎と臨床-)

• 高橋,一広

  山形大学医学部発達生体防御学講座女性医学分野

書誌事項

タイトル別名

• Hormone Replacement Therapy and Selective Estrogen Receptor Modulator : Beneficial Effects for Vasculature and Mammary Cells

抄録

In the Women's Health Initiative (WHI) study, although women on combined estrogen-progestin had an increase in the relative risk of cardio-vascular events, women on estrogen alone did not show adverse effect on the risk of cardiovascular disease. The cardioprotective effect of estrogen itself was not ruled out by the results of the WHI study. It is possible that progestin has adverse effects on the cardiovascular system. We re-evaluated whether hormone replacement therapy (HRT) has cardioprotective effect on healthy postmenoposal women, and studied the effect of raloxifene, which does not require the addition of progestin to protect the uterine endometrium, on vasculature and mammary cells. Aortic stiffness, determined by the pulse wave velocity (PWV), is an independent marker of cardiovascular risk, and carotid intima-media thickness (IMT) is an appropriate intermediate end point to be investigated clinically relevant effects on atherogenesis. We evaluated the effects of HRT on vasculature using these methods. There was a significant relationship between PWV and age in both premenopausal and postmenopausal women. We found that the PWV value of HRT group was significantly lower compared with that of non-HRT group at all ages. Moreover, there was a significant relationship between IMT and age in non-HRT and short-term HRT groups (<2 years of treatment), but no significant relationship between IMT and age was observed in the long-term HRT group (=2 years of treatment). Raloxifene induced endothelial phosphorylation of nitric oxide synthase (eNOS). This phosphorylation was unaffected by actinomycin D and was blocked by the pure estrogen receptor antagonist ICI182,780 in human umbilical vein endothelial cells. The overexpression of dominant-negative Akt (AktK179M) inhibited raloxifene induced phosphorylation of eNOS. Raloxifene inhibited the proliferation of vascular smooth muscle cells (VSMC) which was induced by platelet derived growth factor (PDGF). We found that raloxifene inhibited the PDGF-induced expression of cyclin D1 and phosphorylation of retinoblastoma protein, and suppressed the PDGF-stimulated S-phase progression of the cell cycle in VSMC. Moreover, raloxifene induced the phosphorylation of p38 mitogen-activated protein followed by apoptosis of proliferating VSMC. In MCF-7 cells, raloxifene inhibited the induction of cell growth and telomerase activity by estrogen. Estrogen activated telomerase activity via increase of human telomerase reverse transcriptase (hTERT) expression and phosphorylation of hTERT through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Raloxifene inhibited the estrogen induced up-regulation of telomerase activity not only by transcriptional regulation of hTERT but also by post-translational regulation via phosphorylation of hTERT. Our clinical research showed that HRT may have cardioprotective effects on healthy postmenopausal women. Raloxifene induced phosphorylation of eNOS and inhibited VSMC and mammary cells proliferation in vitro. These effects may be beneficial for protection against cardiovascular disease and breast cancer in postmenopausal women.

収録刊行物

• 日本産科婦人科學會雜誌

  日本産科婦人科學會雜誌 57 (12), 1809-1818, 2005-12-01

  日本産科婦人科学会

キーワード

• Estrogen
• HRT
• Selective estrogen receptor modulator
• Raloxifene
• Cardiovascular disease
• Breast cancer

詳細情報

• CRID: 1541417145268984576
• NII論文ID: 110002545795
• NII書誌ID: AN00190060
• Web Site: http://dl.ndl.go.jp/info:ndljp/pid/10714836
• Web Site: https://search.jamas.or.jp/link/ui/2006126733
• 本文言語コード: ja
• データソース種別:
  • NDL-Digital
  • CiNii Articles