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Basic and Clinical study on endocrine therapy of gynecologic diseases targeting aromatase

芳香酶靶向治疗妇科疾病内分泌的基础与临床研究

基本信息

批准号：
16209049
负责人：
SHOZU Makio
金额：
$ 24.79万
依托单位：
Chiba University (2005-2007)Kanazawa University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209049/
关键词：
aromatase inhibitor uterine leiomyoma endometriosis ovulation induction 催奇形性排卵障害妊孕性脂肪

项目摘要

Estrogen-dependent gynecologic diseases such as endometriosis, uterine leiomyoma and adenomyosis has been increased and worsened with a recent trend to late- or un-marriage in life. The older women become, the more difficult she ovulate. We have shown that an aromatase inhibitor(s) is a theoretical molecular target of endocrine therapy of these estrogen-dependent diseases as well as a specific ovulatory failure (PCOS). Here we examined therapeutic mechanisms of an aromatase inhibitor and showed the possible clinical usefulness of an aromatase inhibitor for management of the situations described earlier. In leiomyoma cells, enhanced expression of aromatase increased in situ estrogen, which possibly promoted the proliferation of their own. Absent activation of MAPK pathway in leiomyoma cells also contributed to enhanced cell proliferation through the reduction in Egr-1, resulting in low Rb expression. IGF-1 enhanced accumulation of aromatase in leiomyoma cells by deprivation of trafficking newly synthesized aromatase into lysosome, probably mediated by IGF-1 action on mTOR. There was a racial difference in aromatase expression of leiomyoma cells. It was shown that local application of a drug delivery system composed of fadrozole- or danazole-loaded hyaluronic acid successfully treated rat chocolate cyst model without systemic effect. Fadrozole was preoperatively administered to leiomyoma patients, who gave their consent for the study. Two third of patients showed reduction in volume by 25% with an improvement of symptoms, within the first 4 weeks. Another inhibitor of aromatase, letrozole, was administered to PCOS patients with an informed consent and found the letrozole was as effective as clomiphene in terms of ovulation induction and might be more beneficial to patients with implantation difficulty compared to clomiphene.

依赖雌激素的妇科疾病，如子宫内膜异位症、子宫肌瘤和子宫腺肌病，已经增加并恶化，最近有晚婚或未婚的趋势。年龄越大的女性排卵越困难。我们已经证明，芳香酶抑制剂(S)是这些雌激素依赖型疾病内分泌治疗的理论分子靶点，也是一种特异性排卵衰竭(PCOS)。在这里，我们研究了芳香酶抑制剂的治疗机制，并展示了芳香酶抑制剂在治疗上述情况下的可能临床用途。在子宫肌瘤细胞中，芳香化酶表达增强，原位雌激素增加，可能促进自身增殖。肌瘤细胞中MAPK通路的缺失也通过减少Egr-1促进细胞增殖，导致Rb低表达。IGF-1通过阻断新合成的芳香酶进入溶酶体而促进芳香酶在肌瘤细胞中的积累，这可能是通过IGF-1对mTOR的作用而实现的。子宫肌瘤细胞芳香化酶表达存在种族差异。结果表明，局部应用Fadrozole或Danazol型透明质酸组成的给药系统成功地治疗了大鼠巧克力囊肿模型，且无全身反应。Fadrozole在手术前用于肌瘤患者，他们同意进行这项研究。三分之二的患者在最初的4周内，随着症状的改善，体积减少了25%。在知情同意的情况下，另一种芳香酶抑制剂来曲唑被用于PCOS患者，发现来曲唑在诱导排卵方面与克罗米芬一样有效，而且与克罗米芬相比，对植入困难的患者可能更有利。

项目成果

期刊论文数量（131）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Treatment of endometriosis by aromatase inhibitors.

通过芳香酶抑制剂治疗子宫内膜异位症。

DOI：
发表时间：
2008
期刊：
Obstet gynecol. 75(1)
影响因子：
0
作者：
Shozu M;Usui H;Omoto A;Tsuruoka N.
通讯作者：
Tsuruoka N.

排卵障害-アロマターゼ阻害剤の不妊治療への応用 PCOS・ホルモン依存性癌患者における排卵誘発

排卵障碍 - 芳香酶抑制剂在不孕症治疗中的应用 PCOS/激素依赖性癌症患者的排卵诱导

DOI：
发表时间：
2007
期刊：
医学のあゆみ 223・1
影响因子：
0
作者：
Takahiko;Hamasaki;Nobuhiro;Tanaka;Naosuke;Kamei;Osamu;Ishida;Shinobu;Yanada;Kazuyoshi;Nakanishi;Koji;Nishida;Yoshiaki;Oishi;Seiichi;Kawamata;Norio;Sakai;Mistuo;Ochi;生水真紀夫
通讯作者：
生水真紀夫

アロマターゼ欠損症

芳香酶缺乏症