THERAPUETIC APPLICATION OF AROMATASE INHIBITOR FOR LEIOMYOMA OF THE UTERUS AND ENDOMETRIOSIS

芳香酶抑制剂在子宫肌瘤及子宫内膜异位症的治疗中的应用

• 批准号: 12557136
• 负责人: AHOZU Makio
• 金额: $ 7.55万
• 依托单位: KANAAWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557136/
• 关键词: Aromatase; Endometriosis; Leromyoma of the uterus; Aromatase inhibitor; Estrogen; GnRH agonist; Clinical trial; アロマターゼ阻害例; アロマターゼインヒビター; GnRH アゴニスト

1. Leiomyoma of the uterus expresses estrogen synthetase (aromatase) and synthesize estrogen in situ. Preoperative GnRH agonist therapy abolishes aromatase expression in leiomyoma tissues in situ in addition to aromatase expression in the ovary. This combined suppression may explain why GnRH agonists induced shrinkage of leiomyoma more rapidly and more profoundly than natural menopause.2. Addition of androstenedione stimulates cell proliferation of leiomyoma cells in culture. This growth stimulatory action was completely canceled by the pretreatment with an aromatase inhibitor (fadrozole).3. Oral administration of fadrozole (1mg/kg/day,>1 weeks) induced anovulatory state in rats. Estrus cycles were recovered within 1 week after the discontinuation of fadrozole.4. Oral fadrozole (2mg/day) induced rapid and profound regression of leiomyoma and resolved bulk-related symptoms of a perimenopausal woman. The potential uses of aromatase inhibitors was demonstrated.5. AF-1/AD4BP binds to a nuclear half site of the most proximal promoter of aromatase (PII) and up-regulates the transcription of aromatase in endometriosis cells. Cis elements of PII promoter of aromatase, therefore its regulation, were quite different between endometriosis and the ovary, suggesting that tissues-specific and promoter-specific modulation of aromatase expression is possible.

1.子宫平滑肌瘤表达雌激素合成酶（芳香化酶）并原位合成雌激素。术前促性腺激素释放激素激动剂治疗除了在卵巢中的芳香化酶表达外，还在原位消除了平滑肌瘤组织中的芳香化酶表达。这种联合抑制可能解释了为什么GnRH激动剂比自然绝经期更快更深地诱导平滑肌瘤缩小。添加雄烯二酮可刺激培养物中平滑肌瘤细胞的细胞增殖。芳香化酶抑制剂（法倔唑）的预处理完全消除了这种生长刺激作用.大鼠口服法倔唑（1 mg/kg/d，>1周）可引起无排卵状态。停药后1周内恢复发情周期.口服法倔唑（2 mg/天）诱导平滑肌瘤快速和深刻的消退，并解决了围绝经期妇女的体块相关症状。展示了芳香化酶抑制剂的潜在用途. AF-1/AD 4 BP与芳香化酶（PII）最近端启动子的核半位点结合，上调子宫内膜异位症细胞芳香化酶的转录。芳香化酶PII启动子的顺式元件，因此其调节在子宫内膜异位症和卵巢之间是相当不同的，这表明芳香化酶表达的组织特异性和启动子特异性调节是可能的。

项目成果

Temporaty amniotic memebrane patching for acute chemical burns.

临时羊膜修补术治疗急性化学烧伤。

• 发表时间: 2003
• 期刊: Eye 17
• 作者: Kobayashi A.;Shirao;Y.;Yoshia T,;Yagami K.;Segawa Y.;Kawasaki K.;Shozu M.;Tseng SC.
• 通讯作者: Tseng SC.

Inhibition of in situ expression of aromatase P450 in leiomyoma of the uterus by leuprorelin acetate

• DOI: 10.1210/jc.86.11.5405
• 发表时间: 2001-11-01
• 期刊: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
• 影响因子: 5.8
• 作者: Shozu, M;Sumitani, H;Inoue, M
• 通讯作者: Inoue, M

Over-expression of aromatase P-450 in leiomyoma tissues is driven through the promoter 1.4 of aromatase P-450.

芳香酶 P-450 在平滑肌瘤组织中的过度表达是通过芳香酶 P-450 的启动子 1.4 驱动的。

• 发表时间: 2002
• 期刊: J Clin Endocrinol Metab 87
• 作者: Shozu;M.;Sumitani;H.;Segawa;T.;Yang;H.-J.;Murakami;K.;Kasai;T.;Inoue;M.
• 通讯作者: M.

Sumitani H,Shozu M,Segawa T,Murakami K,Yang HJ,Simada K.: "In situ estrogen synthesized by aromatase P450 in uterine leionyoma cells promotes cell growth probably via an autocrine fintracrine mechanism"Endocrinol.. 141(10). 3852-61 (2000)

Sumitani H，Shozu M，Sekawa T，Murakami K，Yang HJ，Simada K.：“子宫肌瘤细胞中芳香酶 P450 合成的原位雌激素可能通过自分泌 fintracrine 机制促进细胞生长”Endocrinol.. 141（10）。

In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism.

• DOI: 10.1210/endo.141.10.7719
• 发表时间: 2000-10
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Hiroshi Sumitani;Makio Shozu;T. Segawa;K. Murakami;Hui-Juan Yang;Keiko Shimada;M. Inoue