Inhibition of in situ expression of aromatase P450 in leiomyoma of the uterus by leuprorelin acetate
Inhibition of in situ expression of aromatase P450 in leiomyoma of the uterus by leuprorelin acetate
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DOI：
10.1210/jc.86.11.5405
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发表时间：
2001-11-01
影响因子：
5.8
通讯作者：
Inoue, M
中科院分区：
文献类型：
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作者：
Shozu, M;Sumitani, H;Inoue, M
我们已经证明，子宫平滑肌瘤中原位合成的雌激素可能通过自分泌/旁分泌机制在促进平滑肌瘤细胞生长方面发挥作用。在本研究中，我们证明了醋酸亮丙瑞林（一种GnRH激动剂，广泛用于通过下调垂体-卵巢功能治疗子宫平滑肌瘤）可抑制平滑肌瘤细胞中芳香化酶P450（一种雌激素合成酶）的表达。鉴于原位雌激素在平滑肌瘤细胞生长中的作用，原位雌激素合成的抑制可能在GnRH激动剂诱导的平滑肌瘤快速消退中发挥作用。定量RT-PCR显示，在没有接受药物治疗的妇女子宫平滑肌瘤表达芳香化酶P450 mRNA的水平比周围的子宫肌层高20倍。醋酸亮丙瑞林治疗（1.88 mg，每4周一次，se注射）12-24周可降低平滑肌瘤组织和子宫肌层中芳香化酶P450 mRNA的表达，约为未治疗女性子宫肌层的十分之一。抑制芳香化酶P450的表达也证明了蛋白质印迹分析和芳香化酶活性测定的微粒体组分制备的平滑肌瘤。另一方面，当离体培养细胞并接受各种刺激剂组合（如地塞米松+ IL-1 β）刺激时，在接受和未接受醋酸亮丙瑞林注射剂治疗的女性中获得的平滑肌瘤细胞之间未观察到芳香酶P450的活性和mRNA水平存在差异。添加不同浓度的E2不会影响平滑肌瘤细胞的芳香化酶活性，表明循环（卵巢）雌激素缺乏不是醋酸亮丙瑞林治疗期间芳香化酶表达降低的原因。另一方面，用醋酸亮丙瑞林（100 nmol/L）处理8天使地塞米松+ IL-1 β诱导的活性和芳香酶的mRNA水平分别降低28%和42%。这些结果表明，醋酸亮丙瑞林抑制平滑肌瘤细胞中芳香化酶P450的表达，这有助于醋酸亮丙瑞林治疗期间平滑肌瘤的快速消退。
We have shown that in situ estrogen synthesized in leiomyoma of the uterus plays a possible role in the promotion of leiomyoma cell growth via an autocrine/paracrine mechanism. In the present study, we demonstrated that leuprorelin acetate, a GnRH agonist widely used for treatment of uterine leiomyoma by down-regulation of pituitary-ovarian function, suppressed the expression of aromatase P450 (an estrogen synthetase) in leiomyoma cells. Given the role of in situ estrogen in leiomyoma cell growth, the inhibition of in situ estrogen synthesis may play a role in GnRH agonist-induced rapid regression of leiomyomas. Quantitative RT-PCR revealed that in women receiving no medication uterine leiomyomas express aromatase P450 mRNA at levels 20 times higher than that in the surrounding myometrium. Leuprorelin acetate treatment (1.88 mg every 4 wk, se injection) for 12-24 wk reduced the expression of aromatase P450 mRNA in leiomyoma tissue as well as in the myometrium, to approximately one tenth of that in the myometrium of untreated women. Suppression of aromatase P450 expression was also demonstrated by Western blot analysis and aromatase activity assay of microsomal fractions prepared from leiomyomas. On the other hand, no differences in the levels of activity and mRNA of aromatase P450 were observed between leiomyoma cells obtained from women treated with and without leuprorelin acetate injections when cells were cultured ex vivo and stimulated by various combinations of stimulants such as dexamethasone + IL-1 beta. The addition of various concentrations of E2 did not affect the aromatase activity of leiomyoma cells, suggesting that deprivation of circulating (ovarian) estrogen is not a cause of decreased expression of aromatase during leuprorelin acetate therapy. On the other hand, 8-d treatment with leuprorelin acetate (100 nmol/liter) reduced dexamethasone + IL-1 beta -induced activity and a mRNA level of aromatase by 28% and 42%, respectively. These results indicated that leuprorelin acetate inhibits the expression of aromatase P450 in leiomyoma cells, which contributes to the rapid regression of leiomyoma during leuprorelin acetate, therapy.