来曲唑治疗子宫内膜异位症机制的研究
摘要
目的：子宫内膜异位症(Endometriosis, EMs)是好发于女性生殖系统的一种具有侵袭性、激素依赖性的良性疾病,指具有生长活力的子宫内膜组织在子宫腔以外部位的异常生长。作为妇女常见病,EMs的主要治疗方法为手术治疗和药物治疗。药物治疗主要以激素类为主,如促性腺激素释放激素激动剂(GnRH-a)、孕激素、避孕药和雄激素等。此外,研究发现芳香化酶抑制剂可以有效抑制雌激素合成的限速酶芳香化酶,降低局部雌激素水平,为治疗雌激素依赖性疾病提供了新的方法。来曲唑(Letrozole)是新一代的芳香化酶抑制剂,已被证实可以用于治疗EMs,除影响局部雌激素水平外,还可通过抑制血管生成、细胞增殖、促进凋亡等作用机制治疗EMs。本实验通过建立自体腹壁移植子宫内膜异位症大鼠模型,使用不同剂量来曲唑和常用药物米非司酮治疗EMs,观察、比较治疗效果和指标变化,探讨来曲唑治疗EMs的作用及其机制。旨在阐明芳香化酶抑制剂来曲唑在动物EMs模型中治疗的有效性、可行性及其作用机制,为来曲唑的临床应用提供客观依据及实验依据,进一步丰富、发展EMs治疗的理论体系。
方法：术前5天和术后第10天大鼠灌服己烯雌酚0.02mg/kg,连续5天,无需检测大鼠动情周期。按Vernon等的手术方法建立SD大鼠腹壁自体移植子宫内膜异位症模型,建模4周后二次剖腹测量移植物体积,病理学证实造模成功。成模大鼠随机分为5组：①模型对照组：生理盐水5ml/kg.d；②米非司酮组：2.5mg/kg.d；③来曲唑低剂量组：0.1mg/kg.d；④来曲唑中剂量组：0.25mg/kg.d；⑤来曲唑高剂量组：0.5mg/kg.d。各组按剂量每天灌胃给药1次,连续4周后股动脉放血处死大鼠。收集血液,放射免疫法测定血清E2、P、T、FSH、LH水平；肉眼观察各组大鼠异位移植物生长情况,测量体积大小；并取异位内膜组织,分别做：①HE染色病理切片检查；②免疫组化染色检测MMP-9、ICAM-1、VEGF、IL-6、 TNFa、 NF-k B的表达；③采用RT-PCR检测IL-6、TNF-a及NF-κBmRNA的含量；④采用Western Blot法检测NF-kB蛋白含量。
所有数据都用均数士标准差(X±S)表示,用SPSS13.00统计软件进行统计学分析,单因素方差分析(One-Way ANOVA),以P<0.05为差异显著性。
结果：
1.成功的建立了移植性EMs大鼠模型,成模率76.67%。
2.治疗前各组异位内膜体积差异均无显著性(P>0.05)。治疗后各药物组异位内膜体积均有不同程度得缩小,与治疗前相比,差异有统计学意义(P<0.01)。与模型对照组相比,各组异位子宫内膜体积均小于模型组,差异有显著性意义(P<0.05)。米非司酮组和来曲唑低剂量组之间,来曲唑中剂量组和高剂量组之间异位内膜体积无差异(P>0.05)；米非司酮、来曲唑低剂量组较中、高剂量组异位内膜体积大,差异有显著性意义(P<0.05)。
3.各组大鼠血清E2、P、FSH、LH水平均无显著差异(P>0.05)。但血清T水平各组之间有统计学差异(P<0.05),经两两比较得出：米非司酮组治疗后不影响血清T水平,与模型对照组无差别(P>0.05)；来曲唑对T水平的影响呈剂量依赖性升高,来曲唑各组之间均有差异(P<0.05)。
4.光镜下各组大鼠异位子宫内膜病理形态学观察：模型对照组异位内膜生长良好囊泡由内到外为内膜、肌层和浆膜层,大部分上皮细胞有分泌现象(形成核下空泡)。其余各组异位内膜表现为不同程度的上皮变薄萎缩以及腺体减少,部分异位内膜完全萎缩或退化,仅见周围肌纤维。
5.免疫组化法检测治疗后各组异位子宫内膜ICAM-1、MMP-9、VEGF、 IL-6、TNF-a、NF-kB蛋白的表达情况：各组异位内膜主要表现为腺上皮细胞浆中出现不同程度的染色。模型对照组6种细胞因子的表达均强于各药物组,差异有统计学意义(P<0.05)。来曲唑高剂量组作用最强,其各细胞因子的表达最弱,与其他各组比较差异有显著性(P<0.05)。
6. RT-PCR法检测治疗后各组大鼠异位内膜组织中IL-6mRNA、TNF-a mRNA、NF-k BmRNA的含量：各药物组异位内膜中IL-6、TNF-a及NF-k BmRNA的含量表达低于模型对照组,差异有统计学意义(P<0.05),且表达在米非司酮、来曲唑低剂量、中剂量、高剂量组依次减弱,两两比较有显著性差异(P<0.05)。
7.Western Blot法检测治疗后各组大鼠异位内膜组织中NF-kB蛋白的含量：模型对照组异位内膜NF-kB的表达明显高于各药物组,差异有统计学意义(P<0.05)。来曲唑对NF-kB表达的影响呈剂量依赖性改变,比较米非司酮组差异有统计学意义(P<0.05)。
结论：采用SD大鼠腹壁自体移植的建模方法成功的建立了EMs模型。来曲唑在不改变大鼠循环E2、P、FSH、LH水平的情况下,对异位内膜具有明显的抑制作用。可能与来曲唑降调异位内膜组织中ICAM-1、 MMP-9、VEGF影响其在异位部位的粘附、侵袭、血管形成；降低IL-6、TNF a及NF-kB表达减少局部异位病灶中芳香化酶启动,抑制局部雌激素合成；减少这些细胞因子参与EMs的免疫反应,从而达到治疗子宫内膜异位症的目的。
Objective:Endometriosis is a kind of aggressive, hormone-dependent benign disease in the female reproductive system, refers to the presence of normal endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity. As common gynecopathy, the treatment of endometriosis is directed toward surgical excision and drug therapy. Medications currently recommended is Hormone therapy; include gonadotropin-releasing hormone (GnRH) agonists, progestins, oral contraceptive pills, androgens and so on. There are some data supporting the use of aromatase inhibitors for refractory or recurrent endometriosis. Endometriosis requires estrogen to grow; aromatase is the enzyme which synthesizes estrogen. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase; converts androgens into estrogens by a process called aromatization; reduces local levels of estrogen; provides a new approach for the treatment of estrogen-dependent diseases. Letrozole is a new generation aromatase inhibitor, has been shown for the treatment of endometriosis. It not only affects the local estrogen levels, but inhibits angiogenesis, cell proliferation, apoptosis and other mechanisms to promote treatment endometriosis. In this study, we use the autologous transplantation of abdominal wall to establish rats endometriosis model, utilize different doses of letrozole and mifepristone to treat endometriosis model. Through observation and comparison of change in some dates, the study seeks to clarify the treatment effectiveness and feasibility of letrozole in animal endometriosis models, provides an objective basis for its clinical application; explores its mechanism of action; provides the basis experimental evidence for scientific research; further enriches the theoretical system on the treatment of endometriosis.
Methods:There was not to detect rat estrous cycle. To make rats in estrogen period in unity, all the rats were given0.02mg/kg diethylstilbestrol with intragastric administration for five days before the operation. In the tenth day after the operations, all the rats were given the same dose of diethylstilbestrol for five days to promote the growth of ectopic endometrial. According to Vernon's methods, all SD rats were established endometriosis model of by surgically transplanting autologous uterine tissues to abdominal sites. After4weeks, there were the second laparotomy to measure the volume of transplant and confirmed the success of modeling by pathology. The models were divided randomly into5groups: model control group:saline5ml/kg.d; mifepristone group:2.5mg/kg.d; low-dose letrozole group:0.1mg/kg.d; medium-dose letrozole group:0.25mg/kg.d; high-dose letrozole group:0.5mg/kg.d. Each group was fed by this dose, once a day. After4weeks, rats were killed by bleeding at femoral artery. The blood was collected, levels of E2, P, T, FSH, LH in serum were measured by radioimmunoassay; the volume size of ectopic endometrial tissue was measured; and ectopic tissues were obtained, separately were done: HE stained biopsy; MMP-9, ICAM-1, VEGF, IL-6, TNFα, NF-κB expression by immunohistochemical staining; IL-6, TNF-α and NF-KBmRNA content by RT-PCR; NE-κB protein by Western Blot.
The results were expressed as the (X±S).One-way ANOVA was used to compare the outcomes by statistical package for the social science13.00. It is a statistically significant difference (P<0.05).
Results:
1. The model of endometriosis in rats was established successfully. The survival rate of ectopic endometrium was76.67%. The ectopic lesions showed good growth for the ridgy cystic structure within the fluid, the surface of cystic structure has blood vessels. The histological appearance showed endometrial epithelial cells, glands and stroma by pathological examination.
2. In each group, there was no significant difference in the volume of ectopic endometrium before treatment (P>0.05). But the volume of each group was reduced differently after the treatment. Compared with before treatment, the difference was statistically significant (P<0.01). The volume of each group was less than model group, the difference was significant (P<0.05). No significant difference was found in the volume between mifepristone group and low-dose of letrozole group (P>0.05). It was similar to happen between medium-dose group and high-dose group (P>0.05). In mifepristone group and low-dose group, the volume was larger than medium-dose group and high-dose group (P<0.05).
3. In each group, there were no significant difference in levels of E2, P, FSH, LH (P>0.05). However, levels of T were significantly different among groups (P<0.05), the outcome was showed by paired comparison:the mifepristone group didn't affect T levels in serum, there was no statistical significance with the control group (P>0.05); in letrozole groups, levels of T appeared dose-dependent changes, there were differences among the groups (P <0.05).
4. Each group of ectopic endometrium in rats was done morphological observation by the light microscope:Endometriotic vesicles of the control group grew well; the layers of ectopic tissue were endometrium, myometrium and serosa from the inside to the outside; the most of the epithelial cells appeared secretory phenomena (formation of vacuoles under cell nucleus). In other groups, the ectopic endometrial tissue showed different degrees of epithelial atrophy and reduction of glands, part of ectopic endometrium performed atrophy or degeneration completely and only the surrounding muscle fibers.
5. In each group, protein's expressions of ICAM-1, MMP-9, VEGF, IL-6, TNF-a and NF-kB were detected by Immunohistochemical method:The ectopic endometrium mainly manifested different degrees of staining in cytoplasm of epithelial cells. The expression of kinds of6cytokine in model control group was stronger than each drug group, the difference was statistically significant (P<0.05). The effect of high-dose letrozole group was the strongest, the expression of cytokines was the weakest, and compared with other groups, there were significant difference (P<0.05).
6. After treatment, every group, the content of IL-6mRNA, TNF-amRNA, NF-KBmRNA were assayed by RT-PCR in ectopic endometrial tissue:All kinds of3dates, each drug group was lower than the model control group, the difference was statistically significant (P<0.05); and the expression were reduced gradually in the mifepristone, low-dose, medium-dose and high-dose letrozole group, the outcome was showed significant differences by paired comparison (P<0.05).
7. In ectopic endometrial tissue, the protein of NF-kB was dedectd by Western Blot:In the model control group, NF-kB was significantly higher than other drug group, the difference was statistically significance (P<0.05). Letrozole for NF-kB expression appeared dose-dependent changes, to mifepristone group, differences were statistically significant (P<0.05).
Conclusion:Letrozole can significantly inhibit the rats'ectopic endometrium and not change the rat circulating E2, P, FSH, LH levels. The mechanism may be related to the demotion of expression of some cytokines, such as ICAM-1, MMP-9, VEGF, IL-6, TNFa and NF-kB. In the ectopic site, those cytokines influence the adhesion, invasion and angiogenesis; reduce expression of aromatase; inhibit the immune response of EMs, so as to achieve the treatment of endometriosis.
方法：术前5天和术后第10天大鼠灌服己烯雌酚0.02mg/kg,连续5天,无需检测大鼠动情周期。按Vernon等的手术方法建立SD大鼠腹壁自体移植子宫内膜异位症模型,建模4周后二次剖腹测量移植物体积,病理学证实造模成功。成模大鼠随机分为5组：①模型对照组：生理盐水5ml/kg.d；②米非司酮组：2.5mg/kg.d；③来曲唑低剂量组：0.1mg/kg.d；④来曲唑中剂量组：0.25mg/kg.d；⑤来曲唑高剂量组：0.5mg/kg.d。各组按剂量每天灌胃给药1次,连续4周后股动脉放血处死大鼠。收集血液,放射免疫法测定血清E2、P、T、FSH、LH水平；肉眼观察各组大鼠异位移植物生长情况,测量体积大小；并取异位内膜组织,分别做：①HE染色病理切片检查；②免疫组化染色检测MMP-9、ICAM-1、VEGF、IL-6、 TNFa、 NF-k B的表达；③采用RT-PCR检测IL-6、TNF-a及NF-κBmRNA的含量；④采用Western Blot法检测NF-kB蛋白含量。
所有数据都用均数士标准差(X±S)表示,用SPSS13.00统计软件进行统计学分析,单因素方差分析(One-Way ANOVA),以P<0.05为差异显著性。
结果：
1.成功的建立了移植性EMs大鼠模型,成模率76.67%。
2.治疗前各组异位内膜体积差异均无显著性(P>0.05)。治疗后各药物组异位内膜体积均有不同程度得缩小,与治疗前相比,差异有统计学意义(P<0.01)。与模型对照组相比,各组异位子宫内膜体积均小于模型组,差异有显著性意义(P<0.05)。米非司酮组和来曲唑低剂量组之间,来曲唑中剂量组和高剂量组之间异位内膜体积无差异(P>0.05)；米非司酮、来曲唑低剂量组较中、高剂量组异位内膜体积大,差异有显著性意义(P<0.05)。
3.各组大鼠血清E2、P、FSH、LH水平均无显著差异(P>0.05)。但血清T水平各组之间有统计学差异(P<0.05),经两两比较得出：米非司酮组治疗后不影响血清T水平,与模型对照组无差别(P>0.05)；来曲唑对T水平的影响呈剂量依赖性升高,来曲唑各组之间均有差异(P<0.05)。
4.光镜下各组大鼠异位子宫内膜病理形态学观察：模型对照组异位内膜生长良好囊泡由内到外为内膜、肌层和浆膜层,大部分上皮细胞有分泌现象(形成核下空泡)。其余各组异位内膜表现为不同程度的上皮变薄萎缩以及腺体减少,部分异位内膜完全萎缩或退化,仅见周围肌纤维。
5.免疫组化法检测治疗后各组异位子宫内膜ICAM-1、MMP-9、VEGF、 IL-6、TNF-a、NF-kB蛋白的表达情况：各组异位内膜主要表现为腺上皮细胞浆中出现不同程度的染色。模型对照组6种细胞因子的表达均强于各药物组,差异有统计学意义(P<0.05)。来曲唑高剂量组作用最强,其各细胞因子的表达最弱,与其他各组比较差异有显著性(P<0.05)。
6. RT-PCR法检测治疗后各组大鼠异位内膜组织中IL-6mRNA、TNF-a mRNA、NF-k BmRNA的含量：各药物组异位内膜中IL-6、TNF-a及NF-k BmRNA的含量表达低于模型对照组,差异有统计学意义(P<0.05),且表达在米非司酮、来曲唑低剂量、中剂量、高剂量组依次减弱,两两比较有显著性差异(P<0.05)。
7.Western Blot法检测治疗后各组大鼠异位内膜组织中NF-kB蛋白的含量：模型对照组异位内膜NF-kB的表达明显高于各药物组,差异有统计学意义(P<0.05)。来曲唑对NF-kB表达的影响呈剂量依赖性改变,比较米非司酮组差异有统计学意义(P<0.05)。
结论：采用SD大鼠腹壁自体移植的建模方法成功的建立了EMs模型。来曲唑在不改变大鼠循环E2、P、FSH、LH水平的情况下,对异位内膜具有明显的抑制作用。可能与来曲唑降调异位内膜组织中ICAM-1、 MMP-9、VEGF影响其在异位部位的粘附、侵袭、血管形成；降低IL-6、TNF a及NF-kB表达减少局部异位病灶中芳香化酶启动,抑制局部雌激素合成；减少这些细胞因子参与EMs的免疫反应,从而达到治疗子宫内膜异位症的目的。
Objective:Endometriosis is a kind of aggressive, hormone-dependent benign disease in the female reproductive system, refers to the presence of normal endometrial mucosa (glands and stroma) abnormally implanted in locations other than the uterine cavity. As common gynecopathy, the treatment of endometriosis is directed toward surgical excision and drug therapy. Medications currently recommended is Hormone therapy; include gonadotropin-releasing hormone (GnRH) agonists, progestins, oral contraceptive pills, androgens and so on. There are some data supporting the use of aromatase inhibitors for refractory or recurrent endometriosis. Endometriosis requires estrogen to grow; aromatase is the enzyme which synthesizes estrogen. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase; converts androgens into estrogens by a process called aromatization; reduces local levels of estrogen; provides a new approach for the treatment of estrogen-dependent diseases. Letrozole is a new generation aromatase inhibitor, has been shown for the treatment of endometriosis. It not only affects the local estrogen levels, but inhibits angiogenesis, cell proliferation, apoptosis and other mechanisms to promote treatment endometriosis. In this study, we use the autologous transplantation of abdominal wall to establish rats endometriosis model, utilize different doses of letrozole and mifepristone to treat endometriosis model. Through observation and comparison of change in some dates, the study seeks to clarify the treatment effectiveness and feasibility of letrozole in animal endometriosis models, provides an objective basis for its clinical application; explores its mechanism of action; provides the basis experimental evidence for scientific research; further enriches the theoretical system on the treatment of endometriosis.
Methods:There was not to detect rat estrous cycle. To make rats in estrogen period in unity, all the rats were given0.02mg/kg diethylstilbestrol with intragastric administration for five days before the operation. In the tenth day after the operations, all the rats were given the same dose of diethylstilbestrol for five days to promote the growth of ectopic endometrial. According to Vernon's methods, all SD rats were established endometriosis model of by surgically transplanting autologous uterine tissues to abdominal sites. After4weeks, there were the second laparotomy to measure the volume of transplant and confirmed the success of modeling by pathology. The models were divided randomly into5groups: model control group:saline5ml/kg.d; mifepristone group:2.5mg/kg.d; low-dose letrozole group:0.1mg/kg.d; medium-dose letrozole group:0.25mg/kg.d; high-dose letrozole group:0.5mg/kg.d. Each group was fed by this dose, once a day. After4weeks, rats were killed by bleeding at femoral artery. The blood was collected, levels of E2, P, T, FSH, LH in serum were measured by radioimmunoassay; the volume size of ectopic endometrial tissue was measured; and ectopic tissues were obtained, separately were done: HE stained biopsy; MMP-9, ICAM-1, VEGF, IL-6, TNFα, NF-κB expression by immunohistochemical staining; IL-6, TNF-α and NF-KBmRNA content by RT-PCR; NE-κB protein by Western Blot.
The results were expressed as the (X±S).One-way ANOVA was used to compare the outcomes by statistical package for the social science13.00. It is a statistically significant difference (P<0.05).
Results:
1. The model of endometriosis in rats was established successfully. The survival rate of ectopic endometrium was76.67%. The ectopic lesions showed good growth for the ridgy cystic structure within the fluid, the surface of cystic structure has blood vessels. The histological appearance showed endometrial epithelial cells, glands and stroma by pathological examination.
2. In each group, there was no significant difference in the volume of ectopic endometrium before treatment (P>0.05). But the volume of each group was reduced differently after the treatment. Compared with before treatment, the difference was statistically significant (P<0.01). The volume of each group was less than model group, the difference was significant (P<0.05). No significant difference was found in the volume between mifepristone group and low-dose of letrozole group (P>0.05). It was similar to happen between medium-dose group and high-dose group (P>0.05). In mifepristone group and low-dose group, the volume was larger than medium-dose group and high-dose group (P<0.05).
3. In each group, there were no significant difference in levels of E2, P, FSH, LH (P>0.05). However, levels of T were significantly different among groups (P<0.05), the outcome was showed by paired comparison:the mifepristone group didn't affect T levels in serum, there was no statistical significance with the control group (P>0.05); in letrozole groups, levels of T appeared dose-dependent changes, there were differences among the groups (P <0.05).
4. Each group of ectopic endometrium in rats was done morphological observation by the light microscope:Endometriotic vesicles of the control group grew well; the layers of ectopic tissue were endometrium, myometrium and serosa from the inside to the outside; the most of the epithelial cells appeared secretory phenomena (formation of vacuoles under cell nucleus). In other groups, the ectopic endometrial tissue showed different degrees of epithelial atrophy and reduction of glands, part of ectopic endometrium performed atrophy or degeneration completely and only the surrounding muscle fibers.
5. In each group, protein's expressions of ICAM-1, MMP-9, VEGF, IL-6, TNF-a and NF-kB were detected by Immunohistochemical method:The ectopic endometrium mainly manifested different degrees of staining in cytoplasm of epithelial cells. The expression of kinds of6cytokine in model control group was stronger than each drug group, the difference was statistically significant (P<0.05). The effect of high-dose letrozole group was the strongest, the expression of cytokines was the weakest, and compared with other groups, there were significant difference (P<0.05).
6. After treatment, every group, the content of IL-6mRNA, TNF-amRNA, NF-KBmRNA were assayed by RT-PCR in ectopic endometrial tissue:All kinds of3dates, each drug group was lower than the model control group, the difference was statistically significant (P<0.05); and the expression were reduced gradually in the mifepristone, low-dose, medium-dose and high-dose letrozole group, the outcome was showed significant differences by paired comparison (P<0.05).
7. In ectopic endometrial tissue, the protein of NF-kB was dedectd by Western Blot:In the model control group, NF-kB was significantly higher than other drug group, the difference was statistically significance (P<0.05). Letrozole for NF-kB expression appeared dose-dependent changes, to mifepristone group, differences were statistically significant (P<0.05).
Conclusion:Letrozole can significantly inhibit the rats'ectopic endometrium and not change the rat circulating E2, P, FSH, LH levels. The mechanism may be related to the demotion of expression of some cytokines, such as ICAM-1, MMP-9, VEGF, IL-6, TNFa and NF-kB. In the ectopic site, those cytokines influence the adhesion, invasion and angiogenesis; reduce expression of aromatase; inhibit the immune response of EMs, so as to achieve the treatment of endometriosis.
引文
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4. Dilip Visvanathan, Alfred Cutner, Con Kelleher. The treatment of en dometriosis. The Practitioner, 2001,245:218-322
5. Jaeobson VC.The autotransplantation of endometrial tissue in the rab bit. ArehSurg,5:281-300
6. JonesRC. The efect of a luteinizing hormone releasing hormone (LR H) agonist (Wy-40,972), levonorgestrel, danazol and ovarieetomy o n experimental endometriosis in the rat. Aeta Endoerinologica, 1984, 106:282-288
7. Cotroneo, Michelle S, Lamartiniere, Coral A. Pharmacologic, but Not Dietary, Genistein Supports Endometriosis in a Rat Model. Toxicolo gical Sciences, 2001,61(1):68-75
8. Rajkumar K, Schott PW, Simpson CW, et al. The rat as an animal model for endometrosis toexamine recurrence of ectopic endometrial tis2sue after regression. Fertil Steril,1990,53(5):921
9. Uchiide I, Ihara T, Sugamata M. Pathological evaluation of the rat e ndomet riosis model. Fertil Steril,2002,78(4): 782-786
10.胡春萍,王志刚,季夏芸.大鼠子宫异位症模型建立方法的比较.中国比较医学杂志,2009,19(10)：45-46
11. Vernon MW, Wilson EA, etal.Studies on the surgiealinduction of en dometriosis in the rat. FertilSteril,1985,44(5):684-694
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2. Garcia-Velasco JA, Moreno L, Pacheco A, et al. Tile aro-matase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilizationoutcome in low responder patients:a pilot study. Fertil Steril.2005,84:82-87
3. Verma A, Konje JC. Successful treatment of refractory endometriosis-related chronic pelvic pain with aromatase inhibitors in premenopausa 1 patients. Eur J Obstet Gynecol Reprod Biol.2009, 143(2):112-5
4. Roghaei MA, Tehrany HG, Taherian A, Koleini N. Effects of Letrozole compared with Danazol on patients with confirmed endometriosis:A randomized clinical trial. IJFS.2010,4:67-72
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2. Katsuki Y, Takano Y, Futamura Y, etal.Effectsofdienogest, asyntheti csteroid, endometriosisinrats.EurJEndocrinol,1998,138(2):216-226
3. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gyn ecol Clin North Am,1997, 24(2):235-258
4. Dilip Visvanathan, Alfred Cutner, Con Kelleher. The treatment of en dometriosis. The Practitioner, 2001,245:218-322
5. Jaeobson VC.The autotransplantation of endometrial tissue in the rab bit. ArehSurg,5:281-300
6. JonesRC. The efect of a luteinizing hormone releasing hormone (LR H) agonist (Wy-40,972), levonorgestrel, danazol and ovarieetomy o n experimental endometriosis in the rat. Aeta Endoerinologica, 1984, 106:282-288
7. Cotroneo, Michelle S, Lamartiniere, Coral A. Pharmacologic, but Not Dietary, Genistein Supports Endometriosis in a Rat Model. Toxicolo gical Sciences, 2001,61(1):68-75
8. Rajkumar K, Schott PW, Simpson CW, et al. The rat as an animal model for endometrosis toexamine recurrence of ectopic endometrial tis2sue after regression. Fertil Steril,1990,53(5):921
9. Uchiide I, Ihara T, Sugamata M. Pathological evaluation of the rat e ndomet riosis model. Fertil Steril,2002,78(4): 782-786
10.胡春萍,王志刚,季夏芸.大鼠子宫异位症模型建立方法的比较.中国比较医学杂志,2009,19(10)：45-46
11. Vernon MW, Wilson EA, etal.Studies on the surgiealinduction of en dometriosis in the rat. FertilSteril,1985,44(5):684-694
1. Kilic-Okman T, KucukM, Altamer S. Comparison of the effects of letrozole and clomiphene citrate on ovarian folli-cles, endometrium, and hormone levels in the rat. Fertil Steril.2003,80:1330-1332
2. Garcia-Velasco JA, Moreno L, Pacheco A, et al. Tile aro-matase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilizationoutcome in low responder patients:a pilot study. Fertil Steril.2005,84:82-87
3. Verma A, Konje JC. Successful treatment of refractory endometriosis-related chronic pelvic pain with aromatase inhibitors in premenopausa 1 patients. Eur J Obstet Gynecol Reprod Biol.2009, 143(2):112-5
4. Roghaei MA, Tehrany HG, Taherian A, Koleini N. Effects of Letrozole compared with Danazol on patients with confirmed endometriosis:A randomized clinical trial. IJFS.2010,4:67-72
5. Ailawadi RK, Jobanputra S, Kataria M, et al. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate:a pilot study. Fertil Steril,2004,81(2):290-296
6. Fang Z, Yang S, Gurates B, et al.Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue. J Clin Endocrinol Metab.2002 Jul,87(7):3460-6
7.宋淑芳,尹利荣,齐之迎,等.来曲唑治疗大鼠子宫内膜异位症模型作用及机制的研究.现代妇产科进展2011,1,20(1)：35-38
8.李建超,吕秀萍等.来曲唑对大鼠子宫内膜异位症病灶survivin表达的影响.现代妇产科进展,2009,18(5)：351-353
9.高霞,邢军,聂改红,张文丽.来曲唑对离体异位子宫内膜基质细胞凋亡的影响.实用医学杂志.2009,25(21)：3560-3562
10.Noble, L. S, et al. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J. Clin. Endocrinol. Metab.1997, 82:600-606
11.Kitawaki J,Noguchi T,Amatsu T,et al.Expression of aromatase cytochrome P450 proteinand messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not innormal endometrium.Biol Reprod, 1997, 57(3):514-519
12.Bulun S E, Noble L S, Takayama K, et al.Endocrine disorders associated with inappropriately high aromatase expression. J Steroid Biochem Mol Biol,1997,61(3-6):133-139
13.郎景和.芳香化酶与子宫内膜异位症.子宫内膜异位症的基础研究与临床研究(第一卷).北京：中国协和医科大学出版社.2003,6：235-239
14.Sinha S, Kaseta J, Santner S J, et al.Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat.Breast Cancer Res Treat,1998,48(1):45-51
15.谢凯利,刘静兰,汤巧英,等.ICAM-1,VEGF在子宫内膜异位症中的表达.中国新医药,2003,11(03)：1726
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