巴多昔芬对大鼠子宫内膜异位症的作用及机制

Effect of bazedoxifene on endometriosis in a rat model

目的：探讨第3代选择性ER调节剂巴多昔芬对大鼠子宫内膜异位症（内异症）模型中异位病灶的作用及机制。方法以同系大鼠作为供体，开腹取其子宫内膜，采用皮下种植法对雌性未交配大鼠建立内异症模型，选取建模成功的大鼠20只随机分为巴多昔芬组（3 mg·kg-1·d-1巴多昔芬灌胃，n=10）和对照组（每日等体积的生理盐水灌胃，n=10），比较两组大鼠治疗前后异位病灶的大体形态、体积、组织病理学和大鼠体质量、子宫湿重的差异，并采用免疫组化方法检测在位内膜与异位病灶中增殖细胞核抗原（PCNA）、ER、PR的表达。结果（1）大鼠内异症治疗后异位病灶大体形态和组织病理学的变化：与对照组相比，巴多昔芬组大鼠异位病灶明显萎缩，异位病灶中腺体数目减少或消失，间质内血管减少。（2）大鼠内异症治疗前后体质量、异位病灶体积的变化及治疗后的子宫湿重：治疗前对照组和巴多昔芬组大鼠体质量分别为（201±17）、（202±18）g，治疗后分别为（266±16）、（261±16）g，治疗前、后两组间分别比较，差异均无统计学意义（P〉0.05）。治疗前对照组和巴多昔芬组异位病灶的体积分别为（85±17）、（85±12）mm3，两组比较，差异无统计学意义（P〉0.05）；治疗后分别为（48±11）、（24±9）mm3，巴多昔芬组较对照组体积明显减小，两组比较，差异有统计学意义（P〈0.05）。治疗后对照组和巴多昔芬组子宫湿重分别为（0.77±0.16）、（0.45±0.18）g，两组比较，差异有统计学意义（P〈0.05）。（3）治疗后两组大鼠异位病灶和在位内膜中PCNA、ER、PR蛋白的表达量：异位病灶中对照组3者的表达量分别为0.282±0.044、0.51±0.06、0.49±0.05，巴多昔芬组分别为0.191±0.020、0.23±0.03、0.48±0.06；在位内膜中对照组3者的表达量分别为0.369±0.081、0.56±0.08、0.56±0.10，巴多昔芬组分别为0.211±0.037、0.27±0.05、0.54±0.08；与对照组比较，巴多昔芬组异位病灶及在位内膜中PCNA和ER的表达量均明显降低，两组分别比较，差异均有统计学意义（P〈0.05），而PR的表达量均未见明显差异（P〉0.05）。结论巴多昔芬能明显缩小内异症模型大鼠异位病灶的体积，其机制可能与抑制雌激素诱导的内膜增殖、ER的表达以及对ER的直接拮抗作用有关。

Objective To investigate the therapeutic mechanism of bazedoxifene, the third-generation selective ER modulator （SERM）, on endometriosis lesions in a rat model. Methods Endometriosis was induced by transplanting pieces of endometrium from other syngeneic rats that were as donors onto the subcutaneous of other unmated female rats. The rats with successful ectopic implants were divided into two groups：control group （n=10） and bazedoxifene group （n=10）. The macroscopic morphology, volume, histopathology of ectopic implant and rats uterine wet weight were determined before and after the treatment. Expression of proliferation cell nuclear antigen （PCNA）, ER and PR in the eutopic endometrium and endometriosis lesions detected by immunohistochemistry in the two groups. Results （1） The gross morphology and histological changes of endometriosis lesions in rats after treatment： compared with the control group, it was obviously depauperated and had more less glands and blood vessels in the stroma. （2） The change of rats′weight, the volume of endometriosis lesion before and after treatment and rats uterine wet weigh after treatment respectively in the control group and the bazedoxifene group：rats′ weight were respectively before treatment： （201±17） g, （202±18） g, that were respectively after treatment： （266±16） g, （261±16） g, which showed no significant difference between two groups before and after treatment （P〉0.05）. The volume of ectopic implant before treatment were respectively （85±17） mm3, （85±12） mm3, and showed no significant difference between two groups;that were respectively （48±11） mm3, （24±9） mm3 afte rtreatment, which was significantly decreased compared with the control group （P〈0.05）. Rats uterine wet weight after treatment were respectively：（0.77±0.16） g, （0.45±0.18） g, and was significantly reduced compared with the control group （P〈0.05）. （3） The protein expression levels of PCNA, ER and PR in the endometriosis lesions after treatment were respectively 0.282 ± 0.044, 0.51 ± 0.06, 0.49 ± 0.05 in the control group, 0.191 ± 0.020, 0.23 ± 0.03, 0.48 ± 0.06 in the bazedoxifene group; that in eutopic endometrium were respectively 0.369 ± 0.081, 0.56 ± 0.08, 0.56 ± 0.10 in the control group, 0.211 ± 0.037, 0.27 ± 0.05, 0.54 ± 0.08 in the bazedoxifene group;the protein expression levels of PCNA and ER in endometriosis lesions and the eutopic endometrium were significantly decreased in the bazedoxifene group compared with the control group （P〈0.05）, but the protein levels of PR in endometriosis lesionsand and the eutopic endometrium were not significantly altered by treatment （P〉0.05）. Conclusion Bazedoxifene could obviously reduce the size of endometriosis lesions, the mechanism may be related with suppressing estrogen-induced proliferation, the expression of ER and direct ER antagonism by this SERM.