诺美孕酮微球制剂对子宫内膜异位症的作用机制研究
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摘要
目的:
建立子宫内膜异位症动物模型和大鼠原代培养垂体细胞模型,探讨诺美孕酮对子宫内膜异位症的药效作用和作用机制。
方法:
1.体外释放实验测定诺美孕酮微球的体外释放曲线:选用动情周期规则大鼠,单次皮下注射诺美孕酮微球,阴道涂片,观察诺美孕酮对SD大鼠性周期的影响,确定诺美孕酮微球是否具有长效作用。
2.利用ICR小鼠,以皮下注射法建立一种新的皮下子宫内膜异位症模型,并做组织学观察和评价。
3.①考察诺美孕酮微球对子宫内膜异位症(EMs)大鼠的药效作用:外科移植法建立大鼠EMs模型,三周后剖腹,模型成功者随机分为五组,分别为模型对照组,R2323(1mg/kg.14d)组,诺美孕酮微球0.5mg/kg.d、2.0mg/kg.d和4.0mg/kg.d组。给药3周后解剖,测量异位内膜体积,了解诺美孕酮微球对大鼠异位内膜体积的影响,解剖时,腹主动脉取血,磁分离酶联免疫测定法测量大鼠血清雌二醇(E_2)、孕酮(P)水平;记录子宫卵巢重量,计算脏器系数;子宫组织切片,HE染色,测量子宫内膜上皮高度。②考察诺美孕酮微球对EMs小鼠的药效作用:皮下注射法建立小鼠EMs模型,成功者随机分为七组,分别为正常组、模型对照组,亮丙瑞林(0.02mg/kg.d)组,诺美孕酮微球3、6、12和24.0mg/kg.d组,给药后3周后解剖,测量异位内膜体积,了解诺美孕酮微球对大鼠异位内膜体积的影响;解剖时,腹主动脉取血,ELISA法测度小鼠血清促卵泡激素(FSH)和促黄体激素(LH)水平;记录子宫、卵巢重量,计算脏器系数;子宫组织切片,HE染色,测量子宫内膜上皮高度。
4.①解剖同时,取出小鼠子宫、异位内膜、脑和垂体,固定、切片,免疫组化ABC法测定各组动物子宫及移植异位内膜的雌激素受体(ERα)和孕激素受体(PR)的表达、下丘脑ERα、ERβ和PR的表达、下丘脑弓状核和垂体Kiss-1及其受体GPR54的表达,考察诺美孕酮对小鼠ER、PR、Kiss-1和GPR54表达的影响。②利用大鼠腺垂体组织,采用胰酶消化,体外培养大鼠原代垂体细胞,培养72小时后,加入不同浓度诺美孕酮培养49小时,分别采用GnRH、蛋白激酶C激活剂(PMA)和高浓度钾离子激发垂体细胞的促卵泡素(FSH)和促黄体素(LH)的分泌1小时,考察蛋白激酶C和电压依赖性钙离子通道,在诺美孕酮对垂体细胞分泌FSH和LH的影响中的作用。③解剖同时,迅速取出小鼠脑组织,保存于-70℃液氮,采用Biospring信号转导抗体芯片,比较模型组小鼠和诺美孕酮12mg/kg.d剂量组小鼠下丘脑蛋白表达差异,考察诺美孕酮对下丘脑信号转导通路抗体芯片中蛋白表达的影响。
结果:
1.体外释放试验显示,在体外,一个月的微球经28天可累积释放约85.1%,每天释放约3.04%:三个月的微球经91天可累积释放约96.5%,每天释放约1.06%。SD大鼠单次皮下注射诺美孕酮微球20070109A或20070109B(80mg/kg.3m)后,动情间期维持时间分别为77.00±1.26天和79.67±4.13天,动情间期延长。
2.小鼠造模成功率为83.33%,异位灶主要位于皮下肌层,少数位于游离的皮下黏膜,呈透明的囊状,囊内有清亮的液体积聚;镜下可见囊内壁有内膜上皮细胞生长。
3.①大鼠模型造模成功率为86.9%,诺美孕酮2和4mg/kg.d能显著降低异位内膜体积,抑制率显著高于模型组;诺美孕酮0.5、2和4mg/kg.d能显著降低子宫和卵巢脏器系数;诺美孕酮0.5和2mg/kg.d能显著降低子宫内膜上皮层高度;诺美孕酮0.5和2mg/kg.d能显著降低血清E_2水平;对血清P水平无影响。②小鼠模型造模成功率为82.5%,诺美孕酮6、12和24mg/kg.d能显著降低异位内膜体积,抑制率显著高于模型组;诺美孕酮3、6、12和24mg/kg.d能显著降低卵巢脏器系数,对子宫脏器系数无影响;诺美孕酮对小鼠子宫内膜上皮层高度无影响:诺美孕酮6和12mg/kg.d能显著降低血清FSH和LH水平。
4.①异位内膜上表达的ERα显著低于子宫内膜,PR无显著差异;诺美孕酮3、6、12和24mg/kg.d能显著降低子宫内膜ERα和PR的表达;诺美孕酮6、12和24mg/kg.d能显著降低下丘脑ERα的表达,6mg/kg.d能显著升高ERβ的表达,诺美孕酮各剂量组均显示ERα/ERβ比值显著下降;诺美孕酮6、12和24mg/kg.d能显著降低下丘脑PR的表达。诺美孕酮3、6、12和24mg/kg.d能显著降低下丘脑ARC区Kiss-1和GPR54的表达;诺美孕酮3、6和12mg/kg.d能显著降低腺垂体Kiss-1和GPR54的表达,24mg/kg.d仅显著下调腺垂体Kiss-1的表达。
②与对照组相比,10~(-5)和10~(-6)mol.L~(-1)诺美孕酮能显著抑制GnRH诱导的腺垂体细胞LH释放,10~(-5)、10~(-5)、10~(-8)和10~(-10)mol.L~(-1)诺美孕酮能显著抑制GnRH诱导的FSH释放;10~(-5)、10~(-6)、10~(-8)和10~(10)mol.L~(-1)诺美孕酮能显著抑制PMA诱导的LH释放,10~(-5)、10~(-6)和10~(-10)mol.L~(-1)诺美孕酮能显著抑制PMA诱导的FSH释放:10~(-5)、10~(-6)和10~(-8)mol.L~(-1)诺美孕酮能显著抑制高钾离子诱导的LH释放,10~(-5)和10~(-6)mol.L~(-1)诺美孕酮能显著抑制高钾离子诱导的FSH释放。
③下丘脑的Biospring信号转导抗体芯片结果显示,与模型对照组相比,在164个测定的目标蛋白中,诺美孕酮使48个蛋白表达发生差异,其中显著上调蛋白仅有2个:抗肌萎缩蛋白和碱性磷酸酶(AP);而诺美孕酮显著下调蛋白质有46个:主要包括(1)激素相关通路、(2)细胞因子相关通路(3)血管发生相关通路、(4)致癌基因相关通路、(5)细胞凋亡相关通路、(6)其他:细胞周期、神经细胞相关、腺病毒相关、肿瘤标记物及个别蛋白。
结论:
诺美孕酮微球体内外释放稳定,具有长效缓释作用。
ICR小鼠皮下子宫内膜异位症模型,简单易行,稳定可靠,为成功的Ems新动物模型。
诺美孕酮微球通过抑制血清E_2、FSH和LH水平,降低实验动物的子宫和卵巢脏器系数,降低子宫内膜层高度,抑制异位内膜的生长,发挥对EMs大鼠和小鼠模型的治疗作用。
首次发现,诺美孕酮能选择性降低子宫的ERα和PR的表达;诺美孕酮能作用于HPOA轴的上位,在下丘脑,诺美孕酮选择性降低ERα和PR的表达,一定程度上促进ERβ的表达,诺美孕酮对子宫和下丘脑ERα、ERβ和PR的选择性调节作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
本研究首次发现,与正常组相比,模型组小鼠下丘脑ARC区Kiss-1和GPR54表达显著升高,而模型组小鼠Kiss-1/GPR54的过度表达,可能与EMs的发病机制相关。诺美孕酮作用于ARC发挥激素负反馈作用,反馈性下调ARC区Kiss-1和GPR54的表达。诺美孕酮对Kiss-1-GPR54-GnRH-GnRH受体-促性腺激素分泌级联通路的抑制作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
首次发现,诺美孕酮不仅下调Kiss-1/GPR54在腺垂体的表达,还抑制GnRH诱导的垂体细胞FSH和LH的分泌,这种抑制作用与GnRH信号通路上的蛋白激酶C和电压依赖性钙离子通道有关。抗体芯片发现,诺美孕酮对GnRH通路上的Raf-1表达也有抑制作用,进一步说明诺美孕酮对GnRH信号通路上多个元件的调节作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
芯片结果验证,诺美孕酮的作用虽与垂体PKC有关,但与下丘脑PKC无关;FSH-b的下调与诺美孕酮对FSH的下调相关。诺美孕酮治疗子宫内膜异位症的作用机制与雄激素受体无关,而与孕酮受体相关。
芯片结果首次发现:①诺美孕酮通过抑制IL-6、HGF和NF kappaB等一系列细胞因子相关蛋白的表达,调控细胞因子相关通路;②诺美孕酮通过对血管发生相关蛋白表达的抑制,调控血管发生相关通路;③在下丘脑,诺美孕酮显著下调相关致癌基因的蛋白表达,调控致癌相关基因的蛋白表达相关通路;④诺美孕酮对下丘脑神经元细胞的凋亡通路主要是促进作用,也有一定的抑制作用,诺美孕酮对下丘脑神经元的细胞凋亡的具有双向调节作用,以上发现均与诺美孕酮治疗子宫内膜异位症的作用机制有关。此外,诺美孕酮治疗子宫内膜异位症的作用机制,还可能与细胞周期相关蛋白、神经细胞相关蛋白、肿瘤标记物等有关。
Aim:
To establish animal endometriosis model and pituitary cell model of rat primary culture,and to study the pharmacodynamic action and mechanism of action on endometriosis.
Methods:
1.The release curve of nomegestrol microballoons in vitro was determine by Release Experiment in vitro;The inhibition on sexual cycle and oulation on SD rat for single administration of nomegestrol microballoons was observed.
2.A new ICR mouse model with subcutaneous implants was established by hypodermic injection,and then pathohistologic chanracteristics were observed under the microscope.
3.①The pharmacodynamic action of nomegestrol microballoons on rats EMs model was investigated:The model of endometriosis in rats was made by surgically autotransplanting endometrium to the peritoneum.After 3 weeks,the rats were laparotomized to investigate the growth of transplantation.The rats with peritoneal implants were randomly assigned to 5 groups:model control group; R_(2323) group(1mg/kg.14d);nomegestrol microspheres group(doses of 0.5,2,4 mg/kg.d).After administrations for 3 weeks,the rats were laparotomized again and the volumes of peritoneal implants were mesured.When killing the rats,blood samples in abdominal aortas were collected to measure levels of serum E2,P, using enzymeimmunometric assay(EIMA).The weight of uterus and ovary was recorded for calculating the organ module.Uterus sections were made,then pathohistologic chanracteristics were observed under the microscope.②The pharmacodynamic action of nomegestrol microballoons on mice EMs model was investigated:The model of endometriosis in mice was made by hypodermic injection.After 3 weeks,the mice were laparotomized to investigate the growth of transplantation.The mice with subcutaneous implants were randomly assigned to 7 groups:normal group,model control group;LHRH group(0.02mg/kg.d); nomegestrol microspheres group(doses of 3,6,12,24mg/kg.d).After administrations for 3 weeks,the mice were laparotomized again and the volumes of subcutaneous implants were mesured.When killing the mice,blood samples in abdominal aortas were collected to measure levels of serum FSH,LH,using ELISA.The weight of uterus and ovary was recorded for calculating the organ module.Uterus sections were made,then pathohistologic chanracteristics were observed under the microscope.
4.①When killing the mice,IHC(Immunohistochemistry,ABC method) was used to evaluate ERαand PR expression in the uteri and explants of different groups of mice;IHC was used to evaluate ERα,ERβand PR expression in the hypothalamus of different groups of mice;IHC was used to evaluate kiss-1 and GPR54 expression in nucleus arcuatus hypothalami and pituitary of different groups of mice,to study the effect ofvomegestrol on ER、PR、kiss-1 and GPR54 expression.②Rat anterior pituitary was digested with pancreatic enzyme,rat primary pituitary cells were cultured in vitro for 72h and then treated with different concentration of nomegestrol for 49h.The FSH and LH secretion of the cells was induced by GnRH,PMA and high[K+]e for 1h,to study the action of PKC and VSCC in the effect of nomegestrol on the FSH and LH secretion of the cells.③When killing the mice,the mouse brains were gained quickly and stored in liquid nitrogen of -70℃.By the Biospring signal transduction array the difference of protein expression in hypothalamus of EMs model group and nomegestrol 12mg/kg.d group was compared,to study the effect of nomegestrol on the protein expression in Biospring signal transduction array.
Results:
1.Release profiles of microspheres for one month in vitro showed that accumulated release of 28 days was 85.1%,release 3.04%per day;Release profiles of microspheres for three months in vitro showed that accumulated release of 91 days was 96.5%,release 1.06%per day.Anestrum of SD rat were maintained for 77±1.26 days and 79.67±4.13 days by injecting the 20070109A or 20070109B (80mg/kg.3m).
2.Achievement ratio of the model was 83.33%,subcutaneous implants located on muscular layer subcutaneouly,some was in mucous membrane subcutaneouly, looked diaphanous capsular with fluid in it;endomembrane epithelial cell was in the inner wall of the capsular.
3.①Achievement ratio of Rat EMs model was 86.9%;Both nomegestrol 2 and 4mg/kg.d decreased the volumes of ectopic endometria,suppression efficient was significant;nomegestrol 0.5,2 and 4mg/kg.d decreased the uterus and ovary organ index significantly;nomegestrol 0.5 and 2mg/kg.d decreased the height of endometrium epithelium and serum E2 level significantly;nomegestrol had no effect on serum P level.
②Achievement ratio of mouse EMs model was 82.5%;nomegestrol 6,12 and 24mg/kg.d decreased the volumes of ectopic endometria,suppression efficient was significant;nomegestrol 3,6,12 and 24mg/kg.d decreased the ovary organ index significantly,but not the uterus organ index;nomegestrol had no effect on the height of endometrium epithelium;and serum E_2 level significantly; nomegestrol had no effect on serum P level,nomegestrol 6 and 12 mg/kg.d decreased t serum FSH and LH level significantly.
4.①ERαexpression in ectopic endometria was lower than in eutopic endometria, but PR expression had no difference between ectopic endometria and eutopic endometria;nomegestrol 3,6,12 and 24mg/kg.d decreased ERαand PR expression in eutopic endometria.In hypothalamus,nomegestrol 6,12 and 24mg/kg.d selectively decreased ERαand PR expression,all of nomegestrol dose group decreased the ERα/ERβratio,and nomegestrol 6mg/kg.d increased ERβexpression.In nucleus arcuatus hypothalam(ARC), nomegestrol 3,6,12 and 24mg/kg.d decreased Kiss-1 and GPR54 expression significantly.In anterior pituitary,nomegestrol 3,6 and 12mg/kg.d decreased Kiss-1 and GPR54 expression significantly;nomegestrol 24mg/kg.d only decreased Kiss-1 expression significantly.
②Compared with the control cells without drug treatment,in pituitary primary culture cells,10~(-5) and 10~(-6)mol.L-1 nomegestrol inhibited GnRH induced LH release,10~(-5)、10~(-6)、10~(-8) and 10~(-10)mol.L~(-1) nomegestrol inhibited GnRH induced FSH release,10~(-5)、10~(-6)、10~(-8) and 10~(-10)mol.L~(-1) nomegestrol inhibited PMA induced LH release,10~(-5)、10~(-6)、and 10~(-10) nomegestrol inhibited PMA induced FSH release,10~(-5)、10~(-6) and 10~(-8)mol.L~(-1) nomegestrol inhibited high[K+]e induced LH release,10~(-5) and 10~(-6) mol.L~(-1) nomegestrol inhibited high[K+]e induced FSH release.
③Biospring signal transduction array data of hypothalamic showed that, compared with model control group,of the 164 target proteins,nomegestrol 12mg/kg.d up-regulated two proteins and down-regulated 46 proteins.The two up-regulated proteins included Dystrophin and Alkaline Phosphatase.The 46 down-regulated proteins included(1) hormonal related protein,(2) cytokine related protein,(3) angiogenesis related protein,(4) oncogene related protein, (5) apoptosis related protein,(6) others:Cell cycle related protein,neuroscience related protein,adenovirus related protein,tumor marker related protein and some individual proteins.
Conclusions:
Nomegestrol microspheres delayed release in SD rat.
ICR mouse subcutaneous EMs model was simply established and stable,was a successful animal EMs model.
Nomegestrol microspheres inhibited ectopic endometria in EMs rat and mouse model by decreasing serum E_2,FSH and LH level,decreasing the height of endometrium epithelium,decreasing the uterus and ovary organ index.
ERαand PR expression in eutopic endometria was decreased selectively in nomegestrol treated group;nomegestrol could effected on the top section-hypothalamus and pituitary;in hypothalamus,nomegestrol selectively decreased ERαand PR expression,some extent increased ERβexpression,the selective regulation of nomegestrol on ERα,ERβand PR expression related to the mechanism of nomegestrol for its action on Endometriosis,which we first found.
Compared with normal group,we first found the Kiss-1 and GPR54 expression in nucleus arcuatus hypothalam(ARC) of mouse EMs model was increased significantly,which related to the pathogenesy of EMs;Nomegestrol could effect on ARC by negative feedback,decreasd Kiss-1 and GPR54 expression in ARC; Inhibition of nomegestrol on Kiss-1-GPR54-GnRH-GnRH receptor-FSH/LH secrtion cascade pathway related to the mechanism of nomegestrol for its action on Endometriosis,which we first found.
Nomegestrol decreased not only Kiss-1 and GPR54 expression in pituitary,but also GnRH induced FSH and LH scretion in rat primary pituitary culture cells, dependence of PKC and VCSS,which related to the mechanism of nomegestrol for its action on Endometriosis.
Data in array analysis verificated that effects of nomegestrol on pituitary was PKC-related,but not on hypothalamus.The downregulation of Nomegestrol on FSH-b related to the inhibition of Nomegestrol on serum FSH level.PR expression difference related to the mechanism of nomegestrol for its action on Endometriosis, but not androgen receptor.
Data in array analysis firstly found that:①Nomegestrol regulated cytokine correlation pathway by inhibiting cytokine related proteins expression such as IL-6, HGF,NF kappa B,which related to the mechanism of nomegestrol for its action on Endometriosis.②Nomegestrol regulated angiogenesis correlation pathway by inhibiting angiogenesis related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.③Nomegestrol regulated oncogene correlation pathway by inhibiting oncogene related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.④Nomegestrol two-way regulated apoptosis correlation pathway by inhibiting or promoting apoptosis related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.Beside these,cell cycle related protein,neuroscience related protein,adenovirus related protein,and tumor marker related protein perhaps related to the mechanism of nomegestrol for its action on Endometriosis.
建立子宫内膜异位症动物模型和大鼠原代培养垂体细胞模型,探讨诺美孕酮对子宫内膜异位症的药效作用和作用机制。
方法:
1.体外释放实验测定诺美孕酮微球的体外释放曲线:选用动情周期规则大鼠,单次皮下注射诺美孕酮微球,阴道涂片,观察诺美孕酮对SD大鼠性周期的影响,确定诺美孕酮微球是否具有长效作用。
2.利用ICR小鼠,以皮下注射法建立一种新的皮下子宫内膜异位症模型,并做组织学观察和评价。
3.①考察诺美孕酮微球对子宫内膜异位症(EMs)大鼠的药效作用:外科移植法建立大鼠EMs模型,三周后剖腹,模型成功者随机分为五组,分别为模型对照组,R2323(1mg/kg.14d)组,诺美孕酮微球0.5mg/kg.d、2.0mg/kg.d和4.0mg/kg.d组。给药3周后解剖,测量异位内膜体积,了解诺美孕酮微球对大鼠异位内膜体积的影响,解剖时,腹主动脉取血,磁分离酶联免疫测定法测量大鼠血清雌二醇(E_2)、孕酮(P)水平;记录子宫卵巢重量,计算脏器系数;子宫组织切片,HE染色,测量子宫内膜上皮高度。②考察诺美孕酮微球对EMs小鼠的药效作用:皮下注射法建立小鼠EMs模型,成功者随机分为七组,分别为正常组、模型对照组,亮丙瑞林(0.02mg/kg.d)组,诺美孕酮微球3、6、12和24.0mg/kg.d组,给药后3周后解剖,测量异位内膜体积,了解诺美孕酮微球对大鼠异位内膜体积的影响;解剖时,腹主动脉取血,ELISA法测度小鼠血清促卵泡激素(FSH)和促黄体激素(LH)水平;记录子宫、卵巢重量,计算脏器系数;子宫组织切片,HE染色,测量子宫内膜上皮高度。
4.①解剖同时,取出小鼠子宫、异位内膜、脑和垂体,固定、切片,免疫组化ABC法测定各组动物子宫及移植异位内膜的雌激素受体(ERα)和孕激素受体(PR)的表达、下丘脑ERα、ERβ和PR的表达、下丘脑弓状核和垂体Kiss-1及其受体GPR54的表达,考察诺美孕酮对小鼠ER、PR、Kiss-1和GPR54表达的影响。②利用大鼠腺垂体组织,采用胰酶消化,体外培养大鼠原代垂体细胞,培养72小时后,加入不同浓度诺美孕酮培养49小时,分别采用GnRH、蛋白激酶C激活剂(PMA)和高浓度钾离子激发垂体细胞的促卵泡素(FSH)和促黄体素(LH)的分泌1小时,考察蛋白激酶C和电压依赖性钙离子通道,在诺美孕酮对垂体细胞分泌FSH和LH的影响中的作用。③解剖同时,迅速取出小鼠脑组织,保存于-70℃液氮,采用Biospring信号转导抗体芯片,比较模型组小鼠和诺美孕酮12mg/kg.d剂量组小鼠下丘脑蛋白表达差异,考察诺美孕酮对下丘脑信号转导通路抗体芯片中蛋白表达的影响。
结果:
1.体外释放试验显示,在体外,一个月的微球经28天可累积释放约85.1%,每天释放约3.04%:三个月的微球经91天可累积释放约96.5%,每天释放约1.06%。SD大鼠单次皮下注射诺美孕酮微球20070109A或20070109B(80mg/kg.3m)后,动情间期维持时间分别为77.00±1.26天和79.67±4.13天,动情间期延长。
2.小鼠造模成功率为83.33%,异位灶主要位于皮下肌层,少数位于游离的皮下黏膜,呈透明的囊状,囊内有清亮的液体积聚;镜下可见囊内壁有内膜上皮细胞生长。
3.①大鼠模型造模成功率为86.9%,诺美孕酮2和4mg/kg.d能显著降低异位内膜体积,抑制率显著高于模型组;诺美孕酮0.5、2和4mg/kg.d能显著降低子宫和卵巢脏器系数;诺美孕酮0.5和2mg/kg.d能显著降低子宫内膜上皮层高度;诺美孕酮0.5和2mg/kg.d能显著降低血清E_2水平;对血清P水平无影响。②小鼠模型造模成功率为82.5%,诺美孕酮6、12和24mg/kg.d能显著降低异位内膜体积,抑制率显著高于模型组;诺美孕酮3、6、12和24mg/kg.d能显著降低卵巢脏器系数,对子宫脏器系数无影响;诺美孕酮对小鼠子宫内膜上皮层高度无影响:诺美孕酮6和12mg/kg.d能显著降低血清FSH和LH水平。
4.①异位内膜上表达的ERα显著低于子宫内膜,PR无显著差异;诺美孕酮3、6、12和24mg/kg.d能显著降低子宫内膜ERα和PR的表达;诺美孕酮6、12和24mg/kg.d能显著降低下丘脑ERα的表达,6mg/kg.d能显著升高ERβ的表达,诺美孕酮各剂量组均显示ERα/ERβ比值显著下降;诺美孕酮6、12和24mg/kg.d能显著降低下丘脑PR的表达。诺美孕酮3、6、12和24mg/kg.d能显著降低下丘脑ARC区Kiss-1和GPR54的表达;诺美孕酮3、6和12mg/kg.d能显著降低腺垂体Kiss-1和GPR54的表达,24mg/kg.d仅显著下调腺垂体Kiss-1的表达。
②与对照组相比,10~(-5)和10~(-6)mol.L~(-1)诺美孕酮能显著抑制GnRH诱导的腺垂体细胞LH释放,10~(-5)、10~(-5)、10~(-8)和10~(-10)mol.L~(-1)诺美孕酮能显著抑制GnRH诱导的FSH释放;10~(-5)、10~(-6)、10~(-8)和10~(10)mol.L~(-1)诺美孕酮能显著抑制PMA诱导的LH释放,10~(-5)、10~(-6)和10~(-10)mol.L~(-1)诺美孕酮能显著抑制PMA诱导的FSH释放:10~(-5)、10~(-6)和10~(-8)mol.L~(-1)诺美孕酮能显著抑制高钾离子诱导的LH释放,10~(-5)和10~(-6)mol.L~(-1)诺美孕酮能显著抑制高钾离子诱导的FSH释放。
③下丘脑的Biospring信号转导抗体芯片结果显示,与模型对照组相比,在164个测定的目标蛋白中,诺美孕酮使48个蛋白表达发生差异,其中显著上调蛋白仅有2个:抗肌萎缩蛋白和碱性磷酸酶(AP);而诺美孕酮显著下调蛋白质有46个:主要包括(1)激素相关通路、(2)细胞因子相关通路(3)血管发生相关通路、(4)致癌基因相关通路、(5)细胞凋亡相关通路、(6)其他:细胞周期、神经细胞相关、腺病毒相关、肿瘤标记物及个别蛋白。
结论:
诺美孕酮微球体内外释放稳定,具有长效缓释作用。
ICR小鼠皮下子宫内膜异位症模型,简单易行,稳定可靠,为成功的Ems新动物模型。
诺美孕酮微球通过抑制血清E_2、FSH和LH水平,降低实验动物的子宫和卵巢脏器系数,降低子宫内膜层高度,抑制异位内膜的生长,发挥对EMs大鼠和小鼠模型的治疗作用。
首次发现,诺美孕酮能选择性降低子宫的ERα和PR的表达;诺美孕酮能作用于HPOA轴的上位,在下丘脑,诺美孕酮选择性降低ERα和PR的表达,一定程度上促进ERβ的表达,诺美孕酮对子宫和下丘脑ERα、ERβ和PR的选择性调节作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
本研究首次发现,与正常组相比,模型组小鼠下丘脑ARC区Kiss-1和GPR54表达显著升高,而模型组小鼠Kiss-1/GPR54的过度表达,可能与EMs的发病机制相关。诺美孕酮作用于ARC发挥激素负反馈作用,反馈性下调ARC区Kiss-1和GPR54的表达。诺美孕酮对Kiss-1-GPR54-GnRH-GnRH受体-促性腺激素分泌级联通路的抑制作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
首次发现,诺美孕酮不仅下调Kiss-1/GPR54在腺垂体的表达,还抑制GnRH诱导的垂体细胞FSH和LH的分泌,这种抑制作用与GnRH信号通路上的蛋白激酶C和电压依赖性钙离子通道有关。抗体芯片发现,诺美孕酮对GnRH通路上的Raf-1表达也有抑制作用,进一步说明诺美孕酮对GnRH信号通路上多个元件的调节作用,与诺美孕酮治疗子宫内膜异位症的作用机制有关。
芯片结果验证,诺美孕酮的作用虽与垂体PKC有关,但与下丘脑PKC无关;FSH-b的下调与诺美孕酮对FSH的下调相关。诺美孕酮治疗子宫内膜异位症的作用机制与雄激素受体无关,而与孕酮受体相关。
芯片结果首次发现:①诺美孕酮通过抑制IL-6、HGF和NF kappaB等一系列细胞因子相关蛋白的表达,调控细胞因子相关通路;②诺美孕酮通过对血管发生相关蛋白表达的抑制,调控血管发生相关通路;③在下丘脑,诺美孕酮显著下调相关致癌基因的蛋白表达,调控致癌相关基因的蛋白表达相关通路;④诺美孕酮对下丘脑神经元细胞的凋亡通路主要是促进作用,也有一定的抑制作用,诺美孕酮对下丘脑神经元的细胞凋亡的具有双向调节作用,以上发现均与诺美孕酮治疗子宫内膜异位症的作用机制有关。此外,诺美孕酮治疗子宫内膜异位症的作用机制,还可能与细胞周期相关蛋白、神经细胞相关蛋白、肿瘤标记物等有关。
Aim:
To establish animal endometriosis model and pituitary cell model of rat primary culture,and to study the pharmacodynamic action and mechanism of action on endometriosis.
Methods:
1.The release curve of nomegestrol microballoons in vitro was determine by Release Experiment in vitro;The inhibition on sexual cycle and oulation on SD rat for single administration of nomegestrol microballoons was observed.
2.A new ICR mouse model with subcutaneous implants was established by hypodermic injection,and then pathohistologic chanracteristics were observed under the microscope.
3.①The pharmacodynamic action of nomegestrol microballoons on rats EMs model was investigated:The model of endometriosis in rats was made by surgically autotransplanting endometrium to the peritoneum.After 3 weeks,the rats were laparotomized to investigate the growth of transplantation.The rats with peritoneal implants were randomly assigned to 5 groups:model control group; R_(2323) group(1mg/kg.14d);nomegestrol microspheres group(doses of 0.5,2,4 mg/kg.d).After administrations for 3 weeks,the rats were laparotomized again and the volumes of peritoneal implants were mesured.When killing the rats,blood samples in abdominal aortas were collected to measure levels of serum E2,P, using enzymeimmunometric assay(EIMA).The weight of uterus and ovary was recorded for calculating the organ module.Uterus sections were made,then pathohistologic chanracteristics were observed under the microscope.②The pharmacodynamic action of nomegestrol microballoons on mice EMs model was investigated:The model of endometriosis in mice was made by hypodermic injection.After 3 weeks,the mice were laparotomized to investigate the growth of transplantation.The mice with subcutaneous implants were randomly assigned to 7 groups:normal group,model control group;LHRH group(0.02mg/kg.d); nomegestrol microspheres group(doses of 3,6,12,24mg/kg.d).After administrations for 3 weeks,the mice were laparotomized again and the volumes of subcutaneous implants were mesured.When killing the mice,blood samples in abdominal aortas were collected to measure levels of serum FSH,LH,using ELISA.The weight of uterus and ovary was recorded for calculating the organ module.Uterus sections were made,then pathohistologic chanracteristics were observed under the microscope.
4.①When killing the mice,IHC(Immunohistochemistry,ABC method) was used to evaluate ERαand PR expression in the uteri and explants of different groups of mice;IHC was used to evaluate ERα,ERβand PR expression in the hypothalamus of different groups of mice;IHC was used to evaluate kiss-1 and GPR54 expression in nucleus arcuatus hypothalami and pituitary of different groups of mice,to study the effect ofvomegestrol on ER、PR、kiss-1 and GPR54 expression.②Rat anterior pituitary was digested with pancreatic enzyme,rat primary pituitary cells were cultured in vitro for 72h and then treated with different concentration of nomegestrol for 49h.The FSH and LH secretion of the cells was induced by GnRH,PMA and high[K+]e for 1h,to study the action of PKC and VSCC in the effect of nomegestrol on the FSH and LH secretion of the cells.③When killing the mice,the mouse brains were gained quickly and stored in liquid nitrogen of -70℃.By the Biospring signal transduction array the difference of protein expression in hypothalamus of EMs model group and nomegestrol 12mg/kg.d group was compared,to study the effect of nomegestrol on the protein expression in Biospring signal transduction array.
Results:
1.Release profiles of microspheres for one month in vitro showed that accumulated release of 28 days was 85.1%,release 3.04%per day;Release profiles of microspheres for three months in vitro showed that accumulated release of 91 days was 96.5%,release 1.06%per day.Anestrum of SD rat were maintained for 77±1.26 days and 79.67±4.13 days by injecting the 20070109A or 20070109B (80mg/kg.3m).
2.Achievement ratio of the model was 83.33%,subcutaneous implants located on muscular layer subcutaneouly,some was in mucous membrane subcutaneouly, looked diaphanous capsular with fluid in it;endomembrane epithelial cell was in the inner wall of the capsular.
3.①Achievement ratio of Rat EMs model was 86.9%;Both nomegestrol 2 and 4mg/kg.d decreased the volumes of ectopic endometria,suppression efficient was significant;nomegestrol 0.5,2 and 4mg/kg.d decreased the uterus and ovary organ index significantly;nomegestrol 0.5 and 2mg/kg.d decreased the height of endometrium epithelium and serum E2 level significantly;nomegestrol had no effect on serum P level.
②Achievement ratio of mouse EMs model was 82.5%;nomegestrol 6,12 and 24mg/kg.d decreased the volumes of ectopic endometria,suppression efficient was significant;nomegestrol 3,6,12 and 24mg/kg.d decreased the ovary organ index significantly,but not the uterus organ index;nomegestrol had no effect on the height of endometrium epithelium;and serum E_2 level significantly; nomegestrol had no effect on serum P level,nomegestrol 6 and 12 mg/kg.d decreased t serum FSH and LH level significantly.
4.①ERαexpression in ectopic endometria was lower than in eutopic endometria, but PR expression had no difference between ectopic endometria and eutopic endometria;nomegestrol 3,6,12 and 24mg/kg.d decreased ERαand PR expression in eutopic endometria.In hypothalamus,nomegestrol 6,12 and 24mg/kg.d selectively decreased ERαand PR expression,all of nomegestrol dose group decreased the ERα/ERβratio,and nomegestrol 6mg/kg.d increased ERβexpression.In nucleus arcuatus hypothalam(ARC), nomegestrol 3,6,12 and 24mg/kg.d decreased Kiss-1 and GPR54 expression significantly.In anterior pituitary,nomegestrol 3,6 and 12mg/kg.d decreased Kiss-1 and GPR54 expression significantly;nomegestrol 24mg/kg.d only decreased Kiss-1 expression significantly.
②Compared with the control cells without drug treatment,in pituitary primary culture cells,10~(-5) and 10~(-6)mol.L-1 nomegestrol inhibited GnRH induced LH release,10~(-5)、10~(-6)、10~(-8) and 10~(-10)mol.L~(-1) nomegestrol inhibited GnRH induced FSH release,10~(-5)、10~(-6)、10~(-8) and 10~(-10)mol.L~(-1) nomegestrol inhibited PMA induced LH release,10~(-5)、10~(-6)、and 10~(-10) nomegestrol inhibited PMA induced FSH release,10~(-5)、10~(-6) and 10~(-8)mol.L~(-1) nomegestrol inhibited high[K+]e induced LH release,10~(-5) and 10~(-6) mol.L~(-1) nomegestrol inhibited high[K+]e induced FSH release.
③Biospring signal transduction array data of hypothalamic showed that, compared with model control group,of the 164 target proteins,nomegestrol 12mg/kg.d up-regulated two proteins and down-regulated 46 proteins.The two up-regulated proteins included Dystrophin and Alkaline Phosphatase.The 46 down-regulated proteins included(1) hormonal related protein,(2) cytokine related protein,(3) angiogenesis related protein,(4) oncogene related protein, (5) apoptosis related protein,(6) others:Cell cycle related protein,neuroscience related protein,adenovirus related protein,tumor marker related protein and some individual proteins.
Conclusions:
Nomegestrol microspheres delayed release in SD rat.
ICR mouse subcutaneous EMs model was simply established and stable,was a successful animal EMs model.
Nomegestrol microspheres inhibited ectopic endometria in EMs rat and mouse model by decreasing serum E_2,FSH and LH level,decreasing the height of endometrium epithelium,decreasing the uterus and ovary organ index.
ERαand PR expression in eutopic endometria was decreased selectively in nomegestrol treated group;nomegestrol could effected on the top section-hypothalamus and pituitary;in hypothalamus,nomegestrol selectively decreased ERαand PR expression,some extent increased ERβexpression,the selective regulation of nomegestrol on ERα,ERβand PR expression related to the mechanism of nomegestrol for its action on Endometriosis,which we first found.
Compared with normal group,we first found the Kiss-1 and GPR54 expression in nucleus arcuatus hypothalam(ARC) of mouse EMs model was increased significantly,which related to the pathogenesy of EMs;Nomegestrol could effect on ARC by negative feedback,decreasd Kiss-1 and GPR54 expression in ARC; Inhibition of nomegestrol on Kiss-1-GPR54-GnRH-GnRH receptor-FSH/LH secrtion cascade pathway related to the mechanism of nomegestrol for its action on Endometriosis,which we first found.
Nomegestrol decreased not only Kiss-1 and GPR54 expression in pituitary,but also GnRH induced FSH and LH scretion in rat primary pituitary culture cells, dependence of PKC and VCSS,which related to the mechanism of nomegestrol for its action on Endometriosis.
Data in array analysis verificated that effects of nomegestrol on pituitary was PKC-related,but not on hypothalamus.The downregulation of Nomegestrol on FSH-b related to the inhibition of Nomegestrol on serum FSH level.PR expression difference related to the mechanism of nomegestrol for its action on Endometriosis, but not androgen receptor.
Data in array analysis firstly found that:①Nomegestrol regulated cytokine correlation pathway by inhibiting cytokine related proteins expression such as IL-6, HGF,NF kappa B,which related to the mechanism of nomegestrol for its action on Endometriosis.②Nomegestrol regulated angiogenesis correlation pathway by inhibiting angiogenesis related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.③Nomegestrol regulated oncogene correlation pathway by inhibiting oncogene related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.④Nomegestrol two-way regulated apoptosis correlation pathway by inhibiting or promoting apoptosis related proteins expression,which related to the mechanism of nomegestrol for its action on Endometriosis.Beside these,cell cycle related protein,neuroscience related protein,adenovirus related protein,and tumor marker related protein perhaps related to the mechanism of nomegestrol for its action on Endometriosis.
引文
[1]Koninckx PR,Barlow D,Kennedy S.Implantation versus infiltration:the Sampson versus the endometriotic disease theory.Gynecol Obstet Invest.1999;47 Suppl 1:3-9;discussion 9-10.
[2]Neukomm C,Mueller MD.New insights into the pathophysiology of endometriosis.Gynakol Geburtshilfliche Rundsch.2007;47(3):113-117
[3]Freundl G,Godtke K,Gnoth C,et al.Steroidal ' add-back' therapy in patients treated with GnRH agonists[J].GynecolObstet Invest,1998,45(Suppl 1):22-30.
[4]Pierce SJ,GazvaniMR,Farquharson RG.Longterm use of gonadotrop in releasing hormone analogs and hormone rep lacement therapy in the management of endometriosis arandomized trialwith a 62year follow-up [J].Fertil Steril,2000,74(5):964-968.
[5]Janicki TI.Treatment of the pelvic pain associated with endometriosis using danazol vaginal suppositories.[J].Fertil Steril,2002,77(1):52-60.
[6]Harris HA,Bruner Tran KL,Zhang X,et al.A selective estrogen receptor beta agonist causes lesion regression in an experimentally induced model of endometriosis[J].Hum Rep rod,2005,20(9):936-941.
[7]蒋红清,李亚里.子宫内膜异位症药物及生物治疗新进展[J].现代妇产科进展,2006,15(2):134-137.
[8]Bulun SE,Zeitoun KM,Takayama K,et al.Molecular basis for treating endometriosis with aromatase inhibitors[J].Hum Rep rod Update,2000,6(3):4132418.
[9]Shippen ER,WestWJ J r.Successful treatment of severe endometriosis in two p remenopausal women with an aromatase inhibitor[J].Fertil Steril,2004,8(12):1395-1398.
[10]Ailawadi RK,Jobanputra S,KatariaM,et al.Treatment of endometriosis and chronic pelvic pain with petrozole and norethindrone acetate:a pilot study[J].Fertil Steril,2004,81:290-296.
[11]Soysal S,SoysalME,Ozer S,et al.The effects of post2surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis a prospective randomized trial[J].Hum Rep rod,2004,19(1):160-167.
[12]Olive DL.Medical therapy of endometriosis[J].Semi Rep rod Med,2003,21(2):211-222.
[13]Efstathiou JA,Samp son DA,Levine Z,et al.Nonsteroidal anti inflammatory drugs differentially supp ress endometriosis in a murine model[J].Fetril Steril,2005,83(2):171-181.
[14]Abu J I,Konje JC.Leukotrienes in gynaecology:the hypothetical value of anti-leukotriene therapy in dysmenorrhoea and endometriosis[J].Hum Rep rod Update,2000,6(2):200-207.
[15]Xiao YH,Chen DP,Yah JH,et al.Mechanism of action of tripterygium wilfordii polyglycoside on experimental endometriosis[J].Eur J Gynaecol Oncol,2002,23(1):63-69.
[16]Nishida M,Nasu K,Ueda T,et al.Endometriotic cells are resistant to interferon-gamma-induced cell growth inhibition and apop tosis:a possible mechanism involved in the pathogenesis of endometriosis[J].Mol Hum Rep rod,2005,11(1):29-35.
[17]Mesogitis S,AntsaklisA,Daskalakis G,et al.Combined ultrasonographically guided drainage and methotrexate administration for treament of endometriotic cysts[J].Lancet,2000,355(9210):1160-1168.
[18]Vercellini P,Frontino G,De Giorgi O,et al.Continuous use of an oral contracep rive for endometriosis- associated recurrent dysmenorrheal that does not repond to a cyclic pill regimen[J].Fertil Steril,2003,80:560-563.
[19]Sitruk-Ware R.Pharmocological profile of progestins[J].Maturitas,2004,47(4):277-283.
[20]Doring A,Frohlich M,Lowel H,et al.Third generation oral contraceptive use and cardiovascular risk factors[J].Atherosclerosis,2004,172(2):281-286.
[21]Sitruk-Ware R.New progestogens:a review of their effects in perimenopausal and postmenopausal women[J].Drugs Aging,2004,21(13):865-883.
[22]朱焰,孙祖越,曹霖.第四代孕激素研究进展.中国药学杂志2006,41(8):572-576.
[23]Croxatto HB.Mechanisms that explain the contraceptive action of progestin implants for women[J].Contraception,2002,65(1):21-27.
[24]Couzinet B,Young J,Kujas M et al.The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women[J].J Cli n Endocrinol Metab,1999,84(11):4191-4196.
[25]Charpin C,Illouz S,Dales J P et al.Effects of progestins on human endometrium i n vit ro[J].Bull Acad Natl Med,2002,186(1):125-145.
[26]Illouz S,Dales J P,Sferlazzo K et al.Effects of progestins of human proliferative endometrium:an i n vit ro model of potentialclinical relevance[J].Int J Mol Med,2003,12(4):517 - 523.
[27]Pasqualini JR,Chetrite GS.Estrone sulfatase versus estrone sulfotransferase in human breast cancer:potential clinical applications[J].J Steroid Biochem Mol Biol,1999,69(1 - 6):287 - 292.
[28]Chetrite GS,Pasqualini JR.The selective estrogen enzyme modulator (SEEM) in breast cancer[J].J Steroid Biochem Mol Biol,2001,76(1 - 5):95 - 104.
[29]Li J,Xu LZ,He KL et al.Reversal effects of nomegestrol acetate on multidrug resistance in adriamycin2resistant MCF7 breast cancer cell line[J].B reast Cancer Res,2001,3(4):253 - 263.
[30]Li J,Xu L,He K.Modulation of multiple drug resistance bynomegestrol acetate and droloxifene in K562/ A02[J].中华血液学杂志,1999,20(6):288 - 291.
[31]StomatiM,GenazzaniAD,PatragliaF,et al.Contraception as prevention and therapy:sex steroids and the brain[J].Eur J Contracept Reprod Health Care.1998,3(1):21-28
[32]Stafford L J,Xia C,Ma W,et aI Identification and character- -ization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor [J].Cancer Res,2002,62(19):5399-5404
[33]Kotani M,Detheux M,Vandenbogaerde A,et al.The metastasis suppressor gene KiSS-1 encodes kisspeptins,the natural ligands of the orphan G protein-coupled receptor GPR54[J].J Biol Chem,2001,276(37): 34631-34636
[34]Lee DK,Nguyen T,O'Neill GP,et al.Discovery of a receptor related to the galanin receptors[J].FEBS Lett,1999,446(1):103-107
[35]NavarroVM,CastellanoJM,Fernandez-FernandezR,et al.Developmental and hormonally regulated messenger ribonucleic acid expressionof KiSS-1and its putative receptor,GPR54,in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide[J].Endocrinology,2004,145(10):4565-4574
[36]Shahab M,Mastronardi C,Seminara SB,et al.Increased hypothalamic GPR54 signaling:A potential mechanism for initiation of puberty in primates[J].Proc Natl Acad Sci US A,2005,102(6 ):2129-2134
[37]Seminara SB,Kaiser UB.New Gatekeepers of reproduction:GPR54 and its cognate ligand,KiSS-1[J].Endocrinology,2005,146(4):1686-1688
[38]Brailoiu GC,Dun SL,Ohsawa M,et al.KiSS-1 expression and metastinlikeimmunoreactivity in the rat brain[3].J Comp Neurol,2005,481(3):314-329
[39]IrwigMS,FraleyGS,Smith JT,et al.Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat[J].Neuroendocrinology,2004,80(4):264-272
[40]Seminara SB,Messager S,Chatzidaki EE,et al.The GPR54 gene as a regulator of puberty[J].NEngl J Med,2003,349(17):1614-1627
[41]Lapatto R,Pallais JC,Zhang D,Chan YM,Mahan A,Cerrato F,Le WW,Hoffman GE,Seminara SB.Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice[J].Endocrinology.2007Oct;148(10):4927-36.
[42]Smith JT,Dungan HM,Stoll EA,et al.Differential regulation of KiSS-1mRNA expression by sex steroids in the brain of the male mouse[J].Endocrinology,2005,146(7):2976-2984
[43]Smith JT,Cunningham MJ,Rissman EF,et al.Regulation of Kiss-1gene expression in the brain of the female mouse.Endocrinology,2005,146(9):3686-3692
[44]褚云鸿主编,生殖药理学,人民卫生出版社,1992
[45]Lahteenmaki P,Weiner E,Lahteenmaki P,Johansson ED,Luukkainen T. Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin,ST-1435[J].Contraception,1982,25(3):299-306.
[46]Naor Z,Shacham S,Harris D,et al.Signal transduction of the gonadotropin releasing hormone(GnRH) receptor:cross-talk of calcium protein kinase C (PKC) and arachidonic acid[J].Cell Mol Neurobiol,1995,15:527-544
[47]Ben-Menahem D,Naor Z.Regulation of gonadotropin mRNA levels in cultured rat pituitary cells by gonadotropin- releasing hormone(GnRH):role for Ca2+ and protein kinase C[J].Biochemistry.1994 Mar 29;33(12):3698-3704.
[48]D Ben-Menahem,Z Shraga-Levine,P L Mellon,and Z Naor Mechanism of action of gonadotropin-releasing hormone upon gonadotropin alpha-subunit mRNA levels in the alpha T3-1 cell line:role of Ca2+ and protein kinase C[J].Biochem J.1995 July 1;309(Pt 1):325-329.
[49]SS Stojilkovic,S Izumi and KJ Catt.Participation of voltage- sensitive calcium channels in pituitary hormone release[J].J Biol Chem,1988,263(26):13054-13061
[50]Stojilkovic,S S,Torsello,A IidaT,Rojas E,Catt K J.Calcium signaling and secretory responses in agonist- stimulated pituitary gonadotrophs[J].J Steroid Biochem Mol Biol,1992,41(3-8):453-467
[1]Sathe PM,TsongY,ShahVP.In vitro dissolution profile comparison:statistics and analysis,model dependent approach[J].Pharm Res,1996,13(12):1799-1803.
[2]Gallagher KM,Corrigan Of.Mechanistic aspects of the release of levamisole hydrochloride from biodegradable polymers[J].J Control Release,2000,69:261-272.
[3]Baras B,Benoit MA,Gillard J.Parameters influencing the antigen release from spray-dried poly(DL-lactide) microparticales[J].Int J Pharm,2000,299:133-145.
[4]Narasimhan B,hanger R.Zero-order release of micro- and macromolecules from polymeric devices:the role of the burst effect[J].J Control Release,1997,47:13-20.
[5]Ogawa Y,Yamamoto M,Takada S,et al.Controlled-release of leuprolide acetata from polyactic acid or copoly(lactic/glycolic)acid micropheres:influence of molecular weight and copolymer ratio of polymer[J].Chem Pharm Bull,1988,36(4):1502-1507.
[6]Ravivarapu HB,Burton K,Deluca PP.Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres[J].Euro J Pharm Biopharm,2000,50:263-270.
[1]Jones RC.The effect of a luteinizing hormone releasing hormone (LRH) agonist(Wy-40,972),levonorgestrel,danazol and ovariectomy on experimental endometriosis in the rat[J].Acta Endocrinol(Copenh).1984,106(2):282-288.
[2]Schenken RS,Asch RH.Surgical induction of endometriosis in the rabbit:effects on fertility and concentrations of peritoneal fluid prostaglandins.Fertil Steril.1980,34(8):581-587.
[3]Palatynski A.Dynamics of morphologic changes in the ovaries of guinea pigs modified by implanted endometrium[J].Zentralbl Gynakol.1986,108(9):560-569.
[4]MacKenzie WF,Casey HW.Animal model of human disease.Endometriosis.Animal model:endometriosis in rhesus monkeys[J].Am J Pathol,1975,80(2):341-344.
[5]Nagasawa H,Ishida M,Mori T.Effects of treatment with prolactin or progesterone on the coincidence of mammary tumors and uterine adenomyosis in young SHN mice[J].Lab Anim Sci,1987,37(2):200-202.
[6]Sharpe KL,Zimmer RL,Khan RS,et al.Proliferative and morphogenic changes induced by the coculture of rat uterine and peritoneal cells:a cell culture model for endometriosis[J].Fertil &Steril,1992,58(6):1220- 1229.
[7]杨耀芳,王钦茂,方学明,等.建立大鼠子宫内膜异位症模型的评价方法[J].中国药理学通报,1998,4(5):469-470.
[8]Van Langendonckt A,Casanas-Roux F,Eggermont J.Characterization of iron deposition in endometriotic lesions induced in the nude mouse kf model[J].Hum Reprod,2004,19(6):1265-1271.
[9]Nisolle M,Casanas-Roux F,Donnez J.Early-stage endometriosis:adhesion and growth of human menstrual endometrium in nude mice[J].Fertil & Steril,2000,74(2):306-312.
[10]Aoki D,Katsuki Y,Shimizu A,et al.Successful heterotransplantation of human endometrium in SCID mice[J].Obstet.Gynecol,1994,83(2):220-228.
[11]Scott RB,Ohio C,Te Linde RW,et al.Further studies on experimental endometriosis[J].Am J Obstet Gynecol,1953,66:1082-1099.
[12]Fortin M,Lepine M,Page M,et al.An improved mouse model for endometriosis allows noninvasive assessment of lesion implantation and development[]].Fertil Steril,2003,80(2):832-838.
[13]Somigliana E,Vigano P,Rossi G,et al.Endometriosis ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis[J].Human Reproduction,1999,14(12):2944-2950.
[1]Jones RC.The effect of luteinizing hormone releasing hormone(LRH)agonist(Wy-240972),]evonorgestrel danazol and ovariectomy endometiosis on the rat[J].Acta Endocrinol,1984,106(2):282-288.
[2]杨耀芳,王钦茂,方学明,等.建立大鼠子宫内膜异位症模型的评价方法[J].中国药理学通报,1998,4(5):469-470.
[3]Vernon MW,Wilson EA.Studies on the surgical induction of endometriosis in the rat[J].Fertil Steril,1985,44(5):684-694.
[4]Rajkumar K,Schott P W,Simpson C W,et al.The rat as an animal model for endometriosis to examine recurrence of ectopic endomtrial tissue after regression[J].Fertil Steril,1990,53(5):921.
[5]ILLOUZ S,DALESJ P,SFERLAZZO K,et al.Effects of progestins of human proliferative endometrium:an in vitro model of potential clinical relevance[J].Int J Mol Med,2003,12(4):5172523.
[6]王亚敏,石庭森.微球制剂药物控释研究的进展[J].中国药学杂志,1996,31(3):131-134.
[7]Somigliana E,Vigano P,Rossi G,et al.Endometriosis ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis[J].Human Reproduction,1999,14(12):2944-2950.
[8]Grummer R,Schwarzer F,Bainczyk K,et al.Peritoneal endometriosis:validation of an in-vivo model.Hum Reprod,2001,16(8):1736- 1743
[9]Nisolle M,Casanas-Roux F,Donnez J.Early-stage endometriosis:adhesion and growth of human menstrual endometrium in nude mice[J].Fertil & Steril,2000,74(2):306-312
[10]Aoki D,Katsuki Y,Shimizu A,et al.Successful heterotransplantation of human endometrium in SCID mice[J].Obstet.Gynecol,1994,83(2):220-228.
[11]Gurates B,Bulun SE.Endomet riosis:the ultimate hormonal disease [J].Seminars in Reproductive Medicine,2003,21(2):125-134.
[12]Khaled Zeitoun,Kazuto Takayama,et al.Stimulation of Aromatase P450 Promoter(Ⅱ) Activity in Endometriosis and Its Inhibition in Endometrium Are Regulated by Competitive Binding of Steroidogenic Factor-1 and Chicken Ovalbumin Upstream Promoter Transcription Factor to the Same cis-Acting Element[J].MOL ENDO,1999,13(2):239-253.
[13]KM Zeitoun,K Takayama,H Sasano,et al.Deficient 17 beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis:failure to metabolize 17 beta-estradiol[J].J Clin Endocrinol Metab,1998,83(12):4474-4480.
[14]SE Bulun,KM Zeitoun,K Takayama,and H Sasano.Estrogen biosynthesis in endometriosis:molecular basis and clinical relevance[J].Journal of Molecular Endocrinology(2000)25,35-42.
[15]Schindler AE,Campagnoli C,DruckmannR et al.Classification and pharmacology of progestins[J].Mat uritas,2003,46(Suppl1):7-16.
[16]Qian LH,Yang B,Leng Y et al.Inhibitory effect of nomegestrolacetate on steroidogenesis of cultured granulosa cells from rat ovary in vitro[J].中国药理学报,2001,22(1):40-44.
[17]Pasqualini JR,Chetrite GS.Estrone sulfatase versus estrone sulfotransferase in human breast cancer:potential clinical applications[J].J Steroid Biochem Mol Biol,1999,69(1-6):287-292.
[18]Chetrite GS,Pasqualini JR.The selective estrogen enzyme modulator(SEEM) in breast cancer[J].J Steroid Biochem Mol Biol,2001,76(1-5):95-104.
[19]Charpin C,Illouz S,Dales J Pet al Effects of progestins on human endometrium in vitro[J].Bull Acad Natl Med,2002,186(1):125-45.
[1]Veney SL,Rissman EF.Horm Behav,1998,33(3):151 - 162.
[2]Kuiper GG,Carlsson B,Grandien K,Enmark E,Haggblad J,Nilsson S,Gustafsson JA.Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta[J].Endocrinology.1997,138(3):863-870
[3]Jarvinen TA,Pelto-Huikko M,Holli K et al.Estrogen receptor beta.is coexpressed with ER alpha and PR and associated with nodal status,grade and proliferation rate in breast cancer[J].Am J Pathol,2000,156:29-35
[4]Kamegai J,Tamura H,Shimizu T,Ishii S,Sugihara H,Wakabayashi I.Estrogen receptor(ER)alpha,but not ERbeta,gene is expressed in growth hormone-releasing hormone neurons of the male rat hypothalamus.Endocrinology.2001 Feb;142(2):538-43.
[5]Moutastsou P,Sekeris CE.Steroid receptors in the uterus:implication in endometriosis.Ann N Y Acad Sci,2003,997:209-222
[6]SANCHEZ-CRIADO Jose E,GARRIDO-GRACIA Jose C,BELLIDO Carmina,AGUILAR Rafaela,GUELMES Pedro,ABREU Pedro,ALONSO Rafael,BARRANCO Inmaculada,MILLAN Yolanda,DE LAS MULAS Juana Martin.Oestradiol-17β inhibits tamoxifen-induced LHRH self-priming blocking hormone- dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat.J.endocrinol.2006,190,(1):73-84
[7]Lyndrup J,Thorpe S,Glenthoj A,et al.Altered progesterone /estrogen receptor ratios in endometriosis[J].Acta obstet Gynecol Scand,1987,66:625-629.
[8]Michelle Nisolle M.D,Yvan de Menten B.S,Francoise Casanas-Roux B.S,et al.Immunohistochemical analysis of estrogen and progesterone receptors in endometrium and peritoneal endometriosis:a new quantitative method[J].Fertil Steril,1994,62(4):751-759.
[9]陈琼华,曲军英,邱娜璇,陈达红.VEGF、ER、PR在异位和在位子宫内膜中的表达.厦门大学学报(自然科学版),2005,11(6):870-873
[10]Illouz S,Dales J P,Sferlazzo K et al.Effects of progestins of human proliferative endometrium:an i n vit ro model of potential clinical relevance[J].Int J Mol Med,2003,12(4):517- 23.
[11]Shields2Botella J,Duc I,Duranti E et al An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells[J].J Steroi dBiochem Mol Biol,2003,87(2 - 3):111 - 22.
[12]Jordan A.Toxicology of progestogens of implantable contraceptives for women[J]Cont raception,2002,65(1):3- 8.
[13]Charpin C,Illouz S,Dales J Pet al.Effects of progestins on human endometrium in vit ro[J].Bull Acad Natl Med,2002,186(1):125- 45.
[14]Harris HA,Bruner-Tran KL,Zhang X,Osteen KG,Lyttle CR.A selective estrogen receptor-agonist causes lesion regression in an experimentally induced model of endometriosis.Hum Reprod,2005,20:936- 941
[15]LagrangeAH,Wagner EJ,RonnekleivOK,KellyMJ.Estrogen rapidly attenuates a GABAB response in hypothalamic neurons.Neuroendocrinology1996 64(2):114-123.
[16]Leite CM,Szawka RE,Anselmo-Franci JA.Alpha-oestrogen and progestin receptor expression in the hypothalamus and preoptic area dopaminergic neurones during oestrous in cycling rats.J Neuroendocrinol.2008,20(1):110-9
[17]ZHANG Ji-qing,CAI Wen-qin.DISTRIBUTION OF ESTROGEN ECEPTOR-βIMMUNOREACTIVITY IN THE BRAIN OF ADULT FEMALE RATS[J].ACTA ANATOMICA SINICA,2002,33(2):118-121
[18]Hewitt SC,Harrell JC,Korach KS.Lessons in estrogen biology from knockout and transgenic animals.Annu Rev Physiol,200567:285- 308
[19]Toran-Allerand CD.Minireview:A plethora of estrogen receptors in the brain:where will it end? Ann N Y Acad Sci.2003,1007:89-100
[20]O'Malley BW,Tsai MJ.Molecular pathways of steroid receptor action.Biol Reprod,1992,46:163-167
[21]Lonard DM,O' Malley BW.Nuclear receptor coregulators:judges,juries,and executioners of cellular regulation.Mol Cell,2007,27:691-700
[22]Boonyaratanakornkit V,Scott MP,Ribon V,Sherman L,nderson SM,Maller JL,Miller WT,Edwards DP.Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases.Mol Cell,2001,8:269-280
[23]Zhu Y,Rice CD,Pang Y,Pace M,Thomas P.Cloning,expression,and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fishoocytes.Proc Natl Acad Sci U S A,2003,100:2231-2236.
[24]Boonyaratanakornkit V,Edwards DP.Receptor mechanisms mediating non-genomic actions of sex.steroids.Semin Reprod Med,2007,25:139-153
[25]Lange CA,Gioeli D,Hammes SR,Marker PC.Integration of rapid signaling events with steroid hormone receptor action in breast and prostatecancer.Annu Rev Physiol,2007,69:171-199
[26]Lange CA.Making sense of cross talk between steroid hormone receptors and intracellular signaling pathways:who will have the last word? MolEndocrinol,2004,18:269-278
[27]Mani SK.Signaling mechanisms in progesterone- neurotransmitter interactions.Neuroscience,2006,138:773-781
[28]JAMIN C,BATAELAN A,MADELENAT P.Antigonadotropic effects of a 19-nor-progesterone derivative:the example of nomegestrol acetate[J]Gynecol Obstet Fertil,2003,31(1):70281.
[1]Stomati M,Genazzani AD,Patraglia F,et al.Contraception as prevention and therapy:sex steroids and the brain[J].Eur J Contracept Reprod Health Care.1998,3(1):21-28
[2]Stafford L J,Xia C,Ma W,et al.Identification and character--ization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor[J].Cancer Res,2002,62(19):5399-5404
[3]Kotani M,Detheux M,Vandenbogaerde A,et al.The metastasis suppressor gene KiSS-1 encodes kisspeptins,the natural ligands of the orphan G protein-coupled receptor GPR54[J].J Biol Chem,2001,276(37):34631-34636
[4]Lee DK,NguyenT,O'Neill GP,et al.Discovery of areceptor related to the galanin receptors[J].FEBS Lett,1999,446(1):103-107
[5]NavarroVM,CastellanoJM,Fernandez-FernandezR,et al.Developmental and hormonally regulated messenger ribonucleic acid expressionof KiSS-1 and its putative receptor,GPR54,in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide[J].Endocrinology,2004,145(10):4565-4574
[6]ShahabM,Mastronardi C,SeminaraSB,et al.Increased hypothalamic GPR54 signaling:A potential mechanism for initiation of puberty in primates[J].Proc Natl Acad Sci US A,2005,102(6 ):2129-2134
[7]Seminara SB,Kaiser UB.New Gatekeepers of reproduction:GPR54 and its cognate ligand,KiSS-1[J].Endocrinology,2005,146(4):1686-1688
[8]Brailoiu GC,Dun SL,Ohsawa M,et al.KiSS-1 expression and metastinlikeimmunoreactivity in the rat brain[J].J Comp Neurol,2005,481(3):314-329
[9]IrwigMS,FraleyGS,Smith JT,et al.Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1mRNA in the male rat[J].Neuroendocrinology,2004,80(4):264-272
[10]Seminara SB,Messager S,Chatzidaki EE,et al.The GPR54 gene as a regulator of puberty[J].NEngl J Med,2003,349(17):1614-1627
[11]Lapatto R,Pallais JC,Zhang D,Chan YM,Mahan A,Cerrato F,Le WW,Hoffman GE,Seminara SB.Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice[J].Endocrinology.2007Oct;148(10):4927-36.
[12]de Roux N,Genin E,Carel JC,et al.Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54[J].Proc Natl Acad Sci US A,2003,100(19):10972-10976
[13]Seminara SB,Dipietro MJ,Ramaswamy S,Crowley WF Jr,Plant TM.Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey(Macaca mulatta):a finding with therapeutic implications[J].Endocrinology.2006,147(5):2122-2126.
[14]Navarro VM,Castellano JM,Fernandez-Fernandez R,et al.Effects of KiSS-1 peptide,the natural ligand of GPR54,on follicle-stimulating hormone secretion in the rat[J].Endocrinology,2005,146(4):1689-1697
[15]Matsui H,Takatsu Y,Kumano S,et al.Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat[J].BiochemBiophys Res Commun,2004,320(2):383-388
[16]Smith JT,Dungan HM,Stoll EA,et al.Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse[J].Endocrinology,2005,146(7):2976-2984
[17]Smith JT,Cunningham MJ,Rissman EF,et al.Regulation of Kiss-1gene expression in the brain of the female mouse.Endocrinology,2005,146(9):3686-3692
[1]Croxatto HB.Mechanisms that explain the contraceptive action of progestin implants for women[]].Cont raception,2002,65(1):21-27.
[2]Couzinet B,Young J,Kujas Met al.The antigonadotropic activity of a 192nor2progesterone derivative is exerted both at the hypothalamic and pituitary levels in women[J].J Cli n Endocrinol Metab,1999,84(11):4191 - 4196.
[3]褚云鸿主编,生殖药理学,人民卫生出版社,1992
[4]Lahteenmaki P,Weiner E,Lahteenmaki P,Johansson ED,Luukkainen T.Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin,ST-1435[J].Contraception,1982,25(3):299-306.
[5]Naor Z,Shacham S,Harris D,et al.Signal transduction of the gonadotropin releasing hormone(GnRH) receptor:cross-talk of calcium protein kinase C(PKC) and arachidonic acid[J].Cell Mol Neurobiol,1995,15:527-544
[6]Ben-Menahem D,Naor Z.Regulation of gonadotropin mRNA levels in cultured rat pituitary cells by gonadotropin-releasing hormone(GnRH):role for Ca2+ and protein kinase C[J].Biochemistry.1994 Mar 29;33(12):3698- 3704.
[7]D Ben-Menahem,Z Shraga-Levine,P L Mellon,and Z Naor Mechanism of action of gonadotropin-releasing hormone upon gonadotropin alpha-subunit mRNA levels in the alpha T3-1cell line:role of Ca2+ and protein kinase C[J].Biochem J.1995 July 1;309(Pt 1):325- 329.
[8]SS Stojilkovic,S Izumi and KJ Catt.Participation of voltage- sensitive calcium channels in pituitary hormone release[J].J Biol Chem,1988,263(26):13054-13061
[9]Stojilkovic,S S,rorsello,A Iida T,Rojas E,Catt K J.Calcium signaling and secretory responses in agonist-stimulated pituitary gonadotrophs[J].J Steroid Biochem Mol Biol,1992,41(3-8):453-67
[10]Seger R,Krebs E G.The MAPK signaling cascade.FASEB J, 1995, 9:726-755
[11] Marshal C J. Specificity of receptor tyrosine kinase signaling: transient vs. sustained extracellular signal-regulated kinase activation[J]. Cell, 1995, 80 :179- 185
[12] Brian D. Saunders, Elena Sabbagh, William W. Chin and Ursula B. Kaiser. Differential Use of Signal Transduction Pathways in the Gonadotropin-Releasing Hormone-Mediated Regulation of Gonadotropin Subunit Gene Expression[J]. Endocrinology,1998, 139(4):1835-1843
[13] Sundaresan S, Colin I M, Pestell R G, et al. Stimulation of mitogen-activated protein kinase by gonadotropin releasing hoemone: evidence for the involvement of protein kinase C[J]. Endocrinology, 1996, 137:304-311
[14] Roberson M S, Misra-press A, Laurance M E, et al. A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone α -subunit promoter[J]. Mol Cell Biol, 1995, 15:3531 - 3539
[15] Reiss N, Linet N L, Sharon S, et al. Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary α T3-1 cell line: differential roles of calcium and protein kinase C[J]. Endocrinology, 1997, 138:1677-1681
[16] Dan Cohen H , Naor Z. Mechanism of action of gonadotropin releasing hormone upon gonadotropin secretion: involvement of protein kinase C as revealed by staurosporine inhibition and enzyme depletion[J]. Mol-Cell-Endocrinol. 1990 Mar 5; 69(2-3): 135-144
[17] SS Stojilkovic, JP Chang, D Ngo and KJ Catt. Evidence for a role of protein kinase C in luteinizing hormone synthesis and secretion. Impaired responses to gonadotropin-releasing hormone in protein kinase C-depleted pituitary cells[J].J Biol Chem, 1988,263(33): 17307-17311
[18]LEMUS A. E,ZAGA V,SANTILLAN R,GARCIA G. A, GRILLASCA I, DAMIAN-MATSUMURA P, JACKSON K. J, COONEY A. J, LARREA F, PEREZ-PALACIOS G.The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites[J].Journal of endocrinology. 2000, 165 (3): 693-702
[1]JaminC,BatallanA,Madelenat P.Antigonadotropic effects of a 19-nor-progesterone derivative:the example of nomegestrol acetate[J].Gynecol Obstet Fertil,2003,31(1):70 - 81.
[2]Fukaya T,Sugawara J,Yoshida H,et al.Intercellular adhesion molecule-1 and hepatocyte growth factor in human endometriosis:original investigation and a review of literature[J].Gynecol Obstet Invest,1999,47 Suppl 1:11-17.
[3]Tseng JF,Ryan IP,MilamTD,et al.Interleukin-6 secretion in vitro is up-regulated in ectopic andeutopic endometrial stromal cells from women with endometriosis[J].J Clin Endocrinol Metab.1996,81:1118-1122.
[4]肖丽娟,石建军,杨增明,等.子宫内膜异位症患者子宫内膜和腹腔液成分变化的研究进展[J].中华妇产科杂志,2001,36(6):379-380.
[5]Huang JC,Yeh J.Quantitative analysis of epidermal growth factor receptor gene expression in endometriosis[J].J Clin Endocrinol Metab.1994,79(4):1097-1101.
[6]IwabeT,Haradar,SakamotoY,et al.Gonadotropin-releasing hormoneagonist treatment reduced serum interleukin-6concentrations in patientswith ovarian endometriomas[J].Fertil Steril,2003,80(2):300-304
[7]Yamauchi N,Harada T,Taniguchi F,et al.Tumor necrosis factor-alphainduced the release of interleukin-6 from endometriotic stromal cells by the nuclear factor-kappaB and mitogen-activated protein kinase pathways[J].Fertil Steril,2004,82[Suppl 3]:1023-1028
[8] KHAN Khaleque Newaz, MASUZAKI Hideaki, FUJISHITA Akira, HAMASAKI Tetsushi,KITAJIMA Michio,HASUO Atsuko,MIYAMURA Yasutake,ISHIMARU Tadayuk. Association of interleukin-6 and estradiol with hepatocyte growth factor in peritoneal fluid of women with endometriosis[J]. Acta obstetricia etgynecologica Scandinavica. 2002, 81(8): 764-771
[9]J Sugawara, T Fukaya, T Murakami, H Yoshida and A Yajima. Hepatocyte growth factor stimulated proliferation, migration, and lumen formation of human endometrial epithelial cells in vitro[J]. Biology of Reproduction, 57:936-942
[10]Eric Van Belle, Bernhard Witzenbichler, Donghui Chen, Marcy Silver, Ling Chang, Ralph Schwall, Jeffrey M. Isner. Potentiated Angiogenic Effect of Scatter Factor/ Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor [J]. Circulation. 1998, 97 :381-390
[11]Rostene W, Buckingham JC. Chemokines as modulators of neuroendocrine functions[J]. J Mol Endocrinol. 2007,38 (3):351-3.
[12] Jones TH, Kennedy RL. Cytokines and hypothalamic- pituitary function[J]. Cytokine, 1993, 5:531-538
[13]Gaillard RC 1998 Cytokines in the neuroendocrine system[J]. Int Rev Immunol 17:181 - 216
[14]Yamaguchi M, Koike K, Yoshimoto Y, Matsuzaki N, Miyake A, Tanizawa O. Interleukin-6 stimulates gonadotropin- releasing hormone secretion from rat hypothalamic cells[J]. Horm Res, 1991 ,35:252 - 256
[15]Igaz P, Salvi R, Rey JP, Glauser M, Pralong FP, Gaillard RC. Effects of cytokines on gonadotropin-releasing hormone (GnRH) gene expression in primary hypothalamic neurons and in GnRH neurons immortalized conditionally [J]. Endocrinology. 2006, 147(2):1037-43.
[16]Yamaguchi M, Yoshimoto Y, Komura H, Koike K, Matsuzaki N, Hirota K, Miyake A, Tanizawa 0 1990 Interleukin 16 and tumour necrosis factor α stimulate the release of gonadotropin-releasing hormone and interleukin 6 by primary cultured rat hypothalamic cells[J]. Acta Endocrinol (Copenh) 123:476-480
[17] Deevey S. Endometriosis internet resources [J]. Me Ref Serv, 2005,24 (1) : 67 - 76
[18]Salvi R, Castillo E, Voirol MJ, Glauser M, Rey JP, Gaillard RC, Vollenweider P, Pralong FP. Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway[J]. Endocrinology. 2006 Feb;147(2):816-26
[19] Peters G, Brookes S, Smith R, Dickson C. Tumorigenesis by mouse mammary tumor virus: evidence for a common region for provirus integration in mammary tumors[J]. Cell. 1983 Jun;33(2):369-77.
[20]Niemann C. , Brinkmann, V., Spitzer, E. , Hartmann, G. , Sachs, M. , Naundorf, H. & Birchmeier, W. Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis[J]. J. Cell Biol. 1998, 143:, 533-545.
[21]Elly S. W. Ngan, Zhi-Qing Ma, Steven S. Chua, Francesco J. DeMayo, and Sophia Y. Tsai. Inducible expression of FGF-3 in mouse mammary gland. Proc Natl Acad Sci U S A. 2002 August 20; 99(17): 11187 - 11192.
[22]Bhanoori M, Deenadayal M, Kennedy S, Shivaji S. The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women[J]. Hum Reprod. 2007 Apr;22(4):1026-30.
[23]Sato Y. Role of ETS family transcription factors in vascular development and angiogenesis [J]. Cell Struct Funct. 2001 Feb;26(1) :19-24.
[24] Hopital, et al. Theories of endometriosis [J]. European Journal of Obstetrics & Gynecology and Rep roductive Biology, 2001, 96: 21 -34.
[25]DomouskiWp, et al. Decreased apop tosis and sensitivity to macrophage cytolysis of endometrial alls in endometriosis [J]. Hum Reprod update, 1998, 4 (5): 696.
[26]Jones RK, et al. Phenotyp ic and functional studies of leukocytes in human endometrium and endometriosis [J]. Hum Rep rod Update, 1998, 4(5): 702.
[27]Garcia valasco JA, et al. Macrophage derived growth factorsmodulate Fas ligand exp ress in cultured endometrial stromal cues: a role in endometriosis[J]. Mol Hum Rep rod, 1999, 5(7) :640.
[28]Meresma GF, et al. Oral contracep tive supp ress cell proliferation and enhance apop tosis of eutop ic endometrial tissue from patients with endometriosis [J]. Fertik Steril, 2002 Jun, 77 (6) : 1141-1147.
[29]Warren B, et al. Treating endometriosis as an automune disease[J]. Fertility and Sterility, 2001, 76: 223 - 229.
[30] Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Peyrollier K, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM. Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo[J]. Breast. 2003 Apr;12(2) :142-9.
[31]Hugo Caldas, Florinda O. Jaynes, Michael W. Boyer, Sue Hammond, Rachel A. Altura. Survivin and Granzyme B- induced apoptosis, a novel anticancer therapy [J]. Mol Cancer Ther. 2006:5:693-703
[32] O'Connor L, Huang DC, O'Reilly LA, Strasser A. Apoptosis and cell division. Curr Opin Cell Biol. 2000,12(2):257-63.
[33] Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK[J]. Science. 1997 Oct 31:278(5339):818-9.
[34]Saeki K, Yuo A, Suzuki E, Yazaki Y, Takaku F. Aberrant expression of cAMP-response-element-binding protein ('CREB') induces apoptosis [J]. Biochem J. 1999 Oct 1; 343 Pt 1:249-55.
[35]Horinaka M, Yoshida T, Shiraishi T, Nakata S, Wakada M, Nakanishi R, Nishino H, Matsui H, Sakai T.Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells[J].Oncogene. 2005, 24 (48) : 7180-9.
[36]Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P.Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma[J]. Mod Pathol. 2007,20(4):416-26.
[37] Hyer ML, Samuel T, Reed JC. The FLIP-side of Fas signaling[J]. Clin Cancer Res. 2006 Jun 15 ; 12 (12) : 3705-12.
[38] Guidi AJ, Abu - Jawdeh G, Tognazzi K, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma [J]. Cancer , 1996 ,78 (3) :454-460.
[39] Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT 1989 Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science, 245:57-60
[40]De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT 1992 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989-991
[41] Ullrich A, Schlessinger J 1990 Signal transduction by receptors with tyrosine kinase activity. Cell 61:203 - 212
[42]Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J 1992 The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling [J].Cell 70:431 - 442
[43] Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG 1992 A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction[J]. Cell 70:93 - 104
[44] Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D 1993 The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSosl. Nature 363:83 - 85
[45] Johnson FM, Gallick GE. SRC family nonreceptor tyrosine kinases as molecular targets for cancer therapy [J]. Anticancer Agents Med Chem. 2007 Nov;7(6):651-9.
[46] Lee SJ, Namkoong S, Kim YM, Kim CK, Lee H, Ha KS, Chung HT, Kwon YG, Kim YM. Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eN0S-dependent signal pathways[J]. Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2836-46
[47]Chen L, Marble DJ, Agha R, Peterson JD, Becker RP, Jin T, Li J, Chan LS. The progression of inflammation parallels the dermal angiogenesis in a keratin 14 IL-4-transgenic model of atopic dermatitis[J]. Microcirculation. 2008, 15 (1):49-64.
[48]Post DE, Sandberg EM, Kyle MM, Devi NS, Brat DJ, Xu Z, Tighiouart M, Van Meir EG.Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4[J].Cancer Res. 2007 Jul 15;67(14):6872-81.
[49]Lejeune FJ, Lienard D, Matter M, Ruegg C. Efficiency of recombinant human TNF in human cancer therapy[J].Cancer Immun. 2006 Mar 22;6:6.
[50]Hideshima T, Podar K, Chauhan D, Anderson KC.Cytokines and signal transduction[J]. Best Pract Res Clin Haematol. 2005; 18(4) :509-24.
[51] Abad MA, Enguita M, DeGregorio-Rocasolano N, Ferrer I, Trullas R. Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer's brain[J]. J Neurosci. 2006 Dec 6;26 (49):12735-47
[1]Teichmann A.Pharmacology of estradiol valerate/dienogest[J].Climacteric,2003(6):17- 23.
[2]Sitruk-Ware R.New progestogens:a review of their effects in perimenopausal and postmenopausal women[J].Drugs Aging,2004(21):865- 883.
[3]Kumar N,Koide SS,Tsong YY,et al.Nestorone~(?):a progestin with a unique pharmacological profile[J].Steroids,2000(65):629- 636.
[4]Wiegratz I,Mittmann K,Dietrich H,et al.Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest[J].Fertil Steril,2006,85(6):1812-1819.
[5]Endrikat J,Lange E,Kunz M,et al.A one-year randomized double-blind,multicentre study to evaluate the effects of an oestrogen-reduced,continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate and 2 mg dienogest on metabolism in postmenopausal women[J].Eur J Contracept Reprod Health Care,2007,12(3):229-239.
[6]Fu L,Osuga Y,Morimoto C,et al.Dienogest inhibits BrdU uptake with G(0)/G(1) arrest in cultured endometriotic stromal cells. Fertil Steril, 2007, May 16 [Epub ahead of print]
[7] Schindler AE, Christensen B, Henkel A, et al. High-dose pilot study with the novel progestogen dienogestin patients with endometriosis[J]. Gynecol Endocrinol, 2006, 22(1):9-17.
[8] Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone[J]. Climacteric, 2005, 8 [Suppl 3]: 4-12.
[9] Barbosa IC, Maia H Jr, Coutinho E, et al. Effects of a single Silastic contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year[J]. Contraception, 2006,74(6): 492-497.
[10] Savoca S, D'Agosta S, Lombardo G. Evaluation of the climacteric symptomatology modifications and clinical-instrumental parameters in women in physiological menopause treated with hormone replacement therapy with nomegestrol acetate and in surgical menopause treated with estrogen replacement therapy. Part I[J]. Minerva Ginecol, 2007, 59(3): 205-214.
[11] Sitruk-Ware R, Bossemeyer R, Bouchard P. Preclinical and clinical properties of trimegestone: a potent and selective progestin[J]. Gynecol Endocrinol, 2007, 23(6): 310-319.
[12] Wahab M, Taylor AH, Pringle JH, et al. Trimegestone differentially modulates the expression of matrix metalloproteinases in the endometrial stromal cell[J]. Mol Hum Reprod, 2006,12(3): 157-167.
[13] Sivin I, Mishell DR Jr, Alvarez F, et al. Contraceptive vaginal rings releasing Nestorone and ethynyl estradiol: a 1-year dose-finding trial[J]. Contraception, 2005 (71): 122 -129.
[14] Conard J, Plu-Bureau G, Bahi N, et al. Progestogen-only contraception in women at high risk of venous thromboembolism[J]. Contraception, 2004 (70): 437-441.
[15]Clarkson TB, Appt SE. Controversis about HRT - lessons from monkey models[J]. Maturitas, 2005(51): 64-74.
[16] Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy[J]. Arch Intern Med, 2004,164 (18): 1965-1976.
[17] OelkersW, Drospirenone, a progestogen with anti- mineralocorticoid properties: a short review[J]. Mol Cell Endocrinol, 2004,217(1-2): 255- 261.
[18] Wiegratz I, Kutschera E, Lee JH, et al. Effect of four different oral contraceptives on various sex hormones and serum binding globulins[J]. Contraception, 2003(67): 25-32.
[19] Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort [J]. Int J Cancer, 2005 (114): 448-454.
[20] Xu B, Kitawaki J, Koshiba H, et al. Differential effects of progestogens, by type and regimen, on estrogen-metabolizing enzymes in human breast cancer cells[J]. Maturitas, 2007,56(2): 142-152.
[1] Bodner K, Bodner-Adler B, Kimberger O, et al. Estrogen and progesterone receptor expression in patients with uterine smooth muscle tumors . FERTILITY AND STERILITY, 2004, 81 (4): 1062-1066
[2] Jakimiuk AJ, Bogusiewicz M, Tarkowski R, et al. Estrogen receptor alpha and beta expression in uterine leiomyomas from premenopausal women . Fertil Steril.2004 , 82(Suppl3):1244-1249
[3] Weihua Z, Ekman J, Almkvist A, et al. Involvement of Androgen Receptor in 176- Estradiol- Induced Cell Proliferation in Rat Uterus . Biology of Reproduction, 2002, (67): 616-623
[4] Flake GP, Andersen J and Dixon D, et al. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect, 2003, 111(8): 1037-1054
[5] Wang F L, Chen D G, Sun F C, et al. Study on the relationship between uterine leiomyoma and apoptosis, K i - 67 and progesterone .Journal of Taishan Medical College], 2004, 25 (3) : 183-184
[6] Zhang ZL, Zhang Y, Zhou JH. Expression of bcl-2 and bax protein in uterine leiomyosarcomas and leiomyomas. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005, 30 (2):183-186
[7] Zhang ZL, Zhang Y. Study on cell proliferation and apoptosis in uterine leiomymas . Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005, 15(7) : 969-972
[8] Nakayama T, Yoshizaki A, Naito S, et al. Expression of Ets-1 proto-oncoprotein in gastrointestinal stromal tumors, leiomyomas and schwannomas. World J Gastroenterol. 2006, 2(11): 1743-1746
[9] Mangioni S, Vigano P, Lattuada D, et al. Overexpression of the Wnt5b gene in leiomyoma cells: implications for a role of the Wnt signaling pathway in the uterine benign tumor . J Clin Endocrinol Metab. 2005, 90(9): 5349-5355
[10] Bodner-Adler B, Bodner K, Czerwenka K, et al. Expression of p16 proteinin patients with uterine smooth muscle tumors: an immunohistochemical analysis. Gynecol Oncol. 2005, 96: 62- 66
[11]Ciaran J. O' Neill, W. Glenn Mc Cluggage. p16 Expression in the Female Genital Tract and Its Value in Diagnosis . Adv Anat Pathol 2006, 13:8-15
[12]Armes JE, Lourie R, de Silva M, et al. Abnormalities of the Rb1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16 (INK4a) protein. Int J Gynecol Pathol. 2005; 24:363-368
[13]T Maruo T, Matsuo H, Samoto T, et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids, 2000 (65): 585 - 592
[14] Burroughs KD, Fuchs-Young R, Davis B, et al. Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat . Biology of Reproduction, 2000(63), 1322-1330
[15] Xu Q, Takekida S, Ohara N, et al. Progesterone Receptor Modulator CDB-2914 Down-Regulates Proliferative Cell Nuclear Antigen and Bcl-2 Protein Expression and Up-Regulates Caspase-3 and Poly(Adenosine 5_-Diphosphate-ribose) Polymerase Expression in Cultured Human Uterine Leiomyoma Cells . The Journal of Clinical Endocrinology & Metabolism, 2005, 90(2): 953-961
[16]Shaw-Jenq Tsai, Shu-Jeg Lin, Ya-Ming Cheng, et al. Expression and Functional Analysis of Pituitary Tumor Transforming Growth Factor-1 in Uterine Leiomyomas . The Journal of Clinical Endocrinology & Metabolism, 2005, 90(6) : 3715- 3723
[17] C. D. Swartz, C.A.Afshari, Yu L, et al. Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines. Molecular Human Reproduction, 2005,11(6): 441 - 450
[18] K. A. Kovacs, A. Oszter, P.M. Gocze, et al. Szabo, Comparative analysis of cyclin D1 and oestrogen receptor (_ and _)levels in human leiomyoma and adjacent myometrium, Mol Hum Reprod. 2001, 7: 1085-1091
[19] Kovacs KA, Lengyel F, Kornyei JL, et al. Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium . Journal of Steroid Biochemistry & Molecular Biology, 2003 (87): 233-240
[20] WU Meng-xiang, GAO Ying-min, Wang Xiu-hua, et al. Expression and correlation of survivin and PTEN in uterine leiomyoma . MODERN ONCOLOGY, 2005, 13(1): 52-54
[21] Arslan AA, Gold LI, Mittal K, et al. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review . Human Reproduction, 2005, 20(4): 852-863
[22]Wei JJ,Chiriboga L,Arslan AA,et al.Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata.Human Reproduction,2006,(21) 1:57- 67
[23]Jeon YT,Kim JW,Park NH,et al.DNA repair gene XRCC1Arg399Gln polymorphism is associated with increased risk of uterine leiomyoma.Human Reproduction,2005,(20) 6:1586- 1589
[24]Yasuda K,Okumura T,Okada H,et al.Platelet-Activating Factor Acetylhydrolase Isoforms Ⅰ and Ⅱ in Human Uterus.Comparisons with Pregnant Uterus and Myoma.Biology of Reproduction,2001(64),339-344
[25]Jian-Jun Wei,Luis Chiriboga,et al.Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata.Human Reproduction.2006,21(1):57- 67
[26]Maruo T,Ohara N,Wang J,et al.Sex steroidal regulation of uterine leiomyoma growth and apoptosis.Hum Reprod Update,2004(10):207- 220
[27]Robin L.Parker,Robert H.Young,et al.Skeletal Muscle-like and Rhabdoid Cells inUterine Leiomyomas International Journal of Gynecological Pathology,2005(24):319-325
[2]Neukomm C,Mueller MD.New insights into the pathophysiology of endometriosis.Gynakol Geburtshilfliche Rundsch.2007;47(3):113-117
[3]Freundl G,Godtke K,Gnoth C,et al.Steroidal ' add-back' therapy in patients treated with GnRH agonists[J].GynecolObstet Invest,1998,45(Suppl 1):22-30.
[4]Pierce SJ,GazvaniMR,Farquharson RG.Longterm use of gonadotrop in releasing hormone analogs and hormone rep lacement therapy in the management of endometriosis arandomized trialwith a 62year follow-up [J].Fertil Steril,2000,74(5):964-968.
[5]Janicki TI.Treatment of the pelvic pain associated with endometriosis using danazol vaginal suppositories.[J].Fertil Steril,2002,77(1):52-60.
[6]Harris HA,Bruner Tran KL,Zhang X,et al.A selective estrogen receptor beta agonist causes lesion regression in an experimentally induced model of endometriosis[J].Hum Rep rod,2005,20(9):936-941.
[7]蒋红清,李亚里.子宫内膜异位症药物及生物治疗新进展[J].现代妇产科进展,2006,15(2):134-137.
[8]Bulun SE,Zeitoun KM,Takayama K,et al.Molecular basis for treating endometriosis with aromatase inhibitors[J].Hum Rep rod Update,2000,6(3):4132418.
[9]Shippen ER,WestWJ J r.Successful treatment of severe endometriosis in two p remenopausal women with an aromatase inhibitor[J].Fertil Steril,2004,8(12):1395-1398.
[10]Ailawadi RK,Jobanputra S,KatariaM,et al.Treatment of endometriosis and chronic pelvic pain with petrozole and norethindrone acetate:a pilot study[J].Fertil Steril,2004,81:290-296.
[11]Soysal S,SoysalME,Ozer S,et al.The effects of post2surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis a prospective randomized trial[J].Hum Rep rod,2004,19(1):160-167.
[12]Olive DL.Medical therapy of endometriosis[J].Semi Rep rod Med,2003,21(2):211-222.
[13]Efstathiou JA,Samp son DA,Levine Z,et al.Nonsteroidal anti inflammatory drugs differentially supp ress endometriosis in a murine model[J].Fetril Steril,2005,83(2):171-181.
[14]Abu J I,Konje JC.Leukotrienes in gynaecology:the hypothetical value of anti-leukotriene therapy in dysmenorrhoea and endometriosis[J].Hum Rep rod Update,2000,6(2):200-207.
[15]Xiao YH,Chen DP,Yah JH,et al.Mechanism of action of tripterygium wilfordii polyglycoside on experimental endometriosis[J].Eur J Gynaecol Oncol,2002,23(1):63-69.
[16]Nishida M,Nasu K,Ueda T,et al.Endometriotic cells are resistant to interferon-gamma-induced cell growth inhibition and apop tosis:a possible mechanism involved in the pathogenesis of endometriosis[J].Mol Hum Rep rod,2005,11(1):29-35.
[17]Mesogitis S,AntsaklisA,Daskalakis G,et al.Combined ultrasonographically guided drainage and methotrexate administration for treament of endometriotic cysts[J].Lancet,2000,355(9210):1160-1168.
[18]Vercellini P,Frontino G,De Giorgi O,et al.Continuous use of an oral contracep rive for endometriosis- associated recurrent dysmenorrheal that does not repond to a cyclic pill regimen[J].Fertil Steril,2003,80:560-563.
[19]Sitruk-Ware R.Pharmocological profile of progestins[J].Maturitas,2004,47(4):277-283.
[20]Doring A,Frohlich M,Lowel H,et al.Third generation oral contraceptive use and cardiovascular risk factors[J].Atherosclerosis,2004,172(2):281-286.
[21]Sitruk-Ware R.New progestogens:a review of their effects in perimenopausal and postmenopausal women[J].Drugs Aging,2004,21(13):865-883.
[22]朱焰,孙祖越,曹霖.第四代孕激素研究进展.中国药学杂志2006,41(8):572-576.
[23]Croxatto HB.Mechanisms that explain the contraceptive action of progestin implants for women[J].Contraception,2002,65(1):21-27.
[24]Couzinet B,Young J,Kujas M et al.The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women[J].J Cli n Endocrinol Metab,1999,84(11):4191-4196.
[25]Charpin C,Illouz S,Dales J P et al.Effects of progestins on human endometrium i n vit ro[J].Bull Acad Natl Med,2002,186(1):125-145.
[26]Illouz S,Dales J P,Sferlazzo K et al.Effects of progestins of human proliferative endometrium:an i n vit ro model of potentialclinical relevance[J].Int J Mol Med,2003,12(4):517 - 523.
[27]Pasqualini JR,Chetrite GS.Estrone sulfatase versus estrone sulfotransferase in human breast cancer:potential clinical applications[J].J Steroid Biochem Mol Biol,1999,69(1 - 6):287 - 292.
[28]Chetrite GS,Pasqualini JR.The selective estrogen enzyme modulator (SEEM) in breast cancer[J].J Steroid Biochem Mol Biol,2001,76(1 - 5):95 - 104.
[29]Li J,Xu LZ,He KL et al.Reversal effects of nomegestrol acetate on multidrug resistance in adriamycin2resistant MCF7 breast cancer cell line[J].B reast Cancer Res,2001,3(4):253 - 263.
[30]Li J,Xu L,He K.Modulation of multiple drug resistance bynomegestrol acetate and droloxifene in K562/ A02[J].中华血液学杂志,1999,20(6):288 - 291.
[31]StomatiM,GenazzaniAD,PatragliaF,et al.Contraception as prevention and therapy:sex steroids and the brain[J].Eur J Contracept Reprod Health Care.1998,3(1):21-28
[32]Stafford L J,Xia C,Ma W,et aI Identification and character- -ization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor [J].Cancer Res,2002,62(19):5399-5404
[33]Kotani M,Detheux M,Vandenbogaerde A,et al.The metastasis suppressor gene KiSS-1 encodes kisspeptins,the natural ligands of the orphan G protein-coupled receptor GPR54[J].J Biol Chem,2001,276(37): 34631-34636
[34]Lee DK,Nguyen T,O'Neill GP,et al.Discovery of a receptor related to the galanin receptors[J].FEBS Lett,1999,446(1):103-107
[35]NavarroVM,CastellanoJM,Fernandez-FernandezR,et al.Developmental and hormonally regulated messenger ribonucleic acid expressionof KiSS-1and its putative receptor,GPR54,in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide[J].Endocrinology,2004,145(10):4565-4574
[36]Shahab M,Mastronardi C,Seminara SB,et al.Increased hypothalamic GPR54 signaling:A potential mechanism for initiation of puberty in primates[J].Proc Natl Acad Sci US A,2005,102(6 ):2129-2134
[37]Seminara SB,Kaiser UB.New Gatekeepers of reproduction:GPR54 and its cognate ligand,KiSS-1[J].Endocrinology,2005,146(4):1686-1688
[38]Brailoiu GC,Dun SL,Ohsawa M,et al.KiSS-1 expression and metastinlikeimmunoreactivity in the rat brain[3].J Comp Neurol,2005,481(3):314-329
[39]IrwigMS,FraleyGS,Smith JT,et al.Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat[J].Neuroendocrinology,2004,80(4):264-272
[40]Seminara SB,Messager S,Chatzidaki EE,et al.The GPR54 gene as a regulator of puberty[J].NEngl J Med,2003,349(17):1614-1627
[41]Lapatto R,Pallais JC,Zhang D,Chan YM,Mahan A,Cerrato F,Le WW,Hoffman GE,Seminara SB.Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice[J].Endocrinology.2007Oct;148(10):4927-36.
[42]Smith JT,Dungan HM,Stoll EA,et al.Differential regulation of KiSS-1mRNA expression by sex steroids in the brain of the male mouse[J].Endocrinology,2005,146(7):2976-2984
[43]Smith JT,Cunningham MJ,Rissman EF,et al.Regulation of Kiss-1gene expression in the brain of the female mouse.Endocrinology,2005,146(9):3686-3692
[44]褚云鸿主编,生殖药理学,人民卫生出版社,1992
[45]Lahteenmaki P,Weiner E,Lahteenmaki P,Johansson ED,Luukkainen T. Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin,ST-1435[J].Contraception,1982,25(3):299-306.
[46]Naor Z,Shacham S,Harris D,et al.Signal transduction of the gonadotropin releasing hormone(GnRH) receptor:cross-talk of calcium protein kinase C (PKC) and arachidonic acid[J].Cell Mol Neurobiol,1995,15:527-544
[47]Ben-Menahem D,Naor Z.Regulation of gonadotropin mRNA levels in cultured rat pituitary cells by gonadotropin- releasing hormone(GnRH):role for Ca2+ and protein kinase C[J].Biochemistry.1994 Mar 29;33(12):3698-3704.
[48]D Ben-Menahem,Z Shraga-Levine,P L Mellon,and Z Naor Mechanism of action of gonadotropin-releasing hormone upon gonadotropin alpha-subunit mRNA levels in the alpha T3-1 cell line:role of Ca2+ and protein kinase C[J].Biochem J.1995 July 1;309(Pt 1):325-329.
[49]SS Stojilkovic,S Izumi and KJ Catt.Participation of voltage- sensitive calcium channels in pituitary hormone release[J].J Biol Chem,1988,263(26):13054-13061
[50]Stojilkovic,S S,Torsello,A IidaT,Rojas E,Catt K J.Calcium signaling and secretory responses in agonist- stimulated pituitary gonadotrophs[J].J Steroid Biochem Mol Biol,1992,41(3-8):453-467
[1]Sathe PM,TsongY,ShahVP.In vitro dissolution profile comparison:statistics and analysis,model dependent approach[J].Pharm Res,1996,13(12):1799-1803.
[2]Gallagher KM,Corrigan Of.Mechanistic aspects of the release of levamisole hydrochloride from biodegradable polymers[J].J Control Release,2000,69:261-272.
[3]Baras B,Benoit MA,Gillard J.Parameters influencing the antigen release from spray-dried poly(DL-lactide) microparticales[J].Int J Pharm,2000,299:133-145.
[4]Narasimhan B,hanger R.Zero-order release of micro- and macromolecules from polymeric devices:the role of the burst effect[J].J Control Release,1997,47:13-20.
[5]Ogawa Y,Yamamoto M,Takada S,et al.Controlled-release of leuprolide acetata from polyactic acid or copoly(lactic/glycolic)acid micropheres:influence of molecular weight and copolymer ratio of polymer[J].Chem Pharm Bull,1988,36(4):1502-1507.
[6]Ravivarapu HB,Burton K,Deluca PP.Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres[J].Euro J Pharm Biopharm,2000,50:263-270.
[1]Jones RC.The effect of a luteinizing hormone releasing hormone (LRH) agonist(Wy-40,972),levonorgestrel,danazol and ovariectomy on experimental endometriosis in the rat[J].Acta Endocrinol(Copenh).1984,106(2):282-288.
[2]Schenken RS,Asch RH.Surgical induction of endometriosis in the rabbit:effects on fertility and concentrations of peritoneal fluid prostaglandins.Fertil Steril.1980,34(8):581-587.
[3]Palatynski A.Dynamics of morphologic changes in the ovaries of guinea pigs modified by implanted endometrium[J].Zentralbl Gynakol.1986,108(9):560-569.
[4]MacKenzie WF,Casey HW.Animal model of human disease.Endometriosis.Animal model:endometriosis in rhesus monkeys[J].Am J Pathol,1975,80(2):341-344.
[5]Nagasawa H,Ishida M,Mori T.Effects of treatment with prolactin or progesterone on the coincidence of mammary tumors and uterine adenomyosis in young SHN mice[J].Lab Anim Sci,1987,37(2):200-202.
[6]Sharpe KL,Zimmer RL,Khan RS,et al.Proliferative and morphogenic changes induced by the coculture of rat uterine and peritoneal cells:a cell culture model for endometriosis[J].Fertil &Steril,1992,58(6):1220- 1229.
[7]杨耀芳,王钦茂,方学明,等.建立大鼠子宫内膜异位症模型的评价方法[J].中国药理学通报,1998,4(5):469-470.
[8]Van Langendonckt A,Casanas-Roux F,Eggermont J.Characterization of iron deposition in endometriotic lesions induced in the nude mouse kf model[J].Hum Reprod,2004,19(6):1265-1271.
[9]Nisolle M,Casanas-Roux F,Donnez J.Early-stage endometriosis:adhesion and growth of human menstrual endometrium in nude mice[J].Fertil & Steril,2000,74(2):306-312.
[10]Aoki D,Katsuki Y,Shimizu A,et al.Successful heterotransplantation of human endometrium in SCID mice[J].Obstet.Gynecol,1994,83(2):220-228.
[11]Scott RB,Ohio C,Te Linde RW,et al.Further studies on experimental endometriosis[J].Am J Obstet Gynecol,1953,66:1082-1099.
[12]Fortin M,Lepine M,Page M,et al.An improved mouse model for endometriosis allows noninvasive assessment of lesion implantation and development[]].Fertil Steril,2003,80(2):832-838.
[13]Somigliana E,Vigano P,Rossi G,et al.Endometriosis ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis[J].Human Reproduction,1999,14(12):2944-2950.
[1]Jones RC.The effect of luteinizing hormone releasing hormone(LRH)agonist(Wy-240972),]evonorgestrel danazol and ovariectomy endometiosis on the rat[J].Acta Endocrinol,1984,106(2):282-288.
[2]杨耀芳,王钦茂,方学明,等.建立大鼠子宫内膜异位症模型的评价方法[J].中国药理学通报,1998,4(5):469-470.
[3]Vernon MW,Wilson EA.Studies on the surgical induction of endometriosis in the rat[J].Fertil Steril,1985,44(5):684-694.
[4]Rajkumar K,Schott P W,Simpson C W,et al.The rat as an animal model for endometriosis to examine recurrence of ectopic endomtrial tissue after regression[J].Fertil Steril,1990,53(5):921.
[5]ILLOUZ S,DALESJ P,SFERLAZZO K,et al.Effects of progestins of human proliferative endometrium:an in vitro model of potential clinical relevance[J].Int J Mol Med,2003,12(4):5172523.
[6]王亚敏,石庭森.微球制剂药物控释研究的进展[J].中国药学杂志,1996,31(3):131-134.
[7]Somigliana E,Vigano P,Rossi G,et al.Endometriosis ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis[J].Human Reproduction,1999,14(12):2944-2950.
[8]Grummer R,Schwarzer F,Bainczyk K,et al.Peritoneal endometriosis:validation of an in-vivo model.Hum Reprod,2001,16(8):1736- 1743
[9]Nisolle M,Casanas-Roux F,Donnez J.Early-stage endometriosis:adhesion and growth of human menstrual endometrium in nude mice[J].Fertil & Steril,2000,74(2):306-312
[10]Aoki D,Katsuki Y,Shimizu A,et al.Successful heterotransplantation of human endometrium in SCID mice[J].Obstet.Gynecol,1994,83(2):220-228.
[11]Gurates B,Bulun SE.Endomet riosis:the ultimate hormonal disease [J].Seminars in Reproductive Medicine,2003,21(2):125-134.
[12]Khaled Zeitoun,Kazuto Takayama,et al.Stimulation of Aromatase P450 Promoter(Ⅱ) Activity in Endometriosis and Its Inhibition in Endometrium Are Regulated by Competitive Binding of Steroidogenic Factor-1 and Chicken Ovalbumin Upstream Promoter Transcription Factor to the Same cis-Acting Element[J].MOL ENDO,1999,13(2):239-253.
[13]KM Zeitoun,K Takayama,H Sasano,et al.Deficient 17 beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis:failure to metabolize 17 beta-estradiol[J].J Clin Endocrinol Metab,1998,83(12):4474-4480.
[14]SE Bulun,KM Zeitoun,K Takayama,and H Sasano.Estrogen biosynthesis in endometriosis:molecular basis and clinical relevance[J].Journal of Molecular Endocrinology(2000)25,35-42.
[15]Schindler AE,Campagnoli C,DruckmannR et al.Classification and pharmacology of progestins[J].Mat uritas,2003,46(Suppl1):7-16.
[16]Qian LH,Yang B,Leng Y et al.Inhibitory effect of nomegestrolacetate on steroidogenesis of cultured granulosa cells from rat ovary in vitro[J].中国药理学报,2001,22(1):40-44.
[17]Pasqualini JR,Chetrite GS.Estrone sulfatase versus estrone sulfotransferase in human breast cancer:potential clinical applications[J].J Steroid Biochem Mol Biol,1999,69(1-6):287-292.
[18]Chetrite GS,Pasqualini JR.The selective estrogen enzyme modulator(SEEM) in breast cancer[J].J Steroid Biochem Mol Biol,2001,76(1-5):95-104.
[19]Charpin C,Illouz S,Dales J Pet al Effects of progestins on human endometrium in vitro[J].Bull Acad Natl Med,2002,186(1):125-45.
[1]Veney SL,Rissman EF.Horm Behav,1998,33(3):151 - 162.
[2]Kuiper GG,Carlsson B,Grandien K,Enmark E,Haggblad J,Nilsson S,Gustafsson JA.Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta[J].Endocrinology.1997,138(3):863-870
[3]Jarvinen TA,Pelto-Huikko M,Holli K et al.Estrogen receptor beta.is coexpressed with ER alpha and PR and associated with nodal status,grade and proliferation rate in breast cancer[J].Am J Pathol,2000,156:29-35
[4]Kamegai J,Tamura H,Shimizu T,Ishii S,Sugihara H,Wakabayashi I.Estrogen receptor(ER)alpha,but not ERbeta,gene is expressed in growth hormone-releasing hormone neurons of the male rat hypothalamus.Endocrinology.2001 Feb;142(2):538-43.
[5]Moutastsou P,Sekeris CE.Steroid receptors in the uterus:implication in endometriosis.Ann N Y Acad Sci,2003,997:209-222
[6]SANCHEZ-CRIADO Jose E,GARRIDO-GRACIA Jose C,BELLIDO Carmina,AGUILAR Rafaela,GUELMES Pedro,ABREU Pedro,ALONSO Rafael,BARRANCO Inmaculada,MILLAN Yolanda,DE LAS MULAS Juana Martin.Oestradiol-17β inhibits tamoxifen-induced LHRH self-priming blocking hormone- dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat.J.endocrinol.2006,190,(1):73-84
[7]Lyndrup J,Thorpe S,Glenthoj A,et al.Altered progesterone /estrogen receptor ratios in endometriosis[J].Acta obstet Gynecol Scand,1987,66:625-629.
[8]Michelle Nisolle M.D,Yvan de Menten B.S,Francoise Casanas-Roux B.S,et al.Immunohistochemical analysis of estrogen and progesterone receptors in endometrium and peritoneal endometriosis:a new quantitative method[J].Fertil Steril,1994,62(4):751-759.
[9]陈琼华,曲军英,邱娜璇,陈达红.VEGF、ER、PR在异位和在位子宫内膜中的表达.厦门大学学报(自然科学版),2005,11(6):870-873
[10]Illouz S,Dales J P,Sferlazzo K et al.Effects of progestins of human proliferative endometrium:an i n vit ro model of potential clinical relevance[J].Int J Mol Med,2003,12(4):517- 23.
[11]Shields2Botella J,Duc I,Duranti E et al An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells[J].J Steroi dBiochem Mol Biol,2003,87(2 - 3):111 - 22.
[12]Jordan A.Toxicology of progestogens of implantable contraceptives for women[J]Cont raception,2002,65(1):3- 8.
[13]Charpin C,Illouz S,Dales J Pet al.Effects of progestins on human endometrium in vit ro[J].Bull Acad Natl Med,2002,186(1):125- 45.
[14]Harris HA,Bruner-Tran KL,Zhang X,Osteen KG,Lyttle CR.A selective estrogen receptor-agonist causes lesion regression in an experimentally induced model of endometriosis.Hum Reprod,2005,20:936- 941
[15]LagrangeAH,Wagner EJ,RonnekleivOK,KellyMJ.Estrogen rapidly attenuates a GABAB response in hypothalamic neurons.Neuroendocrinology1996 64(2):114-123.
[16]Leite CM,Szawka RE,Anselmo-Franci JA.Alpha-oestrogen and progestin receptor expression in the hypothalamus and preoptic area dopaminergic neurones during oestrous in cycling rats.J Neuroendocrinol.2008,20(1):110-9
[17]ZHANG Ji-qing,CAI Wen-qin.DISTRIBUTION OF ESTROGEN ECEPTOR-βIMMUNOREACTIVITY IN THE BRAIN OF ADULT FEMALE RATS[J].ACTA ANATOMICA SINICA,2002,33(2):118-121
[18]Hewitt SC,Harrell JC,Korach KS.Lessons in estrogen biology from knockout and transgenic animals.Annu Rev Physiol,200567:285- 308
[19]Toran-Allerand CD.Minireview:A plethora of estrogen receptors in the brain:where will it end? Ann N Y Acad Sci.2003,1007:89-100
[20]O'Malley BW,Tsai MJ.Molecular pathways of steroid receptor action.Biol Reprod,1992,46:163-167
[21]Lonard DM,O' Malley BW.Nuclear receptor coregulators:judges,juries,and executioners of cellular regulation.Mol Cell,2007,27:691-700
[22]Boonyaratanakornkit V,Scott MP,Ribon V,Sherman L,nderson SM,Maller JL,Miller WT,Edwards DP.Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases.Mol Cell,2001,8:269-280
[23]Zhu Y,Rice CD,Pang Y,Pace M,Thomas P.Cloning,expression,and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fishoocytes.Proc Natl Acad Sci U S A,2003,100:2231-2236.
[24]Boonyaratanakornkit V,Edwards DP.Receptor mechanisms mediating non-genomic actions of sex.steroids.Semin Reprod Med,2007,25:139-153
[25]Lange CA,Gioeli D,Hammes SR,Marker PC.Integration of rapid signaling events with steroid hormone receptor action in breast and prostatecancer.Annu Rev Physiol,2007,69:171-199
[26]Lange CA.Making sense of cross talk between steroid hormone receptors and intracellular signaling pathways:who will have the last word? MolEndocrinol,2004,18:269-278
[27]Mani SK.Signaling mechanisms in progesterone- neurotransmitter interactions.Neuroscience,2006,138:773-781
[28]JAMIN C,BATAELAN A,MADELENAT P.Antigonadotropic effects of a 19-nor-progesterone derivative:the example of nomegestrol acetate[J]Gynecol Obstet Fertil,2003,31(1):70281.
[1]Stomati M,Genazzani AD,Patraglia F,et al.Contraception as prevention and therapy:sex steroids and the brain[J].Eur J Contracept Reprod Health Care.1998,3(1):21-28
[2]Stafford L J,Xia C,Ma W,et al.Identification and character--ization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor[J].Cancer Res,2002,62(19):5399-5404
[3]Kotani M,Detheux M,Vandenbogaerde A,et al.The metastasis suppressor gene KiSS-1 encodes kisspeptins,the natural ligands of the orphan G protein-coupled receptor GPR54[J].J Biol Chem,2001,276(37):34631-34636
[4]Lee DK,NguyenT,O'Neill GP,et al.Discovery of areceptor related to the galanin receptors[J].FEBS Lett,1999,446(1):103-107
[5]NavarroVM,CastellanoJM,Fernandez-FernandezR,et al.Developmental and hormonally regulated messenger ribonucleic acid expressionof KiSS-1 and its putative receptor,GPR54,in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide[J].Endocrinology,2004,145(10):4565-4574
[6]ShahabM,Mastronardi C,SeminaraSB,et al.Increased hypothalamic GPR54 signaling:A potential mechanism for initiation of puberty in primates[J].Proc Natl Acad Sci US A,2005,102(6 ):2129-2134
[7]Seminara SB,Kaiser UB.New Gatekeepers of reproduction:GPR54 and its cognate ligand,KiSS-1[J].Endocrinology,2005,146(4):1686-1688
[8]Brailoiu GC,Dun SL,Ohsawa M,et al.KiSS-1 expression and metastinlikeimmunoreactivity in the rat brain[J].J Comp Neurol,2005,481(3):314-329
[9]IrwigMS,FraleyGS,Smith JT,et al.Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1mRNA in the male rat[J].Neuroendocrinology,2004,80(4):264-272
[10]Seminara SB,Messager S,Chatzidaki EE,et al.The GPR54 gene as a regulator of puberty[J].NEngl J Med,2003,349(17):1614-1627
[11]Lapatto R,Pallais JC,Zhang D,Chan YM,Mahan A,Cerrato F,Le WW,Hoffman GE,Seminara SB.Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice[J].Endocrinology.2007Oct;148(10):4927-36.
[12]de Roux N,Genin E,Carel JC,et al.Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54[J].Proc Natl Acad Sci US A,2003,100(19):10972-10976
[13]Seminara SB,Dipietro MJ,Ramaswamy S,Crowley WF Jr,Plant TM.Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey(Macaca mulatta):a finding with therapeutic implications[J].Endocrinology.2006,147(5):2122-2126.
[14]Navarro VM,Castellano JM,Fernandez-Fernandez R,et al.Effects of KiSS-1 peptide,the natural ligand of GPR54,on follicle-stimulating hormone secretion in the rat[J].Endocrinology,2005,146(4):1689-1697
[15]Matsui H,Takatsu Y,Kumano S,et al.Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat[J].BiochemBiophys Res Commun,2004,320(2):383-388
[16]Smith JT,Dungan HM,Stoll EA,et al.Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse[J].Endocrinology,2005,146(7):2976-2984
[17]Smith JT,Cunningham MJ,Rissman EF,et al.Regulation of Kiss-1gene expression in the brain of the female mouse.Endocrinology,2005,146(9):3686-3692
[1]Croxatto HB.Mechanisms that explain the contraceptive action of progestin implants for women[]].Cont raception,2002,65(1):21-27.
[2]Couzinet B,Young J,Kujas Met al.The antigonadotropic activity of a 192nor2progesterone derivative is exerted both at the hypothalamic and pituitary levels in women[J].J Cli n Endocrinol Metab,1999,84(11):4191 - 4196.
[3]褚云鸿主编,生殖药理学,人民卫生出版社,1992
[4]Lahteenmaki P,Weiner E,Lahteenmaki P,Johansson ED,Luukkainen T.Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin,ST-1435[J].Contraception,1982,25(3):299-306.
[5]Naor Z,Shacham S,Harris D,et al.Signal transduction of the gonadotropin releasing hormone(GnRH) receptor:cross-talk of calcium protein kinase C(PKC) and arachidonic acid[J].Cell Mol Neurobiol,1995,15:527-544
[6]Ben-Menahem D,Naor Z.Regulation of gonadotropin mRNA levels in cultured rat pituitary cells by gonadotropin-releasing hormone(GnRH):role for Ca2+ and protein kinase C[J].Biochemistry.1994 Mar 29;33(12):3698- 3704.
[7]D Ben-Menahem,Z Shraga-Levine,P L Mellon,and Z Naor Mechanism of action of gonadotropin-releasing hormone upon gonadotropin alpha-subunit mRNA levels in the alpha T3-1cell line:role of Ca2+ and protein kinase C[J].Biochem J.1995 July 1;309(Pt 1):325- 329.
[8]SS Stojilkovic,S Izumi and KJ Catt.Participation of voltage- sensitive calcium channels in pituitary hormone release[J].J Biol Chem,1988,263(26):13054-13061
[9]Stojilkovic,S S,rorsello,A Iida T,Rojas E,Catt K J.Calcium signaling and secretory responses in agonist-stimulated pituitary gonadotrophs[J].J Steroid Biochem Mol Biol,1992,41(3-8):453-67
[10]Seger R,Krebs E G.The MAPK signaling cascade.FASEB J, 1995, 9:726-755
[11] Marshal C J. Specificity of receptor tyrosine kinase signaling: transient vs. sustained extracellular signal-regulated kinase activation[J]. Cell, 1995, 80 :179- 185
[12] Brian D. Saunders, Elena Sabbagh, William W. Chin and Ursula B. Kaiser. Differential Use of Signal Transduction Pathways in the Gonadotropin-Releasing Hormone-Mediated Regulation of Gonadotropin Subunit Gene Expression[J]. Endocrinology,1998, 139(4):1835-1843
[13] Sundaresan S, Colin I M, Pestell R G, et al. Stimulation of mitogen-activated protein kinase by gonadotropin releasing hoemone: evidence for the involvement of protein kinase C[J]. Endocrinology, 1996, 137:304-311
[14] Roberson M S, Misra-press A, Laurance M E, et al. A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone α -subunit promoter[J]. Mol Cell Biol, 1995, 15:3531 - 3539
[15] Reiss N, Linet N L, Sharon S, et al. Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary α T3-1 cell line: differential roles of calcium and protein kinase C[J]. Endocrinology, 1997, 138:1677-1681
[16] Dan Cohen H , Naor Z. Mechanism of action of gonadotropin releasing hormone upon gonadotropin secretion: involvement of protein kinase C as revealed by staurosporine inhibition and enzyme depletion[J]. Mol-Cell-Endocrinol. 1990 Mar 5; 69(2-3): 135-144
[17] SS Stojilkovic, JP Chang, D Ngo and KJ Catt. Evidence for a role of protein kinase C in luteinizing hormone synthesis and secretion. Impaired responses to gonadotropin-releasing hormone in protein kinase C-depleted pituitary cells[J].J Biol Chem, 1988,263(33): 17307-17311
[18]LEMUS A. E,ZAGA V,SANTILLAN R,GARCIA G. A, GRILLASCA I, DAMIAN-MATSUMURA P, JACKSON K. J, COONEY A. J, LARREA F, PEREZ-PALACIOS G.The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites[J].Journal of endocrinology. 2000, 165 (3): 693-702
[1]JaminC,BatallanA,Madelenat P.Antigonadotropic effects of a 19-nor-progesterone derivative:the example of nomegestrol acetate[J].Gynecol Obstet Fertil,2003,31(1):70 - 81.
[2]Fukaya T,Sugawara J,Yoshida H,et al.Intercellular adhesion molecule-1 and hepatocyte growth factor in human endometriosis:original investigation and a review of literature[J].Gynecol Obstet Invest,1999,47 Suppl 1:11-17.
[3]Tseng JF,Ryan IP,MilamTD,et al.Interleukin-6 secretion in vitro is up-regulated in ectopic andeutopic endometrial stromal cells from women with endometriosis[J].J Clin Endocrinol Metab.1996,81:1118-1122.
[4]肖丽娟,石建军,杨增明,等.子宫内膜异位症患者子宫内膜和腹腔液成分变化的研究进展[J].中华妇产科杂志,2001,36(6):379-380.
[5]Huang JC,Yeh J.Quantitative analysis of epidermal growth factor receptor gene expression in endometriosis[J].J Clin Endocrinol Metab.1994,79(4):1097-1101.
[6]IwabeT,Haradar,SakamotoY,et al.Gonadotropin-releasing hormoneagonist treatment reduced serum interleukin-6concentrations in patientswith ovarian endometriomas[J].Fertil Steril,2003,80(2):300-304
[7]Yamauchi N,Harada T,Taniguchi F,et al.Tumor necrosis factor-alphainduced the release of interleukin-6 from endometriotic stromal cells by the nuclear factor-kappaB and mitogen-activated protein kinase pathways[J].Fertil Steril,2004,82[Suppl 3]:1023-1028
[8] KHAN Khaleque Newaz, MASUZAKI Hideaki, FUJISHITA Akira, HAMASAKI Tetsushi,KITAJIMA Michio,HASUO Atsuko,MIYAMURA Yasutake,ISHIMARU Tadayuk. Association of interleukin-6 and estradiol with hepatocyte growth factor in peritoneal fluid of women with endometriosis[J]. Acta obstetricia etgynecologica Scandinavica. 2002, 81(8): 764-771
[9]J Sugawara, T Fukaya, T Murakami, H Yoshida and A Yajima. Hepatocyte growth factor stimulated proliferation, migration, and lumen formation of human endometrial epithelial cells in vitro[J]. Biology of Reproduction, 57:936-942
[10]Eric Van Belle, Bernhard Witzenbichler, Donghui Chen, Marcy Silver, Ling Chang, Ralph Schwall, Jeffrey M. Isner. Potentiated Angiogenic Effect of Scatter Factor/ Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor [J]. Circulation. 1998, 97 :381-390
[11]Rostene W, Buckingham JC. Chemokines as modulators of neuroendocrine functions[J]. J Mol Endocrinol. 2007,38 (3):351-3.
[12] Jones TH, Kennedy RL. Cytokines and hypothalamic- pituitary function[J]. Cytokine, 1993, 5:531-538
[13]Gaillard RC 1998 Cytokines in the neuroendocrine system[J]. Int Rev Immunol 17:181 - 216
[14]Yamaguchi M, Koike K, Yoshimoto Y, Matsuzaki N, Miyake A, Tanizawa O. Interleukin-6 stimulates gonadotropin- releasing hormone secretion from rat hypothalamic cells[J]. Horm Res, 1991 ,35:252 - 256
[15]Igaz P, Salvi R, Rey JP, Glauser M, Pralong FP, Gaillard RC. Effects of cytokines on gonadotropin-releasing hormone (GnRH) gene expression in primary hypothalamic neurons and in GnRH neurons immortalized conditionally [J]. Endocrinology. 2006, 147(2):1037-43.
[16]Yamaguchi M, Yoshimoto Y, Komura H, Koike K, Matsuzaki N, Hirota K, Miyake A, Tanizawa 0 1990 Interleukin 16 and tumour necrosis factor α stimulate the release of gonadotropin-releasing hormone and interleukin 6 by primary cultured rat hypothalamic cells[J]. Acta Endocrinol (Copenh) 123:476-480
[17] Deevey S. Endometriosis internet resources [J]. Me Ref Serv, 2005,24 (1) : 67 - 76
[18]Salvi R, Castillo E, Voirol MJ, Glauser M, Rey JP, Gaillard RC, Vollenweider P, Pralong FP. Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway[J]. Endocrinology. 2006 Feb;147(2):816-26
[19] Peters G, Brookes S, Smith R, Dickson C. Tumorigenesis by mouse mammary tumor virus: evidence for a common region for provirus integration in mammary tumors[J]. Cell. 1983 Jun;33(2):369-77.
[20]Niemann C. , Brinkmann, V., Spitzer, E. , Hartmann, G. , Sachs, M. , Naundorf, H. & Birchmeier, W. Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis[J]. J. Cell Biol. 1998, 143:, 533-545.
[21]Elly S. W. Ngan, Zhi-Qing Ma, Steven S. Chua, Francesco J. DeMayo, and Sophia Y. Tsai. Inducible expression of FGF-3 in mouse mammary gland. Proc Natl Acad Sci U S A. 2002 August 20; 99(17): 11187 - 11192.
[22]Bhanoori M, Deenadayal M, Kennedy S, Shivaji S. The G2964A 3'-untranslated region polymorphism of the signal transducer and activator of transcription 6 gene is associated with endometriosis in South Indian women[J]. Hum Reprod. 2007 Apr;22(4):1026-30.
[23]Sato Y. Role of ETS family transcription factors in vascular development and angiogenesis [J]. Cell Struct Funct. 2001 Feb;26(1) :19-24.
[24] Hopital, et al. Theories of endometriosis [J]. European Journal of Obstetrics & Gynecology and Rep roductive Biology, 2001, 96: 21 -34.
[25]DomouskiWp, et al. Decreased apop tosis and sensitivity to macrophage cytolysis of endometrial alls in endometriosis [J]. Hum Reprod update, 1998, 4 (5): 696.
[26]Jones RK, et al. Phenotyp ic and functional studies of leukocytes in human endometrium and endometriosis [J]. Hum Rep rod Update, 1998, 4(5): 702.
[27]Garcia valasco JA, et al. Macrophage derived growth factorsmodulate Fas ligand exp ress in cultured endometrial stromal cues: a role in endometriosis[J]. Mol Hum Rep rod, 1999, 5(7) :640.
[28]Meresma GF, et al. Oral contracep tive supp ress cell proliferation and enhance apop tosis of eutop ic endometrial tissue from patients with endometriosis [J]. Fertik Steril, 2002 Jun, 77 (6) : 1141-1147.
[29]Warren B, et al. Treating endometriosis as an automune disease[J]. Fertility and Sterility, 2001, 76: 223 - 229.
[30] Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Peyrollier K, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM. Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo[J]. Breast. 2003 Apr;12(2) :142-9.
[31]Hugo Caldas, Florinda O. Jaynes, Michael W. Boyer, Sue Hammond, Rachel A. Altura. Survivin and Granzyme B- induced apoptosis, a novel anticancer therapy [J]. Mol Cancer Ther. 2006:5:693-703
[32] O'Connor L, Huang DC, O'Reilly LA, Strasser A. Apoptosis and cell division. Curr Opin Cell Biol. 2000,12(2):257-63.
[33] Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK[J]. Science. 1997 Oct 31:278(5339):818-9.
[34]Saeki K, Yuo A, Suzuki E, Yazaki Y, Takaku F. Aberrant expression of cAMP-response-element-binding protein ('CREB') induces apoptosis [J]. Biochem J. 1999 Oct 1; 343 Pt 1:249-55.
[35]Horinaka M, Yoshida T, Shiraishi T, Nakata S, Wakada M, Nakanishi R, Nishino H, Matsui H, Sakai T.Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells[J].Oncogene. 2005, 24 (48) : 7180-9.
[36]Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P.Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma[J]. Mod Pathol. 2007,20(4):416-26.
[37] Hyer ML, Samuel T, Reed JC. The FLIP-side of Fas signaling[J]. Clin Cancer Res. 2006 Jun 15 ; 12 (12) : 3705-12.
[38] Guidi AJ, Abu - Jawdeh G, Tognazzi K, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma [J]. Cancer , 1996 ,78 (3) :454-460.
[39] Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT 1989 Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science, 245:57-60
[40]De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT 1992 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989-991
[41] Ullrich A, Schlessinger J 1990 Signal transduction by receptors with tyrosine kinase activity. Cell 61:203 - 212
[42]Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J 1992 The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling [J].Cell 70:431 - 442
[43] Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG 1992 A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction[J]. Cell 70:93 - 104
[44] Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D 1993 The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSosl. Nature 363:83 - 85
[45] Johnson FM, Gallick GE. SRC family nonreceptor tyrosine kinases as molecular targets for cancer therapy [J]. Anticancer Agents Med Chem. 2007 Nov;7(6):651-9.
[46] Lee SJ, Namkoong S, Kim YM, Kim CK, Lee H, Ha KS, Chung HT, Kwon YG, Kim YM. Fractalkine stimulates angiogenesis by activating the Raf-1/MEK/ERK- and PI3K/Akt/eN0S-dependent signal pathways[J]. Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2836-46
[47]Chen L, Marble DJ, Agha R, Peterson JD, Becker RP, Jin T, Li J, Chan LS. The progression of inflammation parallels the dermal angiogenesis in a keratin 14 IL-4-transgenic model of atopic dermatitis[J]. Microcirculation. 2008, 15 (1):49-64.
[48]Post DE, Sandberg EM, Kyle MM, Devi NS, Brat DJ, Xu Z, Tighiouart M, Van Meir EG.Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4[J].Cancer Res. 2007 Jul 15;67(14):6872-81.
[49]Lejeune FJ, Lienard D, Matter M, Ruegg C. Efficiency of recombinant human TNF in human cancer therapy[J].Cancer Immun. 2006 Mar 22;6:6.
[50]Hideshima T, Podar K, Chauhan D, Anderson KC.Cytokines and signal transduction[J]. Best Pract Res Clin Haematol. 2005; 18(4) :509-24.
[51] Abad MA, Enguita M, DeGregorio-Rocasolano N, Ferrer I, Trullas R. Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer's brain[J]. J Neurosci. 2006 Dec 6;26 (49):12735-47
[1]Teichmann A.Pharmacology of estradiol valerate/dienogest[J].Climacteric,2003(6):17- 23.
[2]Sitruk-Ware R.New progestogens:a review of their effects in perimenopausal and postmenopausal women[J].Drugs Aging,2004(21):865- 883.
[3]Kumar N,Koide SS,Tsong YY,et al.Nestorone~(?):a progestin with a unique pharmacological profile[J].Steroids,2000(65):629- 636.
[4]Wiegratz I,Mittmann K,Dietrich H,et al.Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest[J].Fertil Steril,2006,85(6):1812-1819.
[5]Endrikat J,Lange E,Kunz M,et al.A one-year randomized double-blind,multicentre study to evaluate the effects of an oestrogen-reduced,continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate and 2 mg dienogest on metabolism in postmenopausal women[J].Eur J Contracept Reprod Health Care,2007,12(3):229-239.
[6]Fu L,Osuga Y,Morimoto C,et al.Dienogest inhibits BrdU uptake with G(0)/G(1) arrest in cultured endometriotic stromal cells. Fertil Steril, 2007, May 16 [Epub ahead of print]
[7] Schindler AE, Christensen B, Henkel A, et al. High-dose pilot study with the novel progestogen dienogestin patients with endometriosis[J]. Gynecol Endocrinol, 2006, 22(1):9-17.
[8] Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone[J]. Climacteric, 2005, 8 [Suppl 3]: 4-12.
[9] Barbosa IC, Maia H Jr, Coutinho E, et al. Effects of a single Silastic contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year[J]. Contraception, 2006,74(6): 492-497.
[10] Savoca S, D'Agosta S, Lombardo G. Evaluation of the climacteric symptomatology modifications and clinical-instrumental parameters in women in physiological menopause treated with hormone replacement therapy with nomegestrol acetate and in surgical menopause treated with estrogen replacement therapy. Part I[J]. Minerva Ginecol, 2007, 59(3): 205-214.
[11] Sitruk-Ware R, Bossemeyer R, Bouchard P. Preclinical and clinical properties of trimegestone: a potent and selective progestin[J]. Gynecol Endocrinol, 2007, 23(6): 310-319.
[12] Wahab M, Taylor AH, Pringle JH, et al. Trimegestone differentially modulates the expression of matrix metalloproteinases in the endometrial stromal cell[J]. Mol Hum Reprod, 2006,12(3): 157-167.
[13] Sivin I, Mishell DR Jr, Alvarez F, et al. Contraceptive vaginal rings releasing Nestorone and ethynyl estradiol: a 1-year dose-finding trial[J]. Contraception, 2005 (71): 122 -129.
[14] Conard J, Plu-Bureau G, Bahi N, et al. Progestogen-only contraception in women at high risk of venous thromboembolism[J]. Contraception, 2004 (70): 437-441.
[15]Clarkson TB, Appt SE. Controversis about HRT - lessons from monkey models[J]. Maturitas, 2005(51): 64-74.
[16] Gomes MP, Deitcher SR. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy[J]. Arch Intern Med, 2004,164 (18): 1965-1976.
[17] OelkersW, Drospirenone, a progestogen with anti- mineralocorticoid properties: a short review[J]. Mol Cell Endocrinol, 2004,217(1-2): 255- 261.
[18] Wiegratz I, Kutschera E, Lee JH, et al. Effect of four different oral contraceptives on various sex hormones and serum binding globulins[J]. Contraception, 2003(67): 25-32.
[19] Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort [J]. Int J Cancer, 2005 (114): 448-454.
[20] Xu B, Kitawaki J, Koshiba H, et al. Differential effects of progestogens, by type and regimen, on estrogen-metabolizing enzymes in human breast cancer cells[J]. Maturitas, 2007,56(2): 142-152.
[1] Bodner K, Bodner-Adler B, Kimberger O, et al. Estrogen and progesterone receptor expression in patients with uterine smooth muscle tumors . FERTILITY AND STERILITY, 2004, 81 (4): 1062-1066
[2] Jakimiuk AJ, Bogusiewicz M, Tarkowski R, et al. Estrogen receptor alpha and beta expression in uterine leiomyomas from premenopausal women . Fertil Steril.2004 , 82(Suppl3):1244-1249
[3] Weihua Z, Ekman J, Almkvist A, et al. Involvement of Androgen Receptor in 176- Estradiol- Induced Cell Proliferation in Rat Uterus . Biology of Reproduction, 2002, (67): 616-623
[4] Flake GP, Andersen J and Dixon D, et al. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect, 2003, 111(8): 1037-1054
[5] Wang F L, Chen D G, Sun F C, et al. Study on the relationship between uterine leiomyoma and apoptosis, K i - 67 and progesterone .Journal of Taishan Medical College], 2004, 25 (3) : 183-184
[6] Zhang ZL, Zhang Y, Zhou JH. Expression of bcl-2 and bax protein in uterine leiomyosarcomas and leiomyomas. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005, 30 (2):183-186
[7] Zhang ZL, Zhang Y. Study on cell proliferation and apoptosis in uterine leiomymas . Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005, 15(7) : 969-972
[8] Nakayama T, Yoshizaki A, Naito S, et al. Expression of Ets-1 proto-oncoprotein in gastrointestinal stromal tumors, leiomyomas and schwannomas. World J Gastroenterol. 2006, 2(11): 1743-1746
[9] Mangioni S, Vigano P, Lattuada D, et al. Overexpression of the Wnt5b gene in leiomyoma cells: implications for a role of the Wnt signaling pathway in the uterine benign tumor . J Clin Endocrinol Metab. 2005, 90(9): 5349-5355
[10] Bodner-Adler B, Bodner K, Czerwenka K, et al. Expression of p16 proteinin patients with uterine smooth muscle tumors: an immunohistochemical analysis. Gynecol Oncol. 2005, 96: 62- 66
[11]Ciaran J. O' Neill, W. Glenn Mc Cluggage. p16 Expression in the Female Genital Tract and Its Value in Diagnosis . Adv Anat Pathol 2006, 13:8-15
[12]Armes JE, Lourie R, de Silva M, et al. Abnormalities of the Rb1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16 (INK4a) protein. Int J Gynecol Pathol. 2005; 24:363-368
[13]T Maruo T, Matsuo H, Samoto T, et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids, 2000 (65): 585 - 592
[14] Burroughs KD, Fuchs-Young R, Davis B, et al. Altered Hormonal Responsiveness of Proliferation and Apoptosis During Myometrial Maturation and the Development of Uterine Leiomyomas in the Rat . Biology of Reproduction, 2000(63), 1322-1330
[15] Xu Q, Takekida S, Ohara N, et al. Progesterone Receptor Modulator CDB-2914 Down-Regulates Proliferative Cell Nuclear Antigen and Bcl-2 Protein Expression and Up-Regulates Caspase-3 and Poly(Adenosine 5_-Diphosphate-ribose) Polymerase Expression in Cultured Human Uterine Leiomyoma Cells . The Journal of Clinical Endocrinology & Metabolism, 2005, 90(2): 953-961
[16]Shaw-Jenq Tsai, Shu-Jeg Lin, Ya-Ming Cheng, et al. Expression and Functional Analysis of Pituitary Tumor Transforming Growth Factor-1 in Uterine Leiomyomas . The Journal of Clinical Endocrinology & Metabolism, 2005, 90(6) : 3715- 3723
[17] C. D. Swartz, C.A.Afshari, Yu L, et al. Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines. Molecular Human Reproduction, 2005,11(6): 441 - 450
[18] K. A. Kovacs, A. Oszter, P.M. Gocze, et al. Szabo, Comparative analysis of cyclin D1 and oestrogen receptor (_ and _)levels in human leiomyoma and adjacent myometrium, Mol Hum Reprod. 2001, 7: 1085-1091
[19] Kovacs KA, Lengyel F, Kornyei JL, et al. Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium . Journal of Steroid Biochemistry & Molecular Biology, 2003 (87): 233-240
[20] WU Meng-xiang, GAO Ying-min, Wang Xiu-hua, et al. Expression and correlation of survivin and PTEN in uterine leiomyoma . MODERN ONCOLOGY, 2005, 13(1): 52-54
[21] Arslan AA, Gold LI, Mittal K, et al. Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review . Human Reproduction, 2005, 20(4): 852-863
[22]Wei JJ,Chiriboga L,Arslan AA,et al.Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata.Human Reproduction,2006,(21) 1:57- 67
[23]Jeon YT,Kim JW,Park NH,et al.DNA repair gene XRCC1Arg399Gln polymorphism is associated with increased risk of uterine leiomyoma.Human Reproduction,2005,(20) 6:1586- 1589
[24]Yasuda K,Okumura T,Okada H,et al.Platelet-Activating Factor Acetylhydrolase Isoforms Ⅰ and Ⅱ in Human Uterus.Comparisons with Pregnant Uterus and Myoma.Biology of Reproduction,2001(64),339-344
[25]Jian-Jun Wei,Luis Chiriboga,et al.Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata.Human Reproduction.2006,21(1):57- 67
[26]Maruo T,Ohara N,Wang J,et al.Sex steroidal regulation of uterine leiomyoma growth and apoptosis.Hum Reprod Update,2004(10):207- 220
[27]Robin L.Parker,Robert H.Young,et al.Skeletal Muscle-like and Rhabdoid Cells inUterine Leiomyomas International Journal of Gynecological Pathology,2005(24):319-325