不同作用时间的米非司酮对人早孕蜕膜、绒毛组织超微结构及基质金属蛋白酶系统表达的影响
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摘要
目的:本实验从米非司酮终止早孕的作用机制出发,研究正常早期妊娠、顿服150mg米非司酮12h、24h、48h后对人早孕蜕膜、绒毛组织超微结构及基质金属蛋白酶系统(MMPs)中基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-9(MMP-9)、金属蛋白酶组织抑制因子-1(TIMP-1)表达的影响,比较其不同作用时间对早孕蜕膜、绒毛组织的作用有无差别,为临床缩短药物流产时间,简化药物流产方案提供理论基础。
方法:将80例妊娠49天以内的妇女,随机分为4组,即对照组、用药12h组、24h组、48h组,每组20例;对照组:采用常规负压吸引术终止妊娠。服药组分别一次性口服米非司酮150mg,12h、24h、48h后行负压吸引术。收集各组所得蜕膜、绒毛组织,分别应用光镜、透射电子显微镜观察各组早孕蜕膜、绒毛组织细胞形态结构的改变;同时应用免疫组织化学S-P法检测MMP-2、MMP-9、TIMP-1在各组早孕蜕膜、绒毛组织中的表达情况。运用SPSS(13.0)软件包进行统计学分析。
结果:
1超微结构结果:
在米非司酮的作用下,蜕膜、绒毛细胞超微结构的改变主要表现在大蜕膜细胞皱缩,粗面内质网(RER)和线粒体(Mi)肿胀,颗粒细胞中高电子密度颗粒减少或消失;合体滋养细胞则表现不同程度的退行性改变,细胞滋养细胞仅出现轻度改变。蜕膜、绒毛细胞超微结构受损程度的比较,各服药组均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
2免疫组化结果:
MMP-2、MMP-9、TIMP-1均为胞浆表达,在蜕膜细胞、腺上皮细胞、腔上皮细胞、细胞滋养细胞、合体滋养细胞的胞浆、胞膜均有强烈的表达。
蜕膜组织中,MMP-2在对照组、口服米非司酮12h组、24h组、48h组的阳性目标平均光密度值分别为0.1555±0.0079、0.1952±0.0072、0.1958±0.0010、0.1967±0.0069 ,在绒毛组织分别为0.1555±0.0083、0.2033±0.0059、0.2076±0.0092、0.2079±0.0088,用药组在蜕膜和绒毛组织的表达均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
MMP-9在四组蜕膜组织的阳性目标平均光密度值分别为0.1656±0.0056、0.2032±0.0067、0.2051±0.0070、0.2084±0.0078 ,在绒毛组织分别为0.1617±0.0047、0.2025±0.0074、0.2039±0.0095、0.2099±0.0113,用药组在蜕膜和绒毛组织的表达均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
TIMP-1在四组蜕膜组织的阳性目标平均光密度值分别为0.1679±0.0127、0.1382±0.0071、0.1402±0.0102、0.1355±0.0077 ,在绒毛组织分别为0.1548±0.0098、0.1349±0.0106、0.1349±0.0093、0.1273±0.0095,用药组在蜕膜和绒毛组织的表达均低于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
蜕膜组织中MMP-9/TIMP-1的比值在四组中分别为0.9914±0.0837、1.4493±0.1369、1.4950±0.1352、1.5182±0.0884 ,在绒毛组织分别为0.9937±0.05534、1.5216±0.1066、1.5138±0.1405、1.5994±0.0842,其比值在用药组蜕膜和绒毛组织中均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
结论:
1说明了米非司酮使大蜕膜细胞蛋白合成受阻,颗粒细胞释放松弛素,基质网状纤维溶解,内膜剥脱,滋养细胞失去支持,血供不足,引发流产。
2 MMP-2、MMP-9在药物流产的蜕膜、绒毛组织中的表达水平显著高于正常妊娠,TIMP-1的表达显著降低,而MMP-9/ TIMP-1的比值显著升高,证实了三者在早期妊娠药物流产发生过程中具有重要作用,MMP-9和TIMP-1的平衡对于正常早期妊娠的维持起重要作用。
3本课题通过比较米非司酮不同作用时间对蜕膜、绒毛组织形态结构及MMPs表达的影响,揭示了顿服150mg米非司酮12h、24h对蜕膜、绒毛组织的抑制作用与48h时相似,此时应用米索前列醇的流产效果在理论上具有可行性,药物流产两种药物的用药间隔最早可以缩短到12h。
Objective: This study of mifepristone from terminating the mechanism in early pregnancy, researching the influence of mifepristone on the ultrastructure and the expression of MMP-2、MMP-9、TIMP-1 of human decidua and villus in early pregnancy by swallowing mifepristone 150 mg at one time respectively affect on 12h、24h、48h, to compare whether different treatment time of mifepristone existing distinction of decidua and villus in early pregnancy, so that a theoretical basis for shortening the time and simplifying the schedule of clinical medical abortion might be provided.
Methods: 80 cases pregnant women within 49 days, were randomly divided into four groups: control group, medication 12 h group, 24 h group, 48 h group, and 20 cases each of .The pregnant women in the control group were terminated of pregnancy by conventional suction. The medication groups swallowed mifepristone 150 mg at one time, 12h、24h and 48h later, suction was operated, and the decidua and villus were taken as soon as possible. Specimens were observed by light microscope and transmission electron microscopy. The expression of MMP-2、MMP-9、TIMP-1 were detected in decidua and villus by immunohistochemistry(SP). All data were analysed by SPSS(13.0) for Windows.
Results:
1 Ultrastructural results
On the role of mifepristone, the variance of decidua and villus on the ultrastructure mainly appearance that large decidual cell shrinkage, rough endoplasm reticulum and mitochondria swell;and electron dense particles in the decidual granular cells decrease or disappear; villous syneytiotrophoblast which have active function show various degrees of degenerative changes,and langhans cell only change slightly. As for the damaged degree of decidua and villus on the ultrastructure, the treated group exceed the control group remarkably (P <0.05), and among the treated groups there are no significant difference (P> 0.05).
2 Immunohistochemical results: All of MMP-2、MMP-9、TIMP-1 express strongly in the cytoplasm of decidual cells、glandular epithelial cells、cavitary epithelial cells、cytotrophoblast and syncytiotrophoblast cells、capillary endothelial cells of each group.
In decidua, the positive goal of the average optical density values of MMP-2 are respectively 0.1555±0.0079、0.1952±0.0072、0.1958±0.0010、0.1967±0.0069 in the control group, taking mifepristone 12 h group, 24 h group, 48 h group, and they are respectively 0.1555±0.0083、0.2033±0.0059、 0.2076±0.0092、0.2079±0.0088 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The positive goal of the average optical density values of MMP-9 in decidua are respectively 0.1656±0.0056、0.2032±0.0067、0.2051±0.0070、0.2084±0.0078 in the four groups, and they are respectively 0.1617±0.0047、0.2025±0.0074、0.2039±0.0095、0.2099±0.0113 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The positive goal of the average optical density values of TIMP-1 in decidua are respectively 0.1679±0.0127、0.1382±0.0071、0.1402±0.0102、0.1355±0.0077 in the four groups, and they are respectively 0.1548±0.0098、0.1349±0.0106、0.1349±0.0093、0.1273±0.0095 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The proportionality of MMP-9/TIMP-1 in the villus and decidua of the taking mifepristone groups are higher than the control group(P<0.05). The expression of MMP-9/TIMP-1 in the decidua of the four groups are respectively 0.9914±0.0837、1.4493±0.1369、1.4950±0.1352、1.5182±0.0884, and in the villus are respectively 0.9937±0.0554、1.5216±0.1066、1.5138±0.1405、1.5994±0.0842, and among the treated groups there are no statistical significance (P> 0.05).
Conclusion:
1 This study explaine that mifepristone cause the decidual cells protein synthesis blocked, granule cells released relaxin, reticular fiber of matrix dissolved, endomembrane exfoliated, trophoblast cells lost support, blood supply inadequated, triggered abortion.
2 The expression of MMP-2、MMP-9 in decidua and villus of the taking mifepristone groups are all higher than the control group, and the expression of TIMP-1 is lower than the control group, the proportionality of MMP-9/TIMP-1 are higher significantly, all of which explain MMP-2、MMP-9 and TIMP-1 play an important role in the process of medical abortion in early pregnancy,MMP-9 and TIMP-1 for the balance of the maintenance of normal early pregnancy play an important role.
3 This study research the influence of mifepristone on the ultrastructure and the expression of MMP-2、MMP-9、TIMP-1 of human decidua and villus in early pregnancy, reveal that swallowing mifepristone 150 mg at one time 12h or 24h, the inhibitory action of decidua and villus is as similar as 48h, if misoprostol used at this time, the effect of abortion might be comparable in theory with the traditional treatment for the standard programme of 48 h interval, so that the interval of the two drugs for medical abortion might be shortened to 12 h.
方法:将80例妊娠49天以内的妇女,随机分为4组,即对照组、用药12h组、24h组、48h组,每组20例;对照组:采用常规负压吸引术终止妊娠。服药组分别一次性口服米非司酮150mg,12h、24h、48h后行负压吸引术。收集各组所得蜕膜、绒毛组织,分别应用光镜、透射电子显微镜观察各组早孕蜕膜、绒毛组织细胞形态结构的改变;同时应用免疫组织化学S-P法检测MMP-2、MMP-9、TIMP-1在各组早孕蜕膜、绒毛组织中的表达情况。运用SPSS(13.0)软件包进行统计学分析。
结果:
1超微结构结果:
在米非司酮的作用下,蜕膜、绒毛细胞超微结构的改变主要表现在大蜕膜细胞皱缩,粗面内质网(RER)和线粒体(Mi)肿胀,颗粒细胞中高电子密度颗粒减少或消失;合体滋养细胞则表现不同程度的退行性改变,细胞滋养细胞仅出现轻度改变。蜕膜、绒毛细胞超微结构受损程度的比较,各服药组均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
2免疫组化结果:
MMP-2、MMP-9、TIMP-1均为胞浆表达,在蜕膜细胞、腺上皮细胞、腔上皮细胞、细胞滋养细胞、合体滋养细胞的胞浆、胞膜均有强烈的表达。
蜕膜组织中,MMP-2在对照组、口服米非司酮12h组、24h组、48h组的阳性目标平均光密度值分别为0.1555±0.0079、0.1952±0.0072、0.1958±0.0010、0.1967±0.0069 ,在绒毛组织分别为0.1555±0.0083、0.2033±0.0059、0.2076±0.0092、0.2079±0.0088,用药组在蜕膜和绒毛组织的表达均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
MMP-9在四组蜕膜组织的阳性目标平均光密度值分别为0.1656±0.0056、0.2032±0.0067、0.2051±0.0070、0.2084±0.0078 ,在绒毛组织分别为0.1617±0.0047、0.2025±0.0074、0.2039±0.0095、0.2099±0.0113,用药组在蜕膜和绒毛组织的表达均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
TIMP-1在四组蜕膜组织的阳性目标平均光密度值分别为0.1679±0.0127、0.1382±0.0071、0.1402±0.0102、0.1355±0.0077 ,在绒毛组织分别为0.1548±0.0098、0.1349±0.0106、0.1349±0.0093、0.1273±0.0095,用药组在蜕膜和绒毛组织的表达均低于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
蜕膜组织中MMP-9/TIMP-1的比值在四组中分别为0.9914±0.0837、1.4493±0.1369、1.4950±0.1352、1.5182±0.0884 ,在绒毛组织分别为0.9937±0.05534、1.5216±0.1066、1.5138±0.1405、1.5994±0.0842,其比值在用药组蜕膜和绒毛组织中均高于对照组(P<0.05),而各用药组之间均无统计学意义(P>0.05)。
结论:
1说明了米非司酮使大蜕膜细胞蛋白合成受阻,颗粒细胞释放松弛素,基质网状纤维溶解,内膜剥脱,滋养细胞失去支持,血供不足,引发流产。
2 MMP-2、MMP-9在药物流产的蜕膜、绒毛组织中的表达水平显著高于正常妊娠,TIMP-1的表达显著降低,而MMP-9/ TIMP-1的比值显著升高,证实了三者在早期妊娠药物流产发生过程中具有重要作用,MMP-9和TIMP-1的平衡对于正常早期妊娠的维持起重要作用。
3本课题通过比较米非司酮不同作用时间对蜕膜、绒毛组织形态结构及MMPs表达的影响,揭示了顿服150mg米非司酮12h、24h对蜕膜、绒毛组织的抑制作用与48h时相似,此时应用米索前列醇的流产效果在理论上具有可行性,药物流产两种药物的用药间隔最早可以缩短到12h。
Objective: This study of mifepristone from terminating the mechanism in early pregnancy, researching the influence of mifepristone on the ultrastructure and the expression of MMP-2、MMP-9、TIMP-1 of human decidua and villus in early pregnancy by swallowing mifepristone 150 mg at one time respectively affect on 12h、24h、48h, to compare whether different treatment time of mifepristone existing distinction of decidua and villus in early pregnancy, so that a theoretical basis for shortening the time and simplifying the schedule of clinical medical abortion might be provided.
Methods: 80 cases pregnant women within 49 days, were randomly divided into four groups: control group, medication 12 h group, 24 h group, 48 h group, and 20 cases each of .The pregnant women in the control group were terminated of pregnancy by conventional suction. The medication groups swallowed mifepristone 150 mg at one time, 12h、24h and 48h later, suction was operated, and the decidua and villus were taken as soon as possible. Specimens were observed by light microscope and transmission electron microscopy. The expression of MMP-2、MMP-9、TIMP-1 were detected in decidua and villus by immunohistochemistry(SP). All data were analysed by SPSS(13.0) for Windows.
Results:
1 Ultrastructural results
On the role of mifepristone, the variance of decidua and villus on the ultrastructure mainly appearance that large decidual cell shrinkage, rough endoplasm reticulum and mitochondria swell;and electron dense particles in the decidual granular cells decrease or disappear; villous syneytiotrophoblast which have active function show various degrees of degenerative changes,and langhans cell only change slightly. As for the damaged degree of decidua and villus on the ultrastructure, the treated group exceed the control group remarkably (P <0.05), and among the treated groups there are no significant difference (P> 0.05).
2 Immunohistochemical results: All of MMP-2、MMP-9、TIMP-1 express strongly in the cytoplasm of decidual cells、glandular epithelial cells、cavitary epithelial cells、cytotrophoblast and syncytiotrophoblast cells、capillary endothelial cells of each group.
In decidua, the positive goal of the average optical density values of MMP-2 are respectively 0.1555±0.0079、0.1952±0.0072、0.1958±0.0010、0.1967±0.0069 in the control group, taking mifepristone 12 h group, 24 h group, 48 h group, and they are respectively 0.1555±0.0083、0.2033±0.0059、 0.2076±0.0092、0.2079±0.0088 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The positive goal of the average optical density values of MMP-9 in decidua are respectively 0.1656±0.0056、0.2032±0.0067、0.2051±0.0070、0.2084±0.0078 in the four groups, and they are respectively 0.1617±0.0047、0.2025±0.0074、0.2039±0.0095、0.2099±0.0113 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The positive goal of the average optical density values of TIMP-1 in decidua are respectively 0.1679±0.0127、0.1382±0.0071、0.1402±0.0102、0.1355±0.0077 in the four groups, and they are respectively 0.1548±0.0098、0.1349±0.0106、0.1349±0.0093、0.1273±0.0095 in villus , the treated groups is higher than the control group(P<0.05), and among the treated groups there are no statistical significance (P> 0.05).
The proportionality of MMP-9/TIMP-1 in the villus and decidua of the taking mifepristone groups are higher than the control group(P<0.05). The expression of MMP-9/TIMP-1 in the decidua of the four groups are respectively 0.9914±0.0837、1.4493±0.1369、1.4950±0.1352、1.5182±0.0884, and in the villus are respectively 0.9937±0.0554、1.5216±0.1066、1.5138±0.1405、1.5994±0.0842, and among the treated groups there are no statistical significance (P> 0.05).
Conclusion:
1 This study explaine that mifepristone cause the decidual cells protein synthesis blocked, granule cells released relaxin, reticular fiber of matrix dissolved, endomembrane exfoliated, trophoblast cells lost support, blood supply inadequated, triggered abortion.
2 The expression of MMP-2、MMP-9 in decidua and villus of the taking mifepristone groups are all higher than the control group, and the expression of TIMP-1 is lower than the control group, the proportionality of MMP-9/TIMP-1 are higher significantly, all of which explain MMP-2、MMP-9 and TIMP-1 play an important role in the process of medical abortion in early pregnancy,MMP-9 and TIMP-1 for the balance of the maintenance of normal early pregnancy play an important role.
3 This study research the influence of mifepristone on the ultrastructure and the expression of MMP-2、MMP-9、TIMP-1 of human decidua and villus in early pregnancy, reveal that swallowing mifepristone 150 mg at one time 12h or 24h, the inhibitory action of decidua and villus is as similar as 48h, if misoprostol used at this time, the effect of abortion might be comparable in theory with the traditional treatment for the standard programme of 48 h interval, so that the interval of the two drugs for medical abortion might be shortened to 12 h.
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15 Visse R, Nagase H. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry. Circ. Res. 2003, 92: 827~839
16 Martelli M, Campana A, Bischof P. Section of matrix metalloproteinases by human endometrial cells in vitro. J Repord Fertil, 1993, 98: 67
17 Niu R, Okamoto T, Iwse K, et al. Quantitative analysis of matrix metalloproteinases-2, and -9, and their tissue inhibitor-1 and -2 in human placenta throughout gestation.Life Sci, 2000, 66(12): 1127~1137
18 桂文武,丘彦,等. 排卵正常妇女子宫内膜种植窗期基质金属蛋白酶-9 及其抑制物-1 的表达特点及作用. 重庆医科大学学报,2004,29(1):1~6
19 Liu YX, ZY H, Feng Q, et al. Localization and possible role of membrane type emtalloproteinase and tissue inhibitors of metalloproteinases-1 in early stages of placentation. Chinese Science Bulletin, 2000, 45(16): 1484~1488
20 Xu P, Wang YL, Zhu SJ, et al. Expression of matrix metralloproteinase-2, -9, and-14, tissue inhibitors of metralloproteiase-1,land matrix proteins in human placenta during the first trimester. Biol Reprod, 2000, 62(4): 988~994
21 张鑫圣. 米非司酮对人蜕膜及绒毛内基质金属蛋白酶表达影响的初步研究. 华中科技大学学报,2002,31 (5):570~572
22 唐薇,王自能,等. 米非司酮终止妊娠的分子免疫机制. 海南医学,2005,16(3):124~125
23 刘煜,张嘉宁,朱正美,等. 基质金属蛋白酶与生殖的关系. 生殖医学杂志,1997,6(4):249~253
24 Denison FC, Riley SC, et al. The effect of mifepristone administration on leukocyte populations, matrix metalloproteinases and inflammatory mediators in the first trimester cervix. Mol Hum Repro, 2000, 6(6): 541~548
25 Arkar NN. Mifepristone:bioavailability, pharmacokineticsand use-effectiveness. Eur J Obstet Gynecol Reprod Biol 2002 Mar10, 101(2): 113~120
26 Ulmann A, Silvestre L, Chemana L, et al. Medical termina- tion of early pregnancy with mifepristone(RU486) followed by a prostaglandin analogue. Acta Obstet Gynecol Scand, 1992, 71: 278~283
27 Heikinheimo O, Kekkonen R. Dose-response relationship of RU486. Ann Med 1993, 25: 71~76
1 Spitz IM, Bardin CW. Clinical pharmacology of RU486 Anantiprogestin and antiglucocorticoid. Contracption, 1993, 48:403~444
2 乐杰. 妇产科学(第六版). 北京人民卫生出版社,2005: 397~398
3 翁梨驹. 米非司酮配伍 3 种米索前列醇方案用于早孕药 物流产的 WHO 多国研究. 国外医学妇产科学分 册,2004,31(1):59
4 Arkar NN.Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. Eur J Obstet Gynecol Reprod Biol 2002 Mar10, 101(2): 113~120
5 Wing DA, Rahall A, Joins MM, etal. Misoprostol: an effective agent for cervical ripening and labour indaction. AM J Obstet Gynecal, 1995, 172~1811
6 肖艳萍. 合理使用米非司酮. 中国医院用药评价与分析, 2006, 6(1): 55~56
7 Baird DT. Mode of action of medical abortion. JAMWA 2000, 55: 121~126
8 Bygdeman M, Swahn ML. Progesterone receptor blockage-effect on uterine contractility and early pregnancy. Contraception, 1985, 32: 45~51
9 Ulmann A, Silvestre L, Chemana L, et al. Medical termination of early pregnancy with mifepristone(RU486) followed by a prostaglandin analogue. Acta Obstet Gynecol Scand , 1992, 71: 278~283
10 Heikinheimo O, Kekkonen R. Dose-response relationship of RU486. Ann Med 1993, 25: 71~76
11 Schaff EA, Fielding SL, Westhoff C, et al. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: a randomized trial. JAMA 2000, 284: 1948~53
12 陈建明,胡秀芳. 米非司酮配伍米索前列醇快速流产法终止 5～8 周妊娠 114 例临床应用观察. 国际医药卫生 导报医学学术版,131~132
13 Blum J, Hajri S, Chelli H. The medical abortion experiences of married and unmarried women in Tunis, Tunisia. Contraception, 2004, 69(1): 63~69
14 Pymar EC, Creinin MD, Schwartz JiL, Mifepristone foll- owed the same day by vaginal misoprostol for early abortion. Contraception 2001, 64: 87~92
15 Creinin MD, Fox MC, Teal S. A randomized comparison of misoprostol 6 to 8 hours versus 24 hours after mifepristone for abortion. Obstet Gynecol, 2004, 103(1): 851~859
16 Murthy AS, Creinin MD, Harwood B, et al. A pilot study of mifepristone and misoprostol administered at the same time for abortion up to 49 days gestation. Contraception, 2005, 71: 333~336
17 Schreiber CA, Creinin MD, Bryna Harwood, et al. A pilot study of mifepristone and misoprostol administered at the same time for abortion in women with gestation from 50 to 63 days. Contraception 2005, 71: 447~450
18 Creinin MD, Schreiber CA, Bednarek P. Mifepristone and Misoprostol Administered Simultaneously Versus 24 Hours Apartforabortion.Obstetrics&Gynecology, 2007, 109(4): 885~894
2 Schaff EA, Fielding SL, Westhoff C, et al. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: a randomized trial. JAMA 2000, 284: 1948~53
3 Pymar EC, Creinin MD, Schwartz JL. Mifepristone followed the same day by vaginal misoprostol for early abortion. Contraception 2001, 64: 87~92
4 Murthy AS, Creinin MD, Harwood B, et al. A pilot study of mifepristone and misoprostol administered at the same time for abortion up to 49 days gestation. Contraception 2005, 71: 333~336
5 文源源,金明,等. 丙酸睾丸酮、米非司酮对早孕蜕膜、绒毛组织超微结构的影响.临床与实验病理学杂志,1996,12(2):112~114
6 孙红珠,吴尚纯,徐慧颖,等. RU486 药物流产与手术流产的可接受性比较研究. 生殖医学杂志,1995, 4 (3):138~141
7 Spitz IM, Bardin CW. Clinical pharmacology of RU486: Anantiprogestin and antiglucocorticoid. Contracption, 1993, 48: 403~444
8 乐杰. 妇产科学(第六版). 北京人民卫生出版社,2005:397~398
9 翁梨驹. 米非司酮配伍 3 种米索前列醇方案用于早孕药物流产的 WHO 多国研究. 国外医学妇产科学分册,2004,31(1):59
10 桑国卫,邵庆翔,翁梨驹,等. 米非司酮配伍卡前列甲酯栓终止早孕的多中心、临床随机比较研究. 中国计划生育学杂志,1992,2:10~15
11 Downing SJ, Hollingsworth M. Action of uterinecontractio- n: a review. J Reorod Ferti1. 1993, 99: 275~277
12 周先荣,周剑苹,张俊慧,等. 米非司酮对人早孕蜕膜和绒毛超微结构的影响. 生殖与避孕 1995,15(5):342~346
13 郝增平,胡玉泉,洪明理,等. 米非司酮药物流产胎盘绒毛的组织学和染色体变化的研究. 中国计划生育学杂志,1999,5:218~219
14 Armant DR, Raplan HA, lennary WJ. Fibronectin and laminin promote in Vitro attachment and outgrowth of mouse blastocysts. Dev Bid, 1986, 116~119
15 Visse R, Nagase H. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry. Circ. Res. 2003, 92: 827~839
16 Martelli M, Campana A, Bischof P. Section of matrix metalloproteinases by human endometrial cells in vitro. J Repord Fertil, 1993, 98: 67
17 Niu R, Okamoto T, Iwse K, et al. Quantitative analysis of matrix metalloproteinases-2, and -9, and their tissue inhibitor-1 and -2 in human placenta throughout gestation.Life Sci, 2000, 66(12): 1127~1137
18 桂文武,丘彦,等. 排卵正常妇女子宫内膜种植窗期基质金属蛋白酶-9 及其抑制物-1 的表达特点及作用. 重庆医科大学学报,2004,29(1):1~6
19 Liu YX, ZY H, Feng Q, et al. Localization and possible role of membrane type emtalloproteinase and tissue inhibitors of metalloproteinases-1 in early stages of placentation. Chinese Science Bulletin, 2000, 45(16): 1484~1488
20 Xu P, Wang YL, Zhu SJ, et al. Expression of matrix metralloproteinase-2, -9, and-14, tissue inhibitors of metralloproteiase-1,land matrix proteins in human placenta during the first trimester. Biol Reprod, 2000, 62(4): 988~994
21 张鑫圣. 米非司酮对人蜕膜及绒毛内基质金属蛋白酶表达影响的初步研究. 华中科技大学学报,2002,31 (5):570~572
22 唐薇,王自能,等. 米非司酮终止妊娠的分子免疫机制. 海南医学,2005,16(3):124~125
23 刘煜,张嘉宁,朱正美,等. 基质金属蛋白酶与生殖的关系. 生殖医学杂志,1997,6(4):249~253
24 Denison FC, Riley SC, et al. The effect of mifepristone administration on leukocyte populations, matrix metalloproteinases and inflammatory mediators in the first trimester cervix. Mol Hum Repro, 2000, 6(6): 541~548
25 Arkar NN. Mifepristone:bioavailability, pharmacokineticsand use-effectiveness. Eur J Obstet Gynecol Reprod Biol 2002 Mar10, 101(2): 113~120
26 Ulmann A, Silvestre L, Chemana L, et al. Medical termina- tion of early pregnancy with mifepristone(RU486) followed by a prostaglandin analogue. Acta Obstet Gynecol Scand, 1992, 71: 278~283
27 Heikinheimo O, Kekkonen R. Dose-response relationship of RU486. Ann Med 1993, 25: 71~76
1 Spitz IM, Bardin CW. Clinical pharmacology of RU486 Anantiprogestin and antiglucocorticoid. Contracption, 1993, 48:403~444
2 乐杰. 妇产科学(第六版). 北京人民卫生出版社,2005: 397~398
3 翁梨驹. 米非司酮配伍 3 种米索前列醇方案用于早孕药 物流产的 WHO 多国研究. 国外医学妇产科学分 册,2004,31(1):59
4 Arkar NN.Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. Eur J Obstet Gynecol Reprod Biol 2002 Mar10, 101(2): 113~120
5 Wing DA, Rahall A, Joins MM, etal. Misoprostol: an effective agent for cervical ripening and labour indaction. AM J Obstet Gynecal, 1995, 172~1811
6 肖艳萍. 合理使用米非司酮. 中国医院用药评价与分析, 2006, 6(1): 55~56
7 Baird DT. Mode of action of medical abortion. JAMWA 2000, 55: 121~126
8 Bygdeman M, Swahn ML. Progesterone receptor blockage-effect on uterine contractility and early pregnancy. Contraception, 1985, 32: 45~51
9 Ulmann A, Silvestre L, Chemana L, et al. Medical termination of early pregnancy with mifepristone(RU486) followed by a prostaglandin analogue. Acta Obstet Gynecol Scand , 1992, 71: 278~283
10 Heikinheimo O, Kekkonen R. Dose-response relationship of RU486. Ann Med 1993, 25: 71~76
11 Schaff EA, Fielding SL, Westhoff C, et al. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: a randomized trial. JAMA 2000, 284: 1948~53
12 陈建明,胡秀芳. 米非司酮配伍米索前列醇快速流产法终止 5～8 周妊娠 114 例临床应用观察. 国际医药卫生 导报医学学术版,131~132
13 Blum J, Hajri S, Chelli H. The medical abortion experiences of married and unmarried women in Tunis, Tunisia. Contraception, 2004, 69(1): 63~69
14 Pymar EC, Creinin MD, Schwartz JiL, Mifepristone foll- owed the same day by vaginal misoprostol for early abortion. Contraception 2001, 64: 87~92
15 Creinin MD, Fox MC, Teal S. A randomized comparison of misoprostol 6 to 8 hours versus 24 hours after mifepristone for abortion. Obstet Gynecol, 2004, 103(1): 851~859
16 Murthy AS, Creinin MD, Harwood B, et al. A pilot study of mifepristone and misoprostol administered at the same time for abortion up to 49 days gestation. Contraception, 2005, 71: 333~336
17 Schreiber CA, Creinin MD, Bryna Harwood, et al. A pilot study of mifepristone and misoprostol administered at the same time for abortion in women with gestation from 50 to 63 days. Contraception 2005, 71: 447~450
18 Creinin MD, Schreiber CA, Bednarek P. Mifepristone and Misoprostol Administered Simultaneously Versus 24 Hours Apartforabortion.Obstetrics&Gynecology, 2007, 109(4): 885~894