广州地区汉族妇女瘦素受体基因Gln223Arg多态性与子宫内膜异位症及其腹腔液中BFGF_VEGF_MMP2_TIMP2的关系及意义
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摘要
目的:测量子宫内膜异位症(内异症EMs)患者腹腔液中碱性成纤维细胞生长因子(BFGF)、血管内皮生长因子(VEGF)和基质金属蛋白酶2(MMP-2)及其抑制物(TIMP-2)的含量改变,探讨这些物质与内异症的关系;分析内异症患者的瘦素受体(LEPR)Gln223Arg等位基因多态性,并探讨这种多态性与内异症患者腹腔微环境变化的相关性,进一步探讨子宫内膜异位症的发病机制。
方法:采用ELISA方法检测约30例内异症妇女和30例非内异症对照组妇女腹腔液中MMP-2、TIMP-2、BFGF、VEGF的含量。采用PCR-RFLP法测定两组妇女瘦素受体基因的Gln223Arg等位基因型。
结果:ELISA方法测定提示EMs组腹腔液中VEGF、MMP-2含量高于对照组,TIMP-2含量低于正常对照(P<0.05),差异有统计学意义。两组BFGF含量无明显差异(P>0.05)。两组妇女瘦素受体基因的Gln223Arg等位基因型、等位基因频率分布无显著性差异(P>0.05)。
结论:EMs患者腹腔液中血管生长因子VEGF增高,促进基质降解的基质金属蛋白酶MMP-2增高,而其抑制物TIMP-2降低,这些腹腔微环境的改变有利于内异症的发生和发展。广州地区汉族妇女人群中的LEPR编码基因中存在Gln223Arg的多态性,尚未发现这个多态性在EMs患者中有差异分布。
Objective: To measure the levels of matrix metalloproteinases-2 (MMP-2), tissue inhibitor of metalloprotienases (TIMP-2), Vascular endothelial growth factor(VEGF), basic fibroblast growth factor(bFGF) in peritoneal fluid (PF) from patients with endometriosis so as to investigate the roles these cytokines play in the occurence of endometriosis. To study whether the Gln223Arg polymorphism in the leptin receptor (LEPR) gene is associated with endometriosis and their microenvironment changes of abdominal cavity in order to explore the pathogenesis of endometriosis.
Methods: Peripheral blood and peritoneal fluid specimens were obtained from 30 cases of endometriosis and 30 cases of non-endometriosis controls, concentrations of BFGF、VEGF、MMP-2、TIMP-2 were examined by enzyme linked immunosorbent assays(ELISA). The Gln223Arg polymorphism was studied by restriction fragment length polymorphism(RFLP)-PCR.
Results: The MMP-2 and VEGF concentrations in peritoneal fluids of endometriosis groups were significantly higher than that in controls, while the TIMP-2 concentration was significantly lower than which in controls (P<0.05).The BFGF concentration in peritoneal fluids had no significant difference between these two groups(P>0.05). There were no significant differences on the distributions of genotype and gene frequency of The LEPR Gln223Arg gene between the two groups (P>0.05).
Conclusion: The increase of MMP-2、VEGF and the decrease of TIMP-2 in the peritoneal fluid play roles to the occurrence and development of endometriosis. There exists Gln223Arg Polymoprhism of LEPR gene in PoPulation of Han nationality in Guangzhou area, but no difference was found on the distribution of the Polymoprhism in the endometriosis patients.
方法:采用ELISA方法检测约30例内异症妇女和30例非内异症对照组妇女腹腔液中MMP-2、TIMP-2、BFGF、VEGF的含量。采用PCR-RFLP法测定两组妇女瘦素受体基因的Gln223Arg等位基因型。
结果:ELISA方法测定提示EMs组腹腔液中VEGF、MMP-2含量高于对照组,TIMP-2含量低于正常对照(P<0.05),差异有统计学意义。两组BFGF含量无明显差异(P>0.05)。两组妇女瘦素受体基因的Gln223Arg等位基因型、等位基因频率分布无显著性差异(P>0.05)。
结论:EMs患者腹腔液中血管生长因子VEGF增高,促进基质降解的基质金属蛋白酶MMP-2增高,而其抑制物TIMP-2降低,这些腹腔微环境的改变有利于内异症的发生和发展。广州地区汉族妇女人群中的LEPR编码基因中存在Gln223Arg的多态性,尚未发现这个多态性在EMs患者中有差异分布。
Objective: To measure the levels of matrix metalloproteinases-2 (MMP-2), tissue inhibitor of metalloprotienases (TIMP-2), Vascular endothelial growth factor(VEGF), basic fibroblast growth factor(bFGF) in peritoneal fluid (PF) from patients with endometriosis so as to investigate the roles these cytokines play in the occurence of endometriosis. To study whether the Gln223Arg polymorphism in the leptin receptor (LEPR) gene is associated with endometriosis and their microenvironment changes of abdominal cavity in order to explore the pathogenesis of endometriosis.
Methods: Peripheral blood and peritoneal fluid specimens were obtained from 30 cases of endometriosis and 30 cases of non-endometriosis controls, concentrations of BFGF、VEGF、MMP-2、TIMP-2 were examined by enzyme linked immunosorbent assays(ELISA). The Gln223Arg polymorphism was studied by restriction fragment length polymorphism(RFLP)-PCR.
Results: The MMP-2 and VEGF concentrations in peritoneal fluids of endometriosis groups were significantly higher than that in controls, while the TIMP-2 concentration was significantly lower than which in controls (P<0.05).The BFGF concentration in peritoneal fluids had no significant difference between these two groups(P>0.05). There were no significant differences on the distributions of genotype and gene frequency of The LEPR Gln223Arg gene between the two groups (P>0.05).
Conclusion: The increase of MMP-2、VEGF and the decrease of TIMP-2 in the peritoneal fluid play roles to the occurrence and development of endometriosis. There exists Gln223Arg Polymoprhism of LEPR gene in PoPulation of Han nationality in Guangzhou area, but no difference was found on the distribution of the Polymoprhism in the endometriosis patients.
引文
[1]石一复.子宫内膜异位症,第一版.上海:上海科学技术出版,2002;8-10.
[2] Sillem M,priftis,Koch A,et al.Regulation of matrix metalloproteinases and their inhibitor in uterine endometrial cells of patients with and without endomtriosis. Eur J Obstet Gynecol [J].Reprod Biol,2001;95(2):167-174.
[3] Xavier P, Beires J. Endometriosis: clinical aspects: Sub and endometrial blood flow in patients with endometriosis[J]. Hum Reprod,2004;19:1168.
[4] Rajesh V, Terrance R, Janesh K G et al.Endometriosis and the neo-plastic process.Reproduction, 2004;127: 293-304.
[5] PePPer MS. Manipulating angiogenesis. From basic science to the bedside. Arterioscler Thromb Vase Biol,1997;17:605-19
[6] Kitawaki J, Koshiba H, Ishihara H,et al. Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle [J]. Clin Endocrinol Metab,2000,85:1946-1950.
[7] Considint RV,Considine EL,Williams CJ,et al.The hypithalamic leptin receptor in humans:identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations.Diabetes.1996;45:992-994.
[8] Matarese G,Alviggi C , Sanna V , et al. Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis[J].Clin Endocrinol Metab,2000,85:2483-2487.
[9] Castellucci M, Matteis RD, Meisser R, et al. Leptin modulates extracellular matrix molecules and metalloproteinase: possible implications for trophoblast invasion.Mol HumReprod, 2000, 6(10) : 951-958.
[10] Suganami E, Takagi H, Ohashi H, et al. Leptin stimulates is chemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes, 2004, 53(9): 2443-2448.
[11] Rivilis I, MilkewiczM, Boyd P et al.Differential involvement of MMP- 2 and VEGF during muscle stretch versus shear stress induced angiogenesis.Am J Physiol Heart Circ Physio.2002,283(4): 1430-1438.
[12] Chung HW,Lee JY,Moon HS,et al. Matrix metalloPorteniase-2,membranous type 1 martix metalloproteinase,and tissue ihnibtior of metalloprotneinase-2 expression in ectopic and eutopic endmoertimu.Fertil steril 2002; 78 (4):787-795.
[13] Vladimir Bourlev,Anders Larsson,Matts Olovsson.Elevated levels of fibroblast growth factor-2 in serum from women with endometriosis. American Journal of Obstetrics and Gynecology 2006;194(3):755-759.
[14] Huang JC,Papasakelariou C,Dawood MY. Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endo- metriosis.Fertil Steril,1996,65(5):931-934.
[15] Stefansson H,Geirsson RT,Steinthorsdottir V,et al.Genetic factors contribute to the risk of developing endometriosis.Human Reproduction.2002,17:555-559.
[16]陈祚,郭东双,李莹,等.瘦素受体基因多态性Gln223Arg与肥胖关系的研究.中华流行病学杂志.2006,27(12):1078-1081.
[17] WuM, Chuang P, Chen H, et al.Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up - regulation. Mol Hum Reprod, 2002, 8(4): 456 -464.
[18]矫杰,孟迅吾,邢小平,等.北京地区汉族妇女瘦素受体基因Gln223Arg多态性和骨密度的关系.中华内科杂志.2004, 43(4):276-279.
[19] Matsuoka N , Ogawa Y, Hosoda K, et al. Human leptin receptor gene in obese Japanese subjects:evidence against either obesity causing mutations or association of sequence variants with obesity. Diabetologia. 1997, 40: 1204-1210.
[20] Koh JM , Kim DJ , Hong JS , et al. Estrogen receptor alpha gene polymorphisms PvuII and XbaI influence association between leptin receptor gene polymorphism ( Gln223 Arg ) and bone mineral density in young men. Eur J Endocrinol. 2002,147 :777-783.
[21] Heo M , Leibel RL, Boyer BB, et al. Pooling analysis of genetic data : the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics, 2001, 159: 1163-1178.
[1] O Down MJ ,Philipp E E. The History of Obstetrics and Gynecology [M] . New York : The Parthenon Publishing Group ,2000 :523.
[2] Sampson J . Peritomeal endometriosis is due to t he menstrual dissemination of endometrial tissue into the peritoneal cavitity[J] .Am J Obstet Gynecol , 1927 ,14 (4) :422–469.
[3] Halme J , Hammond M G, Hulka J F , et al . Ret rograde menstruation in healthy women and in patient with endometriosis [J] . Obst st Gynecol , 1984 ,64 (2) :151–154.
[4]郎景和.子宫内膜异位症研究的任务与展望(之一).中华妇产科杂志.2006,41(5):289-290.
[5] Tan XJ, Lang JH, Liu DY, et al. Exp ression of vascular endothelial growth factor and thrombospondin-1 mRNA in patients with endometriosis. Fertil Steril, 2002, 27: 148-153.
[6] Sillem M,priftis,Koch A,et al.Regulation of matrix metalloproteinases and their inhibitor in uterine endometrial cells of patients with and without endomtriosis. Eur J Obstet Gynecol [J].Reprod Biol,2001;95(2):167-174.
[7] Matarese G,Alviggi C , Sanna V , et al. Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis[J].Clin Endocrinol Metab,2000,85:2483-2487.
[8] Brew K,Dinakarpandian D , Nagase H. Tissue inhibitors of metalloproteinases : evolution , structure and function [ J ] . Biochim Biophys Acta .2000 , 1477 (1-2) :267 - 283.
[9] Gilabert-Estelles J,Estelles A,Gilabert J.Expression of several components of the plasminogen activator and matrix metalloproteinase systems in endometriosis.Ann N Y Acad Sci.2002 Mar,955:147-56.
[10] Goffin F,Munaut C,Frankenne F, et al. Expression pattern of metalloproteinases and tissue inhibitors of matrix metalloproteinases in cycling human endometrium. Biol Reprod, 2003, 69(3):976-984.
[11] Curry Jr TE,Osteen KG.Cyclic changes in the matrix metalloproteinase system in the ovary and uterus.Biol Reprod,2001,64:1285-1296.
[12] Ueda M, Yamashita Y,Takehara M, et al . Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol Endocrinol , 2002 ,16(5):391-402.
[13] Egeblad M,Werb Z. New functions for the matrix metalloproteinases in cancer progression [J]. Nature Rev Cancer, 2002, 2(3): 161-174.
[14] Chung HW , Lee JY, Moon HS, et al. Matrix metallop roteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil steril, 2002; 78 (4) : 787-795
[15] Ria R ,Loverro G,Vacca A ,et al . Angiogenesis Extent and Expression of Matrix Metalloproteinase-2 and -9 Agree with Progression of Ovarian Endometriomas [J] . Eur J Clin Invest ,2002 ,32 (3) :199-206
[16]邱晓红.基质金属蛋白酶MMP-2 MMP-9及抑制因子TIMP-1 TIMP-2在子宫内膜异位症中的表达及意义[J] .中国实用妇科与产科杂志.2004 ,20 (3) :158 - 160.
[17]邱芳,高雪梅,罗国林,等.基质金属蛋白酶及其抑制物与子宫内膜异位症关系的研究.四川大学学报(医学版).2006,37(1):118-122.
[18] Huang HF, Hong LH, Tan Y, et al. Matrix metallop roteinase 2 is associated with changes in steroid hormones in the sera and peritoneal fluid of patients with endometriosis[J]. Fertil Steril,2004, 81 (5) : 1235-1239
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[25] Vladimir Bourlev,Anders Larsson,Matts Olovsson. Elevated levels of fibroblast growth factor-2 in serum from women with endometriosis. American Journal of Obstetrics and Gynecology 2006;194(3):755-759.
[26] Oiveira HB, Javier JD, Jarade EF, et al. VEGF is involved in bFGF induced murine corneal neovascularization [J] . ARVO Meeting Abstracts,2003, 44(5): 830-830.
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[29] Mstsuoka N,Ogawa Y,Hosoda K,et al.Human leptin receptor gene in obese Japanese subject: evidence against either obesity causing mutations or association of sequence variants with obesity [J]. Diabetologia,1997,40(10):1204-10.
[30] Kitawaki J, Koshiba H, Ishihara H, et al. Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle. J Clin Endocrinol Metab, 2000, 85(5): 1946-1950.
[31] WuM, Chuang P, Chen H, et al.Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up - regulation. Mol Hum Reprod, 2002, 8(4): 456 -464.
[32] Li L, Mamputu JC,Wiernsperger N, et al. Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2expression induced by leptin: inhibitory effect of metformin. Diabetes,2005,54(7) : 2227-2234.
[33] Castellucci M, Matteis RD, Meisser R, et al. Leptin modulates extracellular matrix molecules and metalloproteinase: possible implications for trophoblast invasion.Mol HumReprod, 2000, 6(10) : 951-958.
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[35] Cao R, Brakenhiclm E, Wahlestedt C, et al. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci, 2001, 98(11): 6390-6395.
[36] Suganami E, Takagi H, Ohashi H, et al. Leptin stimulates is chemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes, 2004, 53(9): 2443-2448.
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[40] Guo SW, Wu Y, Strawn E, et al. Genomic alterations on the endometriosis may be a proximate cause for endometriosis. Eur J Obstet Gynecol Reprod Biol,2004,116(1):89-99.
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[42] Treloar SA, Wick J, Nyholt DR, et al. Genomewide linkage study in 1176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26 [ J ]. Am J Hum Genet,2005, 77: 365 - 376.
[2] Sillem M,priftis,Koch A,et al.Regulation of matrix metalloproteinases and their inhibitor in uterine endometrial cells of patients with and without endomtriosis. Eur J Obstet Gynecol [J].Reprod Biol,2001;95(2):167-174.
[3] Xavier P, Beires J. Endometriosis: clinical aspects: Sub and endometrial blood flow in patients with endometriosis[J]. Hum Reprod,2004;19:1168.
[4] Rajesh V, Terrance R, Janesh K G et al.Endometriosis and the neo-plastic process.Reproduction, 2004;127: 293-304.
[5] PePPer MS. Manipulating angiogenesis. From basic science to the bedside. Arterioscler Thromb Vase Biol,1997;17:605-19
[6] Kitawaki J, Koshiba H, Ishihara H,et al. Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle [J]. Clin Endocrinol Metab,2000,85:1946-1950.
[7] Considint RV,Considine EL,Williams CJ,et al.The hypithalamic leptin receptor in humans:identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations.Diabetes.1996;45:992-994.
[8] Matarese G,Alviggi C , Sanna V , et al. Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis[J].Clin Endocrinol Metab,2000,85:2483-2487.
[9] Castellucci M, Matteis RD, Meisser R, et al. Leptin modulates extracellular matrix molecules and metalloproteinase: possible implications for trophoblast invasion.Mol HumReprod, 2000, 6(10) : 951-958.
[10] Suganami E, Takagi H, Ohashi H, et al. Leptin stimulates is chemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes, 2004, 53(9): 2443-2448.
[11] Rivilis I, MilkewiczM, Boyd P et al.Differential involvement of MMP- 2 and VEGF during muscle stretch versus shear stress induced angiogenesis.Am J Physiol Heart Circ Physio.2002,283(4): 1430-1438.
[12] Chung HW,Lee JY,Moon HS,et al. Matrix metalloPorteniase-2,membranous type 1 martix metalloproteinase,and tissue ihnibtior of metalloprotneinase-2 expression in ectopic and eutopic endmoertimu.Fertil steril 2002; 78 (4):787-795.
[13] Vladimir Bourlev,Anders Larsson,Matts Olovsson.Elevated levels of fibroblast growth factor-2 in serum from women with endometriosis. American Journal of Obstetrics and Gynecology 2006;194(3):755-759.
[14] Huang JC,Papasakelariou C,Dawood MY. Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endo- metriosis.Fertil Steril,1996,65(5):931-934.
[15] Stefansson H,Geirsson RT,Steinthorsdottir V,et al.Genetic factors contribute to the risk of developing endometriosis.Human Reproduction.2002,17:555-559.
[16]陈祚,郭东双,李莹,等.瘦素受体基因多态性Gln223Arg与肥胖关系的研究.中华流行病学杂志.2006,27(12):1078-1081.
[17] WuM, Chuang P, Chen H, et al.Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up - regulation. Mol Hum Reprod, 2002, 8(4): 456 -464.
[18]矫杰,孟迅吾,邢小平,等.北京地区汉族妇女瘦素受体基因Gln223Arg多态性和骨密度的关系.中华内科杂志.2004, 43(4):276-279.
[19] Matsuoka N , Ogawa Y, Hosoda K, et al. Human leptin receptor gene in obese Japanese subjects:evidence against either obesity causing mutations or association of sequence variants with obesity. Diabetologia. 1997, 40: 1204-1210.
[20] Koh JM , Kim DJ , Hong JS , et al. Estrogen receptor alpha gene polymorphisms PvuII and XbaI influence association between leptin receptor gene polymorphism ( Gln223 Arg ) and bone mineral density in young men. Eur J Endocrinol. 2002,147 :777-783.
[21] Heo M , Leibel RL, Boyer BB, et al. Pooling analysis of genetic data : the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics, 2001, 159: 1163-1178.
[1] O Down MJ ,Philipp E E. The History of Obstetrics and Gynecology [M] . New York : The Parthenon Publishing Group ,2000 :523.
[2] Sampson J . Peritomeal endometriosis is due to t he menstrual dissemination of endometrial tissue into the peritoneal cavitity[J] .Am J Obstet Gynecol , 1927 ,14 (4) :422–469.
[3] Halme J , Hammond M G, Hulka J F , et al . Ret rograde menstruation in healthy women and in patient with endometriosis [J] . Obst st Gynecol , 1984 ,64 (2) :151–154.
[4]郎景和.子宫内膜异位症研究的任务与展望(之一).中华妇产科杂志.2006,41(5):289-290.
[5] Tan XJ, Lang JH, Liu DY, et al. Exp ression of vascular endothelial growth factor and thrombospondin-1 mRNA in patients with endometriosis. Fertil Steril, 2002, 27: 148-153.
[6] Sillem M,priftis,Koch A,et al.Regulation of matrix metalloproteinases and their inhibitor in uterine endometrial cells of patients with and without endomtriosis. Eur J Obstet Gynecol [J].Reprod Biol,2001;95(2):167-174.
[7] Matarese G,Alviggi C , Sanna V , et al. Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis[J].Clin Endocrinol Metab,2000,85:2483-2487.
[8] Brew K,Dinakarpandian D , Nagase H. Tissue inhibitors of metalloproteinases : evolution , structure and function [ J ] . Biochim Biophys Acta .2000 , 1477 (1-2) :267 - 283.
[9] Gilabert-Estelles J,Estelles A,Gilabert J.Expression of several components of the plasminogen activator and matrix metalloproteinase systems in endometriosis.Ann N Y Acad Sci.2002 Mar,955:147-56.
[10] Goffin F,Munaut C,Frankenne F, et al. Expression pattern of metalloproteinases and tissue inhibitors of matrix metalloproteinases in cycling human endometrium. Biol Reprod, 2003, 69(3):976-984.
[11] Curry Jr TE,Osteen KG.Cyclic changes in the matrix metalloproteinase system in the ovary and uterus.Biol Reprod,2001,64:1285-1296.
[12] Ueda M, Yamashita Y,Takehara M, et al . Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol Endocrinol , 2002 ,16(5):391-402.
[13] Egeblad M,Werb Z. New functions for the matrix metalloproteinases in cancer progression [J]. Nature Rev Cancer, 2002, 2(3): 161-174.
[14] Chung HW , Lee JY, Moon HS, et al. Matrix metallop roteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil steril, 2002; 78 (4) : 787-795
[15] Ria R ,Loverro G,Vacca A ,et al . Angiogenesis Extent and Expression of Matrix Metalloproteinase-2 and -9 Agree with Progression of Ovarian Endometriomas [J] . Eur J Clin Invest ,2002 ,32 (3) :199-206
[16]邱晓红.基质金属蛋白酶MMP-2 MMP-9及抑制因子TIMP-1 TIMP-2在子宫内膜异位症中的表达及意义[J] .中国实用妇科与产科杂志.2004 ,20 (3) :158 - 160.
[17]邱芳,高雪梅,罗国林,等.基质金属蛋白酶及其抑制物与子宫内膜异位症关系的研究.四川大学学报(医学版).2006,37(1):118-122.
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