多囊卵巢综合征合并胰岛素抵抗患者子宫内膜胰岛素受体底物1、2蛋白表达及酪氨酸磷酸化的研究
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摘要
目的:近年来通过对多囊卵巢综合征(PCOS)患者胰岛素作用的经典组织—脂肪组织和生殖功能单位—卵巢组织的研究表明,胰岛素受体底物(Insulin receptor substrate IRS)-1和IRS-2作为胰岛素受体的主要的船坞蛋白,其蛋白表达和酪氨酸磷酸化异常是引起PCOS胰岛素抵抗(IR)的主要原因。但对PCOS患者另一个重要的生殖功能单位—子宫内膜是否也存在胰岛素抵抗目前尚未见报道。
为了进一步探讨胰岛素抵抗在PCOS发病中的作用,本文通过对PCOS患者子宫内膜IRS-1和IRS-2的蛋白表达及酪氨酸磷酸化程度进行了研究,旨在明确PCOS患者子宫内膜是否存在胰岛素抵抗,探讨PCOS患者子宫内膜胰岛素抵抗的分子机制。讨论子宫内膜胰岛素抵抗对PCOS患者不孕、高流产率及子宫内膜癌的影响。
方法:选择2005年9月至2006年6月在华中科技大学同济医学院附属协和医院妇产科诊断为PCOS合并IR患者15例,平均年龄29±4岁。另外选择月经周期规则,血清性激素、空腹血糖及胰岛素检查正常妇女10例作为对照组,平均年龄28±3岁,与PCOS合并IR组年龄相匹配。两组均除外肾上腺、甲状腺等疾患,3个月内未服用过激素类药物,无心、肝、肾疾病史。所有受试者均于月经第一天,行诊断性刮宫术,术中留取子宫内膜组织,37℃生理盐水冲洗血液。分两组,一组用4%的甲醛固定,石蜡包埋。切片厚度为3-4um,每例均做三张切片,用于免疫组织化学染色。另一组置于-80℃低温箱保存,用于免疫印记及免疫沉淀法。采用免疫组化方法和蛋白印记(western blot)、免疫沉淀技术检测两组子宫内膜IRS-1和IRS-2的蛋白表达及酪氨酸磷酸化程度。
结果:⑴免疫组化结果显示,IRS-1、IRS-2主要表达在子宫内膜的腺上皮的胞浆中,呈黄色颗粒状。PCOS合并IR组和对照组IRS-1、IRS-2蛋白表达的灰度值分别为121.94±16,169.35±13和55.35±0.98,111.65±8.02,两组比较差异有显著性(P<0.01,P<0.05);PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显低于对照组,其灰度值分别为141.98±22.5,102±9.78,两组比较差异有显著性(P<0.05)。⑵蛋白印记分析结果显示,PCOS合并IR组和对照组IRS-1、IRS-2蛋白表达分别为1.4±0.62,6.1±0.23和4.2±0.38,9.1±8.4,两组比较差异有显著性(P<0.01,P<0.05)。⑶免疫沉淀结果显示,PCOS合并IR组和对照组IRS-1、IRS-2蛋白酪氨酸磷酸化程度分别为1.6±0.64,1.4±0.42和1.5±0.23,3.4±0.47,两组比较差异有显著性(P<0.01,P<0.05)。
结论:⑴免疫组化结果显示,IRS-1、IRS-2主要表达在子宫内膜的腺上皮的胞浆中,呈黄色颗粒状。PCOS合并IR组IRS-1、IRS-2蛋白表达的灰度值高于对照组,表明PCOS合并IR患者子宫内膜IRS-1、IRS-2蛋白的表达明显降低。PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显低于对照组,表明PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显减弱。⑵蛋白印记分析结果显示,PCOS合并IR组IRS-1、IRS-2蛋白表达明显低于对照组。⑶免疫沉淀结果显示,PCOS合并IR组IRS-1、IRS-2蛋白酪氨酸磷酸化程度低于对照组。⑷PCOS合并IR患者子宫内膜IRS-1、IRS-2蛋白的表达及酪氨酸磷酸化程度降低导致受体后信号转导障碍,可能是子宫内膜发生胰岛素抵抗(IR)机制之一。
OBJECTIVE: To explore molecular mechanisms of insulin resistance of polycystic ovary sndrome (PCOS) by determining the tyrosine phosphorylation and protein expression of insulin receptor substrate1 and 2 (IRS-1, IRS-2) in endometrium from patients with PCOS
METHODS: The endometrium samples from patients with PCOS with insulin resistance﹝n=15﹞controls﹝n=10﹞were collected. The expression of insulin receptor substrate-1and 2 and tyrosine phosphokinase were analyzed by immunohistochemistry, western blot and immunoprecipitation. The gray degree of sections was determined by image analysis system. The ray density was scan by gelatin image analysis system.
RESULT:﹝1﹞The gray degree of IRS-1/2 expression﹝121.94±16,169.35±13﹞in endometrium in PCOS with insulin resistance were significantly higher than than those in controls﹝55.35±0.98,111.65±8.02﹞﹝P<0.01,P<0.05﹞, indicating that the expression of IRS-1and 2 were decreased in endometrium in PCOS with insulin resistance .The gray degree of tyrosine phosphorylation of IRS﹝141.98±22.5﹞in endometrium in PCOS with insulin resistance were significantly higher than those in controls﹝102.72±9.78﹞﹝P<0.05﹞, indicating that the expression of tyrosine phosphorylation was also decreased in endometrium in PCOS with insulin resistance.﹝2﹞The protein expression of IRS-1 and 2 in PCOS with insulin resistance(4.2±0.38 and 1.4±0.62)were significantly lower than those in control group(9.1±8.4 and 6.1±0.23),(P<0.01,P<0.01﹞.﹝3﹞tyrosine phosphorylation of IRS-1 and IRS-2 in PCOS group with insulin resistance( 1.6±0.64 and 1.5±0.23)were significantly lower than those in control group(1.4±0.42 and 3.4±0.47),(P<0.05,P<0.01﹞
CONCLUSION: The signal transduction malfunction because of protein expression and tyrosine phosphorylation of IRS in endometrium may be one of mechanism leading to insulin resistance in endometrium from patients with PCOS.
为了进一步探讨胰岛素抵抗在PCOS发病中的作用,本文通过对PCOS患者子宫内膜IRS-1和IRS-2的蛋白表达及酪氨酸磷酸化程度进行了研究,旨在明确PCOS患者子宫内膜是否存在胰岛素抵抗,探讨PCOS患者子宫内膜胰岛素抵抗的分子机制。讨论子宫内膜胰岛素抵抗对PCOS患者不孕、高流产率及子宫内膜癌的影响。
方法:选择2005年9月至2006年6月在华中科技大学同济医学院附属协和医院妇产科诊断为PCOS合并IR患者15例,平均年龄29±4岁。另外选择月经周期规则,血清性激素、空腹血糖及胰岛素检查正常妇女10例作为对照组,平均年龄28±3岁,与PCOS合并IR组年龄相匹配。两组均除外肾上腺、甲状腺等疾患,3个月内未服用过激素类药物,无心、肝、肾疾病史。所有受试者均于月经第一天,行诊断性刮宫术,术中留取子宫内膜组织,37℃生理盐水冲洗血液。分两组,一组用4%的甲醛固定,石蜡包埋。切片厚度为3-4um,每例均做三张切片,用于免疫组织化学染色。另一组置于-80℃低温箱保存,用于免疫印记及免疫沉淀法。采用免疫组化方法和蛋白印记(western blot)、免疫沉淀技术检测两组子宫内膜IRS-1和IRS-2的蛋白表达及酪氨酸磷酸化程度。
结果:⑴免疫组化结果显示,IRS-1、IRS-2主要表达在子宫内膜的腺上皮的胞浆中,呈黄色颗粒状。PCOS合并IR组和对照组IRS-1、IRS-2蛋白表达的灰度值分别为121.94±16,169.35±13和55.35±0.98,111.65±8.02,两组比较差异有显著性(P<0.01,P<0.05);PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显低于对照组,其灰度值分别为141.98±22.5,102±9.78,两组比较差异有显著性(P<0.05)。⑵蛋白印记分析结果显示,PCOS合并IR组和对照组IRS-1、IRS-2蛋白表达分别为1.4±0.62,6.1±0.23和4.2±0.38,9.1±8.4,两组比较差异有显著性(P<0.01,P<0.05)。⑶免疫沉淀结果显示,PCOS合并IR组和对照组IRS-1、IRS-2蛋白酪氨酸磷酸化程度分别为1.6±0.64,1.4±0.42和1.5±0.23,3.4±0.47,两组比较差异有显著性(P<0.01,P<0.05)。
结论:⑴免疫组化结果显示,IRS-1、IRS-2主要表达在子宫内膜的腺上皮的胞浆中,呈黄色颗粒状。PCOS合并IR组IRS-1、IRS-2蛋白表达的灰度值高于对照组,表明PCOS合并IR患者子宫内膜IRS-1、IRS-2蛋白的表达明显降低。PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显低于对照组,表明PCOS合并IR组子宫内膜酪氨酸磷酸化程度明显减弱。⑵蛋白印记分析结果显示,PCOS合并IR组IRS-1、IRS-2蛋白表达明显低于对照组。⑶免疫沉淀结果显示,PCOS合并IR组IRS-1、IRS-2蛋白酪氨酸磷酸化程度低于对照组。⑷PCOS合并IR患者子宫内膜IRS-1、IRS-2蛋白的表达及酪氨酸磷酸化程度降低导致受体后信号转导障碍,可能是子宫内膜发生胰岛素抵抗(IR)机制之一。
OBJECTIVE: To explore molecular mechanisms of insulin resistance of polycystic ovary sndrome (PCOS) by determining the tyrosine phosphorylation and protein expression of insulin receptor substrate1 and 2 (IRS-1, IRS-2) in endometrium from patients with PCOS
METHODS: The endometrium samples from patients with PCOS with insulin resistance﹝n=15﹞controls﹝n=10﹞were collected. The expression of insulin receptor substrate-1and 2 and tyrosine phosphokinase were analyzed by immunohistochemistry, western blot and immunoprecipitation. The gray degree of sections was determined by image analysis system. The ray density was scan by gelatin image analysis system.
RESULT:﹝1﹞The gray degree of IRS-1/2 expression﹝121.94±16,169.35±13﹞in endometrium in PCOS with insulin resistance were significantly higher than than those in controls﹝55.35±0.98,111.65±8.02﹞﹝P<0.01,P<0.05﹞, indicating that the expression of IRS-1and 2 were decreased in endometrium in PCOS with insulin resistance .The gray degree of tyrosine phosphorylation of IRS﹝141.98±22.5﹞in endometrium in PCOS with insulin resistance were significantly higher than those in controls﹝102.72±9.78﹞﹝P<0.05﹞, indicating that the expression of tyrosine phosphorylation was also decreased in endometrium in PCOS with insulin resistance.﹝2﹞The protein expression of IRS-1 and 2 in PCOS with insulin resistance(4.2±0.38 and 1.4±0.62)were significantly lower than those in control group(9.1±8.4 and 6.1±0.23),(P<0.01,P<0.01﹞.﹝3﹞tyrosine phosphorylation of IRS-1 and IRS-2 in PCOS group with insulin resistance( 1.6±0.64 and 1.5±0.23)were significantly lower than those in control group(1.4±0.42 and 3.4±0.47),(P<0.05,P<0.01﹞
CONCLUSION: The signal transduction malfunction because of protein expression and tyrosine phosphorylation of IRS in endometrium may be one of mechanism leading to insulin resistance in endometrium from patients with PCOS.
引文
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27.叶明珠林影,子宫内膜胰岛素样生长因子系统的基因表达国外医学妇产科学分册2003.30(5):284-286.
1. Zhang EH, Liang XY, DU J, et al.Features of morphometry of ultrasound and endometrial histology in the anovulatory polycystic ovary syndrome women. Zhonghua Fu Chan Ke Za Zhi. 2006 Jun;41(6):380-3
2. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006 Jun;20(2):235-44
3. Villavicencio A, Bacallao K, Avellaira C, et al. Androgen and estrogen receptors and co-regulators levels in endometria from patients with polycystic ovarian syndrome with and without endometrial hyperplasia. Gynecol Oncol. 2006 May 2;
4. Tingthanatikul Y, Choktanasiri W, Rochanawutanon M, et al .Prevalence and clinical predictors of endometrial hyperplasiain anovulatory women presenting with amenorrhea. Gynecol Endocrinol. 2006 Feb;22(2):101-5
5. Quezada S, Avellaira C, Johnson MC, et al. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril. 2006 Apr;85(4):1017-26. Epub 2006 Mar 9
6. IaIatrakis G, Tsionis C, Adonakis G,. et al. Polycystic ovarian syndrome, insulin resistance and thickness of the endometrium Eur J Obstet Gynecol Reprod Biol. 2006 Aug;127(2):218-21. Epub 2006 Mar 6
7. Marikinti K. Unusual presentation of a woman with polycystic ovaries and complex endometrial pathology. Reprod Biomed Online. 2006 Jan;12(1):39-42.
8. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents Endokrynol Pol. 2005 May-Jun;56(3):308-13
9. Potdar N, Konje JC. The endocrinological basis of recurrent miscarriages Curr Opin Obstet Gynecol. 2005 Aug;17(4):424-8.
10. Mozzanega B, Mioni R, Granzotto M, et al. Obesity reduces the expression of GLUT4 in the endometrium of normoinsulinemic women affected by the polycystic ovary syndrome. Ann N Y Acad Sci. 2004 Dec;1034:364
11. Mioni R, Chiarelli S, Xamin N, et al.Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004 Aug;89(8):4089-96
12. Wang YZ, Qiao J, Liu LL, et al.Expression of leptin and long form of leptin receptors messenger ribonucleic acid and protein in endometrium of patients with polycystic ovary syndrome Zhonghua Fu Chan Ke Za Zhi. 2003 Jul;38(7):398-401.
13. Gregory CW, Wilson EM, Apparao KB, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium.J Clin Endocrinol Metab. 2002 Jun;87(6):2960-6
14. Druckmann R, Rohr UD. IGF-1 in gynaecology and obstetrics: update 2002Maturitas. 2002 Apr 15;41 Suppl 1:S65-83.
15. Apparao KB, Lovely LP, Gui Y, et al. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome Biol Reprod. 2002 Feb;66(2):297-304.
16. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents. Endokrynol Pol. 2005 May-Jun;56(3):308-13.
17. Mitchell M, Armstrong DT, Robker RL, et al. Adipokines:implications for female fertileity and obesity. Reproduction. 2005 Nov;130(5):583-97.
18. Sahin Y, Yirmibes U, Kelestimur F, et al. The effects of metformin on insulin resistance, clomiphene-induced ovulateon and pregnancy rates in women with polycystic ovary syndrome. Eur J Obestet Gynecol Reprod iol. 2004 Apr 15;113(2):214-20.
19. Kocak M, Caliskan E, Simsir C. et al.. Metformin therapy improves ovulatery rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002 Jan:77(1):101-6.
20. Goudas VT, Dumesic DA. Polycystic ovary syndrome. Endocinol Metab Clin North Am. 1997 Dec;26(4):893-912.
21.于传鑫,李诵弦主编。实用妇科内分泌学。上海:复旦大学出版社,2004:137~155。
22.王颖,陈咏健,李美芝.促排卵治疗对多囊卵巢综合征子宫内膜整合素αν、β3表达的影响。中华妇产科杂志,2000,35(3):163~165。
23.扬雪峰多囊卵巢综合征子宫内膜病理改变及bcl-2基因表达。中国煤炭工业医学杂志,2003,6(8):725~726。
2. Strowitzki T, Capp E, von Wolff M, et al. Expression of glucose transporter 1 in human endometrial and decidual tissue. Gynecol Endocrinol. 2001 15:219–224
3. Ioni R, Chiarelli S, Xamin N, et al. Evidence for the Presence of Glucose Transporter 4 in the Endometrium and Its Regulation in Polycystic Ovary Syndrome Patients. J Clin Endocrinol. 2004,89: 4089-4096
4. Mozzanega B, Minoni R, Granzotto M, et al.Obesity reduces the expression of GLUT4 in the endometrium of normoinsulinemic women affected by the polycystic ovary syndrome. Ann N Y Acda Sci, 2004,1034:364-74
5. ShulmanGI. Cellular mechanisms of insulin resistance. J Clin Invest,2000,106:171 176
6. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest. 2000,106:165-169.
7. Takano A, Haruta T, Iwata M et al. Growth hormone induces cellular insulinresistance by uncoupling phosphatidylinositol 3 kinase and its down stream signals in 3T3 liadipocytes. Dibetes, 2001,50:1891-1900
8. IaIatrakis G, Tsionis C, Adonakis G, et al. Polycystic ovarian syndrome, insulin resistance and thickness of the endometrium Eur J Obstet Gynecol Reprod Biol. 2006,127:218-21.
9. RutanenE-Ml. Insulin-like growth factor in endometrial function . Gynecol Endocrinol,1998,12:399-406.
10. Mioni R, Chiarelli S, Xamin N,. et al. Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab.2004 Aug;89(8):4089-96.
11. Lin J, Li R, Zhou J. The influence of insulin on secretion of IGF-I and IGFBP-I in cultures of human endometrial stromal cells. Chin Med J (Engl). 2003 Feb;116(2):301-4.
12. Zhang EH, Liang XY, DU J, et al. Features of morphometry of ultrasound andendometrial histology in the anovulatory polycystic ovary syndrome women. Zhonghua Fu Chan Ke Za Zhi. 2006 Jun;41(6):380-3
13. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006 Jun;20(2):235-44
14. Villavicencio A, Bacallao K, Avellaira C, et al. Androgen and estrogen receptors and co-regulators levels in endometria from patients with polycystic ovarian syndrome with and without endometrial hyperplasia. Gynecol Oncol. 2006 May 2;
15. Tingthanatikul Y, Choktanasiri W, Rochanawutanon M, et al. Prevalence and clinical predictors of endometrial hyperplasiain anovulatory women presenting with amenorrhea. Gynecol Endocrinol. 2006 Feb;22(2):101-5
16. Quezada S, Avellaira C, Johnson MC, et al. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril. 2006 Apr;85(4):1017-26. Epub 2006 Mar 9
17. Marikinti K. Unusual presentation of a woman with polycystic ovaries and complex endometrial pathology. Reprod Biomed Online. 2006 Jan;12(1):39-42.
18. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents Endokrynol Pol. 2005 May-Jun;56(3):308-13
19. Potdar N, Konje JC. The endocrinological basis of recurrent miscarriages Curr Opin Obstet Gynecol. 2005 Aug;17(4):424-8. 1
20.Chekir C, Nakatsuka M, Kamada Y, et al. Impaired uterine perfusion associated with metabolic disorders in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2005 Feb;84(2):189-95.
21. Berstein LM, Kvatchevskaya JO, Poroshina TE, et al. Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol. 2004 Nov;130(11):687-93.
22. Guastamacchia E, Resta F, Triggiani V, et al. Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Mar;4(1):59-66.
23. Berstein LM, Tchernobrovkina AE, Gamajunova VB, et al. Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer J Cancer. Res Clin Oncol. 2003 Apr;129(4):245-9. Epub 2003 Apr 15.
24.Labrie F, Luu-The V, Labrie C, et al. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001 Jul;22(3):185-212.
25初永丽,孙永玉,邱红玉,等胰岛素受体底物1蛋白表达及其酪氨酸磷酸化程度与多囊卵巢综合征发病的关系。中华妇产科杂志,2004,39:176-179
26.邱红玉,初永丽,孙永玉,等多囊卵巢综合征合并胰岛素抵抗患者脂肪组织胰岛素受体底物2蛋白的表达及酪氨酸磷酸化的研究。中华妇产科杂志2005,40:116-119
27.李旻,邱红玉,孙永玉等多囊卵巢综合征患者胰岛素受体基因酪酸蛋白激酶域突变的研究,生殖与避孕,2003,23(5):270-274.
28.武秀峰,李红真,范正红,等IGF-1对卵巢泡内膜细胞增殖及其LH受体表达的影响,生殖与避孕,2002,22(2):84-106.
29.陈咏健,李美芝,王颖,等多囊卵巢综合征临床内分泌代谢对子宫内膜病变的影响,中国实用妇科与产科杂志,2000,16(9):536-538.
30.于传鑫,李诵弦主编。实用妇科内分泌学。上海:复旦大学出版社,2004:137~155.
31.陈咏健,魏兆莲,李美芝,等.多囊卵巢综合征子宫内膜细胞色素p450arom芳香化酶的表达.北京医科大学学报, 2000,32:515- 518
32.初永丽,邱红玉,孙永玉,等多囊卵巢综合征脂肪组织IRS-1介导的磷脂酰肌醇-3激酶活性分析,中华核医学杂志2004,24(2):77-80.
1. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006 Jun;20(2):235-44.
2. Iatrakis G, Tsionis C, Adonakis G, et al. Polycystic ovarian syndrome, insulin resistance and thickness of the endometrium. Eur J Obstet Gynecol Reprod Biol. 2006 Mar 3.
3. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents. Endokrynol Pol. 2005 May-Jun;56(3):308-13.
4. Mitchell M, Armstrong DT, Robker RL,. et al.. Adipokines: implications for female fertility and obesity. Reproduction. 2005 Nov;130(5):583-97.
6. Bugianesi E. Review article: steatosis, the metabolic syndrome and cancer. Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:40-3.
7. Chekir C, Nakatsuka M, Kamada Y, et al... Impaired uterine perfusion associated with metabolic disorders in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2005 Feb;84(2):189-95.
8. Berstein LM, Kvatchevskaya JO, Poroshina TE, et al. Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol. 2004 Nov;130(11):687-93.
9. Mioni R, Chiarelli S, Xamin N, et al.Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004 Aug;89(8):4089-96.
10. Sahin Y, Yirmibes U, Kelestimur F,. et al The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2004 Apr 15;113(2):214-20.
11. Guastamacchia E, Resta F, Triggiani V, et al .Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Mar;4(1):59-66.
12. Berstein LM, Tchernobrovkina AE, Gamajunova VB, et al. Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer. J Cancer Res ClinOncol. 2003 Apr;129(4):245-9. Epub 2003 Apr.
13. Druckmann R, Rohr UD. IGF-1 in gynaecology and obstetrics: update 2002. Maturitas. 2002 Apr 15;41 Suppl 1:S65-83.
14. Kocak M, Caliskan E, Simsir C,. et al. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002 Jan;77(1):101-6.
15. Labrie F, Luu-The V, Labrie C, et al.DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001 Jul;22(3):185-212.
16. Vazquez Hernandez L, Tellez Martinez J, Hicks Gomez JJ. Clinical and metabolic effects of oral contraceptives. Ginecol Obstet Mex. 2000 Feb;68:64-9.
17. Gordon CM. Menstrual disorders in adolescents. Excess androgens and the polycystic ovary syndrome. Pediatr Clin North Am. 1999 Jun;46(3):519-43.
18. Moore MA, Park CB, Tsuda H. Implications of the hyperinsulinaemia-diabetes-cancer link for preventive efforts. Eur J Cancer Prev. 1998 Apr;7(2):89-107.
19. Labrie F, Belanger A, Luu-The V, et al.DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids. 1998 May-Jun;63(5-6):322-8.
20. Solomon CG. 1999 The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinol Metab Clin North Am 28:247-263.
21. Moran LJ, Noakes M, Clifton PM, et al.2003 Dietary composition in restoring reproductive and metabolic physicalogy in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:812-819.
22. Dunaif A. 1997 Insulin resistance and the polycystic ovary syndrome:mechanism and implication for pathogensis. Endocr Rev 18:774-800.
23. Mueckler M. 2001 Insulin resistance and the disruption of GLUT4 trafficking in skeletal muscle. J Clin Invest 107:1211-1213.
24. Rosenfield RL. 2001 Polycystic ovary syndrome and insulin-resistant hyperinsulinemia. J Am Acad Dermatol 45:S95-S102.
25. Iatrakis G., Tsionis C, Adonakis G., et al. Polycystic ovarian syndrome, insulin resistance and thickenss of the endometrium. Eur J Obstet Gynceol Reprod Biol. 2006 Mar3.
26.王玉霞,脂肪内分泌与PCOS胰岛素抵抗的研究进展国外医学妇产科学分册2004.31(5):291-294.
27.叶明珠林影,子宫内膜胰岛素样生长因子系统的基因表达国外医学妇产科学分册2003.30(5):284-286.
1. Zhang EH, Liang XY, DU J, et al.Features of morphometry of ultrasound and endometrial histology in the anovulatory polycystic ovary syndrome women. Zhonghua Fu Chan Ke Za Zhi. 2006 Jun;41(6):380-3
2. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006 Jun;20(2):235-44
3. Villavicencio A, Bacallao K, Avellaira C, et al. Androgen and estrogen receptors and co-regulators levels in endometria from patients with polycystic ovarian syndrome with and without endometrial hyperplasia. Gynecol Oncol. 2006 May 2;
4. Tingthanatikul Y, Choktanasiri W, Rochanawutanon M, et al .Prevalence and clinical predictors of endometrial hyperplasiain anovulatory women presenting with amenorrhea. Gynecol Endocrinol. 2006 Feb;22(2):101-5
5. Quezada S, Avellaira C, Johnson MC, et al. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril. 2006 Apr;85(4):1017-26. Epub 2006 Mar 9
6. IaIatrakis G, Tsionis C, Adonakis G,. et al. Polycystic ovarian syndrome, insulin resistance and thickness of the endometrium Eur J Obstet Gynecol Reprod Biol. 2006 Aug;127(2):218-21. Epub 2006 Mar 6
7. Marikinti K. Unusual presentation of a woman with polycystic ovaries and complex endometrial pathology. Reprod Biomed Online. 2006 Jan;12(1):39-42.
8. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents Endokrynol Pol. 2005 May-Jun;56(3):308-13
9. Potdar N, Konje JC. The endocrinological basis of recurrent miscarriages Curr Opin Obstet Gynecol. 2005 Aug;17(4):424-8.
10. Mozzanega B, Mioni R, Granzotto M, et al. Obesity reduces the expression of GLUT4 in the endometrium of normoinsulinemic women affected by the polycystic ovary syndrome. Ann N Y Acad Sci. 2004 Dec;1034:364
11. Mioni R, Chiarelli S, Xamin N, et al.Evidence for the presence of glucose transporter 4 in the endometrium and its regulation in polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004 Aug;89(8):4089-96
12. Wang YZ, Qiao J, Liu LL, et al.Expression of leptin and long form of leptin receptors messenger ribonucleic acid and protein in endometrium of patients with polycystic ovary syndrome Zhonghua Fu Chan Ke Za Zhi. 2003 Jul;38(7):398-401.
13. Gregory CW, Wilson EM, Apparao KB, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium.J Clin Endocrinol Metab. 2002 Jun;87(6):2960-6
14. Druckmann R, Rohr UD. IGF-1 in gynaecology and obstetrics: update 2002Maturitas. 2002 Apr 15;41 Suppl 1:S65-83.
15. Apparao KB, Lovely LP, Gui Y, et al. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome Biol Reprod. 2002 Feb;66(2):297-304.
16. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents. Endokrynol Pol. 2005 May-Jun;56(3):308-13.
17. Mitchell M, Armstrong DT, Robker RL, et al. Adipokines:implications for female fertileity and obesity. Reproduction. 2005 Nov;130(5):583-97.
18. Sahin Y, Yirmibes U, Kelestimur F, et al. The effects of metformin on insulin resistance, clomiphene-induced ovulateon and pregnancy rates in women with polycystic ovary syndrome. Eur J Obestet Gynecol Reprod iol. 2004 Apr 15;113(2):214-20.
19. Kocak M, Caliskan E, Simsir C. et al.. Metformin therapy improves ovulatery rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002 Jan:77(1):101-6.
20. Goudas VT, Dumesic DA. Polycystic ovary syndrome. Endocinol Metab Clin North Am. 1997 Dec;26(4):893-912.
21.于传鑫,李诵弦主编。实用妇科内分泌学。上海:复旦大学出版社,2004:137~155。
22.王颖,陈咏健,李美芝.促排卵治疗对多囊卵巢综合征子宫内膜整合素αν、β3表达的影响。中华妇产科杂志,2000,35(3):163~165。
23.扬雪峰多囊卵巢综合征子宫内膜病理改变及bcl-2基因表达。中国煤炭工业医学杂志,2003,6(8):725~726。