细胞色素芳香化酶P450在子宫内膜异位症中的表达及诊断价值
|
摘要
目的:测定细胞色素芳香化酶P450(aromatase cytochrom P450,P450arom)在子宫内膜异位症(endometriosis,EMS)患者异位、在位内膜与正常子宫内膜中的表达,探讨P450arom表达水平与EMS的相关性,试图寻求EMS的一种早期辅助筛查方法。
方法:应用免疫组化链霉菌抗生物蛋白-过氧化物酶连接(SP)方法,检测正常子宫内膜(对照组)和EMS(研究组)的在位内膜及异位内膜中P450arom的表达。
结果:研究组30例中29例异位内膜、27例在位内膜组织有P450arom表达,阳性表达率分别为96.7%和90%;对照组内膜仅有1例呈现弱表达,阳性表达率为5%;P450arom在研究组异位内膜中的阳性表达率明显高于对照组内膜,两者有极显著差异(X~2=40.7;P＜0.01);P450arom在研究组在位内膜中的阳性表达率亦明显高于对照组内膜,两者有极显著差异(X~2=27.57;P＜0.01)。P450arom的阳性表达率在研究组的异位内膜和在位内膜间差异无显著性(X~2=2.71;p＞0.05);研究组异位内膜中P450arom表达随rAFS分期的增加而加强(X~2=11.05P＜0.05),而在位内膜中P450arom表达不随rAFS分期的增加而加强(X~2=1.95,P＞0.05)。在EMSⅠ-Ⅱ期中异位内膜与在位内膜P450arom表达强度差异无统计学意义(X~2=2.26,P＞0.05);而Ⅲ-Ⅳ期中异位内膜P450arom表达强度明显高于在位内膜,差异有显著性(X~2=3.86 P＜0.05)。本组研究中子宫内膜组织P450arom阳性表达用于诊断子宫内膜异位症敏感度为90%,特异度为95%。
结论:P450arom在EMS患者的在位内膜及异位内膜中存在过度表达,并且异位内膜中的表达与EMS分期呈一定的正相关性。P450arom在正常子宫内膜中不表达或弱表达,因此,P450arom可以作为EMS一种早期辅助筛查方法。
Objective:Detected the expression of aromatase cytochrom P450 in nomal,the eutopic and ectopic endometrium of endometriosis,to study the correlation of the aromatase cytochrom P450 with endometriosis,and to evaluate its clinical value as a diagnostic method for endometriosis.
Methods:Detemine the expression of aromatase cytochrom P450 in nomal,the eutopic and ectopic endometrium of endometriosis by immunohistochemical assay(stretavidin-peroxidade-biotin,SP).
Result:The positive rate of aromatase cytochrom P450 expression in eutopic endometrium and ectopic endometrium from study group was 96.7%(29/30) and90%(27/30),but it was negative or weakly expressed in nomal endometrium,its positive rate expression was 5%(1/20).The positive rate of aromatase cytochrom P450 expression in eutopic endometrium and ectopic endometrium was significantly higher than that in nomal endometrium(X~2=40.7;X~2=27.57;p＜0.01);But in study group there was no significant diference between the eutopic endometrium and the ectopic endometrium(X~2=2.71;p＞0.05).In EMSⅠ-Ⅱthere was no significant difference of the posistive rate of P450arom between the eutopic endometrium and ectopic endometrium (X~2=2.26,P＞0.05);but inⅢ-Ⅳthe expression of P450arom in eutopic endometrium was significant high than that in ectopic endometrium(X~2=3.86 P＜0.05).there were correlation between the degree of the P450arom expression in eutopic endometrium with rAFS(X~2=11.05 P＜0.05);But in ectopic endometrium there were no such relationship(X~2=1.95,P＞0.05).The aromatase cytochrom P450 expression in ectopic endometrium is useful in diagnostic assessment of EMS with sensitivity 90%and specificity 95%.
Conclusions:There were increased expression of the aromatase cytochrom P450 in the eutopic and the ectopic endometrium of endometriosis,which may play an important role in pathogenesis and the development of endometriosis.P450arom can be used as a marker for diagnosis.
方法:应用免疫组化链霉菌抗生物蛋白-过氧化物酶连接(SP)方法,检测正常子宫内膜(对照组)和EMS(研究组)的在位内膜及异位内膜中P450arom的表达。
结果:研究组30例中29例异位内膜、27例在位内膜组织有P450arom表达,阳性表达率分别为96.7%和90%;对照组内膜仅有1例呈现弱表达,阳性表达率为5%;P450arom在研究组异位内膜中的阳性表达率明显高于对照组内膜,两者有极显著差异(X~2=40.7;P＜0.01);P450arom在研究组在位内膜中的阳性表达率亦明显高于对照组内膜,两者有极显著差异(X~2=27.57;P＜0.01)。P450arom的阳性表达率在研究组的异位内膜和在位内膜间差异无显著性(X~2=2.71;p＞0.05);研究组异位内膜中P450arom表达随rAFS分期的增加而加强(X~2=11.05P＜0.05),而在位内膜中P450arom表达不随rAFS分期的增加而加强(X~2=1.95,P＞0.05)。在EMSⅠ-Ⅱ期中异位内膜与在位内膜P450arom表达强度差异无统计学意义(X~2=2.26,P＞0.05);而Ⅲ-Ⅳ期中异位内膜P450arom表达强度明显高于在位内膜,差异有显著性(X~2=3.86 P＜0.05)。本组研究中子宫内膜组织P450arom阳性表达用于诊断子宫内膜异位症敏感度为90%,特异度为95%。
结论:P450arom在EMS患者的在位内膜及异位内膜中存在过度表达,并且异位内膜中的表达与EMS分期呈一定的正相关性。P450arom在正常子宫内膜中不表达或弱表达,因此,P450arom可以作为EMS一种早期辅助筛查方法。
Objective:Detected the expression of aromatase cytochrom P450 in nomal,the eutopic and ectopic endometrium of endometriosis,to study the correlation of the aromatase cytochrom P450 with endometriosis,and to evaluate its clinical value as a diagnostic method for endometriosis.
Methods:Detemine the expression of aromatase cytochrom P450 in nomal,the eutopic and ectopic endometrium of endometriosis by immunohistochemical assay(stretavidin-peroxidade-biotin,SP).
Result:The positive rate of aromatase cytochrom P450 expression in eutopic endometrium and ectopic endometrium from study group was 96.7%(29/30) and90%(27/30),but it was negative or weakly expressed in nomal endometrium,its positive rate expression was 5%(1/20).The positive rate of aromatase cytochrom P450 expression in eutopic endometrium and ectopic endometrium was significantly higher than that in nomal endometrium(X~2=40.7;X~2=27.57;p＜0.01);But in study group there was no significant diference between the eutopic endometrium and the ectopic endometrium(X~2=2.71;p＞0.05).In EMSⅠ-Ⅱthere was no significant difference of the posistive rate of P450arom between the eutopic endometrium and ectopic endometrium (X~2=2.26,P＞0.05);but inⅢ-Ⅳthe expression of P450arom in eutopic endometrium was significant high than that in ectopic endometrium(X~2=3.86 P＜0.05).there were correlation between the degree of the P450arom expression in eutopic endometrium with rAFS(X~2=11.05 P＜0.05);But in ectopic endometrium there were no such relationship(X~2=1.95,P＞0.05).The aromatase cytochrom P450 expression in ectopic endometrium is useful in diagnostic assessment of EMS with sensitivity 90%and specificity 95%.
Conclusions:There were increased expression of the aromatase cytochrom P450 in the eutopic and the ectopic endometrium of endometriosis,which may play an important role in pathogenesis and the development of endometriosis.P450arom can be used as a marker for diagnosis.
引文
[1]郎景和 《子宫内膜异位症研究的任务与展望》 中华妇产科杂志2006,Vol.41:289-290
[2]周应芳,岳小燕等,子宫内膜异位症的腹腔镜手术治疗,中国内镜杂志,2002;8:9-12
[3]Kitawaki J,Koshiba H,Ishihara et al.Progesterone induction of 17beta-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in hhe endometrium of estrogen-dependent benign diseases but not in normal ensometriun,Jclin Endocrinol Metab,2000,85:3292-3296
[4]Tseng L.Mazella J.Mann WJ.dt al Estrongen synthesis in nomal and malignant human endomctrium.J Clin Enddocrinol Metab.1982.55;1029-1031
[5]Noble L S,Takayama K,Putman JM,et al Prostagland in E2stimulates aromatase expression in endometrosis-derived stromal cells J Clin Endocrino Metab,1997,82(2):600-606
[6]Zhao Y,N ichols JE,Bulun SE,et al A romatase P450 gene expression in human adipose tissue:role of a JAK/STAT pathway in regulation of the adipose-specific promoter JB iol Chen,1995,270(2):16449-1645
[7]prefrontaincM,ShihC,PanCC,etal Applicalicability of the product iaolation and radiometric aromatase assays for the measurement of low levels of anomatase:lack of aromatase activity in the human cndomtrium.J Endocrinol. 1990.127;536-551
[8] Noble L S,Sinpsin ER et al Aromatase eepreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-17
[9] Noble L S,Sinpsin ER et al Aromatase eepreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-17
1.Scthumadhaw an K.Beltino FL.Thotakura NR Estrogen synthase(aromatase).the eytochromc P450 component of the human placental enzyme is a glycoprotcin Mol Cell Endocrinol.1991.78.25-32
2.Mahendroo MS,Means Gdel al Tissue-specific expression of human P450arome the promoter responsible for expression in adipose is different from that utilized in hplacenta J Biol Chem 1991.2661;11276-11281
3.Furbass R.Kalbe C,Vanselow J.Tissue specific expression of the bovine aromatase encoding gesne uses multiple transeripional start site and ahernative first exons.Endocrinology.1997.138(7):2813-2819
4.katsumi T,Satoshi N,Yutakas,et al.Identification and characterization of transcriptional regulatory element of the human aromatase cytochrome P450 gene(cyp 19).J Steroid Biochem Molec Biol,1996,56:151-159
5.Adashi EY,Rock JA,Rosenwaks Z Reproductive endocrinology and technology philadelphia BippincouoRaven pablishers 1996;478-492
6.Tseng L Mazella J.Mznn WJ,ct al Estrogen svnthesis in nomnal and malignant human condimctrium.Jclin Endocrinol Mctab.1982.55;1029-1031
7.Bulun SE.Mahendreoo MS.Smpson ER.Polymcrase chain resction anplification fails to detect aromatase cytociromic P450 transcpts in nommal humna cndoncirium on dccidua Jclin Endocrinol Mctab,1993.76.1458-1463
8.prefrontaincM,ShihC,PanCC,etal Applicalicability of the product iaolation and radiometric aromatase assays for the mcasurcment of low levels of anomatase:lack of aromatase activity in the human cndomtrium.J Endocrinol.1990.127;536-551
9.Tseng L.Mazella J.Mann WJ.dt al Estrongen synthesis in nomal and malignant human endomctrium.J Clin Enddocrinol Metab.1982.55;1029-1031
10.Bulun SE.Smpson ER.Word RA.Expression of the CYP 19gene and its product aromatase cytochrome P450in human uterinc leiom yoma tissues and cells in culture J.Clin Endoerinol M etab.1994.78;736-743
11.黄坚,石一复等芳香化酶P450与雌激素受体在子宫内膜异位症患者在及异位内膜中表达及其相关性研究中华妇产科杂志2005.40;171-174;
12.Zeitoun.K,Takayama K et al Stinulation of aronatase P450 promoter (II) activity in endometrosis and its inhibitionin endometrium are regulated by eompetitive binding of steroidogenic factor and chicken ovalbumin upstream promoter transcription favtor to the same cis-acting clementMol Endocrinol, 1999.13;239-253
13. Kitswaki J KusukiL Kishiba H.et al Deteetion of aromatase cytociromic P450 in endomctrial biopsy specmens as a diagnostic test for endometriosis Fertil Steril. 1999.72; 1100-1106
14. Noble L S,Sinpsin ER etal Aromatase ecpreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-179
15. Bulun SE. Zeitoun K. Takayama K.et at Estrongen biosynthesis in ensometriosis moleeular basis and clinical relevance . J Mol Endocrinol. 2000.25:35-42
16. Zeitoun K,Takayama Ksasano H,et al Deficient 17betahydroxysteriod deydrogenase type expresion in endometriosis failure to metabolize 17beta-estrasiol Jclin Endcrinol Metab, 1998;83(12);4474-4480
17. Zeitoun K,Takayama k,M icael MD,el al Stimulation of aromatase P450 ptomoter (II) activity in endometriosis snd its inhibition in endometrium are regulated by competitive biding of steroidogenic factor-1 and chicken ocalbum in up stream promoter transcription factor to the same cis-acting element MolEndocriol,1999,13(2):239-253
18.Noble L S,Takayama K,Putman JM,et al Prostagland in E2stimulates aromatase expression in endometrosis-derived stromal cells J Clin Endocrino Metab,1997,82(2):600-606
19.Zhao Y,N ichols JE,Bulun SE,et al A romatase P450 gene expression in human adipose tissue:role of a JAK/STAT pathway in regulation of the adipose-specific promoter JB iol Chen,1995,270(2):16449-16457
20.陈咏健、李美芝子宫内膜细胞色素P450芳香化酶的表达研究进展生殖医学杂志2001,10;118-120
21.Randolph JE,Kipersztok S,Ayers JW,et al The effect of insulin on aromatase acticity in isolated human endometerial gland and stroma Am J Obstct Gynccol.1987,157:1534-1539
22.Takahashi K,Nagata H,et al Clinical usefulness of detem ination of estradiol level in the menstrual blood for patients with endonetriosis Acta Obsteet Gynecal Jpn,1989,41(12);1849-1850
23.郎景和.子宫内膜异位症研究的新里程.中华妇产科杂志,2005,40:3-4
24.张爱云,康佳丽等,子宫内膜异位症患者血清CA125及 EMAb的临床评价,实用医学杂志2004;7:750-751
25.周应芳,岳小燕等,子宫内膜异位症的腹腔镜手术治疗,中国内镜杂志,2002;8:9-12
26.Kitawaki J,Kusuki I,et al Detection of aromatase cytochrome P450 in endometrial biopsy specume as a diagnostic test for endometriosis FerstilSteril,1999,72(6)1110-1122
27.Bulun SE.Zeitoun K.Takayama K.et at Estrongen pronduction in condometriosis and use of aromatase inhibitorsto treat condometriosis Endoer Cancer.1999.6:293-301
28.YanoM,Susaki Y,et al Studies on the new nonsteeroidal aromatase Inhibitor fadrozole hydrochloride in anendometriosis model in rats Arzneim ittelforschubg,1996,46(2):192-195
29.Kudoh M,Susaki Y,et al Inhibitory effects of a novel aromatase inhibitor,YM 511,on growth of endometrial explants and insulin-like growth factor-1 gene expreaaion in ratswith exprimental endometriosis Jsteroid Biochem MolBiol,1997,63(1):1-3,75-80
[2]周应芳,岳小燕等,子宫内膜异位症的腹腔镜手术治疗,中国内镜杂志,2002;8:9-12
[3]Kitawaki J,Koshiba H,Ishihara et al.Progesterone induction of 17beta-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in hhe endometrium of estrogen-dependent benign diseases but not in normal ensometriun,Jclin Endocrinol Metab,2000,85:3292-3296
[4]Tseng L.Mazella J.Mann WJ.dt al Estrongen synthesis in nomal and malignant human endomctrium.J Clin Enddocrinol Metab.1982.55;1029-1031
[5]Noble L S,Takayama K,Putman JM,et al Prostagland in E2stimulates aromatase expression in endometrosis-derived stromal cells J Clin Endocrino Metab,1997,82(2):600-606
[6]Zhao Y,N ichols JE,Bulun SE,et al A romatase P450 gene expression in human adipose tissue:role of a JAK/STAT pathway in regulation of the adipose-specific promoter JB iol Chen,1995,270(2):16449-1645
[7]prefrontaincM,ShihC,PanCC,etal Applicalicability of the product iaolation and radiometric aromatase assays for the measurement of low levels of anomatase:lack of aromatase activity in the human cndomtrium.J Endocrinol. 1990.127;536-551
[8] Noble L S,Sinpsin ER et al Aromatase eepreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-17
[9] Noble L S,Sinpsin ER et al Aromatase eepreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-17
1.Scthumadhaw an K.Beltino FL.Thotakura NR Estrogen synthase(aromatase).the eytochromc P450 component of the human placental enzyme is a glycoprotcin Mol Cell Endocrinol.1991.78.25-32
2.Mahendroo MS,Means Gdel al Tissue-specific expression of human P450arome the promoter responsible for expression in adipose is different from that utilized in hplacenta J Biol Chem 1991.2661;11276-11281
3.Furbass R.Kalbe C,Vanselow J.Tissue specific expression of the bovine aromatase encoding gesne uses multiple transeripional start site and ahernative first exons.Endocrinology.1997.138(7):2813-2819
4.katsumi T,Satoshi N,Yutakas,et al.Identification and characterization of transcriptional regulatory element of the human aromatase cytochrome P450 gene(cyp 19).J Steroid Biochem Molec Biol,1996,56:151-159
5.Adashi EY,Rock JA,Rosenwaks Z Reproductive endocrinology and technology philadelphia BippincouoRaven pablishers 1996;478-492
6.Tseng L Mazella J.Mznn WJ,ct al Estrogen svnthesis in nomnal and malignant human condimctrium.Jclin Endocrinol Mctab.1982.55;1029-1031
7.Bulun SE.Mahendreoo MS.Smpson ER.Polymcrase chain resction anplification fails to detect aromatase cytociromic P450 transcpts in nommal humna cndoncirium on dccidua Jclin Endocrinol Mctab,1993.76.1458-1463
8.prefrontaincM,ShihC,PanCC,etal Applicalicability of the product iaolation and radiometric aromatase assays for the mcasurcment of low levels of anomatase:lack of aromatase activity in the human cndomtrium.J Endocrinol.1990.127;536-551
9.Tseng L.Mazella J.Mann WJ.dt al Estrongen synthesis in nomal and malignant human endomctrium.J Clin Enddocrinol Metab.1982.55;1029-1031
10.Bulun SE.Smpson ER.Word RA.Expression of the CYP 19gene and its product aromatase cytochrome P450in human uterinc leiom yoma tissues and cells in culture J.Clin Endoerinol M etab.1994.78;736-743
11.黄坚,石一复等芳香化酶P450与雌激素受体在子宫内膜异位症患者在及异位内膜中表达及其相关性研究中华妇产科杂志2005.40;171-174;
12.Zeitoun.K,Takayama K et al Stinulation of aronatase P450 promoter (II) activity in endometrosis and its inhibitionin endometrium are regulated by eompetitive binding of steroidogenic factor and chicken ovalbumin upstream promoter transcription favtor to the same cis-acting clementMol Endocrinol, 1999.13;239-253
13. Kitswaki J KusukiL Kishiba H.et al Deteetion of aromatase cytociromic P450 in endomctrial biopsy specmens as a diagnostic test for endometriosis Fertil Steril. 1999.72; 1100-1106
14. Noble L S,Sinpsin ER etal Aromatase ecpreaaion in endometriosis Jclin Emdocrinol Metab, 1996,81:174-179
15. Bulun SE. Zeitoun K. Takayama K.et at Estrongen biosynthesis in ensometriosis moleeular basis and clinical relevance . J Mol Endocrinol. 2000.25:35-42
16. Zeitoun K,Takayama Ksasano H,et al Deficient 17betahydroxysteriod deydrogenase type expresion in endometriosis failure to metabolize 17beta-estrasiol Jclin Endcrinol Metab, 1998;83(12);4474-4480
17. Zeitoun K,Takayama k,M icael MD,el al Stimulation of aromatase P450 ptomoter (II) activity in endometriosis snd its inhibition in endometrium are regulated by competitive biding of steroidogenic factor-1 and chicken ocalbum in up stream promoter transcription factor to the same cis-acting element MolEndocriol,1999,13(2):239-253
18.Noble L S,Takayama K,Putman JM,et al Prostagland in E2stimulates aromatase expression in endometrosis-derived stromal cells J Clin Endocrino Metab,1997,82(2):600-606
19.Zhao Y,N ichols JE,Bulun SE,et al A romatase P450 gene expression in human adipose tissue:role of a JAK/STAT pathway in regulation of the adipose-specific promoter JB iol Chen,1995,270(2):16449-16457
20.陈咏健、李美芝子宫内膜细胞色素P450芳香化酶的表达研究进展生殖医学杂志2001,10;118-120
21.Randolph JE,Kipersztok S,Ayers JW,et al The effect of insulin on aromatase acticity in isolated human endometerial gland and stroma Am J Obstct Gynccol.1987,157:1534-1539
22.Takahashi K,Nagata H,et al Clinical usefulness of detem ination of estradiol level in the menstrual blood for patients with endonetriosis Acta Obsteet Gynecal Jpn,1989,41(12);1849-1850
23.郎景和.子宫内膜异位症研究的新里程.中华妇产科杂志,2005,40:3-4
24.张爱云,康佳丽等,子宫内膜异位症患者血清CA125及 EMAb的临床评价,实用医学杂志2004;7:750-751
25.周应芳,岳小燕等,子宫内膜异位症的腹腔镜手术治疗,中国内镜杂志,2002;8:9-12
26.Kitawaki J,Kusuki I,et al Detection of aromatase cytochrome P450 in endometrial biopsy specume as a diagnostic test for endometriosis FerstilSteril,1999,72(6)1110-1122
27.Bulun SE.Zeitoun K.Takayama K.et at Estrongen pronduction in condometriosis and use of aromatase inhibitorsto treat condometriosis Endoer Cancer.1999.6:293-301
28.YanoM,Susaki Y,et al Studies on the new nonsteeroidal aromatase Inhibitor fadrozole hydrochloride in anendometriosis model in rats Arzneim ittelforschubg,1996,46(2):192-195
29.Kudoh M,Susaki Y,et al Inhibitory effects of a novel aromatase inhibitor,YM 511,on growth of endometrial explants and insulin-like growth factor-1 gene expreaaion in ratswith exprimental endometriosis Jsteroid Biochem MolBiol,1997,63(1):1-3,75-80