功血患者血清TPOAb与其子宫内膜性激素受体及TPO表达相关性的研究
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摘要
目的
功能失调性子宫出血(dysfunctional uterine bleeding,DUB)简称功血,是一种妇科常见病,出血机制尚不完全清楚,一般认为是由调节生殖的神经内分泌机制失常引起,随着研究的深入,近年来认为可能与子宫内膜局部微环境的改变有关。临床上我们发现部分DUB患者血清中甲状腺自身抗体出现异常,而FT3,FT4,TSH在正常范围内,提示功血是否与自身免疫性甲状腺疾病有相关性。本实验通过对功血患者和正常妇女血清甲状腺功能的测定以及对子宫内膜性激素受体以及甲状腺过氧化物酶表达的研究,旨在发现功血患者是否存在隐匿性自身免疫性甲状腺疾病,并初步探讨二者之间的相关性,为临床诊治提供一个新的思路。
方法
1.研究对象:选择2007.12～2008.11就诊于天津市第一中心医院妇科门诊的年龄30～48(39.68±5.89)岁的功能失调性子宫出血的患者34例为病例组,以同期年龄25～48(35.95±7.58)岁,因男方精液异常或输卵管堵塞的月经规则不孕患者20例为对照组。
2.研究方法:应用化学发光分析法,检测这54例血清标本中FT3,FT4,TSH,TPOAb的含量;采用免疫组化染色分析法,检测病例组34例功血患者子宫内膜上性激素受体和54例研究对象子宫内膜上甲状腺过氧化物酶的表达情况。
结果
1、34例功血患者中有9例血清TPOAb表现出阳性,阳性率达到26.5%,而对照组20例健康妇女中只有1例血清TPOAb表现出阳性,阳性率为5%,血清TPOAb的浓度,病例组高于正常水平的比率显著高于对照组(P＜0.05)
2、34例功血患者中血清TPOAb高于正常的患者与血清TPOAb正常的患者相比较,子宫内膜上ER、PR、AR的表达无明显差异(P＞0.05)。
3、甲状腺过氧化物酶在人类子宫内膜上确有表达而且主要表达在内膜腺体细胞的胞浆中,间质细胞胞浆有弱表达。所有血清TPOAb高于正常的功血患者,其子宫内膜上TPO的表达均较弱,免疫评分低于血清TPOAb正常的功血患者,将二者进行相关性分析,得出R=-0.571,显示血清TPOAb的水平与子宫内膜上TPO的表达呈负相关。
结论
1、部分功血患者的血清TPOAb出现异常,提示这部分病人存在亚临床的甲状腺疾病。
2、功血患者血清TPOAb是否升高与子宫内膜上ER、PR、AR的表达无相关性。
3、TPO在人类子宫内膜上有表达,主要存在于子宫内膜细胞的胞浆中。功血患者血清TPOAb水平与其子宫内膜上TPO的表达呈负相关,提示亚临床自身免疫性甲状腺疾病可能通过在子宫内膜形成免疫复合物沉积而影响局部微环境,从而导致功血。
Objective
Dysfunctional uterine bleeding(DUB) is an common disease for female,but the exact mechanisms behind the bleeding are uncertain.It is always think that the main cause is dysfunction of the neuroendocrine.Recently,it is found the micro-Environment play a important role in DUB.We found some of the DUB patients have the antithyroid antibodies(ATA) positive,but FT3,FT4 and TSH are normal in clinic,so we doubt is there a related link between DUB and sub-clinical AITD? The purpose of this study was to investigate the expression of TPO in human uterine endometrium,combine with the examination of the serum,to explore the relationship between dysfunctional uterine bleeding and AITD,and provide a new way for DUB'treatment.
Methods
Immunohistochemistry was used to exam the expression of ER,PR,AR in endometrium of 34 DUBs and the expression of TPO in all the cases of our study which were involved in 2007.12～2008.11.
Mean while,we chose Chemiluminescence to exam the levels of FT3,FT4, TSH and TPOAb in serum of all the cases.
Results
1.There are 9 DUB patients have serum TPOAb positive,the positive rate is 26.5%; but only 1 of the controls has serum TPOAb positive,and the rate is 5%.It means the level of TPOAb in DUB is much higher than the controls.
2.There is no significant difference in the expression of ER,PR and AR between the patients of serum TPOAb positive and negative.
3.The results of Immunohistochemistry suggested that TPO exists in endometrium, and the positive expression was in plasma of all kinds of the endometrial cells.We found all the samples which expressed positive results in serum TPOAb have weaker expression in Immunohistochemistry,and there is a negative correlation between serum TPOAb and the expression of TPO in endometrium,R=-0.571
Conclusions
1.Considerable DUB patients have serum TPOAb positive,it suggests that these patient perhaps have sub-clinic AITD.
2.The levels of serum TPOAb in DUB patients is not relevant with the expression of ER,PR or AR in their endometrium.
3.TPO expresss in women's endometrium,it exists in plasma of all kinds of the endometrial cells.There is a negative correlation between serum TPOAb and the expression of TPO in endometrium.
功能失调性子宫出血(dysfunctional uterine bleeding,DUB)简称功血,是一种妇科常见病,出血机制尚不完全清楚,一般认为是由调节生殖的神经内分泌机制失常引起,随着研究的深入,近年来认为可能与子宫内膜局部微环境的改变有关。临床上我们发现部分DUB患者血清中甲状腺自身抗体出现异常,而FT3,FT4,TSH在正常范围内,提示功血是否与自身免疫性甲状腺疾病有相关性。本实验通过对功血患者和正常妇女血清甲状腺功能的测定以及对子宫内膜性激素受体以及甲状腺过氧化物酶表达的研究,旨在发现功血患者是否存在隐匿性自身免疫性甲状腺疾病,并初步探讨二者之间的相关性,为临床诊治提供一个新的思路。
方法
1.研究对象:选择2007.12～2008.11就诊于天津市第一中心医院妇科门诊的年龄30～48(39.68±5.89)岁的功能失调性子宫出血的患者34例为病例组,以同期年龄25～48(35.95±7.58)岁,因男方精液异常或输卵管堵塞的月经规则不孕患者20例为对照组。
2.研究方法:应用化学发光分析法,检测这54例血清标本中FT3,FT4,TSH,TPOAb的含量;采用免疫组化染色分析法,检测病例组34例功血患者子宫内膜上性激素受体和54例研究对象子宫内膜上甲状腺过氧化物酶的表达情况。
结果
1、34例功血患者中有9例血清TPOAb表现出阳性,阳性率达到26.5%,而对照组20例健康妇女中只有1例血清TPOAb表现出阳性,阳性率为5%,血清TPOAb的浓度,病例组高于正常水平的比率显著高于对照组(P＜0.05)
2、34例功血患者中血清TPOAb高于正常的患者与血清TPOAb正常的患者相比较,子宫内膜上ER、PR、AR的表达无明显差异(P＞0.05)。
3、甲状腺过氧化物酶在人类子宫内膜上确有表达而且主要表达在内膜腺体细胞的胞浆中,间质细胞胞浆有弱表达。所有血清TPOAb高于正常的功血患者,其子宫内膜上TPO的表达均较弱,免疫评分低于血清TPOAb正常的功血患者,将二者进行相关性分析,得出R=-0.571,显示血清TPOAb的水平与子宫内膜上TPO的表达呈负相关。
结论
1、部分功血患者的血清TPOAb出现异常,提示这部分病人存在亚临床的甲状腺疾病。
2、功血患者血清TPOAb是否升高与子宫内膜上ER、PR、AR的表达无相关性。
3、TPO在人类子宫内膜上有表达,主要存在于子宫内膜细胞的胞浆中。功血患者血清TPOAb水平与其子宫内膜上TPO的表达呈负相关,提示亚临床自身免疫性甲状腺疾病可能通过在子宫内膜形成免疫复合物沉积而影响局部微环境,从而导致功血。
Objective
Dysfunctional uterine bleeding(DUB) is an common disease for female,but the exact mechanisms behind the bleeding are uncertain.It is always think that the main cause is dysfunction of the neuroendocrine.Recently,it is found the micro-Environment play a important role in DUB.We found some of the DUB patients have the antithyroid antibodies(ATA) positive,but FT3,FT4 and TSH are normal in clinic,so we doubt is there a related link between DUB and sub-clinical AITD? The purpose of this study was to investigate the expression of TPO in human uterine endometrium,combine with the examination of the serum,to explore the relationship between dysfunctional uterine bleeding and AITD,and provide a new way for DUB'treatment.
Methods
Immunohistochemistry was used to exam the expression of ER,PR,AR in endometrium of 34 DUBs and the expression of TPO in all the cases of our study which were involved in 2007.12～2008.11.
Mean while,we chose Chemiluminescence to exam the levels of FT3,FT4, TSH and TPOAb in serum of all the cases.
Results
1.There are 9 DUB patients have serum TPOAb positive,the positive rate is 26.5%; but only 1 of the controls has serum TPOAb positive,and the rate is 5%.It means the level of TPOAb in DUB is much higher than the controls.
2.There is no significant difference in the expression of ER,PR and AR between the patients of serum TPOAb positive and negative.
3.The results of Immunohistochemistry suggested that TPO exists in endometrium, and the positive expression was in plasma of all kinds of the endometrial cells.We found all the samples which expressed positive results in serum TPOAb have weaker expression in Immunohistochemistry,and there is a negative correlation between serum TPOAb and the expression of TPO in endometrium,R=-0.571
Conclusions
1.Considerable DUB patients have serum TPOAb positive,it suggests that these patient perhaps have sub-clinic AITD.
2.The levels of serum TPOAb in DUB patients is not relevant with the expression of ER,PR or AR in their endometrium.
3.TPO expresss in women's endometrium,it exists in plasma of all kinds of the endometrial cells.There is a negative correlation between serum TPOAb and the expression of TPO in endometrium.
引文
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6 Slayden OD,Nayak NR,Burton KA,Chwalisz K,Cameron ST,Critchley HOD,Baird DT,Brenner RM:Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.J Clin Endocrinol Metab 2001,86:2668-2679
7 Conneely OM,Lydon JP:Progesterone receptors in reproduction:functional impact of the A and B isoforms.Steroids 2000,65:571-577.
8 Brosens JJ,Hayashi N,White JO:Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells.Endocrinol 1999,140:4809-4820.
9 Brenner RM,Slayden OD:Steroid receptors in blood vessels of the rhesus macaque endometrium:a review.Arch Histol Cytol 2004,67:411-416.
10 Smith SK:Regulation of angiogenesis in the endometrium.Trends Endocrinol Metab 2001,12:147-51.
11 Meduri G,Bausero P,Perrot-Applanat M:Expression of vascular endothelial growth factor receptors in the human endometrium:modulation during the menstrual cycle.Biol Reprod 2000,62:439-447.
12 Teng CT,Gladwell W,Beard C,Walmer D,Teng CS,Brenner RM:Lactoferrin gene expression is estrogen responsive in human and rhesus monkey endometrium.Mol Hum Reprod 2002,8:58-67.
13 Shifren JL,Tseng JF,Zaloudek CJ＜,Ryan IP,Meng YG,Ferrara N,Jaffe RB,Taylor RN:Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium:mplications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.J Clin Endocrinol Metab 1996,81:3112-3118.
14 Snijders MP,de Goeij AFPM,Debets-Te Baerts MJC,Rousch MJ,Koudstaal J,Bosman FT:Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the humanuterus throughout the menstrual cycle and after the menopause.J Reprod Fertil 1992,94:363-371
15 Leece G,Meduri G,Ancelin M,Bergeron C,Perrot-Applanat:Presence of estrogen receptor 3 in the human endometrium through the cycle:expression in glandular,stromal and vascularcells.J Clin Endocrinol Metab 2001,86:1379-1386.
16 Critchley HO,Henderson TA,Kelly RW,Scobie GS,Evans LR,Groome NP,Saunders PT:Wild-type estrogen receptor (ERbetal)and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium.J Clin Endocrinol Metab 2002,87:5265-5273.
17 Petterson K,Grandien K,Kuiper GGJM,Gustafsson JA:Mouse estrogen receptor β forms estrogen receptor response element-binding heterodimers with estrogen receptor α.MolEndocrinol 1997,11:1486-1496.
18 Hall JM,McDonnell DP:The estrogen receptor β-isoform (ER β) of the human estrogen receptor modulates ER α transcriptional activity and is a key regulator of the cellular responseto estrogens and antiestrogens.Endocrinology 1999,140:5566-5578.
19 钱洪浪,朱依敏,周彩云,等.雌激素受体亚型ERα、ERβ在绝经过渡期妇女子宫内膜病变中的表达[J].中国实用妇科与产科杂志,2006,22(9):673-676
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21 Bardin A,Boulle N,Lazennec G,et al.Loss of ER expression as a common step in estrogen-dependent tumor progression[J].Endocr Relat Cancer,2004,11(3):537-551
22 Burton KA,Henderson Ta,Hiller SG,Mason JI,Habib F,Brenner RM,Critchley HO:Local levonorgestrel regulation of androgen receptor and 17beta-hydroxysteroid dehydrogenase type 2expression in human endometrium.Hum Reprod 2003,18:2610-2617.
23 Narvekar N,Cameron S,Critchley HO,Lin S,Cheng L,Baird DT:Low-dose mifepristone inhibits endometrial proliferation and up-regulates androgen receptor.J Clin Endocrinol Metab2004,89:2491-7.
24 Brenner RM,Slayden OD,Critchley HO:Anti-proliferative effects of progesterone antagonists in the primate endometrium:a potential role for the androgen receptor.Reproduction 2002,124:167-172.
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1 Jabbour HN,Kelly RW,Fraser HM,et al Endocrine regulation of menstruation[J].Endocr Rev,2006,27(1):17-46.
2 Kao LC,Tulac S,Lobo S,Imani B,Yang JP,Germeyer A,Osteen K,Taylor RN,Lessey BA,Giudice LC:Global gene profiling in human endometrium during window of implantation.Endocrinology 2002,143:2119-2138.
3 Talbi S,Hamilton AE,Vo KC,Tulac S,Overgaard MT,Dosiou C,Le Shay N,Nezhat CN,Kempson R,Lessey BA,Nayak NR,Giudice LC:Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.Endocrinology 2006,147:1097-1121.
4 Ponnampalam AP,Weston GC,Trajstam AC,Susil B,Rogers PA:Molecular classification of human endometrial cycle stages by transcriptional profiling.Mol Hum Reprod 2004,10:879-893.
5 Critchley HO,Brenner RM,Henderson TA,Williams K,Nayak NR,Slayden OD,Millar MR,Saunders PT:Estrogen receptor beta,but not estrogen receptor alpha,is present in the vascular endothelium of the human and nonhuman primate endometrium.J Clin Endocrinol Metab 2001,86:1370-8.
6 Slayden OD,Nayak NR,Burton KA,Chwalisz K,Cameron ST,Critchley HOD,Baird DT,Brenner RM:Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.J Clin Endocrinol Metab 2001,86:2668-2679
7 Conneely OM,Lydon JP:Progesterone receptors in reproduction:functional impact of the A and B isoforms.Steroids 2000,65:571-577.
8 Brosens JJ,Hayashi N,White JO:Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells.Endocrinol 1999,140:4809-4820.
9 Brenner RM,Slayden OD:Steroid receptors in blood vessels of the rhesus macaque endometrium:a review.Arch Histol Cytol 2004,67:411-416.
10 Smith SK:Regulation of angiogenesis in the endometrium.Trends Endocrinol Metab 2001,12:147-51.
11 Meduri G,Bausero P,Perrot-Applanat M:Expression of vascular endothelial growth factor receptors in the human endometrium:modulation during the menstrual cycle.Biol Reprod 2000,62:439-447.
12 Teng CT,Gladwell W,Beard C,Walmer D,Teng CS,Brenner RM:Lactoferrin gene expression is estrogen responsive in human and rhesus monkey endometrium.Mol Hum Reprod 2002,8:58-67.
13 Shifren JL,Tseng JF,Zaloudek CJ＜,Ryan IP,Meng YG,Ferrara N,Jaffe RB,Taylor RN:Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium:mplications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.J Clin Endocrinol Metab 1996,81:3112-3118.
14 Snijders MP,de Goeij AFPM,Debets-Te Baerts MJC,Rousch MJ,Koudstaal J,Bosman FT:Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the humanuterus throughout the menstrual cycle and after the menopause.J Reprod Fertil 1992,94:363-371
15 Leece G,Meduri G,Ancelin M,Bergeron C,Perrot-Applanat:Presence of estrogen receptor 3 in the human endometrium through the cycle:expression in glandular,stromal and vascularcells.J Clin Endocrinol Metab 2001,86:1379-1386.
16 Critchley HO,Henderson TA,Kelly RW,Scobie GS,Evans LR,Groome NP,Saunders PT:Wild-type estrogen receptor (ERbetal)and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium.J Clin Endocrinol Metab 2002,87:5265-5273.
17 Petterson K,Grandien K,Kuiper GGJM,Gustafsson JA:Mouse estrogen receptor β forms estrogen receptor response element-binding heterodimers with estrogen receptor α.MolEndocrinol 1997,11:1486-1496.
18 Hall JM,McDonnell DP:The estrogen receptor β-isoform (ER β) of the human estrogen receptor modulates ER α transcriptional activity and is a key regulator of the cellular responseto estrogens and antiestrogens.Endocrinology 1999,140:5566-5578.
19 钱洪浪,朱依敏,周彩云,等.雌激素受体亚型ERα、ERβ在绝经过渡期妇女子宫内膜病变中的表达[J].中国实用妇科与产科杂志,2006,22(9):673-676
20 Hu K,Zhong G,He F.Expression of extrogen receptors ERalpha and ERbeta in endometrial hyperplasis and adenocarcinoma[J].Int J Gynecol Cancer,2005,15(3):537-541
21 Bardin A,Boulle N,Lazennec G,et al.Loss of ER expression as a common step in estrogen-dependent tumor progression[J].Endocr Relat Cancer,2004,11(3):537-551
22 Burton KA,Henderson Ta,Hiller SG,Mason JI,Habib F,Brenner RM,Critchley HO:Local levonorgestrel regulation of androgen receptor and 17beta-hydroxysteroid dehydrogenase type 2expression in human endometrium.Hum Reprod 2003,18:2610-2617.
23 Narvekar N,Cameron S,Critchley HO,Lin S,Cheng L,Baird DT:Low-dose mifepristone inhibits endometrial proliferation and up-regulates androgen receptor.J Clin Endocrinol Metab2004,89:2491-7.
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