基于在位内膜及免疫平衡探讨丹赤饮抑制子宫内膜异位症复发的机理
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摘要
目的：研究在位内膜及免疫平衡与子宫内膜异位症保守术后复发的关系；评估丹赤饮抑制气滞血瘀型子宫内膜异位症保守术后复发的临床疗效，探讨其抑制复发的作用机理。
方法：采用多中心、随机、阳性药对照、前瞻性临床研究方法。中、西药组患者均于保守术后首次月经来潮第1～5天内用药；疗程3个月。中药组采用丹赤饮加减；西药组采用GnRH-a类或孕三烯酮。观察并记录患者痛经、慢性盆腔痛、月经及不良反应情况，进行盆腔B超、血清CA125检查。观察比较中、西药两种治疗方法的临床复发率、不良反应发生率。
临床研究入组患者分别于术前、停药3个月采集子宫内膜组织；术前、用药3个月、停药3个月采集静脉血；另选取正常组采集子宫内膜组织和静脉血做为正常对照组。采用Western blotting、RT-PCR及免疫组化法检测患者手术前和停药3个月在位内膜P450arom、survivin的表达情况；采用ELISA法检测患者手术前、用药3个月和停药3个月血清IL-2、IL-6、IL-2/IL-6比值及CA125的表达水平。
结果：丹赤饮具有很好的抑制EM保守术后复发的作用，疗效与西药（GnRH-a、孕三烯酮）相当，且不影响患者的正常生理功能，不良反应、闭经发生率低（P<0.05）。
中药组、西药组患者术前P450arom、survivin、IL-6、IL-2、CA125的表达水平与正常组比较均有显著差异（P<0.05）。中药组、西药组在停药3个月后P450arom、survivin蛋白及mRNA表达量较术前均下降（P<0.05），且组间比较均无显著差异（P＞0.05）。中药组、西药组在治疗、停药3个月后血清IL-6、CA125的表达水平较术前均下降（P<0.05），血清IL-2表达水平及IL-2/IL-6比值较术前均升高（P<0.05），无论用药后还是停药后各因子表达水平较之正常组均无显著差异（P＞0.05）。
结论：丹赤饮抑制EM保守术后复发疗效肯定，且具有不良反应少、不影响正常生理功能的优势。在位内膜中芳香化酶的过度表达及细胞凋亡的降低可能是子宫内膜异位症的复发机制之一。中药丹赤饮通过抑制在位内膜芳香化酶的异常分泌、调控细胞凋亡从而抑制子宫内膜异位症的复发。血清IL-2、IL-6异常导致的免疫平衡失调是内异症病因及发病机制中重要的因素之一，丹赤饮通过调节细胞因子水平，调整免疫失衡而达到抑制内异症的复发；且丹赤饮对血清CA125具有降调作用。这一结果为丹赤饮抑制内异症保守术后复发的临床应用提供了一定的实验室依据。
Objective:To research the relationship of the eutopic endometrium of paients withEMs and immunologic balance and the recurrence of pelvic endometriosis after aconservative operation; To evaluate the clinical effectiveness of the Danchi decoction forcontrolling the recurrence of endometriosis of qi stasis causes blood stagnation after aconservative operation,and to investigate the mechanisms of endometriosis recurrence.
Methods: The study was a multi-center,randomized,positive drug control,prospective clinical trial. Drugs were given to patients during1–5days of the firstmenstruation after a conservative operation in Chinese herbal medicine group and Westernmedicine group.Patients with endometriosis were treated for3months. The patients in theChinese herbal medicine group (CMG) were treated using the Danchi decoction whilePatients in the Western medicine group (WMG) were treated using GnRH-a or Gestrinone.Any cases of dysmenorrheal, menstruation and any adverse reactions of patients wererecorded. During the period,patients underwent type B ultrasonography of the pelvis andmeasurements of serum CA125levels, routine evaluations of blood, urine, hepatic function(GPT levels), renal function (BUN levels) and electrocardiograms. The two treatmentswere compared for clinical recurrence rates and the incidence of adverse reactions.
The patients in the study were asked to collect the examples of the eutopicendometrium during the preoperative periods and discontinuing the medicine for3months.To collect the venous blood of the patients during the preoperative, treatment anddiscontinuing the medicine for3months. To choose the eutopic endometrium and venousblood in normal group as the control article. In the research,the expressions of P450arom and survivin in eutopic endometrium of patients with EMs were determined with Westernblotting,RT-PCR and immunhistochemisty preoperative period and discontinuing themedicine for3months, and the expressions of IL-2,IL-6,IL-2/IL-6and CA125inperipheral blood were evaluated by ELISA preoperative,3months after treatment anddiscontinuing the medicine for3months.
Result: The Danchi decoction can control the recurrence of endometriosis after aconservative operation effectually, which is equivalent to Western Medicine like GnRH-aor Gestrinone. It has not affect to normal physiological functions and also can have theaccommodation to the patients with endocrine dyscrasia. The rate of the incidence ofadverse reactions and amenorrhea of Danchi decoction is lower than Western Medicine（P<0.05）.
The research indicate that the expressions of P450,survivin,IL-6,IL-2and CA125ofpreoperative period in Chinese Medicine group(CM) and Western Medicine group(WM)were significantly different from the Controlling group(CG)（P<0.05）. The levels ofP450arom,survivin and mRNA of discontinuing the medicine for3months in CM groupand WM group were lower than preoperative period（P<0.05）,and the group comparisonwere not significantly (P＞0.05). The expressions of serum IL-6and CA125aftertreatment and discontinuing the medicine for3months were lower, and the expressions ofserum IL-2and the ratio of IL-2/IL-6were higher than preoperative period in ChineseMedicine group and Western Medicine group (P<0.05). Whatever after treatment ordiscontinuation of medicine, the expressions of factors in Chinese Medicine group andWestern Medicine group were not significantly different from the Controlling group(P＞0.05).
Conclusions: The Danchi decoction can control the recurrence of endometriosis aftera conservative operation effectually which is less the incidence of adverse reactions andhas not affect to normal physiological functions. The excessive expression of aromatizingenzyme and the decreased cell apoptosis in eutopic endometrium may be the one ofmechanisms of endometriosis recurrence. Controlling the recurrence of by DanchiDecoction, through to control the abnormal secretion of aromatizing enzyme and regulatethe cell apoptosis in eutopic endometrium. Serum IL-2and IL-6break the immunebalance,which is one of the important factors of causation and pathogenesis ofendometriosis. Danchi Decoction can control the recurrence of endometriosis by regulating the level of cytokine and immune disbalance,and the Danchi Decoction hasdown-regulation function on serum CA125.This result has laboratory evidence for clinicalapplication to control the recurrence of endometriosis
方法：采用多中心、随机、阳性药对照、前瞻性临床研究方法。中、西药组患者均于保守术后首次月经来潮第1～5天内用药；疗程3个月。中药组采用丹赤饮加减；西药组采用GnRH-a类或孕三烯酮。观察并记录患者痛经、慢性盆腔痛、月经及不良反应情况，进行盆腔B超、血清CA125检查。观察比较中、西药两种治疗方法的临床复发率、不良反应发生率。
临床研究入组患者分别于术前、停药3个月采集子宫内膜组织；术前、用药3个月、停药3个月采集静脉血；另选取正常组采集子宫内膜组织和静脉血做为正常对照组。采用Western blotting、RT-PCR及免疫组化法检测患者手术前和停药3个月在位内膜P450arom、survivin的表达情况；采用ELISA法检测患者手术前、用药3个月和停药3个月血清IL-2、IL-6、IL-2/IL-6比值及CA125的表达水平。
结果：丹赤饮具有很好的抑制EM保守术后复发的作用，疗效与西药（GnRH-a、孕三烯酮）相当，且不影响患者的正常生理功能，不良反应、闭经发生率低（P<0.05）。
中药组、西药组患者术前P450arom、survivin、IL-6、IL-2、CA125的表达水平与正常组比较均有显著差异（P<0.05）。中药组、西药组在停药3个月后P450arom、survivin蛋白及mRNA表达量较术前均下降（P<0.05），且组间比较均无显著差异（P＞0.05）。中药组、西药组在治疗、停药3个月后血清IL-6、CA125的表达水平较术前均下降（P<0.05），血清IL-2表达水平及IL-2/IL-6比值较术前均升高（P<0.05），无论用药后还是停药后各因子表达水平较之正常组均无显著差异（P＞0.05）。
结论：丹赤饮抑制EM保守术后复发疗效肯定，且具有不良反应少、不影响正常生理功能的优势。在位内膜中芳香化酶的过度表达及细胞凋亡的降低可能是子宫内膜异位症的复发机制之一。中药丹赤饮通过抑制在位内膜芳香化酶的异常分泌、调控细胞凋亡从而抑制子宫内膜异位症的复发。血清IL-2、IL-6异常导致的免疫平衡失调是内异症病因及发病机制中重要的因素之一，丹赤饮通过调节细胞因子水平，调整免疫失衡而达到抑制内异症的复发；且丹赤饮对血清CA125具有降调作用。这一结果为丹赤饮抑制内异症保守术后复发的临床应用提供了一定的实验室依据。
Objective:To research the relationship of the eutopic endometrium of paients withEMs and immunologic balance and the recurrence of pelvic endometriosis after aconservative operation; To evaluate the clinical effectiveness of the Danchi decoction forcontrolling the recurrence of endometriosis of qi stasis causes blood stagnation after aconservative operation,and to investigate the mechanisms of endometriosis recurrence.
Methods: The study was a multi-center,randomized,positive drug control,prospective clinical trial. Drugs were given to patients during1–5days of the firstmenstruation after a conservative operation in Chinese herbal medicine group and Westernmedicine group.Patients with endometriosis were treated for3months. The patients in theChinese herbal medicine group (CMG) were treated using the Danchi decoction whilePatients in the Western medicine group (WMG) were treated using GnRH-a or Gestrinone.Any cases of dysmenorrheal, menstruation and any adverse reactions of patients wererecorded. During the period,patients underwent type B ultrasonography of the pelvis andmeasurements of serum CA125levels, routine evaluations of blood, urine, hepatic function(GPT levels), renal function (BUN levels) and electrocardiograms. The two treatmentswere compared for clinical recurrence rates and the incidence of adverse reactions.
The patients in the study were asked to collect the examples of the eutopicendometrium during the preoperative periods and discontinuing the medicine for3months.To collect the venous blood of the patients during the preoperative, treatment anddiscontinuing the medicine for3months. To choose the eutopic endometrium and venousblood in normal group as the control article. In the research,the expressions of P450arom and survivin in eutopic endometrium of patients with EMs were determined with Westernblotting,RT-PCR and immunhistochemisty preoperative period and discontinuing themedicine for3months, and the expressions of IL-2,IL-6,IL-2/IL-6and CA125inperipheral blood were evaluated by ELISA preoperative,3months after treatment anddiscontinuing the medicine for3months.
Result: The Danchi decoction can control the recurrence of endometriosis after aconservative operation effectually, which is equivalent to Western Medicine like GnRH-aor Gestrinone. It has not affect to normal physiological functions and also can have theaccommodation to the patients with endocrine dyscrasia. The rate of the incidence ofadverse reactions and amenorrhea of Danchi decoction is lower than Western Medicine（P<0.05）.
The research indicate that the expressions of P450,survivin,IL-6,IL-2and CA125ofpreoperative period in Chinese Medicine group(CM) and Western Medicine group(WM)were significantly different from the Controlling group(CG)（P<0.05）. The levels ofP450arom,survivin and mRNA of discontinuing the medicine for3months in CM groupand WM group were lower than preoperative period（P<0.05）,and the group comparisonwere not significantly (P＞0.05). The expressions of serum IL-6and CA125aftertreatment and discontinuing the medicine for3months were lower, and the expressions ofserum IL-2and the ratio of IL-2/IL-6were higher than preoperative period in ChineseMedicine group and Western Medicine group (P<0.05). Whatever after treatment ordiscontinuation of medicine, the expressions of factors in Chinese Medicine group andWestern Medicine group were not significantly different from the Controlling group(P＞0.05).
Conclusions: The Danchi decoction can control the recurrence of endometriosis aftera conservative operation effectually which is less the incidence of adverse reactions andhas not affect to normal physiological functions. The excessive expression of aromatizingenzyme and the decreased cell apoptosis in eutopic endometrium may be the one ofmechanisms of endometriosis recurrence. Controlling the recurrence of by DanchiDecoction, through to control the abnormal secretion of aromatizing enzyme and regulatethe cell apoptosis in eutopic endometrium. Serum IL-2and IL-6break the immunebalance,which is one of the important factors of causation and pathogenesis ofendometriosis. Danchi Decoction can control the recurrence of endometriosis by regulating the level of cytokine and immune disbalance,and the Danchi Decoction hasdown-regulation function on serum CA125.This result has laboratory evidence for clinicalapplication to control the recurrence of endometriosis
引文
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[1]董桂苹.子宫内膜异位症的病因与治疗进展[J].中国妇幼保健，2008；23(25)：3634-3637.
[2]郎景和.以转化医学的观念促进子宫内膜异位症的研究[J].国际妇产科学杂志，2011；38(4)：261.
[3]李梅生，谭布珍，张萍.子宫内膜异位症现代治疗[J].北京：人民军医出版社.2003；3（1）：75-92.
[4]张治宁，宋丹.卵巢子宫内膜异位症的腹腔镜治疗及术后随访[J].宁夏医学杂志，2006；28(11)：850-851.
[5]赵宇，耿筱虹，杨海虹，等.腹腔镜联合药物治疗重度子宫内膜异位症及合并不孕症的疗效分析[J].温州医学院学报，2008；1(38)：71-73.
[6]郎景和.子宫内膜异位症基础与临床研究的几个问题[J].中国实用妇科与产科杂志.2002；(3):11-13.
[7] Bulletti C, DeZiegler D, Stefanetti M. Endometriosis: absence of recurrence inpatients after endometrial ablation[J]. Hum Reprod，2001；16(12)：2676-2679.
[8] Matsuzaki S, Canis M, Pouly JL, et al. Analysis of aromatase and17beta-hydroxysteroid dehydrogenase type2messenger ribonucleic acid expressionin deep endometriosis and eutopic endometrium using laser capture microdissection[J]. Fertil Steril,2006；85(2)：308-313.
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[11] Luisi S, Galleri L, Marini F, et al. Estrogen receptor gene polymor-phisms areassociated with recurrence of endometriosis [J]. Fertil Steril，2006；85(3)：764-766.
[12]李明清.子宫内膜异位症：一种自身免疫病[J].国外医学妇产科学分册，2007，34（5）：348-351.
[13] Maeda N, Izumiya C, KusumT, et al. Killer inhibitoryreceptor CD158a overexpression among natural killer cells in women with endometriosis is undiminishedby laparoscopic surgery and gonadotropin releasinghormone agonist treatment[J].AmJ ReprodImmunol，2004；51(5)：364-372.
[14]邵雪峰，李琳琳，邵骏，姚辉.子宫内膜异位症患者治疗前后血清IL-2、SIL-2R和TNF-α检测的临床意义[J].放射免疫学杂志，2008；21（3）：204-206.
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[19] Jackson LW，Schisterman EF，Dey Rao R，et al. Oxidative stress and n-dometriosis[J].Human Reproduction，2005；20（7）：2014-2020.
[20] Lambrinoudaki IV，Augoulea A，Christodoulakos GE，et al. Measurableserum markersof oxidative stress response in women with endometriosis[J]. Fertility and Sterility，2009；91（1）：46-50.
[21]彭华,张燕,朱翠婷,等.子宫内膜异位症疾病复发与个体腹腔镜术后氧化应激状态的关系探讨[J].中国当代医药，2012；19(3)：11-13.
[22]张治宁，宋丹.卵巢子宫内膜异位症的腹腔镜治疗及术后随访[J].宁夏医学杂志，2006；28(11)：850-851.
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[24] Jee BC，Lee JY，Suh CS，et al．Impact of GnRH agonist treatment on recurrence ofovarian endometriomas after conservative laparoscopic surgery [J]．Fertil Steril，2009；91：40-45．
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[1]董桂苹.子宫内膜异位症的病因与治疗进展[J].中国妇幼保健，2008；23(25)：3634-3637.
[2]郎景和.以转化医学的观念促进子宫内膜异位症的研究[J].国际妇产科学杂志，2011；38(4)：261.
[3]李梅生，谭布珍，张萍.子宫内膜异位症现代治疗[J].北京：人民军医出版社.2003；3（1）：75-92.
[4]张治宁，宋丹.卵巢子宫内膜异位症的腹腔镜治疗及术后随访[J].宁夏医学杂志，2006；28(11)：850-851.
[5]赵宇，耿筱虹，杨海虹，等.腹腔镜联合药物治疗重度子宫内膜异位症及合并不孕症的疗效分析[J].温州医学院学报，2008；1(38)：71-73.
[6]郎景和.子宫内膜异位症基础与临床研究的几个问题[J].中国实用妇科与产科杂志.2002；(3):11-13.
[7] Bulletti C, DeZiegler D, Stefanetti M. Endometriosis: absence of recurrence inpatients after endometrial ablation[J]. Hum Reprod，2001；16(12)：2676-2679.
[8] Matsuzaki S, Canis M, Pouly JL, et al. Analysis of aromatase and17beta-hydroxysteroid dehydrogenase type2messenger ribonucleic acid expressionin deep endometriosis and eutopic endometrium using laser capture microdissection[J]. Fertil Steril,2006；85(2)：308-313.
[9] Kitawaki J, Obayashi H, Ishihara H, et al. Oestrogen receptor-alpha genepolymorphism is associated with endometriosis,adenomyosis and leiomyomata[J].Hum Reprod，2001；16(1)：51-55.
[10] BukulmezO,HardyDB,CarrBR,etal.Inflammatorystatusinfluences aromatase andsteroid receptor expression in endometriosis [J].Endocrinology，2008；149(3)：1190-1204.
[11] Luisi S, Galleri L, Marini F, et al. Estrogen receptor gene polymor-phisms areassociated with recurrence of endometriosis [J]. Fertil Steril，2006；85(3)：764-766.
[12]李明清.子宫内膜异位症：一种自身免疫病[J].国外医学妇产科学分册，2007，34（5）：348-351.
[13] Maeda N, Izumiya C, KusumT, et al. Killer inhibitoryreceptor CD158a overexpression among natural killer cells in women with endometriosis is undiminishedby laparoscopic surgery and gonadotropin releasinghormone agonist treatment[J].AmJ ReprodImmunol，2004；51(5)：364-372.
[14]邵雪峰，李琳琳，邵骏，姚辉.子宫内膜异位症患者治疗前后血清IL-2、SIL-2R和TNF-α检测的临床意义[J].放射免疫学杂志，2008；21（3）：204-206.
[15]闵捷燕.子宫内膜异位症患者血清EMAb、VEGF、IL-2及IL-2R水平变化[J].放射免疫学杂志，2009；22（2）：109.
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[17] Koga K，Takemura Y，Osuga Y，etal.Recurrence of ovarian en－dometrioma afterlaparoscopic excision [J].Hum Reprod，2006；21（8）：2171-2174.
[18] Parazzinia F，Bertulessib C，Pasinic A，et al. Determinants ofshort term recurrence rateof endometriosis [J].Eur J Obstet Gy-necol Reprod Biol，2005；121（2）：216-219.
[19] Jackson LW，Schisterman EF，Dey Rao R，et al. Oxidative stress and n-dometriosis[J].Human Reproduction，2005；20（7）：2014-2020.
[20] Lambrinoudaki IV，Augoulea A，Christodoulakos GE，et al. Measurableserum markersof oxidative stress response in women with endometriosis[J]. Fertility and Sterility，2009；91（1）：46-50.
[21]彭华,张燕,朱翠婷,等.子宫内膜异位症疾病复发与个体腹腔镜术后氧化应激状态的关系探讨[J].中国当代医药，2012；19(3)：11-13.
[22]张治宁，宋丹.卵巢子宫内膜异位症的腹腔镜治疗及术后随访[J].宁夏医学杂志，2006；28(11)：850-851.
[23]赵宇，耿筱虹，杨海虹，吕杰强.腹腔镜联合药物治疗重度子宫内膜异位症及合并不孕症的疗效分析[J].温州医学院学报，2008；1(38)：71-73.
[24] Jee BC，Lee JY，Suh CS，et al．Impact of GnRH agonist treatment on recurrence ofovarian endometriomas after conservative laparoscopic surgery [J]．Fertil Steril，2009；91：40-45．
[25] LeverroG，CarrieroC，RossiAC，etal．Arandomized studycomparing trip or expectantmanagement following conservative laparoscopic sur-gical for symptomaticstageⅢ/Ⅳ endometriosis[J]．Eur J Obstet Gy-necol Reprod Biol，2008；136：194-198．
[26] Porpora MG，Pallante D，Ferro A，et al．Pain and ovarian endometrioma recurrenceafter laparoscopic treatment of endomtriosis: a long–term prospective study[J]．Fertil Steril，2010；93：716-721．
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