细胞凋亡与子宫内膜异位症的关系

越来越多的证据表明,子宫内膜异位症患者与正常人子宫内膜存在许多不同之处,表现为内异症患者的子宫内膜细胞粘附、侵袭和血管形成能力明显增强,使之具有异位种植和生长的能力,在内异症的发生和发展中起重要作用。最近研究表明,子宫内膜细胞自发性凋亡减弱和对凋亡信号不敏感,可能是内膜细胞具有异位种植和生长能力的重要因素。本文将细胞凋亡在正常子宫内膜周期变化中的作用,以及对子宫内膜异位症发生发展的影响作一综述。     

不同T细胞亚群及与其他免疫细胞协同作用参与子宫内膜异位病灶的形成和发展

子宫内膜异位症(简称:内异症)是育龄期妇女常见的妇科疾病,虽然内异症的发病机制至今尚未完全阐明,但越来越多的证据表明免疫因素在内异症的发病中具有重要作用。内异症患者盆腹腔异常的免疫微环境是子宫内膜得以异位种植生长的关键因素。T细胞在细胞免疫反应中居于核心地位,不同T细胞亚群则发挥着不同的免疫效应功能,它们与其他免疫细胞如单核巨噬细胞、树突细胞、自然杀伤细胞等协同作用,共同参与内异症的发生发展。     

CA125、抗子宫内膜抗体与子宫内膜异位症的关系

子宫内膜异位症(Endometriosis,EM)简称内异症,是育龄妇女的常见病,其发病率近年有上升趋势,由于其易浸润和复发,故是难治之症.近年来的研究显示,除肿瘤患者外,内异症患者(尤其是晚期患者)的血清CA125水平明显高于正常妇女,故CA125对诊断内异症有一定价值[1].内异症病因复杂,很可能由多种因素引起,其中与免疫功能平衡失调关系密切,抗子宫内膜抗体(EMAb)是一种以子宫内膜为靶抗原并引起一系列免疫病理反应的自身抗体,已成为内异症的标志抗体,其升高或降低与EM发展、消退相关[2].本文就CA125、EMAb和子宫内膜异症的关系研究进行综述.     

子宫内膜异位症动物模型发病极早期的VEGF和MMP-2表达(一)

子宫内膜异位症(内异症)是影响生育期妇女生活质量的常见疾病，其发病机制尚不清楚。利用免疫缺陷鼠种植人子宫内膜的模型是成功的，能够为我们提供研究内异症在腹膜腔环境内早期发生的条件。但因价格较为昂贵限制了该模型的推广，而国内有学者发现利用普通小鼠建立的内异症模型亦适于早期内异症发病的研究。文献报道，内异症患     

血管内皮生长因子及其受体在子宫内膜异位症中的表达和意义

目的:研究血管内皮生长因子(Vascular endothelial growth factor,VEGF)及其受体(Vascular endothelial growth factor receptor1,VEGFR1)在子宫内膜异位症(内异症)患者子宫在位内膜、异位内膜及正常对照组内膜组织中的表达,探讨其在子宫内膜异位症中的作用机制.方法:采用免疫组织化学及Western blot方法检测34例异位症患者在位内膜、异位内膜(内异症组)及34例正常内膜(对照组)组织中VEGF及其受体VEGFR1蛋白的定位及表达.结果:异症组在位及异位子宫内膜组织腺上皮细胞及间质细胞中均有VEGF及VEGFR1蛋白表达,且均高于同期对照组内膜,差异有统计学意义;对照组分泌期内膜VEGF及VEGFR1蛋白表达高于增生期,呈现周期性变化,而内异症组在位及异位内膜VEGF及VEGFR1蛋白表达失去周期性变化,分泌期与增生期均高表达,差异无统计学意义.Western blot检测结果与免疫组化结果一致.结论:内异症患者在位及异位内膜组织中VEGF、VEGFR1蛋白高表达可能与内异症的发生发展有关.     

腹壁子宫内膜异位症19例临床分析

目的 探讨腹壁子宫内膜异位症的临床发病特点、诊治及预防.方法 回顾性分析我院2001年-2009年收治的19例腹壁内异症患者的临床特点、治疗方法及随访情况.结果 19例患者全部行手术治疗,切除病灶外约5mm组织,手术后病检见子宫内膜上皮、腺体、纤维素及出血成分,其中2例镜下仅见少许内膜阃质细胞.手术后随访无复发.结论 剖宫产是腹壁子宫内膜异位症发生的高危因素,与赵学英等专家的意见一致,认为手术是惟一确实有效的治疗方法[1],手术切除是治疗和预防复发的关键.直接种植理论不能解释所有腹壁内异症的发生,但是规范的剖宫产技术是预防该病的关键.     

内异症子宫内膜ER、PR基因表达的研究

目的/:v探讨子宫内膜异位症(内异症)子宫内膜雌激素受体(ER)、孕激素受体(PR)基因表达在内异症发病中的作用。方法:利用大鼠内异症动物模型,采用逆转录聚合酶链反应(RT-PCR)技术,检测子宫内膜ER和PRmRNAs的表达情况。结果:内异症模型组大鼠异位内膜ER、PRmRNAs的表达显著低于在位内膜及对照组正常子宫内膜(P＜0.01);而模型组在位内膜ER、PRmRNAs的表达与正常对照组比较差异无显著(P＞0.05)。内异症模型组异位内膜ER/PRmRNA比值大于在位内膜及正常子宫内膜ER/PRmRNA比值(P＜0.01)。结论:内异症大鼠异位内膜ERmRNA表达的相对增高在内异症的发生与发展中起着一定的作用。     

子宫内膜异位症患者在位和异位内膜上皮细胞ER-α、ER-β的检测

目的探讨ER-α和ER-β在内异症患者在位及异位内膜上皮细胞中的表达与子宫内膜异位症发生机制的关系。方法通过体外细胞培养,利用流式细胞仪检测ER-α和ER-β在正常子宫内膜上皮细胞及内异症患者在位及异位内膜上皮细胞中表达。结果在正常子宫内膜上皮细胞及内异症患者在位及异位内膜上皮细胞中均检测到ER-α和ER-β的表达。而且在正常对照组和在位内膜组上皮细胞中ER-β明显高于ER-α。结论在子宫内膜异位症患者在位内膜,异位内膜上皮细胞中ER-α和ER-β表达有明显差异,表明除了已知的ER-α对子宫内膜增殖和分化的作用,ER-β可能对子宫内膜的功能也有重要影响,并提出深入研究二者之间的关系对子宫内膜异位症的发生发展,临床生物特性,治疗及预后有重要价值。     

子宫内膜异位症模型大鼠子宫内膜雌、孕激素受体表达的变化

利用大鼠子宫内膜异位症 (内异症 )动物模型 ,采用逆转录聚合酶链反应 (RT PCR)技术 ,检测子宫内膜雌激素受体 (ER)和孕激素受体 (PR)mRNAs的表达 ,探讨内异症的发病机理及激素治疗的可能性。结果表明 ,内异症模型组大鼠异位内膜ER、PRmRNAs的表达低于在位内膜及对照组正常子宫内膜 ,与后两者比较差异有显著性意义(P <0 0 1 ) ;而模型组在位内膜ER、PRmRNAs的表达与正常对照组比较差异无显著性意义。内异症模型组异位内膜ER PRmRNA比值大于在位内膜及正常子宫内膜ER PRmRNA比值 (P <0 0 1 )。提示内异症大鼠异位内膜ERmRNA表达的降低在内异症的发生与发展中起着一定的作用     

缺氧诱导因子-1α在子宫内膜异位症患者子宫内膜的表达及意义

目的:观察分析缺氧诱导因子-1α(HIF-1α)在子宫内膜异位症(简称内异症)患者子宫内膜细胞的表达及意义。方法:收集不同r-AFS分期子宫内异症患者(内异症组,n=35)和同期子宫肌瘤患者(对照组,n=40)子宫内膜组织标本,应用免疫组织化学(SP)技术检测各组(期)HIF-1α的表达情况,分析组间差异及与r-AFS分期的相关性。结果:子宫内异症组异位、在位子宫内膜HIF-1α阳性表达率分别为82.86%和77.14%,均明显高于对照组子宫内膜(52.50%)(χ~2=7.741、4.920,P均0.05),且子宫内异症组子宫内膜HIF-1α阳性表达率随r-AFS分期提高而升高(r=0.363,P0.05)。结论:HIF-1α表达上调可能与子宫内异症的发生发展有关。     

Promoter -817C>T variant of B lymphocyte stimulator gene (BLyS) and susceptibility to endometriosis-related infertility and idiopathic infertility in Brazilian population

Many theories have been proposed to explain the development of endometriosis, and recently, autoimmune aetiology has been suggested. Besides, it is well known that endometriosis, especially the advanced disease, may impair fertility. B lymphocyte stimulator (BLyS) is a cytokine produced by macrophages and is necessary for normal B cell development. One of the most studied polymorphisms is the -817C/T in the promoter region of the gene. We aimed to assess the association between endometriosis-related infertility and idiopathic infertility and the BLyS -817C/T polymorphism in a Brazilian population. We performed a case-control study comprising 165 infertile women with endometriosis, 83 with idiopathic infertility and 145 fertile and assessed the association with BLys -817C/T polymorphism. BLyS -817C/T polymorphism was detected using TaqMan PCR. The results were analysed statistically, and a P-value < 0.05 was considered significant. The results disclosed similar genotype and allelic frequencies between endometriosis-related infertility (P = 0.225) and control group, regardless of the disease stage (P = 0.213 and P = 0.462, respectively). However, a statistically significant difference was observed regarding idiopathic infertile group (P = 0.048) compared with controls. Considering the dominant and recessive inheritance models, no significant differences in both endometriosis and idiopathic infertility group were found. The genotype frequencies were in Hardy-Weinberg equilibrium in all studied groups. The results point to a possible association between BLyS -817C/T polymorphism and idiopathic infertility in Brazilian population.     

Evaluation of germline sequence variants within the promoter region of RANTES gene in a cohort of women with endometriosis from Spain

The RANTES (regulated upon activation normal T cells expressed and secreted) chemokine, is known to be expressed in endometriotic lesions in a concentration correlating with the severity of endometriosis. Since it has been widely demonstrated that endometriosis has a genetic basis, we postulated that the gene encoding RANTES could be a good candidate gene for the disease. We have used fluorescence resonance energy transfer (FRET) technology to genotype and evaluate the role of the variants -403G-->A and -28C-->G, located within the promoter region of the gene, as susceptibility factors in a cohort of Spanish women with endometriosis. No differences have been found in the allelic frequencies of both variants nor in the haplotype/ genotype distribution between patients and controls. These data are consistent with the lack of association between these polymorphisms and endometriosis in our population. They do not exclude completely a possible role of other variants within RANTES gene in this pathology.     

Variants of the CTLA4 gene that segregate with autoimmune diseases are not associated with endometriosis

An autoimmune etiology has been suggested for endometriosis mostly on the basis of an increased prevalence of autoimmune diseases in affected women. Cytotoxic T lymphocyte antigen (CTLA) 4 gene is recognized as a primary determinant for autoimmunity since specific polymorphisms have been associated with predisposition to most autoimmune disorders. This study was aimed to evaluate whether two variants of CTLA4 gene might be associated with endometriosis in an Italian population. We examined the +49A/G polymorphism and the CT60A/G dimorphism in n = 146 endometriosis subjects classified according to Holt and Weiss criteria. Controls were represented by n = 165 women without laparoscopic evidence of the disease. We found no statistically significant difference in the genotype frequencies between women with and without endometriosis. The proportion of the mutant G allele of the +49A/G polymorphism in the former and in the latter group resulted 34 and 30%, respectively. The proportion of the susceptible G allele of the CT60 A/G dimorphism resulted 51% in both groups. No association was demonstrated between the polymorphisms and the clinical forms of the disease and no susceptibility haplotypes were found. These findings suggest that endometriosis aetiology is not primarily associated with the development of CTLA4-linked autoimmunity.     

Immune interactions in endometriosis

Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial glands and stroma at extrauterine (ectopic) sites. In women who develop this disease, alterations in specific biological processes involving both the endocrine and immune systems have been observed, which may explain the survival and growth of displaced endometrial tissue in affected women. In the past decade, a considerable amount of research has implicated a role for alterations in progesterone action at both eutopic and ectopic sites of endometrial growth which may contribute to the excessive inflammation associated with progression of endometriosis; however, it remains unclear whether these anomalies induce the condition or are simply a consequence of the disease process. In this article, we summarize current knowledge of alterations within the immune system of endometriosis patients and discuss how endometrial cells from women with this disease not only have the capacity to escape immunosurveillance, but also use inflammatory mechanisms to promote their growth within the peritoneal cavity. Finally, we discuss evidence that exposure to an environmental endocrine disruptor, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, can mediate the development of an endometrial phenotype that exhibits both reduced progesterone responsiveness and hypersensitivity to proinflammatory stimuli mimicking the endometriosis phenotype. Future studies in women with endometriosis should consider whether a heightened inflammatory response within the peritoneal microenvironment contributes to the development and persistence of this disease.     

Immune interactions in endometriosis

Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial glands and stroma at extrauterine (ectopic) sites. In women who develop this disease, alterations in specific biological processes involving both the endocrine and immune systems have been observed, which may explain the survival and growth of displaced endometrial tissue in affected women. In the past decade, a considerable amount of research has implicated a role for alterations in progesterone action at both eutopic and ectopic sites of endometrial growth which may contribute to the excessive inflammation associated with progression of endometriosis; however, it remains unclear whether these anomalies induce the condition or are simply a consequence of the disease process. In this article, we summarize current knowledge of alterations within the immune system of endometriosis patients and discuss how endometrial cells from women with this disease not only have the capacity to escape immunosurveillance, but also use inflammatory mechanisms to promote their growth within the peritoneal cavity. Finally, we discuss evidence that exposure to an environmental endocrine disruptor, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, can mediate the development of an endometrial phenotype that exhibits both reduced progesterone responsiveness and hypersensitivity to proinflammatory stimuli mimicking the endometriosis phenotype. Future studies in women with endometriosis should consider whether a heightened inflammatory response within the peritoneal microenvironment contributes to the development and persistence of this disease.     

Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report

Several studies have shown that tumour necrosis factor (TNF)-alpha levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF-alpha concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids' TNF-alpha levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF-alpha receptor immunoglobulin fusion protein which inhibits TNF-alpha activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF-alpha blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF-alpha-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF-alpha showed no effect on infertility. However, use of TNF-alpha-blockers before IVF might increase the success rate in advanced endometriosis.     

Endometrioseassoziierte Tumorerkrankungen des Ovars

Endometriosis is a frequent gynecological disease of unknown etiology and pathogenesis. It affects the gynecological organs and the peritoneum with varying frequency and can lead to severe symptoms, mainly pain and to infertility. Despite the fact that causal therapy is not feasible diagnostic and therapeutic procedures are necessary in many cases. In a small percentage of cases endometriosis is associated with neoplastic disease and in some cases it might develop into a neoplasm via the stage of atypical endometriosis, notably in the ovaries. Tumors which are most frequently associated with endometriosis are endometrioid carcinoma, clear cell carcinoma, and low grade serous carcinoma. According to some authors tumors associated with endometriosis have a better prognosis than those without. Other tumors are Mullerian adenosarcoma, endometrioid stromal sarcoma, and seromucinous borderline tumor. In addition to the morphological findings more recent molecular findings serve to demonstrate the origin of the different types of carcinoma from endometriosis. In both endometrioid and clear cell carcinoma, loss of heterozygosity (LOH) can be found in different gene loci. Mutations in CTNNB1 (beta catenin), PTEN, KRAS and ARID1a genes have been demonstrated in endometrioid carcinoma. Cases of clear cell carcinoma have been characterized by mutations of ARID1a gene, PIK3CA and less frequently PPP2R1A and KRAS.     

The possible role of genetic variants in autoimmune-related genes in the development of endometriosis

Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti-inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis-associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen-receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis.     

CYP17及 ERα基因多态性与南方妇女子宫内膜异位症的相关性

目的 探讨细胞色素氧化酶17基因(cytochrome P450c17 gene,CYP17)和雌激素受体α基因(estrogen receptor α gene,ERα)多态性与中国南方妇女子宫内膜异位症(endometriosis,EM)的相关性.方法 应用高分辨率溶解曲线(high resolution melting curve,HRM)技术对432例EM患者和499例无EM的妇女 CYP17基因5′端非翻译区rs743572位点多态性(34T/C)和 ERα基因rs932233 位点多态性(-397T/C)进行分析.结果 两组均存在 CYP17 T/C和 ERα T/C多态性,但两组中基因型频率比较差异均无统计学意义(P>0.05),且在患病组和对照组中也未发现两个基因的相互作用与疾病相关.结论 CYP17基因启动子区rs743572位点多态性(34T/C)和 ERα基因rs932233 位点多态性(-397T/C)与中国南方妇女EM发病无明显相关.

Abstract：

Objective To investigate the association of single nucleotide polymorphisms in cytochrome P450 17 (CYP17) and estrogen receptor alpha (ERα) genes with the risk of endometriosis among southern Chinese women. Methods Two SNPs rs743572 (CYP17 gene 34T/C) and rs9322331 (ERα gene -397T/C) were genotyped by high resolution melting curve in 432 endometriosis patients and 499 matched controls. Results There was no significant difference in the genotype frequencies of the two loci between endometriosis patients and the control subjects (P>0.05). And there was no significant interaction effect of these two genes on the disease either. Conclusion CYP17 gene and ERα gene may not be genetic risk factors for endometriosis among southern women in China.     

Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata

Endometriosis, adenomyosis and leiomyomata develop in women of reproductive age and regress after menopause or ovariectomy, suggesting that they grow in an oestrogen-dependent fashion. We investigated whether polymorphism in the oestrogen receptor-alpha (ERalpha) gene is related to oestrogen-dependent benign uterine disease. A total of 203 women with regular menstrual cycles underwent laparotomy or laparoscopy and were diagnosed histologically with endometriosis, adenomyosis and/or leiomyomata. Patients with cervical carcinoma in situ, tubal occlusion or adhesion but no other gynaecological disease were considered to be disease-free. A total of 179 women undergoing annual health examination were grouped as reference population. The distribution of PVUII genotypes (PP, Pp, and pp) of the ERalpha gene was different between each pair of the four groups of endometriosis, adenomyosis/leiomyomata, disease-free, and reference population (P = 0.022-0.0005), except between the former two groups. The PP genotype was less frequent in the groups of endometriosis (P = 0.0002) and adenomyosis/leiomyomata (P = 0.002) as compared to that in the disease-free group. In the endometriosis group, there was no difference in the distribution of PVUII genotypes due to complicating diseases (adenomyosis and/or leiomyomata) or severity of the clinical stages. These results suggest that the PVUII polymorphism of the ERalpha gene is associated with the risk for endometriosis, adenomyosis, and leiomyomata.