雌激素对子宫内膜异位症在位内膜间质细胞β-catenin mRNA的影响

目的:探讨Wnt信号通路在子宫内膜异位症(EMs)发病机制中的作用。方法:体外分离培养内异症患者在位内膜间质细胞,应用RT-PCR检测不同浓度(0mol/L,10-14mol/L,10-12mol/L,10-10mol/L,10-8mol/L,10-6mol/L)17β-雌二醇(17β-E2)作用子宫内膜间质细胞48h和17β-E2(10-10mol/L)作用子宫内膜间质细胞不同时间(0h,12h,24h,48h)后β-catenin mRNA的表达水平。同法检测雌激素受体拮抗剂ICI182,780(10-6mol/L)对17β-E2促进β-catenin mRNA表达的影响。结果:17β-E2体外能明显促进在位内膜间质细胞β-catenin mRNA的表达,并呈剂量和时间依赖性,于10-10mol/L17β-E2作用48h最明显。ICI182,780能明显抑制雌激素对在位内膜间质细胞β-catenin mRNA的表达。结论:Wnt信号通路可能参与了EMs的发生及发展。     

子宫内膜异位症对输卵管的结构和功能的影响

<正>子宫内膜异位症(endometriosis,EMs)定义为子宫内膜组织生长于子宫腔以外,其在普通人群中的患病率为5%,育龄女性为10%,而在不孕患者中则高达25%~50%[1]。尽管EMs与不孕之间的关联性尚无法确定,但大多数研究报道EMs患者比正常对照组妊娠率低,而具体机制还知之甚少。正常育龄夫     

Meis1在子宫内膜异位症不孕患者子宫内膜中的表达研究

目的:初步探索HOXA10的辅因子(Meis1)与子宫内膜异位症(EMs)患者不孕和发病的相关性。方法:采用免疫组织化学方法进行组织学定位并进行半定量分析,采用Westernblot-ting方法在蛋白水平上进行定量分析,检测EMs不孕患者异位和在位子宫内膜中Meis1的表达水平。结果:免疫组织化学结果显示,Meis1在异位内膜和在位内膜中仅有弱表达,而在正常同期内膜中呈较明显的阳性表达,差异显著(P<0.01);比较Meis1在分泌中期在位内膜与正常内膜中的表达,差异亦有显著性(P<0.01)。Westernblotting显示,Meis1在分泌中期在位内膜中仅有弱表达,而在同期正常内膜中呈高表达(P<0.001)。结论:Meis1在EMs患者分泌中期在位内膜中低表达,可能是影响子宫内膜容受性的建立,从而影响胚胎着床导致不孕的重要因素之一。同时,Meis1在异位内膜中的低表达说明异位内膜可能对体内雌、孕激素正常调控具有抵抗性,异位内膜细胞具备了对抗凋亡的能力,提示Meis1可能参与了EMs的发生与发展。     

激活素A对子宫内膜异位症患者在位内膜间质细胞的调节作用

目的:探讨激活素A(activin A)对子宫内膜异位症(endometriosis,EMs)患者在位子宫内膜间质细胞(endometrial stromal cells,ESCs)活性的调节作用。方法:分别用RT-PCR和Real-timePCR的方法检测5例正常、45例EMs在位、异位组织中激活素AβA亚基和芳香化酶CYP19A1mRNA的表达。分离培养5例正常、5例EMs在位、异位组织ESCs,用不同剂量的激活素A刺激EMs在位ESCs不同时间后,应用免疫电化学发光法检测ESCs分泌雌二醇(E2)的水平,MTT检测ESCs活性,流式细胞仪检测ESCs凋亡和细胞周期。结果:激活素AβA亚基在EMs异位ESCs的表达明显高于正常对照ESCs和EMs在位ESCs。经25 ng/ml激活素A刺激24 h后,与正常对照组相比,在位ESCs的E2分泌和芳香化酶CYP19A1mRNA的表达均显著升高。但激活素A未引起ESCs增殖活性的显著变化,对细胞凋亡和细胞周期亦无影响。结论:激活素A可能通过促进芳香化酶表达而增加ESCs的E2分泌,这可能是EMs异位灶存活和病理发生的机制之一。     

芳香化酶在子宫内膜异位症研究中的进展

<正>随着人们对芳香化酶(aromatase cytochromep450,p450arom)在子宫内膜异位症(EMs)发生、发展过程中作用的进一步认识,越来越多的学者对芳香化酶及其编码基因CYPl9(cytochrome p450 complex)的结构、功能及组织特异性表达的调控作了     

植物性雌激素对子宫内膜及异位子宫内膜的影响

植物性雌激素(phytoestrogens,PEs)是一类结构及生物学活性类似于雌激素的天然非甾体类化合物,可与雌激素受体结合,对内源性雌激素起双向调节作用。研究表明,植物雌激素可以缓解妇女围绝经期相关症状,且不会引起子宫内膜的复杂型增生及癌变;植物雌激素还能降低子宫内膜癌的发病风险,具有一定抗癌作用;此外,植物雌激素通过其弱的雌激素活性,既能抑制体内异位病灶的生长又能避免发生骨质疏松等副作用,将会给子宫内膜异位症(EMs)患者带来福音。     

子宫内膜异位症相关信号通路研究进展

子宫内膜异位症（EMs）作为妇科公认的疑难病,严重影响女性身心健康,因其病变多态性、侵袭性、广泛性,其发病机制目前尚无统一定论。相关信号通路的异常激活、多细胞因子的共同作用均会导致异位内膜细胞黏附、侵袭以及炎症的形成,目前丝裂原活化蛋白激酶（MAPKs）、Wnt/β-连环蛋白（β-catenin）、转化生长因子β（TGF-β）/Smad、核因子κB（NF-κB）、Ras同源基因/Rho相关螺旋卷曲蛋白激酶（Rho/ROCK）、Janus激酶2/转录活化因子3（JAK2/STAT3）等信号通路与EMs的发生、发展密切相关。现从以上6条通路阐述EMs的发病机制,为其寻找有效靶向药物治疗提供新的思路。     

腹腔微环境中巨噬细胞与子宫内膜异位症关系的研究进展

越来越多的研究认为,免疫调节在子宫内膜异位症(EMs)的发生、发展过程中起重要作用,腹腔免疫微环境的变化是EMs发生的前提和腹腔症状的病理基础。巨噬细胞通过不同功能的分化和时序变化,通过腹腔免疫微环境影响EMs的血管生成和异位内膜成功植入的分子机制。腹腔微环境发生变化体现在特定的炎症反应过程,其中巨噬细胞功能的改变作为基础性因素,介入异位病灶和腹腔微环境之间。巨噬细胞的功能分化体现在其通过吞噬或促进凋亡以清除异位病灶的同时,对血管生成和子宫内膜植入产生促进作用。     

二噁英对子宫内膜异位症患者子宫内膜细胞TNF-α表达的影响

目的:探讨二噁英(TCDD)在子宫内膜异位症(EMs)发病中的作用。方法:通过预实验,加入一定浓度的TCDD分别作用于11例EMs患者离体在位子宫内膜细胞和12例离体对照组子宫内膜细胞24 h,应用Real-time RT-PCR和ELISA法检测TCDD处理前后子宫内膜细胞肿瘤坏死因子-α(TNF-α)mRNA和蛋白的表达。结果:TCDD未处理前,EMs组子宫内膜细胞分泌TNF-α蛋白和mRNA水平均显著高于对照组(P<0.05)。TCDD呈剂量依赖方式促进子宫内膜细胞TNF-α蛋白的分泌,以10 nmol/L TCDD作用最明显(P<0.01),但TCDD对子宫内膜细胞TNF-αmRNA表达均无明显影响(P>0.05)。结论:二噁英可能通过影响子宫内膜细胞TNF-α蛋白水平的表达而参与EMs的发病过程,其主要机制可能不是通过调节其转录途径。     

子宫内膜异位症与自然流产的相关性分析

目的:探讨子宫内膜异位症(EMs)与自然流产的相关性。方法:回顾性分析行IVF-ET妊娠的周期,其中EMs患者903个周期、单纯男性因素者643个周期及单纯输卵管因素者720个周期,比较分析基础FSH值、β-hCG检测阳性率(临床妊娠前)、稽留流产率和自然流产率(临床妊娠后)等指标。结果:基础FSH值EMs组高于男性因素组和输卵管因素组;平均年龄EMs组略大于输卵管因素组及男性因素组,平均不孕年限3组间无统计学差异;临床妊娠率EMs组(32.1%)与输卵管因素不孕组(33.6%)无统计学差异(P>0.05),但显著低于男性因素组(45.7%);稽留流产率、异位妊娠率妊娠率3组间无统计学差异(P>0.05);EMs组自然流产率(9.1%)高于男性因素不孕组(1.0%)和输卵管因素组(4.5%),差异显著(P<0.05)。结论:EMs患者自然流产率高于输卵管因素不孕及单纯男性因素不孕的患者。     

子宫内膜异位症有关信号通路的研究进展

子宫内膜异位症(endometriosis,EMS)在生育年龄妇女中多发且发病率呈上升趋势,但其具体机制未完全明确,近年国内外学者研究表明EMS中存在的多种细胞凋亡/存活信号转导通路的异常,这些通路的异常启动及其复杂的相互作用会导致异位内膜组织的异常增殖、分化、侵入性增强及炎症反应,促进异位病灶形成,引起不孕、宫腔粘连、痛经等,对患者身心及经济带来极大挑战。因此,进一步研究EMS有关的信号通路对其所致的不孕症的临床治疗提供可靠依据,本文就EMS有关的MAPs通路、PI3K/AKT(PKB)通路、腺上皮-间质相互作用通路、Rho/ROCK通路的研究进展作一综述。     

Pathogenesis and pathophysiology of endometriosis

Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition.     

2-methoxyestradiol in the pathophysiology of endometriosis: focus on angiogenesis and therapeutic potential

Endometriosis is a common condition among women of childbearing potential in which ectopic endometrial tissue is found outside the uterine cavity. Neoangiogenesis plays a major role in the development of endometriotic implants. Some evidence suggests that a disorder in the balance of proangiogenic and antiangiogenic factors that favors the former is induced by local hypoxia and is mediated by the hypoxia-inducible factor-vascular endothelium growth factor pathway could partially explain the development of this condition in some women. 2-methoxyestradiol is a biologically active metabolite of estradiol having antiangiogenic action. Changes in estradiol homeostasis have been locally observed in endometriosis. In this review, we summarize current knowledge of endometriosis pathophysiology, in particular, the balance between local 2-methoxyestradiol production and angiogenesis, which could promote the development of endometriotic lesions. 2-Methoxyestradiol emerges as a promising new candidate for the treatment of endometriosis.     

New insights into the pathophysiology of endometriosis

Endometriosis is a fascinating and complex disease resulting from a dysregulation between exfoliated menstrual endometrium and the intra-abdominal environment. Increased concentrations of activated pelvic macrophages and lymphocytes and elevated levels of specific cytokines and growth factors in the peritoneal fluid support this hypothesis. The precise roles of these soluble factors are currently unknown, but we propose that a complex interplay of these locally produced cytokines, growth factors, steroids and eicosanoids modulates the growth and inflammatory behavior of ectopic endometrial implants via neovascularization. The enhanced secretion of local proangiogenic proteins by endometriosis lesions and associated immune cells (and the concomitant reduction of antiangiogenic principles) promotes the recruitment of capillaries toward the growing lesions. Ultimately, a cascade of effects on the peritoneal microenvironment results in implant proliferation and invasion. Future therapeutic strategies to target these angiogenic stimuli have the potential to block the vascular pathogenesis of endometriosis. This article gives an overview of the different factors involved in the development, growth and progression of endometriosis.     

The potential role of environmental toxins in the pathophysiology of endometriosis

Environmental contaminants that are known to disrupt steroid action can influence the development of reproductive diseases. Our group has focused on whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) can disrupt steroid regulation of endometrial matrix metalloproteinase (MMP) expression. The MMPs regulate extracellular matrix turnover in normal tissues, but the inappropriate expression of these enzymes is associated with numerous disease states that involve invasive processes. We have previously shown that secretion of MMPs by human endometrium is critical for establishment of ectopic lesions in a nude mouse model of experimental endometriosis. In this report, we show that TCDD exposure promotes establishment of experimental endometriosis by interfering with the ability of progesterone to suppress endometrial MMP expression. Copyrightz1999S. KargerAG,Basel     

The pathophysiology of endometriosis and adenomyosis: tissue injury and repair

Introduction  This study presents a unifying concept of the pathophysiology of endometriosis and adenomyosis. In particular, a physiological model is proposed that provides a comprehensive explanation of the local production of estrogen at the level of ectopic endometrial lesions and the endometrium of women affected with the disease. Methods  In women suffering from endometriosis and adenomyosis and in normal controls, a critical analysis of uterine morphology and function was performed using immunohistochemistry, MRI, hysterosalpingoscintigraphy, videohysterosonography, molecular biology as well as clinical aspects. The relevant molecular biologic aspects were compared to those of tissue injury and repair (TIAR) mechanisms reported in literature. Results and conclusions  Circumstantial evidence suggests that endometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial–myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of ‘tissue injury and repair’ (TIAR). This results in the local production of estrogen. With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues. In most cases of endometriosis/adenomyosis, a causal event early in the reproductive period of life must be postulated leading rapidly to uterine hyperperistalsis. In late premenopausal adenomyosis, such an event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life leads to the same extent of microtraumatization. With the activation of the TIAR mechanism followed by infiltrative growth and chronic inflammation, endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principle the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of ‘tissue injury and repair’ (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary.     

Voiding dysfunction after surgical resection of deeply infiltrating endometriosis: pathophysiology and management

Autonomic nerve (sympathic and parasympathic) damage plays a crucial role in the aetiology of bladder dysfunction that occurs after resection of deeply infiltrating endometriosis (uterosacral ligaments, colorectal bowel, rectovaginal wall). This review presents an overview of the pathophysiology and management of voiding dysfunction that occur after this kind of surgery. The rate of significant post-voiding residual volume and/or hypoactive bladder after colorectal resection for endometriosis ranges from 15 to 20%. This rate seems to be higher (up to 30%) after proximal utero-sacral ligaments resection. This is explained by the location of the inferior hypogastric plexus at the proximal portion of the utero-sacral ligaments. Urodynamics investigations show non specific hypoactive bladder and altered uroflowmetry. Concerning treatment, further controlled studies are needed to assess the hypothetical usefulness of parasympathomimetic and prokinetic agents for hypoactive bladder occurring after pelvic autonomic denervation. Neuromodulation is a successful treatment for patients with refractory lower urinary tract dysfunction. However, there is no controlled study that focused on its efficacy in voiding dysfunction after radical pelvic surgery. Overall, the main objective of the treatment is to avoid the complications of post-voiding residue (such as infection) and of abdominal pushing effort (deterioration of perineal tissues). Therefore, self catheterization should be recommended when this postoperative complication occurs. An understanding of the location of the autonomic pelvic network should help prevent iatrogenic injury through the adoption of surgical techniques, such as nerve sparing, that reduce postoperative autonomic dysfunction.     

Analysis of key candidate genes and pathways of endometriosis pathophysiology by a genomics-bioinformatics approach

Endometriosis is a common disease in women, but the signaling pathways and driven genes involved remain unclear. This study integrated four datasets to elucidate potential key candidate genes and pathways in endometriosis. Four expression profile datasets including 29 endometriosis lesions and 37 normal tissues were integrated and analyzed. Differentially expressed genes (DEGs) were sorted, and the gene ontology, pathway enrichment, and protein–protein interaction network of candidate genes were then analyzed. A total of 94 shared DEGs were identified from the four datasets. The DEGs were clustered based on functions and signaling pathways through the analysis of significant enrichment. Among the DEG protein-protein interaction network complex, 87 nodes/DEGs were identified. Furthermore, 18 central node genes were identified, and most of the corresponding genes were involved in the angiotensin system, smooth muscle contraction, cell junction organization, and lipoxin pathways. Through integrated bioinformatic analysis, we identified candidate genes and pathways in endometriosis, which could improve our understanding of endometriosis.