Endometriosis: New concepts in the pathogenesis

Endometriosis is a gynaecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity. Though there are several theories, research scientists remain unsure as to the definitive cause(s) of endometriosis. Considering the relevant health problems caused by endometriosis, all new information on the pathogenesis of this disease, may have important clinical implications. Goal of this article is to summarize the latest advances in the pathogenesis of endometriosis, with particular emphasis on the embryological theory, that has been recently re-proposed. The possible clinical implications of these findings will be discussed.     

Growth mechanisms of endometriotic cells in implanted places: a review

Endometriosis is a common gynecological disease defined by extrauterine growth of endometrial glands and stroma. A variety of theories have been proposed to account for the pathogenesis of this disease, including retrograde transplantation theory, metaplasia of coelomic epithelium, hematogenic and lymphogenic spread, and remnants of the M?llerian duct. However, the etiopathology of endometriosis is still obscure. In this article, we aim to summarize recent researches concerning the growth mechanisms of endometriotic cells in implanted sites systematically, including the adhesion, invasion, angiogenesis, proliferation, apoptosis of endometriotic cells, variations of the immune molecules and endometriotic cells themselves, which may provide clues for future researches in the pathogenesis of endometriosis.     

miRNA的重要调节者Dicer和Drosha与子宫内膜异位症的相关性研究

利用荧光定量PCR和Western blot检测证实,在异位的子宫内膜组织中Dicer和Drosha的表达低于在位子宫内膜组织,随后体外培养在位子宫内膜组织,采用siRNA干扰Dicer和Drosha,发现与干扰对照组相比,子宫内膜细胞的增殖加快而凋亡减少;同时ELISA检测显示转化生长因子-β1(transforming growth factor-beta 1, TGF-β1)的表达上调;Western blot检测显示凋亡抑制蛋白Bcl2表达增加而促凋亡蛋白Bax的表达减少．结果表明,miRNA的重要调节者Dicer和Drosha可以影响TGF-β1及Bcl2/Bax的表达进而影响细胞的增殖和凋亡,从而参与了子宫内膜异位症的形成．     

Clarithromycin and telithromycin increases interleukin-10 expression in the rat endometriosis model

Endometriosis is a common gynecological disorder associated with infertility. However, treatment options remain limited at present. Since the pathogenesis involves immune responses, the immunomodulatory effect of macrolide on endometriosis has been the focus of much research. A previous study showed that clarithromycin decreased stromal proliferation and promoted apoptosis of fibroblasts in an endometriosis model in rats; however, the mechanism of the effect remains unknown. The aim of this study is to investigate the effect of clarithromycin, one of the major macrolides, and telithromycin, one of the antibiotics belonging to a macrolide group (ketolide), on IL6, IL10 and Ccl2 expression in a rat endometriosis model induced by the surgical transplantation of endometrium onto the peritoneum in 8-week-old female Sprague-Dawley rats. After autotransplantation, the rats were given daily administration of clarithromycin (16 mg/kg/day or telithromycin (12 mg/kg/day) for 3 days. The induced lesions were examined 4 days after autotransplantation. After treatment, IL10 expression in the lesions was increased in rats treated with clarithromycin (1.70-fold) and telithromycin (2.88-fold). The drugs attenuated proliferative stromal lesion of the endometriosis model. The results showed that in the endometriosis model, the drugs enhanced expression of IL10, which may play a role in inhibiting excess inflammatory reaction with its therapeutic effect on the lesion. Macrolide and ketolide therapy may have significant value for the treatment of human endometriosis.     

Proteomics technologies in endometriosis

Endometriosis is a common disorder that is associated with infertility and pelvic pain. Diagnosis is based on the visualization of endometriotic lesions during surgery as no reliable serum marker is currently available. The etiology of endometriosis is largely unknown. Over the last 20 years, several proteomics technologies have been used to research novel proteins with a potential etiological role in endometriosis, and to identify candidate serum markers for this condition. While some molecules identified by proteomics technologies may have a relevant role in the pathogenesis of endometriosis, the research of potential serum markers for this condition is still far from any clinical application. This review summarizes the state of the art and potential applications of proteomics in endometriosis research.     

Mitochondrial DNA 4977-bp deletion in endometriosis

Endometriosis is a multifactorial gynecological condition characterized by the presence of ectopic endometrial and stromal tissue outside the uterus. Free radicals and Oxidative stress have been proposed to be involved in the pathogenesis of the endometriosis. It has been shown that mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage and mutations due to the high rate of reactive oxygen species production and limited DNA repair capacity in mitochondria. While a number of deletions can occur, the most commonly studied in human is a 4977-bp deletion that removes all or parts of the genes for NADH dehydrogenase subunits 3, 4, 4L and 5, cytochrome C oxidase subunit III and ATP synthase subunits 6 and 8.” We evaluated whether mtDNA common deletion is related with the susceptibility to endometriosis in northern Iran. In this study 80 endometriosis cases and 100 controls were enrolled. Total DNA was extracted from endometrial tissue samples. The mitochondrial common deletion was determined by Gap- polymerase chain reaction (Gap-PCR). It was found that the mitochondrial common deletion was more likely to be present in patients with endometriosis. Assessing indicate that 60 % of patients and 8 % of controls show mtDNA 4977-bp deletion (Odds Ratio [OR] = 17.25, P < 0.0001, confidence interval [CI] = 5.18–57.36). The mtDNA 4977 deletion may play a role in endometriosis. Further studies with larger numbers of patients are required for further evaluation and confirmation of our finding.     

Circulating miRNAs Related to Epithelial–Mesenchymal Transitions (EMT) as the New Molecular Markers in Endometriosis

Endometriosis is a chronic gynecological disease defined by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves. The complex etiopathogenesis and heterogenity of the clinical symptoms, as well as the lack of a specific non-invasive diagnostic biomarkers, underline the need for more advanced diagnostic tools. Unfortunately, the contribution of environmental, hormonal and immunological factors in the disease etiology is insufficient, and the contribution of genetic/epigenetic factors is still fragmentary. Therefore, there is a need for more focused study on the molecular mechanisms of endometriosis and non-invasive diagnostic monitoring systems. MicroRNAs (miRNAs) demonstrate high stability and tissue specificity and play a significant role in modulating a range of molecular pathways, and hence may be suitable diagnostic biomarkers for the origin and development of endometriosis. Of these, the most frequently studied are those related to endometriosis, including those involved in epithelial–mesenchymal transition (EMT), whose expression is altered in plasma or endometriotic lesion biopsies; however, the results are ambiguous. Specific miRNAs expressed in endometriosis may serve as diagnostics markers with prognostic value, and they have been proposed as molecular targets for treatment. The aim of this review is to present selected miRNAs associated with EMT known to have experimentally confirmed significance, and discuss their utility as biomarkers in endometriosis.     

An Update on the Multifaceted Role of NF-kappaB in Endometriosis

Endometriosis remains a common but challenging gynecological disease among reproductive-aged women with an unclear pathogenesis and limited therapeutic options. Numerous pieces of evidence suggest that NF-κB signaling, a major regulator of inflammatory responses, is overactive in endometriotic lesions and contributes to the onset, progression, and recurrence of endometriosis. Several factors, such as estrogen, progesterone, oxidative stress, and noncoding RNAs, can regulate NF-κB signaling in endometriosis. In the present review, we discuss the mechanisms by which these factors regulate NF-κB during endometriosis progression and provide an update on the role of NF-κB in affecting endometriotic cells, peritoneal macrophages (PMs) as well as endometriosis-related symptoms, such as pain and infertility. Furthermore, the preclinical drugs for blocking NF-κB signaling in endometriosis are summarized, including plant-derived medicines, NF-κB inhibitors, other known drugs, and the potential anti-NF-κB drugs predicted through the Drug-Gene Interaction Database. The present review discusses most of the studies concerning the multifaceted role of NF-κB signaling in endometriosis and provides a summary of NF-κB-targeted treatment in detail.     

子宫内膜异位症发病机制的研究进展

子宫内膜异位症(内异症)仍是医学上的一个难题,给育龄期的妇女带来了极大的痛苦,可以引起继发性痛经、慢性盆腔痛、不孕等临床症状。内异症的具体发病机制仍不清楚,在经典的"经血逆流"学说提出以后,又出现了体腔上皮化生学说、苗勒管残迹学说等。近几年的研究又提出了一系列与内异症发病相关的因素,包括在位内膜的生物学特点、雌激素作用、免疫炎症反应、血管形成等,这些因素的提出对子宫内膜异位症的发病机制进行了补充和深入,也为现在子宫内膜异位症的诊治提供了新的思路和方向。文章对近年来子宫内膜异位症发病机制的相关研究进展进行了回顾与总结,作一综述。     

Increased c-Jun N-terminal kinase activation in human endometriotic endothelial cells

Endometriosis is a common inflammatory gynecological disease characterized by the presence of endometrial tissue outside of the uterine cavity. The c-Jun N-terminal kinase (JNK) is a subfamily of the mitogen-activated protein kinases (MAPKs) involved in cellular processes ranging from cytokine expression to apoptosis, and is activated in response to inflammation and cellular stress. We hypothesized that inflammatory cytokines in the peritoneal microenvironment increase JNK MAPK activity in endometriotic endothelial cells, and that human endometrial endothelial cells (HEECs) may be involved in inflammatory pathogenesis of endometriosis. Thus, we evaluated the expression of the total- and phosphorylated-(phospho)-JNK in endometrial and endometriotic endothelial cells in vivo, and in HEECs treated with normal peritoneal fluid (NPF), endometriotic peritoneal fluid (EPF), and the inflammatory cytokines interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in vitro. Phospho-JNK immunoreactivity in HEECs in normal endometrium was significantly higher in the early proliferative and late secretory phases compared to other phases. Both eutopic and ectopic HEECs from the early secretory phase also revealed higher phospho-JNK immunoreactivity, compared to their respective cycle-matched normal HEECs. Moreover, HEECs treated with EPF showed significantly higher phospho-JNK levels compared to that in HEECs treated with NPF. In conclusion, our in vivo and in vitro findings suggest that increased phosphorylation of JNK in HEECs from women with endometriosis is likely due to high level of IL-1β and TNF-α in peritoneal fluid; this in turn may up-regulate inflammatory cytokine expression and thus play a role in the pathogenesis of endometriosis.     

The role of inflammation,oxidative stress,angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression

Endometriosis is a frequent and chronic illness in young women which could be defined by the existence of endometrial stroma and glands outside of the normal site of the lining of the uterus. It has painful symptoms. The advanced stage of endometriosis may lead to gynecological malignancies, such as ovarian cancer, and other complications, including infertility. However, its exact physiopathology is not well known. Recent studies have shown the possible roles of inflammation along with oxidative stress. Additionally, angiogenesis and apoptosis dysregulation contribute to endometriosis pathophysiology. Therapeutic strategies and continuing attempts, to conquer endometriosis should be done regarding molecular signaling pathways. Thus, the present review summarizes current studies and focuses on molecular mechanisms.     

Myricetin inhibits endometriosis growth through cyclin E1 down-regulation in vitro and in vivo

Endometriosis is a benign gynecological condition prevalent among reproductive-aged women. Although active research and studies have been carried out to discover new drugs, surgery and hormone therapy are still the gold standard for endometriosis treatment. Nowadays, various flavonoids are considered long-term supplements for different diseases. Myricetin, a flavonol, has antiproliferative, anti- or pro-oxidant, and anticancer effects in gynecological diseases. Here, we reveal for the first time, to our knowledge, the antigrowth effects of myricetin in endometriosis. Myricetin inhibited cell proliferation and cell cycle progression of human VK2/E6E7 and End1/E6E7 cells and induced apoptosis, with the loss of mitochondrial membrane potential and accumulation of reactive oxygen species and calcium ions. Additionally, myricetin decreased the activation of AKT and ERK1/2 proteins, whereas it induced p38 activation in both cell lines. Moreover, myricetin decreased lesion size in the endometriosis mouse model via Ccne1 inhibition. Thus, myricetin has antiproliferative effects on endometriosis through cell cycle regulation.     

Mitochondrial genome variations in advanced stage endometriosis: a study in South Indian population

Background

Endometriosis is a chronic gynecological benign disease that shares several features similar to malignancy. Mitochondrial DNA (mtDNA) mutations have been reported in all most all types of tumors. However, it is not known as to whether mtDNA mutations are associated with endometriosis.

Methodology

We sequenced the entire mitochondrial genome of analogous ectopic and eutopic endometrial tissues along with blood samples from 32 advanced stage endometriosis patients to analyze the role of somatic and germ-line mtDNA variations in pathogenesis of endometriosis. All ectopic tissues were screened for tumor-specific mtDNA deletions and microsatellite instability (MSI). We also performed mtDNA haplogrouping in 128 patients and 90 controls to identify its possible association with endometriosis risk.

Principal Findings

We identified 51 somatic (novel: 31; reported: 20) and 583 germ-line mtDNA variations (novel: 53; reported: 530) in endometriosis patients. The A13603G, a novel missense mutation which leads to a substitution from serine to glycine at the codon 423 of ND5 gene showed 100% incidence in ectopic tissues. Interestingly, eutopic endometrium and peripheral leukocytes of all the patients showed heteroplasmy (A/G; 40–80%) at this locus, while their ectopic endometrium showed homoplasmic mutant allele (G/G). Superimposition of native and mutant structures of ND5 generated by homology modeling revealed no structural differences. Tumor-specific deletions and MSI were not observed in any of the ectopic tissues. Haplogrouping analysis showed a significant association between haplogroup M5 and endometriosis risk (P: 0.00069) after bonferroni correction.

Conclusions

Our findings substantiate the rationale for exploring the mitochondrial genome as a biomarker for the diagnosis of endometriosis.     

子宫内膜异位症的临床诊断及治疗新进展

子宫内膜异位症是至今为止仍让人迷茫的疾病,现在引起人们越来越多地关注。内异症是一种进展性疾病,国内外医疗界学者试图将其早期诊断彻底治愈,但结果颇为不佳。通过临床的不断摸索,期望更全面更合理的诊断与治疗系统问世。目前其发病机制尚未彻底阐明,而在其诊断及治疗方面也缺乏特异性的方法,现就其诊断及治疗进展综述如下。     

旋转恒定磁场治疗盆腔子宫内膜异位症初步疗效观察

目的:探讨旋转恒定磁场治疗盆腔子宫内膜异位症的效果.方法:选择山东省立医院2008年1月-2009年1月妇科确诊及收治的72例患者.采用双旋磁治疗机对照治疗观察,在月经周期前10天,每天1小时,共3个周期,观察痛经的缓解情况.结果:研究发现治疗组36例患者中完全缓解率为94％,部分缓解率为2.6％,复发率为2.7％,完全缓解率明显高于对照组.结论:旋转磁场治疗盆腔子宫内膜异位症具有安全简便、无痛苦、患者易接受和效果显著的特点,有一定的应用价值.     

Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis

Endometriosis, characterized by ectopic endometrium growth in the extrauterine environment, is one of the most notable diseases of the female reproductive system. Worldwide, endometriosis affects nearly 10 % of women in their reproductive years and causes a significant decline in quality of life. Despite extensive investigations of endometriosis over the past years, the mechanisms of endometriosis pathogenesis remain unclear. In recent years, metabolic factors have increasingly been considered factors in endometriosis. There is compelling evidence regarding the progress of endometriosis in the context of severe metabolic dysfunction. Hence, the curative strategies and ongoing attempts to conquer endometriosis might start with metabolic pathways. This review focuses on metabolic mechanisms and summarizes current research progress. These findings provide valuable information for the non-intrusive diagnosis of the disease and may contribute to the understanding of the pathogenesis of endometriosis.     

Cytokine and chemokine expression in a rat endometriosis is similar to that in human endometriosis

The pathogenesis of endometriosis, a gynecologic disorder associated with infertility, appears to involve immune responses. However, the details involved have not been clarified. In this study, we analyzed expression levels of interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1, eosinophil chemotactic protein, macrophage inflammatory protein-1α, and regulated on activation normal T cell expressed and secreted (RANTES) and CC chemokine receptor 1 in endometriotic lesions in a rat model in which endometrium is autotransplanted onto peritoneal tissue and found that they were remarkably increased, while those of IL-2, IL-4, and interferon-γ were not. These results were obtained in a rat model induced by autologous, not allogeneic, transplantation of endometrial epithelium to the peritoneum. Expression of these factors is consistent with that of endometriosis in humans. Therefore, this model may be useful in the investigation of the pathogenesis and treatment of endometriosis.     

Müllerianosis

Müllerianosis may be defined as an organoid structure of embryonic origin; a choristoma composed of müllerian rests--normal endometrium, normal endosalpinx, and normal endocervix--singly or in combination, incorporated within other normal organs during organogenesis. A choristoma is a mass of histologically normal tissue that is "not normally found in the organ or structure in which it is located" (Choristoma, 2006). Müllerian choristomas are a subset of non-müllerian choristomas found throughout the body. Histologically, endometrial-müllerianosis and endometriosis are both composed of endometrial glands and stroma, but there the similarity ends. Their pathogenesis is different. Sampson faced the same difficulty with pathogenesis and nomenclature when he wrote: "The nomenclature of misplaced endometrial or müllerian lesions is a difficult one to decide upon." "The term müllerian would be inclusive and correct, but unfortunately it suggests an embryonic origin." Sampson then divided "misplaced endometrial or müllerian tissue" into "four or possibly five groups, according to the manner in which this tissue reached its ectopic location" (Sampson, 1925). Sampson's classification of heterotopic or misplaced endometrial tissue is based on pathogenesis: 1) "direct or primary endometriosis" [adenomyosis]; "a similar condition occurs in the wall of the tube from its invasion by the tubal mucosa" [endosalpingiosis]; 2) "peritoneal or implantation endometriosis;" 3) "transplantation endometriosis;" 4) "metastatic endometriosis;" and 5) "developmentally misplaced endometrial tissue. (I admit the possibility of such a condition, but have never been able to appreciate it.)" (Sampson, 1925). It is precisely this condition "developmentally misplaced endometrial tissue," [müllerianosis] that is the subject of this review.