**2. Protein molecular mechanism involving in endometriosis**

There should be some factors present in the ectopic lesions of endometriosis, peritoneal fluid and blood that stimulate the lesion to proliferate, implant and invade [11, 12]. And comparing with eutopic endometrium, endometriosis lesions has different biochemical and functional expression including steroid receptivity and invasive potential [13]. Over all, the specific markers of endometriosis may be classified into three main categories: (i) serum and/or peritoneal: growth factors, cytokines, hormones, glycoproteins, proteolytic enzymes and their specific inhibitors, soluble adhesion molecules, autoantibodies and environmental contaminants. (ii) endometrial and biochemical-endometrial: stromal, glandular, neuronal, hormonal receptors, mesenchymal stem cells, proteolytic enzymes and their specific inhibitors, adhesion molecules, osteopontin.(iii) genetic types: oxidative stress genes, tumor suppressor genes, oncogenes, regulatory genes, DNA repair genes, chromosomal aberrations or amplifications, loss of heterozygosity, genetic polymorphism of variable genes, and genome-wide alterations. And we show the focus continuously.

#### **2.1 Hormones regulation proteins in the pathogenesis of endometriosis**

Steroid hormones play an important role in endometriosis physiology and pathology. The production of cytokines in endometriosis is the altered responsiveness to progesterone, showing a characteristic very low expression of progesterone receptor A (PR-A) and the absence of PR-B in rodent models, and with decreased PR-B/A ratio and reduced PR-B immunoreactivity, demonstrated in human endometriosis lesions [14, 15]. Hormonal dependence in endometriosis is demonstrated by an increased ER-β expression (approximately 100 times), due to altered

**25**

*Proteomics Research and Its Possibility of Application in Endometriosis*

**2.2 Proteins of angiogenesis process of endometrial tissue**

peritoneal endometriosis compared with normal peritoneum [29].

**2.3 Proteins in invading process of endometrial tissue**

**2.4 Proteins in carcinogenesis possibility of endometriosis**

methylation in the ESR2 gene promoter [16]. In experimental model of endometriosis, ER-β may be involved in inhibiting apoptosis and increasing cytokine production in endometriosis, such as MCP-5, IL-1b and IL-16, which seem to enhance cells adhesion and proliferation [17]. The secretion of PGE2 is regulated by MIF through stimulating COX-2 activity. PGE2 is considered to be one of the main proinflammatory regulating factors which appears to be confirmed by its elevated level

On behalf of endometriosis lesions, neovascularization and angiogenesis factors should be introduced. Angiogenic factors such as VEGF [19], ENDO-I [20], angiogenin [21], pleiotrophin, midkine [22], PGF [23], angiopoietin [24], and glycodelin [25, 26] have been identified association with the lesions angiogenesis in endometriosis. Angiogenic activity is supplemented by the co-existence of pathologic angiogenesis, immune suppression, and immune activation. Study from human being indicated the correlation between high MVD and symptom of pelvic pain in patients with endometriosis by transvaginal color doppler ultrasound evaluation. MVD has been described using immunohistochemical evaluation with CD34 labeled endothelial cells of vessels [27, 28]. There was no significantly increased VEGF expression but it has been found in the involvement of other angiogenic factors with the active implants showing high mitotic index and increased MVD [27]. Further findings were reported in other articles that VEGF-A role was demonstrated by its increased concentrations in the endometrium of patients with endometriosis. Moreover, it was confirmed that the expression of VEGF-A gene was higher in

In endometriosis, after the attachment to the ectopic sites, the epithelial endometrial cells invade to the extracellular matrix with MMPs and TIMPs secretion playing an important role in degradation in extracellular matrix and basement membrane components [30]. It has been proved that this process is related to the involvement of MMPs, which is stimulated by TNF-a and IL-1 at high concentrations in peritoneal fluid. Meanwhile, TNF-a inhibits TIMP-1 and TIMP-2, leading to an imbalance of MMPs/TIMPs ratio. In patients of endometriosis, MMP-2 and membranous type 1 of eutopic endometrium have been found higher, TIMP-2 was lower than normal women [31]. Increased MT5- MMP expression and alterations of the balances between MMP-9/TIMP-1, MMP-9/TIMP-3, MMP-3/uPA, VEGF/MMP-3/uPA, VEGF/ /MMP-2/CD44/Ki67, PAI/TIMP-1, and IL-1/ /MMP-1 indicated that implantation and invasion might participate the mechanism of endometriosis [32–38].

Clinicopathological, molecular, and genetic evidences support the hypothesis of endometriosis as a neoplastic process, with a potential to malignant transformation. Polypoid endometriosis, premalignant changes, borderline tumors and malignant tumors were described. Except for an increased MMPs expression associated to deregulation of the intercellular adherence signaling, tumor suppressor genes, oncogenes, CAMs, furthermore LOH and inflammatory immunomodulation were detected [39, 40]. The progressive accumulations of genetic alterations of tumorsuppressing genes and oncogenes are probably responsible for endometriosis development and its possible association with the development of malignancies [41–45].

*DOI: http://dx.doi.org/10.5772/intechopen.81850*

in endometriosis tissues of human being [18].

*Molecular Bases of Endometriosis - The Integration Between Research and Clinical Practice*

environment such as dioxins can devote to the progress of the disease [4, 5]. Generally, severity of endometriosis is classified by the revised American Fertility Society (rAFS) system [6], dividing patients into one of four stages (I–IV, minimal-severe) based on lesion size and pelvic adhesions associated with infertility. However, it remains uncertain whether the disease progresses through these stages. Actually some surgeon would prefer to stage on the basis of the sites and extent of the lesions under the laparoscopy or laparotomy and describe without AFS or r-AFS stage. Sometimes they may give some complementary suggestion [7]. Meanwhile, endometriosis has a variable symptom profile which does not relate with severity of this disease [8]. Furthermore, the patients often suffer from the symptoms of infertility or chronic pain for several years before the diagnosis is lately confirmed. So it makes the clinical diagnosis even more difficult. And actually there has been a lack of precise diagnosis method in previous researches. On the aspects of clinical application and financial consideration, more effective and

noninvasive test will be needed in endometriosis disease.

considered as perspective view of the retrograde menstruation theory [3]. Other theories like immune system dysfunction, genetic susceptibility and exposure to the

Currently, laparoscopy offers the most widely accepted technique and method for evaluating and treating endometriosis. And most of endometriosis patients are treated by surgical removal of lesions and/or hormonal suppression focused on reducing estrogen, such as progestins, androgens, gonadotropin-releasing hormone (GnRH) agonists, and recent aromatase inhibitors. However, both approaches are associated with various side effects and a highly recurrent incidence [9, 10]. Therefore, identification of protein molecular mechanisms involved in the patho-

genesis of endometriosis and strategic therapies for treatment are critical.

There should be some factors present in the ectopic lesions of endometriosis, peritoneal fluid and blood that stimulate the lesion to proliferate, implant and invade [11, 12]. And comparing with eutopic endometrium, endometriosis lesions has different biochemical and functional expression including steroid receptivity and invasive potential [13]. Over all, the specific markers of endometriosis may be classified into three main categories: (i) serum and/or peritoneal: growth factors, cytokines, hormones, glycoproteins, proteolytic enzymes and their specific inhibitors, soluble adhesion molecules, autoantibodies and environmental contaminants. (ii) endometrial and biochemical-endometrial: stromal, glandular, neuronal, hormonal receptors, mesenchymal stem cells, proteolytic enzymes and their specific inhibitors, adhesion molecules, osteopontin.(iii) genetic types: oxidative stress genes, tumor suppressor genes, oncogenes, regulatory genes, DNA repair genes, chromosomal aberrations or amplifications, loss of heterozygosity, genetic polymorphism of variable genes, and

**2. Protein molecular mechanism involving in endometriosis**

genome-wide alterations. And we show the focus continuously.

**2.1 Hormones regulation proteins in the pathogenesis of endometriosis**

Steroid hormones play an important role in endometriosis physiology and pathology. The production of cytokines in endometriosis is the altered responsiveness to progesterone, showing a characteristic very low expression of progesterone receptor A (PR-A) and the absence of PR-B in rodent models, and with decreased PR-B/A ratio and reduced PR-B immunoreactivity, demonstrated in human endometriosis lesions [14, 15]. Hormonal dependence in endometriosis is demonstrated by an increased ER-β expression (approximately 100 times), due to altered

**24**

methylation in the ESR2 gene promoter [16]. In experimental model of endometriosis, ER-β may be involved in inhibiting apoptosis and increasing cytokine production in endometriosis, such as MCP-5, IL-1b and IL-16, which seem to enhance cells adhesion and proliferation [17]. The secretion of PGE2 is regulated by MIF through stimulating COX-2 activity. PGE2 is considered to be one of the main proinflammatory regulating factors which appears to be confirmed by its elevated level in endometriosis tissues of human being [18].
