**5.2.1 Genetic polymorphism of MMPs family**

Genetic polymorphisms located in the promoter region of the MMP genes could lead to increased gene expression and could be associated with predisposition to endometriosis (Ye, 2006). Nevertheless, the genetic susceptibility of endometriosis in relation to MMPs polymorphism is very complex, because for several polymorphisms, allele frequencies were found to be significantly different according to ethnic origin (MMP2.1, MMP2.2, MMP3 and MMP12).

Borghese et al., investigated the role of MMP1, MMP2, MMP3, MMP7, MMP12 and MMP13 polymorphisms as endometriosis risk factors in a case – control study of patients affected by superficial, deep infiltrating or endometrioma in the Caucasian population. The study found a potential role for MMP12 -82 A/G and MMP13 -77 A/G combined polymorphisms, which modulate transcriptional activity, in superficial endometriosis. As no association was found with deep infiltrating endometriosis, this combination of polymorphisms might protect from a more in-depth penetration of tissues (Borghese et al., 2008). On the other hand, they did not find any correlation between endometriosis and MMP1, MMP2, MMP3, MMP7 polymorphism (Borghese et al., 2008). Data regarding the lack of association between MMP-1 e MMP-3 polymorphism and endometriosis susceptibility were confirmed in another study concerning the Italian population (Ferrari et al., 2006).

A case-control study in women of caucasian origin, evaluated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more common in control group (Saare et al., 2010).

A genetic study regarding North Chinese women on three polymorphisms in the MMP-2 (MMP-2; -1306C-->T and -735C-->T) and TIMP-2 (TIMP-2; -418G-->C) genes found that the TIMP-2 -418C/C homozygote may be a protective factor against the development of endometriosis (Kang et al., 2008). A analogous study in the same population showed that MMP-7-181A/G polymorphism has a potential to be a susceptibility factor for endometriosis and adenomyosis while MMP-9-1562C/T polymorphism may not provide a useful marker to predict susceptibility to endometriosis and adenomyosis (Shan et al., 2006). On the other hand, an increase in the distribution of the MMP-9R279Q/P574R (2678G>A/4859C>G) and -1562C>T/R668Q (-1562C>T/5546G>A) haplotypes was significantly associated with endometriosis (Han et al., 2009).

#### **5.2.2 Relevance of MMPs serum/urinary levels as diagnostic markers**

The balance between MMPs and their inhibitors is preserved in the serum of women with endometriosis; however MMP-3 mRNA seems to be a promising peripheral blood marker that discriminates between patients with endometriosis and healthy subjects. Circulating mRNA for MMP-3 is significantly higher in patients with endometriosis than in control patients, regardless of the degree of severity. (De Sanctis et al., 2010).

Conversely, the clinical relevance of MMP-2 and MMP-9 as markers of endometriosis is controversial; some data report that serum concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 cannot be considered to represent a valid measure of the severity of endometriosis

Genetic polymorphisms located in the promoter region of the MMP genes could lead to increased gene expression and could be associated with predisposition to endometriosis (Ye, 2006). Nevertheless, the genetic susceptibility of endometriosis in relation to MMPs polymorphism is very complex, because for several polymorphisms, allele frequencies were found to be significantly different according to ethnic origin (MMP2.1, MMP2.2, MMP3 and

Borghese et al., investigated the role of MMP1, MMP2, MMP3, MMP7, MMP12 and MMP13 polymorphisms as endometriosis risk factors in a case – control study of patients affected by superficial, deep infiltrating or endometrioma in the Caucasian population. The study found a potential role for MMP12 -82 A/G and MMP13 -77 A/G combined polymorphisms, which modulate transcriptional activity, in superficial endometriosis. As no association was found with deep infiltrating endometriosis, this combination of polymorphisms might protect from a more in-depth penetration of tissues (Borghese et al., 2008). On the other hand, they did not find any correlation between endometriosis and MMP1, MMP2, MMP3, MMP7 polymorphism (Borghese et al., 2008). Data regarding the lack of association between MMP-1 e MMP-3 polymorphism and endometriosis susceptibility were confirmed in another

A case-control study in women of caucasian origin, evaluated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more

A genetic study regarding North Chinese women on three polymorphisms in the MMP-2 (MMP-2; -1306C-->T and -735C-->T) and TIMP-2 (TIMP-2; -418G-->C) genes found that the TIMP-2 -418C/C homozygote may be a protective factor against the development of endometriosis (Kang et al., 2008). A analogous study in the same population showed that MMP-7-181A/G polymorphism has a potential to be a susceptibility factor for endometriosis and adenomyosis while MMP-9-1562C/T polymorphism may not provide a useful marker to predict susceptibility to endometriosis and adenomyosis (Shan et al., 2006). On the other hand, an increase in the distribution of the MMP-9R279Q/P574R (2678G>A/4859C>G) and -1562C>T/R668Q (-1562C>T/5546G>A) haplotypes was

The balance between MMPs and their inhibitors is preserved in the serum of women with endometriosis; however MMP-3 mRNA seems to be a promising peripheral blood marker that discriminates between patients with endometriosis and healthy subjects. Circulating mRNA for MMP-3 is significantly higher in patients with endometriosis than in control

Conversely, the clinical relevance of MMP-2 and MMP-9 as markers of endometriosis is controversial; some data report that serum concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 cannot be considered to represent a valid measure of the severity of endometriosis

**5.2.1 Genetic polymorphism of MMPs family** 

study concerning the Italian population (Ferrari et al., 2006).

significantly associated with endometriosis (Han et al., 2009).

**5.2.2 Relevance of MMPs serum/urinary levels as diagnostic markers** 

patients, regardless of the degree of severity. (De Sanctis et al., 2010).

common in control group (Saare et al., 2010).

MMP12).

(Salata et al., 2008; De Sanctis et al., 2010). On the other hand a prospective, blinded, longitudinal study show that MMP-2, MMP-9, and MMP-9/neutrophil gelatinase-associated lipocalin were significantly more likely to be detected in the urine of patients with endometriosis than in controls (Beker et al. 2010).

Bruner-Tran et al. described progesterone treatment inhibits expression of MMP-3 and -7 in human endometrium and prevents the establishment of ectopic lesions in a nude mouse model (Bruner-Tran et al., 2002).

A study concerning human endometrium intraperitoneally transplanted into nude mice, demonstrated a significant suppression of MMP-2 transcription by all progestins tested, and a significant down-regulation of MMP-3 by dydrogesterone (Mönckedieck et al., 2009).

In conclusion, angiogenesis is proposed as an important mechanism for the pathogenesis of endometriosis. Different evidences support the hypothesis that the endometrium of women with endometriosis has an increased capacity to proliferate, implant and grow in the peritoneal cavity. Further studies are needed to better understand critical steps of the pathogenesis of endometriosis; nevertheless excessive endometrial angiogenesis suggests novel new medical treatments.

#### **6. References**


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 **11** 

*Russia* 

**The Local Immune Mechanisms** 

*Federal State Establishment Ivanovo's Research Institute of Maternity* 

According to common view, endometriosis is characterized by the presence and growth of the endometrium-like glandular tissue and stroma outside the uterus. So, endometriosis would represent an autotransplant in which tissue is transplanted to an ectopic location in an organism. It is well known that the immune system plays the main role in regulation of tissue homeostasis in an organism. Thus, immunologists have a special interest in this disease as insights in the pathogenesis of endometriosis would help not only to understand how ectopic lesions grow but also allow searching new approaches to the medical treatment

Numerous theories have been proposed to explain the endometriosis pathogenesis till date. The most widely accepted Sampson's transplantation theory proposes that, during menstruation, there is reflux of endometrial tissue via fallopian tubes into abdominal cavity where endometrium could attach to peritoneal surfaces, proliferate, invade, and become the disease known as endometriosis. However, this theory does not account for the fact that most of women of reproductive age exhibit some degree of reflux of endometrial debris, but only some patients develop endometriosis (Harada et al., 2004; Vinatier et al., 2001). There are two main suggestions explaining this contradiction. The first explanation propose that there are some changes in the endometrium of women with endometriosis and these changes can promote the resistance of endometrial cells to normal peritoneal cleaning (Vinatier et al., 2001). The second theory suggests that impaired immune recognition in peritoneal cavity due to abnormalities of the cellular and humoral immunity can promote

The suggestion that the primary defect in endometriosis is located in the eutopic endometrium, was proposed many years ago and supported now by many investigators (Vinatier et al., 2001; Kyama et al., 2003; Harada et al., 2004), though the eutopic endometrium of women with and without endometriosis is histologically similar. This hypothesis is confirmed by different studies revealing that there are many fundamental differences between these two tissues. Invasive properties, decreased apoptosis, and increased steroid hormones and cytokine production have been identified in eutopic

**1. Introduction** 

of this disease.

the endometriosis development (Kyama et al., 2003).

**Involved in the Formation of** 

Yulia Antsiferova and Natalya Sotnikova

**Endometriotic Lesions** 

*and Childhood Named V. N. Gorodkov,* 

