MEMORIA DE LA INSTALACIÓN DE ENERGIA SOLAR 1 OBJETO DEL PROYECTO

Cytokines are glycoproteins that play a role in controlling cell proliferation, immune cell activation, motility, cell adhesion and chemotaxis. They are secreted into the extra-cellular environment by leucocytes, macrophages and other inflammatory cells. It is widely known that retrograde menstruation occurs in most women but why some end up developing endometriosis is still unknown and it has been hypothesiszed that a change in the function of the immune cells in the peritoneal environment may be a major reason (Wu and Ho, 2003, Lebovic et al., 2001).

Macrophages are major secretors of cytokines and have been shown to be increased in the peritoneal cavity of women with endometriosis inducing a local inflammatory response (Sukhikh et al., 2004, Haney et al., 1981). Changes in cytokine concentrations reflects the immune system’s response to initial disease. Therefore many studies have focused on finding alterations in markers of inflammation between women with and without endometriosis to define potential biomarkers but also aid in understanding the pathogenesis of the disease.

The most studied cytokines as biomarkers of endometriosis are IL-6 and TNF-α, but the results have been conflicting (May et al., 2011). IL-6 is a pro-inflammatory cytokine involved in the activation of T cells and differentiation of B cells. Alterations in IL-6 in endometriosis have been studied by several groups (Bedaiwy et al., 2002, Bedaiwy and Falcone, 2004, Somigliana et al., 2004, Martinez et al., 2007, Seeber et al., 2008a, Othman et al., 2008, Iwabe et al., 2002). In a multi-marker panel study, increased levels of IL-6 were demonstrated in women with early stage endometriosis (Bedaiwy et al., 2002). At a threshold of 2 pg/mL, IL-6 was able to discriminate between groups with a sensitivity of 90% and specificity of 47%. The other markers tested (IL-1β, IL-8, IL-12, IL-13 and TNF-α) were not discriminatory. The authors however noted that they were unable to obtain sufficient serum to measure all the cytokines in all subjects and their findings were based on the comparison of only 20 cases and 11 controls.

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In a prospective study to compare the diagnostic performance of IL-6 and CA125, elevated levels of IL-6 were found in women with endometriosis, but only those with minimal-mild disease yielding a sensitivity and specificity of 75% and 83% respectively, at a threshold of 5.75 pg/mL (Martinez et al., 2007). CA125 was increased 3 fold in women with late stage disease. However, the combination of both markers did not offer any additional value. These data do suggest that IL-6 may be a good marker for early stage disease where ultrasound is not as helpful and because IL-6 levels were not affected by other pelvic pathologies e.g. myomas, benign ovarian cysts. A protein array system using cytokine-specific antibody coated beads was used to quantify cytokine concentrations in samples from 68 women with endometriosis and controls (Othman et al., 2008). IL-6, MCP1 and IFN-γ were found to be higher in women with endometriosis compared to controls. At a threshold of 1.9 pg/mL, IL-6 gave the best results in discriminating endometriosis from controls. Combining IL-6, MCP1 and IFN-γ did not provide additional discriminatory power over using IL-6 alone. Combination with CA125 was not reported. In another prospective cohort study of CA125 and IL-6 no significant improvements in diagnostic accuracy were reported for this combination. In another study (Somigliana et al., 2004) classification tree analysis was applied to determine the diagnostic ability of IL-6, TNF-α, MCP1, MIF, CA125 and leptin. Combination of some of the markers improved diagnostic performance; CA125, MCP1 and leptin was able to diagnose 51% of cases with 89% accuracy, while CA125, MCP1, leptin and MIF could diagnose 48% of cases with 93% accuracy (Seeber et al., 2008a). The discrepancies observed in these studies can be attributed to various factors including the type of assay used and the different study sets used. Whilst the same ELISA kit was used in two of these studies, different results were reported (Somigliana et al., 2004, Bedaiwy et al., 2002). In addition IL-6 evaluation methods are not properly standardised and IL-6 is likely to reflect non- specific inflammatory responses that differ from case to case.

TNF-α is a monocyte-derived cytokine with pro-inflammatory and pro-angiogenic roles. An increase in serum TNF-α concentrations in endometriosis has been reported by several studies (Matalliotakis et al., 1997, Pizzo et al., 2002, Darai et al., 2003,

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Xavier et al., 2006), whilst others have failed to show any significant difference (Vercellini et al., 1993, Seeber et al., 2008a, Othman et al., 2008). In one of these studies, elevated TNF-α levels were decreased after treatment with danazol (Matalliotakis et al., 1997). Significantly higher levels of TNF-α were reported in women with endometriomas compared to those with benign cysts, but were not higher in those with malignant cysts (Darai et al., 2003). High levels of serum TNF-α were shown in endometriosis patients throughout the menstrual cycle compared to controls (Xavier et al., 2006). Another study evaluating TNF-α, TGF-β, IL-8 and MCP1 in serum and peritoneal fluid reported increased TNF-α levels in early stage disease, but a significant decrease as the disease progressed (Pizzo et al., 2002). This is contrary to another report whose findings showed no difference in TNF-α levels between women with endometriosis-associated infertility to those with idiopathic infertility (Bedaiwy et al., 2002). In summary, the diagnostic potential of TNF-α is as yet unclear and more studies are required to evaluate its worth as a marker either individually or as part of a panel of other markers.