Biochemical markers for endometriosis: a long way to go.

Sir, We have enjoyed reading the review by Borrelli et al. (2014) on the use of chemokines as potential biomarkers for endometriosis. There is currently no reliable biochemical marker to screen, diagnose or stage endometriosis and the above rely on more expensive and/or invasive radiological or laparoscopic procedures. The authors investigated the expression of chemokines in peripheral blood, peritoneal fluid and eutopic endometrium in women with endometriosis compared with controls. As a whole, the results are conflicting especially in peripheral blood for the three identified biomarkers: CXCL8, CCL2 and CCL5. Results are slightly more consistent in peritoneal fluid but this is an invasive procedure best performed during laparoscopy when endometriosis can be visually assessed and biopsied and thus defies the whole purpose of obtaining fluid for biochemical analysis. The original studies discussed in Borrelli et al. (2014) used samples from different phases of the menstrual cycle; follicular, luteal or unspecified. Recently Whitcomb et al. (2014) concluded that chemokines, including CXCL8, CCL2 and CCL5, vary during the menstrual cycle. Therefore, this heterogeneity in regards to the phase of the menstrual cycle may explain the conflicting results seen in Borrelli et al. (2014). On the same note, there was significant variation in the controls used in the original studies included in this review. These included myomas, tubal ligations, benign and malignant ovarian tumours. Chemokines have been implicated in inflammatory and mitotic processes; hence the above controls which, with endometriosis, will be listed as differential diagnoses in women with pelvic symptoms are likely to have a varied chemokine profile. This is likely to make the biochemical diagnosis of endometriosis challenging. We have published extensive reviews on proteomic biomarkers for PCOS and associated conditions (Galazis et al., 2012, 2013a,b). We are thus aware of the potential limitations of such studies particularly the considerable heterogeneity seen among the original articles, which has already been highlighted above. Although individually each chemokine may produce conflicting results, a panel of biomarkers, in this case CXCL8, CCL2 and CCL5, could and should be validated in subsequent hypothesis-driven research. This, in combination with other markers known to be raised in endometriosis like CA125 (as investigated by Agic et al. (2008)), could be subjected to mathematical modelling with a strong diagnostic or screening potential (Galazis et al., 2012). Moreover, this biochemical panel could be combined with other parameters (including clinical and/or radiological) for further mathematical modelling with greater diagnostic or screening significance. Mathematical modelling has been applied in the UK in ovarian cancer patients; women with a high Risk of Malignancy Index, which takes into account the levels of C125, menopausal status and suspicious radiological features, are referred to tertiary centres for further workup and management (Obeidat et al., 2004). We agree that such statements are speculative at this stage. They are however, a valid hypothesis on which to base further research in the field. We still have a long way to go in optimizing biochemical markers for diagnosing or screening for endometriosis. However, the review by Borrelli et al. (2014) and the points raised in this letter should serve as a catalyst in stimulating further validation studies and mathematical modelling for screening, diagnosis or staging of endometriosis.