Hum. Reprod. Advance Access originally published online on October 24, 2006
Human Reproduction 2007 22(3):836-842; doi:10.1093/humrep/del419
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Serum interleukin-6 levels are elevated in women with minimal–mild endometriosis
1 Department of Obstetrics and Gynecology, Hospital Universitario Dr Peset 2 Instituto Universitario Valenciano de Infertilidad (IVI), University of Valencia, Valencia 3 Servicio de Laboratorio, Hospital Santa Barbara, Puertollano, Ciudad Real and 4 IVI-Madrid, Rey Juan Carlos University, Madrid, Spain
5 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Hospital Universitario Dr Peset, Avda Gaspar Aguilar 90, 46017 Valencia, Spain. E-mail: pellicer_ant{at}gva.es
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Abstract |
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BACKGROUND: There is a need for a reliable marker of endometriosis, especially in early stages of peritoneal disease during which imaging is not effective. The use of serum interleukin (IL)-6 as a marker is controversial. To readdress the matter, patients undergoing laparoscopy were prospectively evaluated for serum IL-6 levels. MATERIALS AND METHODS: A total of 119 women 31 years old who underwent laparoscopy were divided into groups: control patients (n = 38) with no pathologic findings; endometriosis sufferers (n = 47) with minimal–mild (MM, n = 11) or moderate–severe (MS, n = 36) endometriosis; uterine myomas (n = 13) and benign ovarian pathologies (n = 21). Blood was drawn on cycles days 5–12 and stored for subsequent analysis of IL-6 and carbohydrate antigen (CA)-125 levels. RESULTS: Serum IL-6 levels were significantly (P = 0.002) higher in women with MM endometriosis (29.4 9.0 pg/ml) than in controls (15.7 9.3 pg/ml). When all the non-endometriosis patients were grouped together (n = 72) and serum IL-6 (17.8 12.1 pg/ml) compared with MS (n = 36; 17.6 10.3 pg/ml) and MM (n = 11; 29.4 9.0 pg/ml) endometriosis significantly (P < 0.01) higher levels in MM endometriosis were observed as compared to the other two groups. Serum Ca-125 levels were significantly (P < 0.01) elevated in MS endometriosis. A serum IL-6 threshold of 25.75 pg/ml afforded a sensitivity of 75% and specificity of 83% in the diagnosis of MM endometriosis. Sensitivity and specificity for CA-125 in the diagnosis of MS endometriosis, using 35 IU/ml as the cut-off value, were 47% and 97%, respectively. CONCLUSIONS: IL-6 is a reliable non-invasive marker of MM endometriosis, whereas Ca-125 is of use as a marker of severe cases.
Key words: endometriosis/interleukin-6/carbohydrate antigen-125/diagnosis/non-invasive marker
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Introduction |
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Endometriosis is a highly common benign gynaecological disease, found particularly in infertile women, but also in the general population (Goldman and Cramer, 1989
; Mahmood and Templeton, 1991). There is considerable evidence to suggest that endometriosis, even in the minimal and mild stages of extension, causes infertility. Prospective studies on the prevalence of endometriosis in women undergoing laparoscopy have shown that endometriotic lesions are more frequently found in infertile women and those with pain or dysfunctional bleeding than in women requesting tubal sterilization (Mahmood and Templeton, 1991). Moreover, a study in which women were found to have endometriotic lesions during a diagnostic laparoscopy and who were randomly treated by surgery or managed expectantly indicated that cumulative pregnancy rates significantly increased in treated patients (Marcoux et al., 1997), demonstrating that mild lesions also hinder the reproductive process. In addition, the classic study by Jansen (1986) demonstrated that endometriosis in women inseminated with donor sperm was a detrimental factor for outcome.
The mechanism of infertility associated with endometriosis without obvious pelvic adhesive disease is poorly understood, and an effective diagnosis of this condition at a time when laparoscopy’s appropriateness in the work-up of infertility is being questioned (Fatum et al., 2002) is of great relevance. A serum marker of minimal–mild (MM) endometriosis would be highly beneficial.
Endometriosis is a disease that alters the immune system (Vinatier et al., 1996; Lebovic et al., 2001). It involves an inflammatory response in which cytokines, and specifically interleukin (IL)-6, are involved. IL-6 promotes T-cell activation and B-cell differentiation (Lebovic et al., 2001) and inhibits the proliferation of human endometrial cells (Zarmakoupis et al., 1995). High IL-6 levels have been found in the peritoneal fluid of patients with endometriosis (Buyalos et al., 1992; Koyama et al., 1993; Keenan et al., 1994; Rier et al., 1995), and the values of IL-6 have been correlated with the degree of severity of the disease (Cheong et al., 2002; Khan et al., 2002).
Serum IL-6 levels have also been assayed as a marker of endometriosis. Our group described for the first time an elevation of serum IL-6 levels in infertile women with endometriosis with respect to controls (Pellicer et al., 1998). The findings of this study were endorsed in some subsequent studies (Bedaiwy et al., 2002; Iwabe et al., 2003), whereas others failed to detect such a difference (D’Hooghe et al., 2001; Somigliana et al., 2004). The stage of the disease did not affect serum IL-6 levels, thus discrediting this cytokine as a reliable marker of MM endometriosis (D’Hooghe et al., 2001; Bedaiwy et al., 2002). However, one of these studies employed a considerably smaller sample size (D’Hooghe et al., 2001), and the other somewhat surprisingly did not provide the data (Bedaiwy et al., 2002). In this way, the subject remains, to some extent, up in the air. That said, reports that women with endometriomas have higher serum IL-6 levels than controls (Iwabe et al., 2003), and women with benign ovarian cysts (Daraï et al., 2003), would suggest that women with moderate–severe (MS) rather than MM endometriosis are those that present high levels of serum IL-6.
The serum carbohydrate antigen (CA)-125 is a classic biochemical marker of endometriosis that still is not generally employed. It was shown to have a greater diagnostic value in MS rather than in MM endometriosis in a meta-analysis of 23 studies (Mol et al., 1998). However, most recently, the value of CA-125 in the diagnosis of MM endometriosis in the absence of ovarian endometriomas has been highlighted (Kitawaki et al., 2005).
As previously mentioned, our group was the first to report higher serum IL-6 levels in women with endometriosis than in controls (Pellicer et al., 1998). However, due to the small sample size (eight patients) in that study, of whom half were in the early stages and the other half in advanced stages of the disease (Pellicer et al., 1998), and due to so much controversy in the literature with regard to this issue, we decided to readdress the matter prospectively, including a higher number of women and establishing controls of other frequently found benign gynaecological conditions in infertile women that could affect the serum levels of IL-6. Therefore, the main purpose of the study was to evaluate whether serum IL-6 levels could serve as a marker of the early stages of endometriosis. Additionally, we decided to determine the value of CA-125 as a diagnostic marker.
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Materials and methods |
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This is a prospective, observational, case–control study of 128 women undergoing laparoscopy at Hospital Universitario Dr Peset in Valencia between February 2003 and February 2005. Indications for laparoscopy were pelvic pain (n = 5), infertility (n = 11), tubal sterilization (n = 37), myomas (n = 16), suspicion of endometrioma (n = 33) and other benign ovarian pathologies (n = 26). Inclusion criteria were reproductive age and regular menstrual cycles. Exclusion criteria were the administration of any medication over the previous 2 years that could have influenced the progression of endometriosis, processes that could increase the levels of IL-6 in blood independently of endometriosis (such as chronic or acute inflammatory diseases or neoplasms) and two or more concomitant findings at laparoscopy. A total of 119 patients were finally included in the study. Of the remaining women, four rejected laparoscopy for various reasons, two had adhesions that were secondary to pelvic inflammatory disease and three presented peritoneal endometriosis plus myomas.
The study was approved by the ethics committee of our hospital, and all the participants signed the appropriate consent forms. Blood was drawn in the follicular phase (days 5–12) during one of the 3 months before surgery, centrifuged to obtain serum and then stored at –80°C for subsequent analysis. Patients were classified at surgery into four groups: a control group (n = 38) without any pathology; an endometriosis group (n = 47) in which 11 women had MM and 36 MS disease (ASRM, 1997); a uterine myomas group (n = 13) in which the size of the patient’s myoma was 3–7 cm and in which none were shown to have adenomyosis at pathology and an ovarian pathology group (n = 21) in which 6 patients had simple ovarian cysts, 7 had teratomas, 1 had a serous cystoadenoma, 1 had a fibroma, 1 had polycystic ovaries and 5 had paraovarian cysts. The study design is shown in Figure 1.
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Serum IL-6 was measured employing an immunoassay (Quantikine, R&D Systems Inc., Minneapolis, MN, USA). Inter- and intra-assay coefficients of variation were 6.4 and 4.2%, respectively. The minimum detectable value of IL-6 was 0.7 pg/ml.
The quantitative detection of CA-125 was performed using a commercially available chemiluminescent microparticle immunoassay (ARCHITECT CA 125 II Abbott Diagnositics, Madrid, Spain) with inter- and intra-assay coefficients of variation of 
10% and a sensitivity of <1.0 IU/ml.
Data were expressed as mean ± SD. Also, boxplot analysis of the serum values of IL-6 and CA-125 was performed employing the medians and interquartile range. Analysis of variance was applied to compare among categorical variables. The Bonferroni’s test was employed to discriminate between the differences observed. When homogeneity and normality (Kolgomorov–Smirnov) of the samples were not appropriate, non-parametric statistical methods (Kruskal–Wallis and Mann–Whitney tests) were applied for comparison. Threshold values, sensitivity and specificity were calculated using receiver operating characteristic (ROC) curves. To determine the concomitant use of serum IL-6 and CA-125 to detect the presence of endometriosis, we performed a multivariate analysis by polychotomus logistic regression. Statistical significance was calculated using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) and was considered to be P < 0.05.
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Results |
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Table I summarizes the comparison of different epidemiological data in the various groups including age, body mass index (BMI), day of the cycle on which blood samples were drawn and erythrocyte sedimentation rate (ESR), which is a marker of inflammation.
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Table II summarizes serum IL-6 levels in the different groups. Women with MM endometriosis displayed significantly (P < 0.05) higher levels of IL-6 than the remaining groups. No significant differences among control, myoma and ovarian pathology groups were observed. Table III summarizes how, when all the subgroups were compared with that of women with endometriosis, a significant (P < 0.01) increase was observed in serum IL-6 in MM endometriosis when compared with the other patients, including MS cases of endometriosis (Figure 2).
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,* represent outlying values.Serum CA-125 levels are also analysed in Tables II and III. MS endometriosis patients exhibited significantly (P < 0.01) higher levels than the remaining groups. This is clearly observed in Table III, which compares endometriosis patients with all the remaining women grouped together as a single group. Again, MS endometriosis was related to significantly (P < 0.01) higher levels of CA-125 than an MM degree of the disease or its absence (Figure 2).
The ROC curve analysis revealed a high diagnostic value for serum IL-6 with respect to MM endometriosis, with an area under the curve (AUC) of 0.829 [95% confidence interval (95% CI) 0.748–0.892] (Figure 3). The optimal serum IL-6 threshold found using the ROC curve was 25.75 pg/ml, with a sensitivity of 75.0%, specificity of 83.3%, positive predictive value of 65.8% and negative predictive value of 88.6%. The diagnostic accuracy was 82%.
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CA-125, however, performed well in its diagnosis for endometriosis with an AUC of 0.759 (95% CI 0.670–0.833) and even better in the diagnosis of MS endometriosis, reaching a value of 0.812 (P < 0.001). That said, CA-125 was not effective in its diagnosis of MM endometriosis (AUC < 0.5) (Figure 3). Sensitivity, specificity, positive predictive value and negative predictive value of CA-125 in the diagnosis of MS endometriosis using 35 IU/ml as the threshold value were 47.2, 97.5, 89.0 and 81.1%, respectively. The combination of serum IL-6 and CA-125 did not offer any additional value to any of those markers employed alone in the diagnosis of endometriosis (data not shown).
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Discussion |
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The results of this study show that MM endometriosis patients display higher serum IL-6 levels than other patients. Our studies would need to be confirmed in larger prospective trials in which serum IL-6 levels are measured before laparoscopy and/or transvaginal hydroendoscopy to reinforce the serum marker’s value in diagnosing MM endometriosis which is a novel direction in this field. We have thrown light on a marker of the early stages of the disease which is not affected by other possible pelvic pathologies found in young infertile patients, such as uterine myomas. Additionally, serum IL-6 allows us to discriminate between MM endometriosis and MS endometriosis (mainly endometriomas) and other benign ovarian tumours, although this finding is of less clinical relevance because of the important role of vaginal ultrasound in the diagnosis of organic pathology in gynaecology.
Elevated serum IL-6 levels observed in cases of MM endometriosis in our study confirm findings of some reports (Bedaiwy et al., 2002) but diverge with those of others who found no value for serum IL-6 in the diagnosis of any stage of endometriosis (D’Hooghe et al., 2001; Somigliana et al., 2004) reports. Our results also challenge reports of higher serum IL-6 in endometriomas than other benign ovarian cysts (Daraï et al., 2003; Iwabe et al., 2003).
It is important to critically analyse patient selection in this type of study. We were concerned about the coexistence of any inflammatory processes at the time of blood collection. This is why we tested ESR in our patients, finding similar values among the groups. A key study in this area and whose findings our data challenge is that by Somigliana et al. (2004). They included 35 patients as controls, but 6 of whom (17%) had pelvic inflammatory disease. These cases should be ruled out of the data (or analysed in a different subgroup) when an inflammatory marker, such as a cytokine, is being evaluated. Another related report by D’Hooghe et al. (2001) used a small and uncontrolled sample size.
The second issue to be addressed is the stage of the disease. In our first report in the literature of elevated serum IL-6 levels in women with endometriosis, we did not distinguish between the various stages of the disease (Pellicer et al., 1998). Subsequent reports have pointed out that levels of IL-6 are elevated only when there are endometriomas (Daraï et al., 2003), whereas others have observed a difference between women with and without the disease but were unable to distinguish between its stages (Bedaiwy et al., 2002). It should be pointed out that the latter report does not provide data for appropriate analysis.
It is unclear why more inflammatory markers are secreted during the early stages rather than the later stages of a given disease. Halis and Arici (2004) have reported that most of the inflammatory reactions occur at the earlier stages of the disease, when most cytokines, chemokines and growth factors are secreted into peritoneal fluid. Haney et al. (1991) showed an inverse relationship between the total number of peritoneal macrophages and the extension of pelvic endometriosis. Moreover, macrophage cytotoxicity was shown to be less marked in women with severe endometriosis than those with mild disease and controls (Braun et al., 1992). Thus, these data provide further evidence that the inflammatory response may only be observed in early stages of the disease.
Referring once again to the differences in serum IL-6 levels observed in our study and other reports in the literature (D’Hooghe et al., 2001; Bedaiwy et al., 2002; Daraï et al., 2003; Somigliana et al., 2004), a third source of discrepancy is the phase of the menstrual cycle in which samples are collected. We decided to collect blood in the follicular phase because we observed that ovarian stimulation with gonadotrophins altered the serum secretion of IL-6 (Pellicer et al., 1998). As evidence shows that estrogens affect IL-6 secretion in menopausal women and ovariectomy increases systemic levels of IL-6 in animals (Yokose et al., 1996), we considered the stage of the cycle to be relevant. That said, others have evaluated this particular issue and described no difference between cycle phases in the secretion of serum IL-6 (Bedaiwy et al., 2002; Daraï et al., 2003; Iwabe et al., 2003). Thus, this should not be an issue.
Finally, the use of different commercially available kits, and even those from the same manufacturer (Bedaiwy et al., 2002; Somigliana et al., 2004), may influence results. Somigliana et al. (2004) detected serum IL-6 levels 10 times lower that those reported with the same in the present study and in another report (Bedaiwy et al., 2002) and those of studies that employed different kits (Daraï et al., 2003; Iwabe et al., 2003).
We established an optimal threshold value of 25.75 pg/ml to be able to diagnose MM endometriosis with a sensitivity of 75% and a specificity of 83%. Bedaiwy et al. (2002) suggested a discriminatory threshold of 2 pg/ml serum IL-6 with a sensitivity of 90% and a specificity of 67% for endometriosis patients. Despite using a similar kit, these low levels of IL-6 were found in many control patients included in our study and in all the pathologies evaluated, which we are not certain were ruled out in the aforementioned publication. Similarly, others have found low IL-6 values in women with benign ovarian tumours (Daraï et al., 2003). These findings make serum IL-6 determination a most promising tool for screening purposes and, combined with clinical data, will allow doctors to detect which women are at high risk of endometriosis. Whether a laparoscopy should follow is a matter to be discussed further, because we may face situations in which dysmenorrhoea is associated with elevated serum IL-6 levels. However, if infertility is the main symptom, we may recommend laparoscopy.
Serum CA-125, a 200000-Da glycoprotein typically expressed in fetal tissues and absent in adults, is elevated in many benign and malignant gynaecological pathologies, particularly if inflammation and adhesions are present, which is the case of endometriosis (Kabawat et al., 1983). Many studies have addressed this particular association, and typically, only patients with advanced endometriosis have been found to have elevated serum CA-125 levels. Thus, CA-125 is usually employed as a marker of recurrence or of success in a surgical intervention (Fedele et al., 1988; Mol et al., 1998; Bedaiwy and Falcone, 2004). The classic threshold value of 35 U/ml set to detect epithelial ovarian cancer (Bast et al., 1983) has been employed in all studies, ours included.
Recently, Kitawaki et al. (2005) reported that although the diagnostic accuracy for endometriosis without endometriomas was inferior to that for endometriosis with endometriomas, the area under the ROC curve for mild endometriosis was 0.788. As a result, they established 20 and 30 U/ml CA-125 as threshold values for screening of early stages of the disease. They included higher numbers of subjects, but all were patients undergoing surgery. We failed to confirm the extra value of measuring CA-125 for peritoneal endometriosis; however, the previously mentioned report deserves careful consideration, and the role of CA-125 in the diagnosis of early stages of the disease should be re-evaluated.
In summary, serum IL-6 is a reliable, non-invasive marker of minimal and mild endometriosis. Combined with clinical data, this will allow doctors to detect which women are at risk of having early stages of the disease.
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Submitted on April 7, 2006; resubmitted on July 21, 2006; accepted on September 27, 2006.
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