{"paper_id":"980f8fb5-a6e9-43ba-b594-cf85bbdb85f7","body_text":"Evaluation of Serum Endocan Levels in Endometriosis: A case-control study                                                                                   e517\nEvaluation of Serum Endocan Levels in Endometriosis: \nA case-control study\nOnur Güralp1, Serdar Acikgöz2, Nevin Tüten3, Hakan Ekmekci4, Meike Schild-Suhren1, Eduard Malik1, \nAbdullah Tüten2\n1Carl von Ossietzky Oldenburg University, Department of Obstetrics and Gynecology, Klinikum Oldenburg, Oldenburg, Germany; \n2Istanbul Cerrahpasa University, Department of Obstetrics and Gynecology, Istanbul, Turkey; 3Kanuni Sultan Suleyman Education \nand Research Hospital, Obstetrics and Gynecology, Atakent Mahallesi, Halkalı Altınşehir İstanbul Cd. Istanbul, Turkey; 4Istanbul \nCerrahpasa University, Department of Biochemistry, Kocamustafapasa Cad. Istanbul, Turkey\nResearch article                      Clin Ter 2020; 171 (6):e517-522.     doi: 10.7417/CT.2020.2266\nCopyright © Società Editrice Universo (SEU)\nISSN 1972-6007\nCorrespondence: Onur Güralp, MD. Senior Consultant. Department of Obstetrics and Gynecology, Klinikum Oldenburg, AöR \nCarl von Ossietzky Oldenburg University, Rahel-Strauß-Straße 10, 26133, Oldenburg, Germany. e-mail: onur.gueralp@uni-oldenburg.de\nTel.: 0049 441 403 2288\nAbstract\nObjective. To evaluate the possible associations between serum \nendocan levels and endometriosis.\nStudy Design. A total of 60 women with histologically proven \nendometriosis and 40 women who underwent laparoscopy due to \nunexplained infertility without endometriosis were evaluated in a case-\ncontrol study. Serum endocan, CA125, CA19.9, and CA15.3 levels \nwere measured. Demographic, clinical, and laboratory parameters \nwere compared.\nResults There was no significant difference between the groups re-\ngarding age, body-mass-index, parity, and serum CRP and WBC levels. \nSerum endocan (p<0.001), CA125 (p<0.001), CA19.9 (p=0.022) and \nCA15.3 (p=0.013) levels were significantly higher in the endometriosis \ngroup compared to the control group. The correlation analysis showed \nthat serum endocan level was positively correlated with the stage of \nthe disease, CRP, and WBC, but not with remaining parameters, age, \nBMI, dysmenorrhea score, CA125, CA19.9, and CA15.3.\nSerum CA125 can predict endometriosis (Cut off=26.2 IU/mL, \nAUC=0.955) with a sensitivity of 89% and specificity of 88%. Serum \nendocan can predict endometriosis (Cut off=454 ng/mL AUC=0.749) \nwith a 93% sensitivity and 61% specificity.\nConclusion. The serum endocan levels were significantly elevated \nin women with endometriosis compared to the control group. Serum \nendocan can predict endometriosis with a sensitivity of 93% and \nspecificity of 61%. Clin Ter 2020; 171 (6):e517-522. doi: 10.7417/\nCT.2020.2266\nKey words: Angiogenesis, CA125, endometrioma\nIntroduction\nEndometriosis is one of the most important benign disor-\nders in gynecology. It affects nearly one in every ten women \nof reproductive age and is associated with pelvic pain and \nsub- or infertility as well as reduced quality of life (1).\n Endocan, also known as human endothelial cell-specific \nmolecule 1, is a circulating proteoglycan mainly released by \nendothelial cells (2) and thought to be associated with the \nregulation of cell adhesion, inflammation, and tumor prog-\nression. Endocan is especially high in tumor endothelium \n(3). The serum concentrations of endocan are elevated in \ndisorders characterized by endothelial hyperactivation or \ndysfunction. The studies have shown that endocan levels \nwere increased (compared to the control group) in asthma \n(4), juvenile idiopathic arthritis (5), multiple myeloma (6), \nsarcoidosis (7), and hypertension (8). Moreover, in gyneco-\nlogical and obstetric points of view, elevated serum endocan \nlevels were associated with polycystic ovary syndrome (7), \nendometrial and ovarian carcinoma (10), preeclampsia (11), \nand intrauterine growth retardation (12). \nAngiogenesis is crucial for the implantation and develop-\nment of ectopic endometriotic cells. An increasing number \nof studies suggest that multiple mechanisms contribute \nto the vascularization of endometriotic lesions, includ -\ning angiogenesis, vasculogenesis, and inosculation.  The \ntransformation of tumors in the sleeping phase to rapidly \ngrowing tumors is shown to be correlated with endocan (13). \nConsidering the central role of endocan in angiogenesis and \ninflammation, we aimed to evaluate the possible associations \nbetween serum endocan levels and endometriosis for the first \ntime in the literature. \nMaterials and methods\nSixty women with endometriosis and forty women \nwithout endometriosis were evaluated in a cross-sectional, \ncase-control study. Informed consent was obtained from \nall women. The study was approved by the Istanbul Uni-\nversity, Cerrahpasa Faculty of Medicine Ethics Committee \n(01.10.2012/29095 and 16.11.2018/93785). All women \nwere operated in Istanbul University Cerrahpasa Faculty \nof Medicine, Department of Obstetrics and Gynecology \nbetween 2015 and 2018.\nThe study group’s inclusion criteria were consecutive \nwomen between 18 and 45 years old who had regular men-\nstrual cycles with histologically proven endometriosis by \nlaparoscopy. The endometriosis was diagnosed histologi-\ncally by the samples taken during laparoscopy.\n\ne518                                                   Onur Güralp et al.\nThe control group’s inclusion criteria were consecutive \nwomen who underwent diagnostic laparoscopy due to unex-\nplained primary or secondary infertility and did not have any \nmacroscopic endometriotic lesion.\nExclusion criteria for both study and control groups \nincluded the history of ovarian surgery, systemic diseases; \nendocrine disorders; autoimmune disorders; malignancy; \nmenopause, and hormonal treatment, including oral con-\ntraceptive pills in the last six months. \nOn admission, the demographic and clinical data were \nrecorded, and the visual analog scale (V AS) score was calcu-\nlated for each woman for the severity of pelvic pain and dy-\nsmenorrhea. A V AS score of 0 indicated no pain, and a V AS \nscore of 10 indicated the worst pain ever experienced.\nThe severity of endometriosis was classified accor -\nding to the recommendations of the American Society for \nReproductive Medicine (ASRM) (14). The patients were \nclassified as mild (stage 1-2) and moderate-to-severe (stage \n3-4) endometriosis.\nSamples were obtained in the operating theatre, and \n5–10 ml of venous blood samples were collected using a \nperipheral venous catheter (PVC). In order to allow clot-\nting, the blood samples were kept at room temperature for \nat least 30 minutes. The serum supernatants were separated \nfollowing centrifugation at 5000g for 10 min. The superna-\ntants were stored at -80°C until analysis. C-reactive protein \n(CRP) and white blood cell count (WBC) were measured. \nSerum CA125 and CA15.3 levels were measured with the \nelectrochemiluminescence technique. CA19.9 was measured \nby immunometric assay. Enzyme-linked immunosorbent \nassay (ELISA) was used to measure the serum endocan \nlevels (Aviscera Bioscience Inc, Cat. No: SK00318-01, CA, \nUSA). The measurement steps were performed as instructed \nby the manufacturer.\n \nStatistical analysis\nAll statistical analyses were performed using the Sta-\ntistical Package for the Social Sciences (SPSS) software \nversion 18.0. \nA preliminary study with ten women with endometrio-\nsis and ten women without endometriosis was performed \nusing the serum endocan levels (613.2±178.0 ng/mL vs. \n422.1±61.9 ng/mL, respectively). The preliminary results \nrevealed a sample size of at least 32 cases in each group \n(alpha Error=0.05, power=99%)\nThe Kolmogorov-Smirnov test was performed in order to \nevaluate the homogeneity of variances. Parametric variables \nwere presented as mean ± standard deviation (SD) and were \nevaluated using the T-test or ANOV A. Pearson’s correlation \ntest was used to evaluate the possible correlations between \nthe parametric variables. The receiver operating characteri-\nstic (ROC) curve analysis was used to determine the markers’ \nsensitivity and specificity for predicting endometriosis. \nP<0.05 was accepted as statistically significant.\nResults\nA total of 60 women with histologically proven endome-\ntriosis and 40 women without any macroscopic endometrio-\ntic lesions were included in statistical evaluation. Clinical \nand demographical features and laboratory parameters of \nendometriosis and non-endometriosis groups were presented \nin Table 1. All parameters were equally distributed. There \nwas no significant difference between the groups regarding \nage, BMI, and parity. The dysmenorrhea rate was signifi-\ncantly higher in the endometriosis group (68.3% vs. 35%; \np<0.001). Serum CRP and WBC levels were comparable \nbetween the groups. \nTable 1. Demographic and clinical features of endometriosis and \nnon-endometriosis groups\nEndometriosis\n(n=60)\n(mean±SD)\nControl\n(n=40)\n(mean±SD)\np\nAge (years) 32.5±8.0 30.8±7.8 0.295\nBMI (kg/m2) 24.3±4.5 24.7±4.5 0.760\nParity (n) 0.63±0.88 0.95±1.0 0.094\nDysmenorrhea rate \n(n,%) 41/60 (68.3%) 14/40 (35%) <0.001\nCA125 (IU/mL) 80.6±64.9 15.3±7.0 <0.001\nCA15.3 (IU/mL) 19.1±10.9 14.4±5.2 0.013\nCA19.9 (IU/mL) 20.9±16.5 12.8±15.8 0.022\nCRP (mg/L) 3.4±4.4 2.2±2.1 0.07\nWBC (n/µl) 7356±1592 6975±1778 0.08\nEndocan (ng/mL) 590.8±206.0 442.3±93.8 <0.001\nBMI, body mass index; CRP , C-reactive protein; SD, standard \ndeviation; WBC, white blood cell.\np<0.05 is significant, the significant p-values are written in bold\nIn our study group, unilateral and bilateral endometrioma \nrates were 58.3% and 41.7%, respectively. Douglas pouch \nobliteration was not seen in 28 (46.6%) women, whereas 11 \n(18.3%) and 21 (35%) women had a partial and complete \nobliteration, respectively. Peritoneal endometriosis and deep \ninfiltrating endometriosis were observed in 24 (40%) and \n16 women (26.7%), respectively.\nSerum endocan levels were significantly higher in \nthe endometriosis group compared to the control group \n(590.8±206.0 ng/mL vs. 442.3±93.8 ng/mL, p<0.001, alpha \nError=0.05, power=98%). Serum CA125, CA 19.9, and CA \n15.3 levels were also significantly higher in the endometrio-\nsis group compared to the control group (see Table 1).\nSerum endocan and CA 125 levels were slightly elevated \nin the stage 3–4 group compared to the stage 1–2 group, \nalthough the differences both remained nonsignificant \n(p=0.122 and 0.171, respectively). CA 19-9 levels were \nsignificantly higher in the stage 3–4 group compared to the \nstage 1–2 group (p=0.040). There was no significant diffe-\nrence between the stage 1–2 and stage 3–4 groups regarding \nother parameters evaluated (see Table 2). \n\nEvaluation of Serum Endocan Levels in Endometriosis: A case-control study                                                                                   e519\nTable 2. Comparison of age, BMI, tumor markers and inflammatory markers between stage 1–2 and stage 3–4 endometriosis \ngroups\nStage 1-2\n(n=33)\n(mean±SD)\nStage 3-4\n(n=27)\n(mean±SD)\np\nAge (years) 31.7±7.8 33.5±8.4 0.407\nBMI (kg/m2) 23.6±3.9 25.4±5.0 0.191\nCA125 (IU/mL) 69.8±57.0 94.7±72.9 0.171\nCA15.3 (IU/mL) 17.5±7.8 20.8±13.7 0.301\nCA19.9 (IU/mL) 16.9±12.0 25.9±20.0 0.040\nCRP (mg/L) 3.0±3.0 5.0±5.4 0.089\nWBC (n/µl) 7647±1591 7000±1549 0.118\nEndocan (ng/mL) 551.7±158.4 638.5±247.2 0.122\nBMI, body mass index; CRP , C-reactive protein; SD, standard deviation; WBC, white blood cell.\np<0.05 is significant, the significant p-values are written in bold\nSerum endocan values in the control group and according \nto endometriosis stages are also presented in Figure 1. There \nis a gradual increase with the advancing stage, although the \ndifferences both remained nonsignificant. The correlation \nanalysis showed that serum endocan level was positively \ncorrelated with the stage of the disease (r=459; p<0.001), \nCRP (r=0.257, p=0.012), and WBC (r=0.251, p=0.012), \nbut not with remaining parameters (Table 3). The box-plot \nrepresentation of serum endocan levels according to the \nstages of endometriosis is shown in Fig. 1.\nFig. 1. The box-plot representation of serum endocan levels accor-\nding to the stages of endometriosis.\nTable 3. Correlation analysis of serum endocan with demogra-\nphic and clinical parameters\nEndocan\nr p\nAge 0.119 0.237\nBMI -0.163 0.140\nDysmenorrhea score 0.256 0.052\nCA125 0.194 0.063\nCA15.3 0.200 0.069\nCA19.9 0.168 0.115\nCRP 0.257 0.012\nWBC 0.251 0.012\nEndometriosis stage 0.459 <0.001\nBMI, body mass index; CRP , C-reactive protein; WBC, white \nblood cell.\nPearson’s correlation analysis\nP<0.05 is significant, the significant p-values are written in bold.\nSerum endocan and the three tumor markers were evalua-\nted for their ability to predict endometriosis (Table 4). ROC \nanalysis revealed that CA125 had the highest AUC of 0.955 \nfor predicting endometriosis followed by endocan, CA15.3, \nand CA19.9 in descending order (0.749, 0.673 and 0.646; \nrespectively) (Fig. 2). All four parameters were significant \nto predict endometriosis.\nTable 4. ROC Analysis of CA125, endocan, CA15.3 and CA19.9 for prediction of endometriosis\nAUC (95% CI) Cut-off value Sensitivity Specificity p\nCA125 0.955 (0.915-0.995) 26.2 IU/mL 89% 88% <0.001\nEndocan 0.749 (0.633-0.865) 454 ng/mL 93% 61% <0.001\nCA19.9 0.673 (0.555-0.791) 11.5 IU/mL 66% 66% 0.007\nCA15.3 0.646 (0.527-0.765) 15.0 IU/mL 68% 66% 0.023\nAUC, area under curve; CI, confidence interval; ROC, receiver operator characteristics\nP<0.05 is significant, the significant p-values are written in bold.\n\ne520                                                   Onur Güralp et al.\nSerum endocan has significant positive correlations with \nendometriosis, but there is no correlation with age, BMI, and \ntumor markers, CA125, CA15.3, and CA19.9.\nDiscussion\nAccording to our search in Medline and Google Scholar \nwith the keywords “endocan AND endometriosis”, “endocan \nAND endometrioma”, “endocan AND endometrium”, this \nis the first study to evaluate the association between serum \nendocan and endometriosis. In our study, the serum endo-\ncan, CA125, CA19.9, and CA15.3 levels were significantly \nelevated in the endometriosis group compared to the control \ngroup. Serum endocan and CA125 levels were slightly hi-\ngher in the stage 3–4 group compared to the stage 1–2 group, \nalthough the difference remained nonsignificant.\nEndocan, a novel endothelial cell dysfunction marker, is \na soluble proteoglycan released from the vascular endothe-\nlium. It may play a central role in the pathogenesis of endo-\nthelial dysfunction (15,16) and organ-specific inflammation \n(17). Endocan is known to be associated with endometrial \nand ovarian cancer, inflammation, and diseases characterized \nby endothelial dysfunction such as preeclampsia and sepsis \n(15,18,19). Its secretion is mediated by various cytokines \nand growth factors, such as the tumor necrosis factor-a \n(TNF-a) and the vascular endothelial growth factor (VEGF) \n(20,21). In accordance with the growing evidence suggesting \na link between endocan and inflammation, we observed a \nsignificant positive correlation between serum endocan and \nCRP and WBC.\nRecent studies suggest that endocan expression is as-\nsociated with the vascular transformation of stem cells and \nendothelium to mesenchyme shift processes such as arterial \nwall remodeling (22-25). El Behery et al. (26) have shown \nthat endocan levels were elevated in ovarian cancer compared \nto the controls, and endocan was an independent prognostic \nmarker in overall survival in epithelial ovarian cancer. Lalo-\nglu et al. (10) evaluated 27 women with endometrial cancer, \n20 women with ovarian cancer, 19 women with benign \novarian pathology, and 19 women with benign endometrial \npathology and healthy controls. They have shown that se-\nrum endocan levels in women with endometrial and ovarian \ncancer were significantly higher than those of women with \nbenign disorders and healthy women. Median serum levels \nwere 560.4 pg/mL in endometrial cancer cases, and 0.0 pg/\nmL in the benign disorder group and healthy controls. Since \nall the values were given only as a median, it is not possible \nto compare our results with the results from the study of \nLaloglu et al. (10). Moreover, they reported that the endocan \nlevels in the benign disorder group and healthy women were \ncomparable. Unfortunately, the authors did not define the \ndistribution of benign endometrial lesions; therefore, it is \nnot clear if they evaluated women with simple or complex \nendometrial hyperplasia. They evaluated all endometrial and \novarian benign lesions as a group and compared this single \ngroup with healthy controls or the malignancy group. For \nthat reason, it is hard to interpret their results relating to our \nstudy. Besides, in our study, we did not evaluate women with \nendometrial hyperplasia. The pathogeneses of endometrial \nhyperplasia and endometriosis are quite different. It may be \npossible that endocan is increased in endometriosis but not in \nendometrial hyperplasia, but this finding must be evaluated \nin the same study group.\nEndometrioma is a common pathology among women \nwith endometriosis and affects 17%-44% of patients with \nendometriosis. (27) Alcázar and García-Manero (28) evalu-\nated 65 women with endometrioma by transvaginal color \nDoppler and microvessel density and concluded that the vas-\ncularization of ovarian endometriomas was higher in women \nwith pelvic pain compared to the asymptomatic women. In \nour study, the correlation analysis between endocan and \ndysmenorrhea showed a borderline p-value of 0.052, which \nmay be evaluated in greater scale studies.\nThe results from studies about endocan in bacteremia \nand sepsis are inconsistent. Scherpereel et al. (19) suggested \nthat the serum endocan was significantly elevated in patients \nadmitted to the intensive care unit with sepsis compared to \nhealthy donors and patients with systemic inflammatory \nresponse syndrome. Adekola et al. (11) have observed that \npregnancies complicated by acute pyelonephritis with bac-\nteremia were associated with reduced endocan levels. \nConsidering the molecular associations of endocan in \nendothelial dysfunction, inflammation, and angiogenesis, \nit is difficult to explain which one is more dominant in \nwhich disorder. Preeclampsia and IUGR are conditions \nmainly associated with endothelial dysfunction and hypo-\nxia. Endometrial and ovarian cancers are mainly associated \nwith neoangiogenesis and inflammation. Endometriosis is a \ncombination of all three mechanisms.\nIn our study, we observed that serum endocan was in-\ndependent of age and BMI. For that reason, endocan may \nbe used in all age and BMI groups and needs no correction \nfor other parameters. \nIn our study, the ROC analysis for the prediction of en-\ndometriosis revealed that CA125 had the highest AUC for \npredicting endometriosis compared to endocan, CA15.3, and \nCA19.9 in descending order. The sensitivity and specificity \nfor the prediction of endometriosis were 89% and 88% for \nCA125 and 93% and 61% for endocan. The sensitivity of \nFig. 2. ROC Analysis of CA125, endocan, CA15.3, and CA19.9 for \nprediction of endometriosis.\n\nEvaluation of Serum Endocan Levels in Endometriosis: A case-control study                                                                                   e521\nendocan was higher than CA125. Furthermore, endocan was \nnot correlated with the other tumor markers, indicating that \nit is elevated in a different patient group than CA125. The \nsensitivity and the specificity rates were not given to suggest \nendocan as a diagnostic marker for endometriosis alone and \nby itself, rather to define where it stands in comparison with \nthe other well-known markers and potential use as panel \nmarker in combination with other relevant markers. \nThe main limitation of our study and many other marker \nstudies about endometriosis is that the control group does \nnot consist of completely healthy women. The diagnosis of \nendometriosis is proved and excluded only with laparoscopy, \nand it is not ethical to perform laparoscopy in completely \nhealthy women without any indication. Our study’s main \nstrength is that it is the first study evaluating the possible \nassociations between serum endocan levels and endome-\ntriosis, which is also crucial for the understanding of the \npathophysiology of endometriosis.\nConclusion\nOur study is the first study to evaluate the associations \nbetween serum endocan and endometriosis. The serum en-\ndocan levels were significantly higher in the endometriosis \ngroup compared to the control (unexplained infertility) \ngroup. Serum endocan levels were slightly higher in the \nstage 3–4 group compared to the stage 1–2 group, although \nthe difference remained nonsignificant. Serum endocan can \npredict endometriosis with a sensitivity of 93%, however a \nlow specificity of 61%.\nAcknowledgment\nNone.\nFunding\nNone.\nConflict of Interest\nNone.\nAuthor contributions:\nOnur GÜRALP\nManuscript writing/editing, statistical analyses\nSerdar ACIKGÖZ\nData collection or management\nNevin TÜTEN \nData collection or management\nHakan EKMEKCI\nBiochemical analyses\nMeike SCHILD-SUHREN\nManuscript editing\nEduard MALIK\nManuscript writing/editing\nAbdullah TÜTEN\nProtocol/project development, Data analysis\nReferences\n1. Rogers PA, D’Hooghe TM, Fazleabas A, et al. Priorities for \nendometriosis research: recommendations from an interna-\ntional consensus workshop. 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