{"paper_id":"7b58416a-c244-4dcf-9edc-e0d284c60c1c","body_text":"Endometriosis is a benign disorder, which is dependent on\nestrogen hormone levels. The main feature of this disease is\nthe travelling of endometrial tissue out of the uterine cavity\nand into the lower abdominal cavity, along with inflammatory responses ( 1 - 3 ). The endometriosis prevalence in women of reproductive age ranges from 2 to 10%, which can\nincrease to 30-50% in females with infertility or persistent\npelvic pain ( 2 ,  4 - 6 ). Clinical manifestations of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain,\nirregular menstrual cycles, pain during urination and defecation, blood in urine and feces, and chronic fatigue ( 2 ,  5 ). Additionally, endometriosis is related to an augmented risk of\nobstetric complications, including infertility and spontaneous abortion ( 7 ). The precise pathogenesis of endometriosis\nis currently unknown ( 8 ,  9 ). However, based on the results\nof some studies, some genetic and environmental factors,\nsuch as nutrition, body mass index (BMI), menarche age,and number of cesarean deliveries, may influence the probability of endometriosis onset ( 10 ,  11 ).\nThe gold standard diagnostic method for endometriosis\nis direct observation of endometriosis foci during laparoscopic surgery and histopathological examination of obtained tissue samples ( 12 ). Numerous studies have been\nconducted to discover non-invasive diagnostic measurements for endometriosis, including hormones, chemokines,\nangiogens, cytokines, inflammatory and autoimmune factors, imaging methods, and direct examination of uterine\nendometrial tissue. However, there is still no non-invasive\nmethod with acceptable specificity and sensitivity for accurate diagnosis of endometriosis before surgery ( 13 ,  14 ).\nCancer antigen 125 or CA-125 is a protein produced\nin coelomic epithelial cells present in the endometrium,\novary, fallopian tubes, and peritoneum. CA-125 is important in the diagnosis of ovarian cancers ( 15 ). According to\nsome studies, the level of CA-125 increases in endometriosis patients. Nevertheless, its level varies during the\nmenstrual phases and between different types of endometriosis. Therefore, the role of this biomarker in the diagnosis and screening of endometriosis, especially in mild\nto moderate types (grades 1 to 3), has not yet been proven\nand requires more investigation ( 16 ,  17 ). An increase in\nthe neutrophil to lymphocyte ratio (NLR) indicates a systemic inflammation that can be seen in various diseases\n( 18 ). The use of NLR as both a diagnostic factor and a\ntool for monitoring treatment has been extensively studied. Its diagnostic efficacy has been demonstrated across a\nrange of inflammatory medical conditions, including neonatal sepsis, diabetic peripheral neuropathy, Parkinson’s\ndisease, allergic disorders, and sarcoidosis ( 19 - 23 ). Considering that endometriosis is an inflammatory disorder,\nhigher values of NLR are expected in this disease. Nonetheless, previous research has not accurately recognized\nthe role of this factor in the diagnosis or screening of\nendometriosis patients, thus, further studies are required\n( 16 ,  24 ,  25 ). Several studies have investigated the diagnostic performance of carcinoembryonic antigen (CEA),\nanti Mullerian hormone (AMH), cancer antigen 19-9 (CA\n19-9), and platelet and WBC count in endometriosis.\nHowever, the exact diagnostic cut-off value of these factors, as well as CA-125 and NLR, are not identified and\ncurrently, the available data are inconclusive ( 26 - 29 ).\nSince endometriosis frequently affects young women,\noffering more accessible and non-invasive diagnostic\nmethods leads to earlier detection and treatment, preventing serious related complications, such as infertility.\nRegarding the importance of this issue and the limited\navailable evidence in this field, particularly in the population of Iranian women, this study was carried out with the\nobjective of investigating the role of CA-125, CA 19-9,\nCEA, WBC count, PLT count, AMH, and NLR in endometriosis diagnosis.\n\nWe retrospectively investigated the recorded data of\n346 patients who underwent elective surgery from March\n2016 to February 2023 at the obstetrics and gynecology\ndepartment of Shohada Tajrish Hospital, Tehran, Iran.\nThis study enrolled all patients who had complete medical data, including the report of pathological evaluation\nafter the surgery, as well as the values of complete blood\ncount (CBC), CA-125, CA 19-9, CEA, and AMH. We excluded the patients who had received any treatment for\nendometriosis or were experiencing any gynecological\nconditions (such as uterine leiomyoma, adenomyosis,\nuterine polyp, endometrial hyperplasia, pelvic inflammatory disease, and malignant ovarian tumors). Additionally,\nwe excluded pregnant or breastfeeding patients and those\nwith a history of chronic diseases (including infectious,\nautoimmune, and endocrine diseases), and malignancies.\nWe have extracted socio-demographic, clinical, and paraclinical data of all included individuals from the hospital\ndata system as follows: age, occupation, weight, height,\nBMI, signs and symptoms, past obstetric history (gravidity, parity, abortion, and infertility), menstrual phase, levels of AMH, CA-125, CEA, CA 19-9, WBC and platelet\ncount, NLR, histopathological report, and the interval\nfrom the symptom onset to diagnosis.\nThe case group consisted of 230 patients with pathological confirmation of endometriosis. The control group\nincluded 116 women with pathological confirmation of\nbenign tumors of the ovary or other benign conditions\nsuch as Müllerian anomalies.\nIn this study, data analysis was done using SPSS statistical software (version 21, IBM Corp., USA). We used\nrange, mean ± standard deviation (SD), 95% confidence\nintervals (95% CI), and range for the quantitative variables. Qualitative variables were described using the frequency (%). We verified the normality of quantitative\nvariables by Kolmogorov-Smirnov analysis. To compare\nthe means between case and control groups, an independent sample t test was used for normally distributed data,\nwhile the Mann-Whitney U test was performed for nonparametric data. The area under the curve (AUC) was\ncalculated for each hematological marker (NLR, WBC\nand platelet count, CA-125, AMH, CEA, CA 19-9, and\nthe combination of CA-125 and NLR) using the receiver\noperating curve (ROC) analysis. A statistically significant\nP value was set at <0.05.\nAn ethical approval was taken prior to data collection\nfrom the Ethical Committee of Shahid Beheshti University\nof Medical Sciences (IR.SBMU.RETECH.REC.1402.131).\nPatients’ confidentiality was maintained throughout the\nstudy. Patients’ consent was obtained after the objectives\nand steps of the study were clearly explained to them.\n\nThe total number of patients in the case and control groups was 230 and 116, respectively.\nSpecifically, the control group consisted of 27 cases of serous cystadenomas, 26 patients\nwith dermoid cyst, 15 cases of paratubal cysts, 12 cases of corpus luteum cysts, 11 patients\nwith mucinous cystadenomas, 10 cases of follicular cysts, one individual with a Müllerian\nanomaly, one transmasculine individual who underwent total hysterectomy, and 13 healthy\nindividuals. The mean age of individuals was 34.08 ± 7.83 years for the case group and 31.31\n± 11.97 for the control group. The mean BMI of the individuals in the control and case\ngroups were 24.88 ± 4.22 and 24.97 ± 3.98 kg/m 2  , respectively. The most common\nmanifestation among the patients of the case group was a persistent ovarian cyst (68.3%),\nfollowed by dysmenorrhea (63%), chronic pelvic pain (58.3%), dyspareunia (36.5%), abnormal\nuterine bleeding (AUB) (23.9%), gastrointestinal symptoms (22.59%), and urinary symptoms\n(7.8%). The most frequent manifestation in the control group was abdominal pain (57.8%),\nfollowed by incidental finding (22.5%), AUB (16.4%), and dysmenorrhea (3.4%). The period\nfrom the onset of symptoms to endometriosis diagnosis was 30.79 ± 39.04 (range: 0-240)\nmonths. Among the patients with endometriosis, 12.3% had a history of abortion, 24.7% had a\nhistory of infertility, and 6.2% experienced both conditions.\nTable 1 presents the mean and 95% CI of CA-125, CEA,\nCA 19-9, NLR, WBC count, platelet count, and AMH in\nboth the case and control groups. The factors CA-125,\nCA 19-9, NLR, and WBC were significantly higher in the\ncase group.\nThe mean and 95% CI of CA-125, CEA, CA 19-9, NLR, WBC count,\nplatelet count, and AMH in case and control groups\nCI; Confidence interval, CA-125; Cancer antigen 125, CEA; Carcinoembryonic antigen,\nNLR; Neutrophil to lymphocyte ratio, WBC; White blood cell, AMH; Anti Müllerian hormone, and *; The P<0.05 were considered significant.\nThe diagnostic performance of CA-125, CEA, CA 19-9,\nNLR, WBC count, platelet count, AMH, and the combination of CA-125 and NLR were evaluated for the detection\nof endometriosis by analyzing the ROC curve ( Table 2 ).\nDiagnostic performance of CA-125, CEA, CA 19-9, NLR, WBC\ncount, platelet count, AMH, and the combination of CA-125 and NLR using ROC curve analysis\nCA-125; Cancer antigen 125, CA 19-9; Cancer antigen 19-9, CEA; Carcinoembryonic antigen, NLR; Neutrophil to lymphocyte ratio, WBC; White blood cell, AMH; Anti Müllerian\nhormone, ROC; Receiver operating curve, AUC; Area under the curve, CI; Confidence\ninterval, and *; The P<0.05 were considered significant.\nDiagnostic performance of CA-125 (purple curve), NLR (blue curve),\nand the combination of CA-125 and NLR (green curve). CA-125; Cancer\nantigen 125, NLR; Neutrophil to lymphocyte ratio, and ROC; Receiver operating curve.\nThe combination of CA 125 and NLR showed the best\ndiagnostic performance with an AUC of 0.903 (95% CI:\n0.869-0.937). The AUC of the combination of CA 125\nand NLR was greater than the AUC for each of CA-125\nor NLR alone. The AUC for CA-125 was 0.896 (95% CI:\n0.862-0.930), and the most appropriate cut-off value was\n12.7 IU/mL with sensitivity of 93.9% and specificity of\n60.9%. We also assessed the utility of CA-125 for endometriosis detection at the value of 35 (sensitivity=61.4%,\nspecificity=98.3%). The AUC for NLR was 0.699 (95%\nCI: 0.637-0.760), and the ideal cut-off value was 1.5 with\nsensitivity of 83.4% and specificity of 52.6% ( Fig .1 ). The\nAUC for CA 19-9 was 0.692 (95% CI: 0.614-0.769). The\nROC curve analysis identified the value of 13.2 IU/mL as the optimal cut-off, balancing both sensitivity (73%) and\nspecificity (65%).\n\nBased on the findings of the current study, the average\nvalues of CA 19-9, CA-125, WBC count, and NLR were\nsignificantly greater in the case group compared to the\ncontrol group. Consistent with the findings of the present\nstudy, a recent meta-analysis demonstrated significantly\ngreater NLR in endometriosis patients compared to both\npatients with other benign tumors and healthy subjects\n( 18 ). Several studies revealed that CA 19-9 and CA-125\nlevels, and WBC count were remarkably higher in endometriosis patients than in patients with other benign conditions ( 30 - 33 ). However, the results of a study suggested\nthat the level of CA-125 was not significantly different in\nendometriosis patients compared to patients with benign\novarian cysts ( 27 ). Contrary to our study, in which the\nplatelet count did not differ between the control and case\ngroups, a study discovered a higher level of platelet count\nin endometriosis patients ( 34 ).\nIn the current study, AUC (0.896) and the most ideal\ncut-off value (12.7) were calculated (specificity=60.9%,\nsensitivity=93.9%). We also examined both specificity\n(98.3%) and sensitivity (61.4%) at the cut-off value of 35\nfor CA-125. The cut-off value equal to 35 was initially\nrecognized for the detection of epithelial ovarian cancer.\nWhile this value is commonly used in the literature as the\ncut-off for CA-125 in diagnosing endometriosis, numerous studies have reported varying optimal cut-off levels\nfor endometriosis diagnosis ( 26 ).\nIn our findings, the AUC for the NLR was 0.699 and 1.5\nwas found to be the best cut-off value (specificity=52.6%,\nsensitivity=83.4%). However, a study conducted in South\nKorea suggested 2.01 as the optimal cut-off for NLR\n(specificity=60.1%, sensitivity=59.7%). In that study, the\nAUC for the NLR was 0.615 ( 33 ).\nSimilar to NLR, other markers, such as platelet to lymphocyte ratio (PLR) and monocyte to lymphocyte ratio\n(MLR), were found to be higher in endometriosis patients\ncompared with normal females ( 17 ).\nOur results revealed the CA 19-9 sensitivity (73%) and\nspecificity (65%) at the cut-off of 13.2 IU/mL. However,\nthe most favorable cut-off of this biomarker ranges from\n7.5 to 37.0 in the literature ( 26 ).\nThe highest diagnostic performance was achieved by\ncombining both CA-125 and NLR values, resulting in an\nAUC of 0.903. Consistent with our findings, several studies have found that combined CA-125 and NLR leads to\na greater diagnostic performance than each marker alone,\nwhen detecting endometriosis ( 33 ,  35 ).\nIn a similar study conducted in Turkey, it was found\nthat the average CA-125 values, NLR, and combined\nbiomarkers were remarkably greater in endometriosis patients. The optimal CA-125 cut-off point was 23.7 (specificity=81%, sensitivity=75%). For NLR, a cut-off value\nof 1.89 resulted in 70% sensitivity and 74% specificity.\nThe best cut-off value for combined biomarkers was 41.0\n(sensitivity=80%, specificity=82%). Additionally, positive associations between NLR and CA-125, and also\nbetween NLR and endometriosis score were discovered\n( 31 ).\nA study was carried out in 2021 with the aim of differentiating benign adnexal cysts from endometrioma in adolescents and pre-menopausal women ( 29 ). Based on the\nfindings of this study, females with ovarian endometriomas had significantly greater levels of CA-125, platelet\ncount, average serum PLR, and plateletcrit. However, the\nfindings of that study showed that hematological markers\ndo not have the ability to differentiate ovarian endometrioma from other benign cysts in any of the two age groups\nof young and older women ( 29 ).\n\nCurrently, there is no simple non-invasive diagnostic method, accurate enough for a definite diagnosis of\nendometriosis. Different studies have measured various biomarkers to improve endometriosis diagnosis and\nscreening. However, the optimal cut-off values vary in\nthe literature for each marker. Our study showed that the\nmeasurement of NLR and CA-125 may serve as convenient diagnostic methods. However, the combination of\nCA-125 and NLR had higher specificity and sensitivity.\nMore studies are necessary to discover the optimal cutoff points for each biomarker, and to determine the most\nappropriate combination, particularly with regard to the\ncombined value of NLR and CA-125.","source_license":"CC0","license_restricted":false}