Is Complement C3 a Reliable Indicator of Endometriosis Severity? Insights from a Retrospective Study

Is Complement C3 a Reliable Indicator of Endometriosis Severity? Insights from a Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Is Complement C3 a Reliable Indicator of Endometriosis Severity? Insights from a Retrospective Study Yuyan Guo, Penghui Huang, Jinna Zhang, Chaobin Liu, Xi Xie, Zhenna Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5988604/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This study evaluates the potential of complement C3 as a predictive biomarker for endometriosis severity and examines its correlation with clinical features and biochemical markers. Methods In this retrospective analysis, 82 women diagnosed with endometriosis were classified into severe and minimal-to-moderate groups based on revised American Society for Reproductive Medicine (rASRM) scores. Peripheral blood samples were analyzed for complement components (C3, C4), tumor markers (CA125, CA199), and other biochemical indices. Results Patients with severe endometriosis exhibited significantly higher frequencies of dysmenorrhea, larger cyst dimensions, and elevated serum levels of complement C3, CA125, and triglycerides compared to those with less severe disease (p < 0.05). Notably, complement C3 and CA125 levels were strongly correlated with disease severity, highlighting their potential role in clinical assessment. Conclusion Complement C3 shows promise as a biomarker for assessing the severity of endometriosis. The integration of complement components into diagnostic and prognostic frameworks could facilitate earlier detection and the development of personalized therapeutic approaches for endometriosis. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Signs and symptoms Endometriosis Complement system C3 Severity Figures Figure 1 Figure 2 Introduction Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity, resulting in persistent inflammation. Affecting approximately 10% of reproductive-age women, endometriosis is a leading cause of infertility, contributing to 30–50% of infertility cases. 1 , 2 In addition to its impact on fertility, the disorder is associated with diminished ovarian reserve (DOR) and hormonal dysregulation. 3 Clinically, women with endometriosis endure chronic pelvic pain, dysmenorrhea, and dyspareunia, significantly impairing their quality of life. The global economic burden of this condition is substantial, with healthcare costs and productivity losses reaching billions of dollars annually. 4 Complicating management, endometriosis has a recurrence rate as high as 50% within two to five years post-treatment, posing challenges for long-term care. 5 , 6 Despite being the gold standard, the current diagnostic approach of histopathological confirmation via laparoscopy is invasive, and the subtlety of symptoms often delays diagnosis. The average time from symptom onset to definitive diagnosis is between 8 and 10 years. 7 , 8 This delay underscores the need for non-invasive diagnostic tools. While biomarkers such as CA125 have been explored, their low specificity and sensitivity limit their clinical application. 9 – 11 Thus, there is an urgent demand for more accurate biomarkers that can facilitate early detection and effective disease monitoring. Immune dysregulation plays a central role in endometriosis pathogenesis, particularly in sustaining chronic inflammation and autoantibody production. 12 – 14 The complement system, an integral component of innate immunity, has emerged as a key player in modulating inflammatory responses and tissue clearance. Complement component C3, a pivotal element of this system, mediates critical processes such as opsonization, cell lysis, and the amplification of inflammation. 15 , 16 Recent studies suggest that C3 activation may be intricately linked to the inflammatory processes in endometriosis, yet large-scale clinical investigations into this relationship remain limited. 17 , 18 In light of these considerations, this study aims to investigate the role of serum complement C3 levels in endometriosis and to evaluate its association with key clinical parameters, including disease severity, symptomatology, cyst size, and recurrence rates. By exploring these relationships, we seek to provide further insights into the pathophysiology of endometriosis and to assess the potential of C3 as a non-invasive diagnostic and prognostic biomarker. If validated, complement C3 could be incorporated into clinical practice, offering a more precise and tailored approach to the diagnosis and management of endometriosis, ultimately improving patient outcomes. Materials and Methods Patient Characteristics This retrospective study included 82 women aged 21 to 51 years, treated at Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, between January and December 2020. Endometriosis was diagnosed via laparoscopic surgery and confirmed through histopathological examination. To ensure diagnostic consistency, all surgeries were performed during the proliferative phase of the menstrual cycle. Exclusion criteria included recent use of hormonal or anti-inflammatory medications (within three months prior to surgery), confirmed gynecological malignancies based on surgical or imaging findings, acute inflammatory conditions, pregnancy, and postmenopausal status. The severity of endometriosis was classified according to the revised American Society for Reproductive Medicine (rASRM) classification, which evaluates the size and depth of lesions, adhesions, and cul-de-sac obliteration. Patients were categorized into two groups: severe endometriosis (Stage IV, rASRM > 40) and mild to moderate endometriosis (Stages I-III, rASRM ≤ 40). Data Collection and Ethical Considerations Data from 82 patients were retrospectively collected and categorized into two groups based on endometriosis severity. Clinical symptoms, including menstrual cycle characteristics (regularity, volume, duration), dysmenorrhea, pelvic pain, and dyspareunia, were recorded. The maximum cyst diameter was documented, and for patients with peritoneal endometriosis without an ovarian cyst, the diameter was recorded as 0, based on intraoperative findings. Preoperative blood samples were collected within 48 hours before surgery to ensure consistency in sample timing relative to the surgical intervention. This uniform sample collection time frame minimized variability related to the menstrual cycle phase or transient physiological changes. Preoperative laboratory data included complement components (C3, C4), cancer antigens (CA125, CA199), and other biomarkers such as albumin, globulin, HDL-C, LDL-C, triglycerides, total cholesterol, neutrophils, monocytes, and lymphocytes. These variables were analyzed to evaluate their association with the severity of endometriosis. This study was approved by the Research Ethics Committee of Fujian Maternity and Child Health Hospital (approval number 2021-KRD022). Written informed consent was obtained from all participants, ensuring adherence to ethical guidelines and maintaining patient confidentiality. Biochemical Assessment Peripheral blood samples were processed within two hours of collection to ensure sample integrity. Complement C3 and C4 levels were quantified using enzyme-linked immunosorbent assay (ELISA) kits, and all measurements were conducted in duplicate to ensure assay reliability. Levels of CA125 and CA199 were also measured to explore their correlation with endometriosis severity. Additional biochemical markers such as albumin, globulin, HDL-C, LDL-C, triglycerides, total cholesterol, neutrophils, monocytes, and lymphocytes were evaluated using the chemiluminescence enzyme immunoassay method (Abbott Laboratories, ARCHITECT CI16200, Abbott, USA). To ensure the reliability of results, all biochemical assays were repeated twice. If the coefficient of variation (CV) between duplicate assays exceeded 5%, a third measurement was conducted, and the mean of the two closest values was used in the final analysis. Additionally, regular calibration of laboratory equipment and quality control samples with known concentrations were utilized to maintain assay accuracy. Any missing or insufficient data points were documented, and a sensitivity analysis was conducted to assess the potential impact of missing data on study outcomes. Data Analysis All statistical analyses were conducted using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation (SD) or median (range), depending on the data distribution. Group comparisons were performed using independent t-tests, chi-square tests, or Mann-Whitney U tests, as appropriate. The diagnostic potential of serum C3, C4, and tumor markers (CA125, CA199) was assessed using receiver operating characteristic (ROC) curves, with the area under the curve (AUC) calculated to evaluate diagnostic accuracy. Optimal cutoff values were determined using the Youden index. Univariate and multivariate linear regression analyses were conducted to identify factors associated with serum C3 levels and rASRM scores. A p-value of < 0.05 was considered statistically significant. Results Baseline Characteristics of the Study Population The baseline characteristics, as summarized in Table 1 , show no significant differences in age or BMI between the severe and minimal-to-moderate endometriosis groups ( P = 0.075 and P = 0.281, respectively). However, dysmenorrhea was significantly more prevalent in the severe group (62.5% vs. 47.06%, P = 0.048). Serum C3 and CA125 levels, as shown in Fig. 1 , were both significantly higher in the severe group compared to the minimal-to-moderate group ( P = 0.032 and P = 0.012, respectively). No significant differences were observed in C4 levels or the incidence of chronic pelvic pain and dyspareunia between the groups. Table 1 Baseline Characteristics of the Study Population Variables Severe EMT (rASRM>40) Minimal to Moderate EMT(rASRM ≤ 40) P value Age 32.00 (24.00–51.00) 30.00 (21.00–47.00) 0.075 BMI(kg/m 2 ) 20.98 (16.38–26.80) 20.49 (17.48–33.76) 0.281 Menstrual disorders 3(6.25%) 2(5.89%) 0.950 Dysmenorrhea 33(62.50%) 16(47.06%) 0.048* Chronic pelvic pain 4(8.33%) 0(0%) 0.228 Dyspareunia 3(6.25%) 2(5.88%) 0.945 C3(g/L) 1.00 ± 0.21 0.91 ± 0.14 0.032* C4(g/L) 0.21 ± 0.06 0.21 ± 0.06 0.745 CA125(kU/L) 72.35(10.82–322.90) 37.20(11.00-220.50) 0.012* CA199(kU/L) 23.92(2.00-976.35) 18.60(1.00-269.77) 0.099 NOTE: EMT = endometriosis. Data are presented as median (range) for continuous variables and n (%) for categorical variables. P values were calculated using the Mann-Whitney U test for continuous variables and the Chi-square test or Fisher’s exact test for categorical variables. * P < 0.05 indicates statistical significance. Serum Complement and Tumor Marker Levels by Clinical Features Serum C3 levels were slightly higher in patients with adenomyosis compared to those without, though this difference was not statistically significant ( P = 0.076). Similarly, dysmenorrhea was associated with elevated C3 levels ( P = 0.198), but without reaching significance. However, as depicted in Table 2 , a significant elevation in the C3/C4 ratio was observed in patients with cysts ≥ 4.0 cm compared to those with smaller cysts ( P = 0.036). Additionally, CA125 and CA199 levels, as illustrated in Fig. 1 , were significantly elevated in patients with dysmenorrhea and larger cysts, respectively ( P < 0.001 and P = 0.02). Table 2 Serum Complement and Tumor Marker Levels by Clinical Features Variables Adenomyosis Non-Adenomyosis P -value Dysmenorrhea Non-Dysmenorrhea P-value Cyst ≥ 4.0cm Cyst < 4.0cm P -value C3 (g/L) 0.98 ± 0.18 0.95 ± 0.20 0.076 0.98 ± 0.21 0.95 ± 0.15 0.198 0.99 ± 0.20 0.93 ± 0.15 0.48 C4 (g/L) 0.20 ± 0.05 0.21 ± 0.07 0.644 0.20 ± 0.07 0.21 ± 0.05 0.67 0.20 ± 0.06 0.22 ± 0.06 0.177 C3/C4 5.13 ± 1.50 4.78 ± 1.14 0.36 5.09 ± 1.45 4.78 ± 1.17 0.411 5.18 ± 1.37 4.60 ± 1.25 0.036 CA125 (kU/L) 77.25 ± 57.63 71.32 ± 73.39 0.034* 94.54 ± 71.77 44.56 ± 38.88 0.000178** 79.46 ± 65.87 66.15 ± 64.43 0.315 CA199 (kU/L) 78.68 ± 154.37 46.62 ± 128.69 0.002** 88.25 ± 178.75 26.00 ± 36.47 0.006** 83.36 ± 174.13 30.65 ± 52.14 0.02* NOTE: P -value comparisons are as follows: Adenomyosis vs Non-Adenomyosis, Dysmenorrhea vs Non-Dysmenorrhea, and Cyst ≥ 4.0cm vs Cyst < 4.0cm. * P < 0.05, ** P < 0.01 indicate statistical significance. Linear Regression Analysis of C3, C4, and rASRM Scores In univariate regression, serum C3 levels were significantly associated with higher rASRM scores ( B = 58.19, P = 0.020), but this association was not retained in multivariate analysis ( P = 0.294). Table 3 shows that CA125 levels remained significantly associated with rASRM scores in both univariate and multivariate analyses ( P = 0.007 and P = 0.028, respectively). No significant correlations were found between C4 levels and rASRM scores ( P = 0.745). Figure 2 demonstrates the linear correlation between C3, C4, and rASRM scores. Table 3 Linear regression analysis of C3, C4, and rASRM Variables Univariate (B) P -value(Univariat) Multivariate (B) P -value (Multivariate) C3 (g/L) 58.19 0.020* 26.97 0.294 C4 (g/L) -27.90 0.723 - - rASRM 1.13 0.020* 0.40 0.371 Intraoperative cyst diameter (cm) 6.80 <0.001* 5.84 0.001* CA125 (kU/L) 0.195 0.007* 0.15 0.028* CA199 (kU/L) 0.055 0.099 - - NOTE: * P < 0.05, ** P < 0.01 indicate statistical significance. Multivariate analysis adjusted for age, BMI, and other relevant covariates. ROC Curve Analysis for Endometriosis Severity and Clinical Features ROC analysis, as seen in Table 4 , revealed moderate diagnostic accuracy for complement C3 in predicting severe endometriosis (AUC = 0.663, P = 0.021) and adenomyosis (AUC = 0.574, P = 0.032). C4 showed higher accuracy in predicting adenomyosis (AUC = 0.696, P = 0.005). CA125 had the highest diagnostic accuracy for identifying severe endometriosis (AUC = 0.611, P = 0.024) and larger cysts (AUC = 0.639, P = 0.019). Table 4 Area Under the ROC Curve for Different Variables Variables Severe Endometriosis Cyst ≥ 4.0cm Adenomyosis C3 (g/L) 0.663 (0.542–0.784, P = 0.021) 0.599 (0.466–0.731, P = 0.045) 0.574 (0.448-0.700, P = 0.032) C4 (g/L) 0.608 (0.485–0.730, P = 0.038) 0.654 (0.533–0.775, P = 0.017) 0.696 (0.581–0.810, P = 0.005) C3/C4 0.631 (0.510–0.752, P = 0.029) 0.577 (0.450–0.704, P = 0.062) 0.550 (0.424–0.676, P = 0.041) C3 + C4 0.479 (0.350–0.607, P = 0.081) 0.411 (0.283–0.538, P = 0.112) 0.486 (0.360–0.612, P = 0.053) CA125 (kU/L) 0.611 (0.480–0.742, P = 0.024) 0.639 (0.511–0.767, P = 0.019) 0.559 (0.434–0.684, P = 0.037) CA199 (kU/L) 0.609 (0.486–0.732, P = 0.026) 0.547 (0.419–0.675, P = 0.047) 0.536 (0.410–0.662, P = 0.050) NOTE: The area under the ROC curve (AUC) provides a measure of diagnostic accuracy. AUC values between 0.5 and 0.7 suggest low accuracy, 0.7 to 0.9 indicate moderate accuracy, and above 0.9 suggest high accuracy. * P < 0.05 indicates statistical significance. Discussion This study provides critical insights into the potential role of complement C3 as a biomarker for assessing the severity of endometriosis. Our findings reveal that patients with severe endometriosis exhibit significantly elevated serum C3 levels compared to those with milder forms, aligning with previous studies that have implicated complement activation in endometriosis pathogenesis. Earlier research has highlighted the involvement of the complement system, particularly C3, in driving inflammatory processes central to the progression of endometriosis. 17 – 25 Our study adds to this body of knowledge by demonstrating a direct correlation between C3 levels and disease severity, reinforcing the hypothesis that complement dysregulation plays a pivotal role in advanced stages of the disease. Interestingly, we observed no significant correlation between complement C4 levels and disease severity, diverging from findings in other autoimmune conditions where C4 often plays a more prominent role. This highlights the specificity of C3 in the context of endometriosis and suggests that while C3 may serve as a more reliable biomarker, C4’s role may be less relevant in this particular condition. The association between elevated C3 levels and clinical symptoms, such as dysmenorrhea, further emphasizes the clinical significance of complement activation. 26 Prior studies have suggested immune dysregulation contributes to pain in endometriosis, but our findings extend this by identifying C3 activation as a potential driver of symptom severity. 27 , 28 This suggests that complement-targeted therapies could offer new avenues for symptom management. A novel aspect of our study is the observed elevation of C3/C4 ratios in patients with larger endometriotic cysts (≥ 4 cm). While previous studies have primarily focused on complement activation as a whole, few have examined the specific implications of C3/C4 ratio imbalances in relation to cyst development. 29 Our results suggest that such imbalances may contribute to lesion growth and disease progression, providing a fresh perspective on complement dysregulation in endometriosis. While considerable efforts were made to minimize the study's limitations, certain constraints persist. The relatively small sample size may affect the generalizability of the findings, and the cross-sectional design limits the ability to establish causal relationships between complement activation and disease progression. Although we employed strict inclusion criteria and rigorous statistical analyses, these limitations underscore the need for larger, longitudinal studies to further validate our results. Nevertheless, this study offers several notable strengths. In particular, it provides new insights into the relationship between complement C3/C4 ratios and cyst size in endometriosis, an area that has been insufficiently explored. The observed elevation in C3/C4 ratios in patients with larger cysts suggests a potential role for complement dysregulation in lesion growth and disease progression. Moreover, the integration of complement markers with traditional tumor markers such as CA125 and CA199 offers a multi-marker approach that could enhance diagnostic accuracy and enable earlier detection, addressing existing gaps in endometriosis diagnostics. In conclusion, complement C3 demonstrates significant potential as a biomarker for assessing endometriosis severity. While its diagnostic value as an individual marker is limited, its integration into a multi-marker panel, alongside CA125 and CA199, could substantially improve diagnostic accuracy and facilitate earlier detection. Future research should focus on elucidating the dynamic role of complement activation in relation to disease progression and therapeutic response, with an emphasis on the potential for immune-modulating therapies. By advancing our understanding of complement dysregulation in endometriosis, we can better optimize disease management and improve patient outcomes. Declarations Conflict of interest All authors of this study declare no conflicts of interest. Funding information This work was sponsored by grants from the Fujian Provincial Natural Science Foundation ( No. 2021J01414 and No. 2021J01421 ) and Fujian provincial health technology project ( No. 2022GGB004 ) of China. Author Contribution SHL, GL, YL and YYG contributed to designing the study. SHL, CBL, YSC and PHH collected the data and wrote the manuscript. YYG, JNZ, ZNW and XX contributed to data collection and data analyzing. All authors read and approved the final manuscript. Acknowledgements The authors are grateful to their patients’ participation and the medical staff for retrieving the case files. Data Availability The data that supports the findings of this study are not available because sharing data compromises privacy of human data. However, the data can be available from the corresponding author upon reasonable request after ethical approval. References Ye L, Whitaker LHR, Mawson RL, et al. Endometriosis. BMJ (Clinical research ed.). 2022;379：e068950.doi:10.1136/bmj-2021-068950. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020, 382, 1244-1256. doi: 10.1056/NEJMra1810764. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. Lancet. 2021, 397, 839-852. doi:10.1016/s0140-6736(21)00389-5. Shafrir AL, Farland LV, Shah DK, et al. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract. Res Clin Obstet Gynaecol. 2018, 51, 1-15. doi:10.1016/j.bpobgyn.2018.06.001. Harris Emily. Study: Bacterial Infection Tied to Some Endometriosis Cases. JAMA-J AM MED ASSOC. 2023-07-11;330(2):112. doi:10.1001/jama.2023.10747. Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379：e070750. doi:10.1136/bmj-2022-070750. Sivajohan Brintha, Elgendi Mohamed, Menon Carlo, et al. Clinical use of artificial intelligence in endometriosis: a scoping review. NPJ digital medicine. 2022;5 (1)：109. doi:10.1038/s41746-022-00638-1. Agarwal SK,Chapron C, Giudice L C,et al. Clinical diagnosis of endometriosis: a call to action. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. 2019;220 (4)：354.e1-354.e12. doi:10.1016/j. ajog.2018.12.039 Cicinelli Ettore, de Ziegler Dominique, Vitagliano Amerigo. In women with endometriosis, effective treatment of chronic endometritis with antibiotics lowers serum CA-125 levels. FERTILITY AND STERILITY. 2024;121 (6)：1066-1068. doi:10.1016/j.fertnstert. 2024.02.041. Shin KH, Kim HH, Kwon BS, et al. Clinical Usefulness of Cancer Antigen (CA) 125, Human Epididymis 4, and CA72-4 Levels and Risk of Ovarian Malignancy Algorithm Values for Diagnosing Ovarian Tumors in Korean Patients With and Without Endometriosis. Annals of Laboratory Medicine. 2020; 40 (1)：40-47. doi:10. 3343/alm. 2020.40.1.40. Knific T, Vouk K, Vogler A, et al. Models including serum CA-125, BMI, cyst pathology, dysmenorrhea or dyspareunia for diagnosis of endometriosis. Biomarkers in Medicine. 2018;12 (7)：737-747. doi:10. 2217/ bmm-2017-0426. Li W, Wang X, Zhang X, et al. A mendelian randomization approach to study causal association between four types of endometriosis and immune cells: experimental studies.International Journal of Surgery. 2024. doi: 10. 1097/JS9. 0000000000001909. Huang Z,Lin Dian C, Zhang H, et al. The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis. IMMUNOLOGY. 2024; 172 (3)：469-485.doi:10.1111/imm.13786 Abobeleira J, Neto A, Mauersberger J, et al. Evidence of Browning and Inflammation Features in Visceral Adipose Tissue of Women with Endometriosis. ARCHIVES OF MEDICAL RESEARCH. 2024;55 (7)：103064. doi:10.1016/ j.arcmed. 2024. 103064 Chen Ying, Chu John Man-Tak, Wong Gordon Tin-Chun, et al. Complement C3 From Astrocytes Plays Significant Roles in Sustained Activation of Microglia and Cognitive Dysfunctions Triggered by Systemic Inflammation After Laparotomy in Adult Male Mice.Journal of Neuroimmune Pharmacology. 2024;19 (1)：8. doi: 10.1007/ s11481-024-10107-z. Dong Xinyan, Fan Jianchen, Lin Donghui, et al. Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis. Journal of neuroinflammation. 2022;19 (1)：226. doi: 10.1186/ s12974-022-02587-8 Hasan Aisha, Rahim Amena, Afzal Muhammad, et al. Serum Albumin and C3 Complement Levels in Endometriosis. JCPSP-Journal of the College of Physicians and Surgeons Pakistan. 2019;29 (8)：702-705. doi:10.29271/jcpsp.2019.08.702. Agostinis Chiara, Zorzet Sonia, Balduit Andrea, et al. The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis. Frontiers in immunology. 2021;12：693118. doi: 10.3389/ fimmu. 2021.693118 Yu Liang, Shen Huaji, Ren Xiaohan, et al. Multi-omics analysis reveals the interaction between the complement system and the coagulation cascade in the development of endometriosis.Scientific reports. 2021;11 (1)：11926. doi:10.1038/s41598-021-90112-x. Agostinis Chiara, Toffoli Miriam, Zito Gabriella, et al.Proangiogenic properties of complement protein C1q can contribute to endometriosis. Frontiers in immunology. 2024;15：1405597.doi:10.3389/fimmu.2024.1405597. Agostinis Chiara, Balduit Andrea, Mangogna Alessandro, et al. Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target. Frontiers in immunology. 2020;11：599117. doi:10. 3389/ fimmu. 2020. 599117. Rahal Danilo, Andrade Fabiana, Nisihara Renato. Insights into the role of complement system in the pathophysiology of endometriosis.IMMUNOLOGY LETTERS. 2021;231：43-48. doi:10.1016/j.imlet.2021.01.005. Edwards RP, Huang X, Vlad AM. Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: New roles for the "old" complement pathway. Oncoimmunology.2015;4 (5)：e1002732. doi: 10.1080/ 2162402X. 2014. 1002732. Bielen D, Tomassetti C, Van Schoubroeck D, et al. IDEAL study: magnetic resonance imaging for suspected deep endometriosis assessment prior to laparoscopy is as reliable as radiological imaging as a complement to transvaginal ultrasonography. ULTRASOUND IN OBSTETRICS & GYNECOLOGY.2020;56 (2)：255-266. doi:10.1002/uog.21868. Aslan Cigdem, Ak Handan, Askar Niyazi, et al. Overexpression of complement C5 in endometriosis.CLINICAL BIOCHEMISTRY. 2014;47 (6)：496-8. doi: 10.1016/ j.clinbiochem. 2013.11.020 Karadadas Elif, Hortu Ismet, Ak Handan, et al. Evaluation of complement system proteins C3a, C5a and C6 in patients of endometriosis. CLINICAL BIOCHEMISTRY. 2020; 81：15-19.doi:10.1016/j.clinbiochem. 2020.04.005. Palomino Wilder A, Tayade Chandrakant, Argandoña Felipe, et al. The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid secretory phase. JOURNAL OF REPRODUCTIVE IMMUNOLOGY. 2018;125：1-7. doi:10.1016/j.jri.2017.10.046. Wattiez A, Schindler L, Ussia A, et al. A proof of concept that experience-based management of endometriosis can complement evidence-based guidelines.Facts Views and Vision in ObGyn. 2023;15 (3)：197-214.doi:10.52054/FVVO.15.3.094 Wang Yeh, Nicholes Kristen, Shih Ie-Ming. The Origin and Pathogenesis of Endometriosis. Annual Review of Pathology-Mechanisms of Disease. 2020;15：71-95. doi:10.1146/annurev-pathmechdis-012419-032654 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5988604","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":414001562,"identity":"2be84349-a9fc-4de0-a6e2-11566569fb96","order_by":0,"name":"Yuyan Guo","email":"","orcid":"","institution":"Fujian Medical University Union Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuyan","middleName":"","lastName":"Guo","suffix":""},{"id":414001564,"identity":"47110be6-0878-4b57-b576-44d5629e3493","order_by":1,"name":"Penghui Huang","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Penghui","middleName":"","lastName":"Huang","suffix":""},{"id":414001567,"identity":"990c3442-ab88-48a9-8516-043ac69cb2bd","order_by":2,"name":"Jinna Zhang","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinna","middleName":"","lastName":"Zhang","suffix":""},{"id":414001568,"identity":"b632354c-7e54-42b7-a5df-d25d711e5ee6","order_by":3,"name":"Chaobin Liu","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chaobin","middleName":"","lastName":"Liu","suffix":""},{"id":414001569,"identity":"0771d696-6b96-480a-b393-7d15af391d9d","order_by":4,"name":"Xi Xie","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Xie","suffix":""},{"id":414001570,"identity":"192535a7-4335-4d45-8216-ee664b31da85","order_by":5,"name":"Zhenna Wang","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhenna","middleName":"","lastName":"Wang","suffix":""},{"id":414001571,"identity":"54512a90-a522-4238-9d7e-d62ea27cdada","order_by":6,"name":"Yan Lin","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Lin","suffix":""},{"id":414001572,"identity":"fc9af9a7-04c7-460f-9e7f-1f86e2322751","order_by":7,"name":"Guan Lin","email":"","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guan","middleName":"","lastName":"Lin","suffix":""},{"id":414001573,"identity":"2b02cf1b-0d50-451f-b5f9-c46c4647820b","order_by":8,"name":"Shunhe Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACPgYexgcfDGzkGJiJ1cLGwMNsOKMgzZgkLWzSPB8OJTYQ7TA2/rMHJGcYHEif38578ANDjU00YS0SeQkGHwzu5G44zJcswXAsLZegdWwSPAaJMwye5W5g5jGQYGw4TIQW/jMGh3kMDqfLN/MY/yBOC0OOYTNQSwLDYR4zIm2RyDFmnGGQZrgBqMUigRi/8POfMf/x4Y+NvHz/GeMbH2psCGtBBQmkKR8Fo2AUjIJRgAsAAJKNOfJ7KcO6AAAAAElFTkSuQmCC","orcid":"","institution":"Fujian Maternity and Child Health Hospital, Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shunhe","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-02-08 15:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5988604/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5988604/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76178760,"identity":"5e0e4988-b9e0-40a2-80ee-6aec0217fdcd","added_by":"auto","created_at":"2025-02-13 07:01:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37791,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScatter Diagram and Average Levels of Complement System and Tumor Markers in Patients with Severe and Minimal to Moderate Endometriosis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5988604/v1/a88df093acd42b8b44511a23.png"},{"id":76179694,"identity":"43d37b03-c756-4cd6-93a5-cd16f1fd1096","added_by":"auto","created_at":"2025-02-13 07:09:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18121,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLinear correlation between complement C3, C4 and rASRM score\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5988604/v1/8b3e526f3a28c65ca8f61487.png"},{"id":92059103,"identity":"088d1375-9253-4230-8a8f-def655932339","added_by":"auto","created_at":"2025-09-24 07:38:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":886573,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5988604/v1/789e3d0b-c536-4a01-ba69-525bebf9fcc0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Is Complement C3 a Reliable Indicator of Endometriosis Severity? Insights from a Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity, resulting in persistent inflammation. Affecting approximately 10% of reproductive-age women, endometriosis is a leading cause of infertility, contributing to 30\u0026ndash;50% of infertility cases.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e In addition to its impact on fertility, the disorder is associated with diminished ovarian reserve (DOR) and hormonal dysregulation.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Clinically, women with endometriosis endure chronic pelvic pain, dysmenorrhea, and dyspareunia, significantly impairing their quality of life. The global economic burden of this condition is substantial, with healthcare costs and productivity losses reaching billions of dollars annually.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Complicating management, endometriosis has a recurrence rate as high as 50% within two to five years post-treatment, posing challenges for long-term care.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite being the gold standard, the current diagnostic approach of histopathological confirmation via laparoscopy is invasive, and the subtlety of symptoms often delays diagnosis. The average time from symptom onset to definitive diagnosis is between 8 and 10 years.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e This delay underscores the need for non-invasive diagnostic tools. While biomarkers such as CA125 have been explored, their low specificity and sensitivity limit their clinical application.\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Thus, there is an urgent demand for more accurate biomarkers that can facilitate early detection and effective disease monitoring.\u003c/p\u003e \u003cp\u003eImmune dysregulation plays a central role in endometriosis pathogenesis, particularly in sustaining chronic inflammation and autoantibody production.\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The complement system, an integral component of innate immunity, has emerged as a key player in modulating inflammatory responses and tissue clearance. Complement component C3, a pivotal element of this system, mediates critical processes such as opsonization, cell lysis, and the amplification of inflammation.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Recent studies suggest that C3 activation may be intricately linked to the inflammatory processes in endometriosis, yet large-scale clinical investigations into this relationship remain limited.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn light of these considerations, this study aims to investigate the role of serum complement C3 levels in endometriosis and to evaluate its association with key clinical parameters, including disease severity, symptomatology, cyst size, and recurrence rates. By exploring these relationships, we seek to provide further insights into the pathophysiology of endometriosis and to assess the potential of C3 as a non-invasive diagnostic and prognostic biomarker. If validated, complement C3 could be incorporated into clinical practice, offering a more precise and tailored approach to the diagnosis and management of endometriosis, ultimately improving patient outcomes.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThis retrospective study included 82 women aged 21 to 51 years, treated at Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, between January and December 2020. Endometriosis was diagnosed via laparoscopic surgery and confirmed through histopathological examination. To ensure diagnostic consistency, all surgeries were performed during the proliferative phase of the menstrual cycle. Exclusion criteria included recent use of hormonal or anti-inflammatory medications (within three months prior to surgery), confirmed gynecological malignancies based on surgical or imaging findings, acute inflammatory conditions, pregnancy, and postmenopausal status.\u003c/p\u003e \u003cp\u003eThe severity of endometriosis was classified according to the revised American Society for Reproductive Medicine (rASRM) classification, which evaluates the size and depth of lesions, adhesions, and cul-de-sac obliteration. Patients were categorized into two groups: severe endometriosis (Stage IV, rASRM\u0026thinsp;\u0026gt;\u0026thinsp;40) and mild to moderate endometriosis (Stages I-III, rASRM\u0026thinsp;\u0026le;\u0026thinsp;40).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection and Ethical Considerations\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eData from 82 patients were retrospectively collected and categorized into two groups based on endometriosis severity. Clinical symptoms, including menstrual cycle characteristics (regularity, volume, duration), dysmenorrhea, pelvic pain, and dyspareunia, were recorded. The maximum cyst diameter was documented, and for patients with peritoneal endometriosis without an ovarian cyst, the diameter was recorded as 0, based on intraoperative findings.\u003c/p\u003e\u003cp\u003ePreoperative blood samples were collected within 48 hours before surgery to ensure consistency in sample timing relative to the surgical intervention. This uniform sample collection time frame minimized variability related to the menstrual cycle phase or transient physiological changes.\u003c/p\u003e\u003cp\u003ePreoperative laboratory data included complement components (C3, C4), cancer antigens (CA125, CA199), and other biomarkers such as albumin, globulin, HDL-C, LDL-C, triglycerides, total cholesterol, neutrophils, monocytes, and lymphocytes. These variables were analyzed to evaluate their association with the severity of endometriosis.\u003c/p\u003e\u003cp\u003e This study was approved by the Research Ethics Committee of Fujian Maternity and Child Health Hospital (approval number 2021-KRD022). Written informed consent was obtained from all participants, ensuring adherence to ethical guidelines and maintaining patient confidentiality.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eBiochemical Assessment\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePeripheral blood samples were processed within two hours of collection to ensure sample integrity. Complement C3 and C4 levels were quantified using enzyme-linked immunosorbent assay (ELISA) kits, and all measurements were conducted in duplicate to ensure assay reliability. Levels of CA125 and CA199 were also measured to explore their correlation with endometriosis severity. Additional biochemical markers such as albumin, globulin, HDL-C, LDL-C, triglycerides, total cholesterol, neutrophils, monocytes, and lymphocytes were evaluated using the chemiluminescence enzyme immunoassay method (Abbott Laboratories, ARCHITECT CI16200, Abbott, USA).\u003c/p\u003e \u003cp\u003eTo ensure the reliability of results, all biochemical assays were repeated twice. If the coefficient of variation (CV) between duplicate assays exceeded 5%, a third measurement was conducted, and the mean of the two closest values was used in the final analysis. Additionally, regular calibration of laboratory equipment and quality control samples with known concentrations were utilized to maintain assay accuracy. Any missing or insufficient data points were documented, and a sensitivity analysis was conducted to assess the potential impact of missing data on study outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAll statistical analyses were conducted using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (range), depending on the data distribution. Group comparisons were performed using independent t-tests, chi-square tests, or Mann-Whitney U tests, as appropriate. The diagnostic potential of serum C3, C4, and tumor markers (CA125, CA199) was assessed using receiver operating characteristic (ROC) curves, with the area under the curve (AUC) calculated to evaluate diagnostic accuracy. Optimal cutoff values were determined using the Youden index. Univariate and multivariate linear regression analyses were conducted to identify factors associated with serum C3 levels and rASRM scores. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics of the Study Population\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe baseline characteristics, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, show no significant differences in age or BMI between the severe and minimal-to-moderate endometriosis groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.075 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.281, respectively). However, dysmenorrhea was significantly more prevalent in the severe group (62.5% vs. 47.06%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048). Serum C3 and CA125 levels, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, were both significantly higher in the severe group compared to the minimal-to-moderate group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012, respectively). No significant differences were observed in C4 levels or the incidence of chronic pelvic pain and dyspareunia between the groups.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of the Study Population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere EMT\u003c/p\u003e \u003cp\u003e(rASRM\u0026gt;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMinimal to Moderate EMT(rASRM\u0026thinsp;\u0026le;\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.00 (24.00\u0026ndash;51.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.00 (21.00\u0026ndash;47.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.98 (16.38\u0026ndash;26.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.49 (17.48\u0026ndash;33.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenstrual disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(5.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.950\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysmenorrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33(62.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16(47.06%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.048*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pelvic pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(8.33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspareunia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(5.88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3(g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4(g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.745\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125(kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72.35(10.82\u0026ndash;322.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.20(11.00-220.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199(kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.92(2.00-976.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.60(1.00-269.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNOTE: EMT\u0026thinsp;=\u0026thinsp;endometriosis. Data are presented as median (range) for continuous variables and n (%) for categorical variables. \u003cem\u003eP\u003c/em\u003e values were calculated using the Mann-Whitney U test for continuous variables and the Chi-square test or Fisher\u0026rsquo;s exact test for categorical variables. *\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates statistical significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSerum Complement and Tumor Marker Levels by Clinical Features\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSerum C3 levels were slightly higher in patients with adenomyosis compared to those without, though this difference was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.076). Similarly, dysmenorrhea was associated with elevated C3 levels (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.198), but without reaching significance. However, as depicted in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, a significant elevation in the C3/C4 ratio was observed in patients with cysts\u0026thinsp;\u0026ge;\u0026thinsp;4.0 cm compared to those with smaller cysts (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036). Additionally, CA125 and CA199 levels, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, were significantly elevated in patients with dysmenorrhea and larger cysts, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum Complement and Tumor Marker Levels by Clinical Features\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-Adenomyosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDysmenorrhea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNon-Dysmenorrhea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCyst\u0026thinsp;\u0026ge;\u0026thinsp;4.0cm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCyst\u0026thinsp;\u0026lt;\u0026thinsp;4.0cm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e \u003cp\u003e0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.177\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3/C4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e5.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e4.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e \u003cp\u003e5.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e4.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e77.25\u0026thinsp;\u0026plusmn;\u0026thinsp;57.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e71.32\u0026thinsp;\u0026plusmn;\u0026thinsp;73.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.034*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e94.54\u0026thinsp;\u0026plusmn;\u0026thinsp;71.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e44.56\u0026thinsp;\u0026plusmn;\u0026thinsp;38.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.000178**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e \u003cp\u003e79.46\u0026thinsp;\u0026plusmn;\u0026thinsp;65.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e66.15\u0026thinsp;\u0026plusmn;\u0026thinsp;64.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e78.68\u0026thinsp;\u0026plusmn;\u0026thinsp;154.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e46.62\u0026thinsp;\u0026plusmn;\u0026thinsp;128.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e88.25\u0026thinsp;\u0026plusmn;\u0026thinsp;178.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e26.00\u0026thinsp;\u0026plusmn;\u0026thinsp;36.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.006**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e \u003cp\u003e83.36\u0026thinsp;\u0026plusmn;\u0026thinsp;174.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e30.65\u0026thinsp;\u0026plusmn;\u0026thinsp;52.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.02*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eNOTE: \u003cem\u003eP\u003c/em\u003e-value comparisons are as follows: Adenomyosis vs Non-Adenomyosis, Dysmenorrhea vs Non-Dysmenorrhea, and Cyst\u0026thinsp;\u0026ge;\u0026thinsp;4.0cm vs Cyst\u0026thinsp;\u0026lt;\u0026thinsp;4.0cm. * \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, ** \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 indicate statistical significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eLinear Regression Analysis of C3, C4, and rASRM Scores\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn univariate regression, serum C3 levels were significantly associated with higher rASRM scores (\u003cem\u003eB\u003c/em\u003e\u0026thinsp;=\u0026thinsp;58.19, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020), but this association was not retained in multivariate analysis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.294). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows that CA125 levels remained significantly associated with rASRM scores in both univariate and multivariate analyses (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028, respectively). No significant correlations were found between C4 levels and rASRM scores (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.745). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates the linear correlation between C3, C4, and rASRM scores.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLinear regression analysis of C3, C4, and rASRM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate (B)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value(Univariat)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMultivariate (B)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value (Multivariate)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.020*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-27.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.723\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erASRM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.020*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.371\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraoperative cyst diameter (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.028*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNOTE: *\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 indicate statistical significance. Multivariate analysis adjusted for age, BMI, and other relevant covariates.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eROC Curve Analysis for Endometriosis Severity and Clinical Features\u003c/h2\u003e \u003cp\u003eROC analysis, as seen in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, revealed moderate diagnostic accuracy for complement C3 in predicting severe endometriosis (AUC\u0026thinsp;=\u0026thinsp;0.663, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) and adenomyosis (AUC\u0026thinsp;=\u0026thinsp;0.574, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032). C4 showed higher accuracy in predicting adenomyosis (AUC\u0026thinsp;=\u0026thinsp;0.696, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). CA125 had the highest diagnostic accuracy for identifying severe endometriosis (AUC\u0026thinsp;=\u0026thinsp;0.611, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and larger cysts (AUC\u0026thinsp;=\u0026thinsp;0.639, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eArea Under the ROC Curve for Different Variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere Endometriosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCyst\u0026thinsp;\u0026ge;\u0026thinsp;4.0cm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.663 (0.542\u0026ndash;0.784, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.599 (0.466\u0026ndash;0.731, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.574 (0.448-0.700, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4 (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.608 (0.485\u0026ndash;0.730, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.038)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.654 (0.533\u0026ndash;0.775, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.696 (0.581\u0026ndash;0.810, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3/C4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.631 (0.510\u0026ndash;0.752, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.577 (0.450\u0026ndash;0.704, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.062)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.550 (0.424\u0026ndash;0.676, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3\u0026thinsp;+\u0026thinsp;C4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.479 (0.350\u0026ndash;0.607, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.081)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.411 (0.283\u0026ndash;0.538, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.486 (0.360\u0026ndash;0.612, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.053)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.611 (0.480\u0026ndash;0.742, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.639 (0.511\u0026ndash;0.767, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.559 (0.434\u0026ndash;0.684, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199 (kU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.609 (0.486\u0026ndash;0.732, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.547 (0.419\u0026ndash;0.675, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.536 (0.410\u0026ndash;0.662, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.050)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNOTE: The area under the ROC curve (AUC) provides a measure of diagnostic accuracy. AUC values between 0.5 and 0.7 suggest low accuracy, 0.7 to 0.9 indicate moderate accuracy, and above 0.9 suggest high accuracy. *\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicates statistical significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides critical insights into the potential role of complement C3 as a biomarker for assessing the severity of endometriosis. Our findings reveal that patients with severe endometriosis exhibit significantly elevated serum C3 levels compared to those with milder forms, aligning with previous studies that have implicated complement activation in endometriosis pathogenesis. Earlier research has highlighted the involvement of the complement system, particularly C3, in driving inflammatory processes central to the progression of endometriosis.\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Our study adds to this body of knowledge by demonstrating a direct correlation between C3 levels and disease severity, reinforcing the hypothesis that complement dysregulation plays a pivotal role in advanced stages of the disease.\u003c/p\u003e \u003cp\u003eInterestingly, we observed no significant correlation between complement C4 levels and disease severity, diverging from findings in other autoimmune conditions where C4 often plays a more prominent role. This highlights the specificity of C3 in the context of endometriosis and suggests that while C3 may serve as a more reliable biomarker, C4\u0026rsquo;s role may be less relevant in this particular condition. The association between elevated C3 levels and clinical symptoms, such as dysmenorrhea, further emphasizes the clinical significance of complement activation.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Prior studies have suggested immune dysregulation contributes to pain in endometriosis, but our findings extend this by identifying C3 activation as a potential driver of symptom severity.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e This suggests that complement-targeted therapies could offer new avenues for symptom management.\u003c/p\u003e \u003cp\u003eA novel aspect of our study is the observed elevation of C3/C4 ratios in patients with larger endometriotic cysts (\u0026ge;\u0026thinsp;4 cm). While previous studies have primarily focused on complement activation as a whole, few have examined the specific implications of C3/C4 ratio imbalances in relation to cyst development.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Our results suggest that such imbalances may contribute to lesion growth and disease progression, providing a fresh perspective on complement dysregulation in endometriosis.\u003c/p\u003e \u003cp\u003eWhile considerable efforts were made to minimize the study's limitations, certain constraints persist. The relatively small sample size may affect the generalizability of the findings, and the cross-sectional design limits the ability to establish causal relationships between complement activation and disease progression. Although we employed strict inclusion criteria and rigorous statistical analyses, these limitations underscore the need for larger, longitudinal studies to further validate our results. Nevertheless, this study offers several notable strengths. In particular, it provides new insights into the relationship between complement C3/C4 ratios and cyst size in endometriosis, an area that has been insufficiently explored. The observed elevation in C3/C4 ratios in patients with larger cysts suggests a potential role for complement dysregulation in lesion growth and disease progression. Moreover, the integration of complement markers with traditional tumor markers such as CA125 and CA199 offers a multi-marker approach that could enhance diagnostic accuracy and enable earlier detection, addressing existing gaps in endometriosis diagnostics.\u003c/p\u003e \u003cp\u003eIn conclusion, complement C3 demonstrates significant potential as a biomarker for assessing endometriosis severity. While its diagnostic value as an individual marker is limited, its integration into a multi-marker panel, alongside CA125 and CA199, could substantially improve diagnostic accuracy and facilitate earlier detection. Future research should focus on elucidating the dynamic role of complement activation in relation to disease progression and therapeutic response, with an emphasis on the potential for immune-modulating therapies. By advancing our understanding of complement dysregulation in endometriosis, we can better optimize disease management and improve patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eAll authors of this study declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding information\u003c/h2\u003e \u003cp\u003eThis work was sponsored by grants from the Fujian Provincial Natural Science Foundation ( No. 2021J01414 and No. 2021J01421 ) and Fujian provincial health technology project ( No. 2022GGB004 ) of China.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSHL, GL, YL and YYG contributed to designing the study. SHL, CBL, YSC and PHH collected the data and wrote the manuscript. YYG, JNZ, ZNW and XX contributed to data collection and data analyzing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003e The authors are grateful to their patients\u0026rsquo; participation and the medical staff for retrieving the case files.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that supports the findings of this study are not available because sharing data compromises privacy of human data. However, the data can be available from the corresponding author upon reasonable request after ethical approval.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYe L, Whitaker LHR, Mawson RL, et al. Endometriosis. BMJ (Clinical research ed.). 2022;379：e068950.doi:10.1136/bmj-2021-068950.\u003c/li\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020, 382, 1244-1256. doi: 10.1056/NEJMra1810764.\u003c/li\u003e\n\u003cli\u003eTaylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. Lancet. 2021, 397, 839-852. doi:10.1016/s0140-6736(21)00389-5.\u003c/li\u003e\n\u003cli\u003eShafrir AL, Farland LV, Shah DK, et al. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract. Res Clin Obstet Gynaecol. 2018, 51, 1-15. doi:10.1016/j.bpobgyn.2018.06.001.\u003c/li\u003e\n\u003cli\u003eHarris Emily. Study: Bacterial Infection Tied to Some Endometriosis Cases. JAMA-J AM MED ASSOC. 2023-07-11;330(2):112. doi:10.1001/jama.2023.10747.\u003c/li\u003e\n\u003cli\u003eHorne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379：e070750. doi:10.1136/bmj-2022-070750.\u003c/li\u003e\n\u003cli\u003eSivajohan Brintha, Elgendi Mohamed, Menon Carlo, et al. Clinical use of artificial intelligence in endometriosis: a scoping review. NPJ digital medicine. 2022;5 (1)：109. doi:10.1038/s41746-022-00638-1.\u003c/li\u003e\n\u003cli\u003eAgarwal SK,Chapron C, Giudice L C,et al. Clinical diagnosis of endometriosis: a call to action. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. 2019;220 (4)：354.e1-354.e12. doi:10.1016/j. ajog.2018.12.039\u003c/li\u003e\n\u003cli\u003eCicinelli Ettore, de Ziegler Dominique, Vitagliano Amerigo. In women with endometriosis, effective treatment of chronic endometritis with antibiotics lowers serum CA-125 levels. FERTILITY AND STERILITY. 2024;121 (6)：1066-1068. doi:10.1016/j.fertnstert. 2024.02.041.\u003c/li\u003e\n\u003cli\u003eShin KH, Kim HH, Kwon BS, et al. Clinical Usefulness of Cancer Antigen (CA) 125, Human Epididymis 4, and CA72-4 Levels and Risk of Ovarian Malignancy Algorithm Values for Diagnosing Ovarian Tumors in Korean Patients With and Without Endometriosis. Annals of Laboratory Medicine. 2020; 40 (1)：40-47. doi:10. 3343/alm. 2020.40.1.40.\u003c/li\u003e\n\u003cli\u003eKnific T, Vouk K, Vogler A, et al. Models including serum CA-125, BMI, cyst pathology, dysmenorrhea or dyspareunia for diagnosis of endometriosis. Biomarkers in Medicine. 2018;12 (7)：737-747. doi:10. 2217/ bmm-2017-0426.\u003c/li\u003e\n\u003cli\u003eLi W, Wang X, Zhang X, et al. A mendelian randomization approach to study causal association between four types of endometriosis and immune cells: experimental studies.International Journal of Surgery. 2024. doi: 10. 1097/JS9. 0000000000001909.\u003c/li\u003e\n\u003cli\u003eHuang Z,Lin Dian C, Zhang H, et al. The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis. IMMUNOLOGY. 2024; 172 (3)：469-485.doi:10.1111/imm.13786\u003c/li\u003e\n\u003cli\u003eAbobeleira J, Neto A, Mauersberger J, et al. Evidence of Browning and Inflammation Features in Visceral Adipose Tissue of Women with Endometriosis. ARCHIVES OF MEDICAL RESEARCH. 2024;55 (7)：103064. doi:10.1016/ j.arcmed. 2024. 103064\u003c/li\u003e\n\u003cli\u003eChen Ying, Chu John Man-Tak, Wong Gordon Tin-Chun, et al. Complement C3 From Astrocytes Plays Significant Roles in Sustained Activation of Microglia and Cognitive Dysfunctions Triggered by Systemic Inflammation After Laparotomy in Adult Male Mice.Journal of Neuroimmune Pharmacology. 2024;19 (1)：8. doi: 10.1007/ s11481-024-10107-z.\u003c/li\u003e\n\u003cli\u003eDong Xinyan, Fan Jianchen, Lin Donghui, et al. Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis. Journal of neuroinflammation. 2022;19 (1)：226. doi: 10.1186/ s12974-022-02587-8\u003c/li\u003e\n\u003cli\u003eHasan Aisha, Rahim Amena, Afzal Muhammad, et al. Serum Albumin and C3 Complement Levels in Endometriosis. JCPSP-Journal of the College of Physicians and Surgeons Pakistan. 2019;29 (8)：702-705. doi:10.29271/jcpsp.2019.08.702.\u003c/li\u003e\n\u003cli\u003eAgostinis Chiara, Zorzet Sonia, Balduit Andrea, et al. The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis. Frontiers in immunology. 2021;12：693118. doi: 10.3389/ fimmu. 2021.693118\u003c/li\u003e\n\u003cli\u003eYu Liang, Shen Huaji, Ren Xiaohan, et al. Multi-omics analysis reveals the interaction between the complement system and the coagulation cascade in the development of endometriosis.Scientific reports. 2021;11 (1)：11926. doi:10.1038/s41598-021-90112-x.\u003c/li\u003e\n\u003cli\u003eAgostinis Chiara, Toffoli Miriam, Zito Gabriella, et al.Proangiogenic properties of complement protein C1q can contribute to endometriosis. Frontiers in immunology. 2024;15：1405597.doi:10.3389/fimmu.2024.1405597.\u003c/li\u003e\n\u003cli\u003eAgostinis Chiara, Balduit Andrea, Mangogna Alessandro, et al. Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target. Frontiers in immunology. 2020;11：599117. doi:10. 3389/ fimmu. 2020. 599117.\u003c/li\u003e\n\u003cli\u003eRahal Danilo, Andrade Fabiana, Nisihara Renato. Insights into the role of complement system in the pathophysiology of endometriosis.IMMUNOLOGY LETTERS. 2021;231：43-48. doi:10.1016/j.imlet.2021.01.005.\u003c/li\u003e\n\u003cli\u003eEdwards RP, Huang X, Vlad AM. Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: New roles for the \u0026quot;old\u0026quot; complement pathway. Oncoimmunology.2015;4 (5)：e1002732. doi: 10.1080/ 2162402X. 2014. 1002732.\u003c/li\u003e\n\u003cli\u003eBielen D, Tomassetti C, Van Schoubroeck D, et al. IDEAL study: magnetic resonance imaging for suspected deep endometriosis assessment prior to laparoscopy is as reliable as radiological imaging as a complement to transvaginal ultrasonography. ULTRASOUND IN OBSTETRICS \u0026amp; GYNECOLOGY.2020;56 (2)：255-266. doi:10.1002/uog.21868.\u003c/li\u003e\n\u003cli\u003eAslan Cigdem, Ak Handan, Askar Niyazi, et al. Overexpression of complement C5 in endometriosis.CLINICAL BIOCHEMISTRY. 2014;47 (6)：496-8. doi: 10.1016/ j.clinbiochem. 2013.11.020\u003c/li\u003e\n\u003cli\u003eKaradadas Elif, Hortu Ismet, Ak Handan, et al. Evaluation of complement system proteins C3a, C5a and C6 in patients of endometriosis. CLINICAL BIOCHEMISTRY. 2020; 81：15-19.doi:10.1016/j.clinbiochem. 2020.04.005.\u003c/li\u003e\n\u003cli\u003ePalomino Wilder A, Tayade Chandrakant, Argando\u0026ntilde;a Felipe, et al. The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid secretory phase. JOURNAL OF REPRODUCTIVE IMMUNOLOGY. 2018;125：1-7. doi:10.1016/j.jri.2017.10.046.\u003c/li\u003e\n\u003cli\u003eWattiez A, Schindler L, Ussia A, et al. A proof of concept that experience-based management of endometriosis can complement evidence-based guidelines.Facts Views and Vision in ObGyn. 2023;15 (3)：197-214.doi:10.52054/FVVO.15.3.094\u003c/li\u003e\n\u003cli\u003eWang Yeh, Nicholes Kristen, Shih Ie-Ming. The Origin and Pathogenesis of Endometriosis. Annual Review of Pathology-Mechanisms of Disease. 2020;15：71-95. doi:10.1146/annurev-pathmechdis-012419-032654\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Complement system, C3, Severity","lastPublishedDoi":"10.21203/rs.3.rs-5988604/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5988604/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study evaluates the potential of complement C3 as a predictive biomarker for endometriosis severity and examines its correlation with clinical features and biochemical markers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective analysis, 82 women diagnosed with endometriosis were classified into severe and minimal-to-moderate groups based on revised American Society for Reproductive Medicine (rASRM) scores. Peripheral blood samples were analyzed for complement components (C3, C4), tumor markers (CA125, CA199), and other biochemical indices.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePatients with severe endometriosis exhibited significantly higher frequencies of dysmenorrhea, larger cyst dimensions, and elevated serum levels of complement C3, CA125, and triglycerides compared to those with less severe disease (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Notably, complement C3 and CA125 levels were strongly correlated with disease severity, highlighting their potential role in clinical assessment.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eComplement C3 shows promise as a biomarker for assessing the severity of endometriosis. The integration of complement components into diagnostic and prognostic frameworks could facilitate earlier detection and the development of personalized therapeutic approaches for endometriosis.\u003c/p\u003e","manuscriptTitle":"Is Complement C3 a Reliable Indicator of Endometriosis Severity? Insights from a Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-13 07:01:54","doi":"10.21203/rs.3.rs-5988604/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dc0ef34e-c63e-414e-82b5-095cf45d9b58","owner":[],"postedDate":"February 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44144477,"name":"Health sciences/Diseases"},{"id":44144478,"name":"Health sciences/Health care"},{"id":44144479,"name":"Health sciences/Medical research"},{"id":44144480,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-09-24T07:38:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-13 07:01:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5988604","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5988604","identity":"rs-5988604","version":["v1"]},"buildId":"2u56kwukJI3zHK-uzyFNs","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}