Interleukin-6: A Potential Biomarker for Dysmenorrhea and Disease Severity in Adenomyosis

Interleukin-6: A Potential Biomarker for Dysmenorrhea and Disease Severity in Adenomyosis | 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 Research Article Interleukin-6: A Potential Biomarker for Dysmenorrhea and Disease Severity in Adenomyosis Ying Tang, Hua-dong Tian, Bin Su, Hong-ni He, Xin Cai, Hui-quan Hu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7472436/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background The pathogenesis of adenomyosis remains incompletely understood, and no well-established biomarkers related to its inflammatory mediators have been identified. Aim This retrospective study aimed to investigate the association between interleukin-6 (IL-6) and dysmenorrhea in adenomyosis, as well as factors influencing IL-6 levels in patients with adenomyosis. Methods Patients were categorized based on the presence of dysmenorrhea and lesion subtype. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic utility of IL-6 for dysmenorrhea. Binary logistic regression was employed to identify factors associated with dysmenorrhea and IL-6 levels. Results IL-6 levels were significantly higher in patients with dysmenorrhea compared to those without dysmenorrhea in the total cohort (Z = -3.783, P < 0.001), as well as in both the diffuse subtype group (Z = -2.525, P = 0.012) and the focal subtype group (Z = -2.883, P = 0.004). An IL-6 level of 3.02 pg/mL was identified as the optimal cutoff value for discriminating dysmenorrhea via ROC analysis. Patients with IL-6 levels ≥ 3.02 pg/mL were more likely to experience dysmenorrhea compared to those with IL-6 levels below this threshold. Furthermore, multiple regression analysis revealed a positive correlation between IL-6 levels and uterus volume in both the total cohort and the diffuse subtype group. Conclusion IL-6 was associated with dysmenorrhea in adenomyosis, and its level correlated positively with disease severity. Adenomyosis Serum interleukin 6 Dysmenorrhea Biomarker Risk factor Figures Figure 1 Figure 2 1 Background Adenomyosis is a common chronic estrogen-dependent disorder, affecting approximately 5–10% of women of reproductive age, with dysmenorrhea being one of its most frequent symptoms 1 . The primary pathological features involve cyclic hemorrhage from ectopic endometrial tissue and subsequent fibrosis of surrounding tissues, which collectively contribute to the development of dysmenorrhea 2 . Nevertheless, the pathogenesis of dysmenorrhea remains inadequately understood 3 . One proposed explanation implicates inflammatory processes in its pathogenesis 4 . Previous studies have suggested a significant association between interleukin-6 (IL-6), a key pro-inflammatory cytokine, and pain 5 . However, there are no identified biomarkers associated with the inflammatory mediators for dysmenorrhea in adenomyosis 6 . IL-6, the pleiotropic cytokine, is predominantly synthesized via monocytes, macrophages, lymphocytes, fibroblasts and endothelial cells 7 , 8 . It plays a crucial role in mediating inflammatory responses and has been implicated in the pathogenesis of various benign and malignant diseases due to altered expression levels 4 , 9 , 10 . Nonetheless, few earlier studies have specifically examined the relationship between IL-6 and dysmenorrhea in adenomyosis patients. Furthermore, the distribution patterns and expression levels of IL-6 in the context of dysmenorrhea pathogenesis remain unclear. This retrospective study examined patient data prior to focused ultrasound ablation surgery (FUAS, a common treatment for patients hoping to preserve uterine), aiming to analyze the relation of IL-6 with dysmenorrhea in adenomyosis and investigate factors contributing to dysmenorrhea, thus providing clues for mechanism of dysmenorrhea in adenomyosis. 2 Materials and methods 2.1 Study design and patients The retrospective study was conducted involving 173 patients diagnosed with adenomyosis at Nanchong Central Hospital between December 3, 2021, and November 30, 2022. Diagnosis was confirmed by magnetic resonance imaging (MRI) or ultrasound, with 51 patients classified as without dysmenorrhea and 122 with dysmenorrhea. Dysmenorrhea and menorrhagia assessments were performed in the context of focused ultrasound ablation surgery (FUAS). The study protocol was approved by the Ethics Committee of the Affiliated Nanchong Central Hospital, North Sichuan Medical College (Approval No: 2021/104). Informed consent was waived due to the retrospective nature of the study and full anonymization of patient data. Inclusion criteria were as follows: female participants of reproductive age (over 18 years old); presence of symptoms suggestive of dysmenorrhea and/or increased menstrual flow; confirmed diagnosis of uterine adenomyosis via MRI, with a single-layer myometrial wall thickness of ≥ 2 cm; and absence of gynecological malignancies. Exclusion criteria included: current pregnancy or lactation; acute inflammation; presence of intrapelvic endometriosis; suspicious or confirmed malignant lesions; inability to achieve adequate preoperative acoustic channel positioning; inability to maintain a prone position; refusal to undergo FUAS treatment; and unwillingness to provide peripheral venous blood samples. 2.2 Assessments Adenomyosis was diagnosed via MRI using the criteria of a junctional zone maximum thickness (JZmax) ≥ 12 mm and a JZmax-to-total myometrium ratio exceeding 40% 7 . The diffuse subtype was defined as the widespread distribution of adenomyotic lesions throughout the uterus, while the focal subtype (also referred to as adenomyoma) was characterized by localized lesions [12]. Based on preoperative MRI images, each uterine and adenomyotic lesion was measured three times in the long, right-left, and anteroposterior diameters. The volumes of the uterus and lesions were then calculated using the ellipsoid formula: 0.52 × length × anteroposterior diameter × transverse diameter 11 . Dysmenorrhea was defined as patient-reported menstrual pain documented in medical records during clinical encounters or FUAS consultations prior to follow-up 12 . Menorrhagia occurring following adenomyosis referred to the clinically-documented elevation of menstrual blood volume 13 , reported by the patient, and documented in clinical encounter prior to FUAS and follow-up. Peripheral venous blood samples were collected from all 173 adenomyosis patients within 24 hours before FUAS. After collection, samples were allowed to coagulate for 30 minutes, then centrifuged at 4000 rpm for 10 minutes, and stored at − 80°C until analysis. IL-6 levels were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (eBioscience, Zhuocai Biotechnology, Shanghai, China) 14 . All procedures were performed in strict accordance with standardized protocols in a single laboratory, with technicians blinded to clinical information. For cytokine quantification, flow microsphere array technology 15 was employed using a MAGPIX® flow cytometer. Capture microspheres coated with IL-6-specific antibodies and differentiated by fluorescence intensity were used. Cytokines in the samples bound simultaneously to the capture microspheres and phycoerythrin (PE)-conjugated detection antibodies, forming a sandwich immunocomplex. Cytokine concentrations (pg/mL) were determined based on the fluorescence intensity measured by the flow cytometer. All assays were conducted under standardized operating procedures by personnel blinded to patient group assignments. 2.3 Statistical methods Analyses were performed on the total sample and further stratified by adenomyosis subtypes (focal vs. diffuse). Continuous variables are presented as mean ± standard deviation or median with interquartile range (IQR), while categorical variables are expressed as numbers and percentages. Differences in demographic and clinical characteristics between patients with and without dysmenorrhea were assessed using the χ² test, t-test, or Mann–Whitney U test, as appropriate. A logistic regression model was applied to evaluate the association between clinicopathological features (including age, adenomyotic lesion volume, uterine volume, subcutaneous fat thickness, and preoperative IL-6 level) and the presence of dysmenorrhea, with results expressed as odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The optimal cutoff value for IL-6 levels in predicting dysmenorrhea prior to FUAS was determined using receiver operating characteristic (ROC) curve analysis in both the total cohort and subtype subgroups. Additionally, logistic regression was used to examine the relationship between elevated IL6 levels and dysmenorrhea before FUAS. A multivariate logistic regression model was employed to identify factors influencing preoperative IL-6 levels, incorporating variables such as age and adenomyotic lesion volume. All figures were prepared using GraphPad Prism 7.0 (La Jolla, CA, USA). Statistical analyses were conducted with SPSS 22.0 (IBM, Armonk, NY), and a two-sided p-value < 0.05 was considered statistically significant. 3 Results 3.1 Clinicopathological features in the total cohort A total of 122 patients (70.5%) were assigned to the dysmenorrhea group and 51 (29.5%) to the non-dysmenorrhea group. Compared to the non-dysmenorrhea group, patients with dysmenorrhea were significantly younger (42.7 ± 5.5 years, P = 0.027) and had higher preoperative IL-6 levels (4.6 ± 3.7 pg/ml, P < 0.001), larger uterine volumes [median: 209.0, IQR: 115.9–304.1 cm³, P < 0.001], and greater adenomyotic lesion volumes [median: 106.5, IQR: 29.0–158.7 cm³, P < 0.001] (Table 1 ). Table 1 Clinicopathological features in dysmenorrhea and non-dysmenorrhea Variable Total cohort (n = 173) Dysmenorrhea group (n = 122) Non-dysmenorrhea group (n = 51) P Age (years) 43.4 ± 5.4 42.7 ± 5.5 45.1 ± 4.8 0.027 BMI (kg/m2) 24.3 ± 4.2 24.2 ± 4.2 24.6 ± 4.1 0.785 Uterus position (n(%)) 0.116 Anteverted 92(53.2%) 69(56.6%) 23(45.1%) Retroverted 65(37.6%) 40(32.8%) 25(49.0%) Neutral 16(9.2%) 13(10.7%) 3(5.9%) Uterus volume(cm3) 176.0(103.0-279.2) 209.0(115.9-304.1) 103.4(69.8-215.8) < 0.001 Subtype of lesion (n(%)) 0.882 Focal 42(24.3%) 30(24.6%) 12(23.5%) Diffuse 131(75.7%) 92(75.4%) 39(76.5%) Adenomyosis location (n(%)) 0.071 Anterior 76(43.9%) 47(38.6%) 29(56.9%) Posterior 53(30.6%) 44(36.1%) 9(17.6%) Fundus 35(20.2%) 24(19.6%) 11(21.6%) lateral wall 9(5.3%) 7(5.7%) 2(3.9%) Adenomyotic lesions volume (cm3) 67.0(23.5-145.5) 106.5(29.0-158.7) 27.0(13.0-116.0) < 0.001 Subcutaneous fat thickness (mm) 2.1 ± 0.7 2.1 ± 0.7 2.0 ± 0.6 0.706 Distance (mm) 6.1 ± 2.3 5.8 ± 2.2 6.5 ± 2.4 0.304 Serum IL-6 (pg/ml) 3.4(2.9–4.3) 3.5(3.0-4.9) 3.0(2.4–3.6) < 0.001 Menorrhagia (n(%)) 0.265 Yes 98(59.0%) 74(61.7%) 24(52.2%) No 68(41.0%) 46(38.3%) 22(47.8%) BMI, body mass index; IL-6, Interleukin-6 3.2 Clinicopathological Features by Lesion Subtype Patients were classified into diffuse (n = 131, 75.7%) or focal (n = 42, 24.3%) subtype groups. IL6 levels in patients with dysmenorrhea were higher than those in patients without dysmenorrhea in total cohort (Z=-3.783, P<0.001), diffuse subtype group (Z=--2.525, P = 0.012) and focal subtype group (Z=--2.883, P = 0.004). In both subtype groups, those with dysmenorrhea exhibited significantly higher uterine volumes, and adenomyotic lesion volumes compared to those without dysmenorrhea (Table 2 , Fig. 1 ). Table 2 Patient characteristics in subtype groups. Variable Diffuse subtype group Focal subtype group Total cohort (n = 131, 75.7%) Dysmenorrhea group (n = 92, %) Non-dysmenorrhea group (n = 39, %) P Total cohort (n = 42,24.3%) Dysmenorrhea group (n = 30) Non-dysmenorrhea group (n = 12) P Age (years) 43.2 ± 5.6 42.3 ± 5.7 45.3 ± 4.8 0.015 44.2 ± 4.7 44.2 ± 4.7 44.2 ± 5.1 0.925 BMI (kg/m2) 24.2 ± 4.3 24.1 ± 4.3 24.7 ± 4.2 0.711 25.1 ± 4.0 25.3 ± 4.0 24.8 ± 4.5 1.000 Uterus position 0.125 0.740 Anteverted 66(50.4) 50(54.3) 16(41.0) 26(61.9) 19(63.3) 7(58.3) Retroverted 50(38.2) 30(32.6) 20(51.3) 15(35.7) 10(33.3) 5(41.7) Neutral 15(11.5) 12(13.0) 3(7.7) 1(2.4) 1(3.3) 0(0.0) Uterus volume(cm3) 197.5(103.0-260.2) 207.9(116.6-281.4) 103.4(74.0-220.9) 0.002 135.5(102.0-309.6) 232.0(109.1-339.8) 111.0(54.1-135.7) 0.006 Adenomyosis location 0.148 0.336 Anterior 58(44.3) 35(38.0) 23(59.0) 18(42.9) 12(40.0) 6(50.0) Posterior 42(32.1) 34(37,0) 8(20.5) 11(26.2) 10(33.3) 1(8.3) Fundus 26(19.8) 19(20.7) 7(17.9) 9(21.4) 5(16.7) 4(8.3) lateral wall 5(3.8) 4(4.3) 1(2.6) 4(9.5) 3(10.0) 1(33.3) Adenomyotic lesion (cm3) 89.0(23.0-144.0) 102.0(29.0-150.7) 30.0(15.0-132.0) 0.008 39.5(22.8-161.7) 116.0(29.5-212.2) 23.0(3.2–30.7) 0.001 Subcutaneous fat thickness (mm) 2.1 ± 0.7 2.2 ± 0.8 1.9 ± 0.6 0.282 2.0 ± 0.6 1.9 ± 0.6 2.2 ± 0.8 0.330 Distance (mm) 5.9 ± 2.4 5.5 ± 2.3 6.7 ± 2.6 0.125 6.4 ± 1.8 6.6 ± 1.8 5.9 ± 2.0 0.620 IL-6 (pg/ml) 3.4(2.9–4.2) 3.5(3.0-4.4) 3.0(2.7–3.8) 0.012 3.1(2.6–4.8) 3.8(2.9–5.5) 2.9(1.7–3.1) 0.004 Menorrhagia 0.319 1.000 Yes 73(57.9) 55(61.1) 18(50.0) 25(62.5) 19(63.3) 6(60.0) No 53(42.1) 35(38.9) 18(50.0) 15(37.5) 11(36.7) 4(40.0) BMI, body mass index; IL-6, Interleukin-6 3.3 Factors Associated with Dysmenorrhea Multivariate analysis confirmed that both age (OR = 0.914, 95% CI: 0.850–0.984, P = 0.017) and IL-6 level (OR = 1.944, 95% CI: 1.291–2.928, P = 0.001) remained independently associated with dysmenorrhea in the total cohort. Similarly, in the diffuse subtype group, age (OR = 0.899, 95% CI: 0.821–0.971, P = 0.008) and IL-6 level (OR = 1.159, 95% CI: 1.089–2.563, P = 0.019) were also independently associated with dysmenorrhea. In contrast, no significant associations were observed in the focal subtype group (Table 3 ). Table 3 Multivariate binary logistic regression analysis of factors for dysmenorrhea in total cohort. IL-6, Interleukin-6 Variable Total cohort Diffuse subtype group Focal subtype group OR 95%CI P OR 95%CI P OR 95%CI P Age 0.914 0.850–0.984 0.017 0.999 0.821–0.971 0.008 0.999 0.819–1.219 0.992 Serum IL-6 (pg/ml) 1.944 1.291–2.928 0.001 1.159 1.089–2.563 0.019 1.159 0.139–9.660 0.892 Adenomyotic lesions volume(cm3) 0.999 0.996–1.001 0.309 1.062 0.995–1.001 0.308 1.062 0.965–1.170 0.216 3.4 Diagnostic Performance of IL-6 for Dysmenorrhea ROC curve analysis was performed to assess the predictive performance of IL-6 for dysmenorrhea in various patient groups. The sensitivity and specificity were 71.3% and 47.1% in the total cohort, 65.2% and 59.0% in the diffuse subtype group, and 63.3% and 91.7% in the focal subtype group, respectively. Given that the highest sensitivity was observed in the total cohort, an IL-6 cutoff value of 3.02 pg/ml was chosen (Supplementary Table 1; Fig. 2 ). 3.5 Factors Influencing Preoperative IL-6 Levels Binary regression analysis identified preoperative uterine volume (OR = 1.028, 95% CI: 1.007–1.050, P = 0.007) as a factor positively associated with elevated IL-6 levels (≥ 3.02 pg/ml) in the total cohort. Subsequent multivariate logistic regression within subtype groups showed that uterine volume was significantly associated with higher IL-6 levels in the diffuse subtype group (OR = 1.024, 95% CI: 1.002–1.046, P = 0.028) (Table 4 ). Table 4 Multivariate binary logistic regression analysis of adenomyosis according to IL6 (≥ 3.02 pg / ml vs.<3.02 pg/ml). Variable Total cohort Diffuse subtype group Focal subtype group OR 95%CI P OR 95%CI P OR 95%CI P BMI 0.996 0.864–1.148 0.959 0.923 0.776–1.097 0.365 1.531 0.705–3.323 0.281 Uterus volume (cm3) 1.028 1.007–1.050 0.007 1.024 1.002–1.046 0.028 1.344 0.890–1.344 0.393 Adenomyotic lesions volume(cm3) 1.012 0.980–1.045 0.439 1.017 0.984–1.051 0.311 1.058 0.847–1.322 0.615 IL-6, Interleukin-6; BMI, body mass index 4 Discussion 4.1 Summary The pathogenesis of adenomyosis remains incompletely understood, and no well-established biomarkers related to its inflammatory mediators have been identified. This retrospective study aimed to investigate the association between IL-6 and dysmenorrhea in adenomyosis, as well as factors influencing IL-6 levels in patients with adenomyosis. Our study demonstrated that IL-6 levels were significantly elevated in patients with dysmenorrhea compared to those without, a trend consistently observed across total cohort, as well as in both the diffuse subtype group and the focal subtype group. Additionally, we identified preoperative uterine volume as a significant factor associated with increased IL-6 levels in adenomyosis. 4.2 Comparison with existing literature and clinical implications These findings are consistent with previous studies reporting elevated IL-6 levels in patients with dysmenorrhea 16 . Elevated IL-6 may contribute to heightened pain perception in adenomyosis through inflammatory mechanisms 17 . Furthermore, Velascoz et al. discovered that IL-6 was significantly correlated with chronic pelvic pain in individuals with uterine adenomyosis 18 . Additionally, these findings have been validated in animal models using IL-6 antagonists for the treatment of pelvic pain 19 . The findings demonstrate that IL-6 contents are related to the occurrence of dysmenorrhea among patients diagnosed with adenomyosis 20 . Nevertheless, the aforementioned studies fail to establish an appropriate threshold of IL-6 contents among dysmenorrhea patients. Our research not only revealed distinct serum IL-6 contents among dysmenorrhea patients but also indicated the relatively high sensitivity at the IL-6 threshold of 3.02 pg/mL. Levels above this threshold were significantly associated with increased risk of dysmenorrhea, suggesting its potential utility as a predictive biomarker. Additionally, we observed an association between IL-6 and the increased uterine volume. Adenomyosis tissues are characterized by the presence of inflammatory immune cells and various cytokines 9 , 21 , among which IL-6 has been extensively studied for its role in inflammatory processes 22 . As a pleiotropic cytokine, IL-6 plays a central role in regulating immune and inflammatory responses 23 , 24 . On the one hand, IL-6, as a pro-inflammatory factor, heralds the onset of pain and inflammatory response when its serum concentration increases substantially 25 , 26 . Dysmenorrhea is often accompanied by a local inflammatory response, and IL-6 may exacerbate pain by enhancing this inflammatory response 27 , 28 . On the other hand, IL-6 can affect the synthesis of prostaglandins (such as PGF2α), which are the known mediators of dysmenorrhea and can cause uterine contractions leading to pain 29 . Thus, IL-6 may influence the severity of dysmenorrhea by regulating the prostaglandin levels. As shown by relevant studies on Chinese medicine, certain medicines can improve the dysmenorrhea symptoms by lowering the serum IL-6 content. For example, Anti-IL-6 drugs can reduce the serum PGF2α and IL-6 levels, thus effectively improving the clinical symptoms of patients with primary dysmenorrhea 30 . Based on the above studies, IL-6 is associated with dysmenorrhea through a variety of mechanisms, including the promotion of inflammatory responses and the regulation of prostaglandin synthesis. These findings provide potential targets for the future treatment of dysmenorrhea, like alleviating the dysmenorrhea symptoms by inhibiting the activity of IL-6 or blocking those signaling pathway. 4.3 Strengths and limitations The primary strength of this retrospective study lies in our identification of an association between IL-6 levels and dysmenorrhea for adenomyosis. This finding provides a potential avenue for researchers to further investigate the relationship between serum IL-6 and the pathogenesis of dysmenorrhea in adenomyosis. Nevertheless, our study has some limitations. Firstly, due to the retrospective nature of this study, we cannot definitively conclude that IL-6 was a risk factor for dysmenorrhea in adenomyosis; however, our results confirmed a significant association between IL-6 and dysmenorrhea in adenomyosis. Secondly, as all data were obtained from patients prior to FUAS, and the retrospective design necessitated the exclusion of some patients due to incomplete records, potential selection bias cannot be ruled out. Nevertheless, the clinicopathological characteristics of our cohort were consistent with established epidemiological profiles of adenomyosis 31 . Thirdly, although we cannot entirely eliminate potential preanalytical biases related to IL-6 measurement before FUAS, all blood samples were collected and processed within 24 hours before the procedure to minimize confounding factors. Future multicenter studies are planned to provide further evidence and enhance the generalizability of our findings. Conclusions In summary, IL-6 was implicated in the dysmenorrhea pathophysiology associated with adenomyosis, underscoring the importance of investigating the underlying mechanisms of dysmenorrhea in adenomyosis. Furthermore, we observed that IL-6 levels were positively related to the disease severity. Declarations Acknowledgements We would like to thank all the faculty at the Department of Medical Records in Nanchong Central Hospital for their diligent clinical work. The authors also sincerely thank all the nurses and staff at the Department of Gynecology for the excellent care they provided patients and precise data recording. Author’s contribution YT conceived and designed the study. HNH collected data and wrote the original draft. BS, JW and XC participated in the operations and management of patients. JL and HQH amended the manuscript. All authors have read and approved the final manuscript. Funding This work was supported by National Key R&D Plan for Intergovernmental Cooperation, the Ministry of Science and Technology of China (Grant No.2022YFE0133100), Foundation of State Key Laboratory of Ultrasound in Medicine and Engineering (Grant No. 2024KFKT016）and the Project of North Sichuan Medical College Youth Program (Grant No. CBY23-QNA19, CBY23-ZDA12, CBY23-QNA11）. Availability of data and material Due to the sensitive nature of the interview scripts and privacy concerns of study participants, we will share qualitative data only upon reasonable request by the corresponding author. Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Affiliated Nanchong Central Hospital of North Sichuan Medical College (approval number: 2021/104). Consent for publication Not applicable. Informed consent Due to the study was retrospective in nature and fully anonymous, the requirement for written informed consent was waived. 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Atzeni F, Nucera V, Masala IF, Sarzi-Puttini P, Bonitta G. Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab. Pharmacol Res. 2019; 149:104402. doi:10.1016/j.phrs.2019.104402. Yu N, Cui H, Jin S, Liu P, Fang Y, Sun F, et al. IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve. J Neuroinflammation. 2024; 21(1):60. doi:10.1186/s12974-024-03049-z. Svensson CI. Interleukin-6: a local pain trigger? Arthritis Res Ther. 2010; 12(5):145. doi:10.1186/ar3138. Tang Y, Ming-Tao Y, Xiang RM, Xu W, Zhang RY, Weng MB, et al. Preoperative CA125 as a risk factor for symptom recurrence of adenomyosis after ultrasound-guided high-intensity focused ultrasound ablation surgery. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2022; 39(1):1164-9. doi:10.1080/02656736.2022.2107716. Pandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in Rheumatoid Arthritis. Int J Mol Sci. 2020; 21(15). doi:10.3390/ijms21155238. Upson K, Missmer SA. Epidemiology of Adenomyosis. Seminars in reproductive medicine. 2020; 38(2-03):89-107. doi:10.1055/s-0040-1718920. Additional Declarations No competing interests reported. Supplementary Files IL6SupplementaryTable.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 15 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers invited by journal 08 Oct, 2025 Editor invited by journal 05 Sep, 2025 Editor assigned by journal 04 Sep, 2025 Submission checks completed at journal 04 Sep, 2025 First submitted to journal 27 Aug, 2025 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-7472436","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532543731,"identity":"7ae80c28-e05a-457c-8ffc-325986b11404","order_by":0,"name":"Ying Tang","email":"","orcid":"","institution":"The Affiliated Nanchong Central Hospital of North Sichuan Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Tang","suffix":""},{"id":532543733,"identity":"f3936138-81f6-41a7-aa92-484e21f6f0f6","order_by":1,"name":"Hua-dong Tian","email":"","orcid":"","institution":"The Affiliated Nanchong Central Hospital of North Sichuan Medical College","correspondingAuthor":false,"prefix":"","firstName":"Hua-dong","middleName":"","lastName":"Tian","suffix":""},{"id":532543734,"identity":"8fa8c64d-9d1a-41b2-b64d-e3958855df98","order_by":2,"name":"Bin Su","email":"","orcid":"","institution":"The Affiliated Nanchong Central Hospital of North Sichuan Medical College","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Su","suffix":""},{"id":532543735,"identity":"769d12c3-7ee1-43c3-9bd3-c1e1c2637602","order_by":3,"name":"Hong-ni He","email":"","orcid":"","institution":"The Affiliated Nanchong Central Hospital of North Sichuan Medical College","correspondingAuthor":false,"prefix":"","firstName":"Hong-ni","middleName":"","lastName":"He","suffix":""},{"id":532543736,"identity":"a1faa039-74e4-471d-b2fc-36bf2d640174","order_by":4,"name":"Xin Cai","email":"","orcid":"","institution":"The Affiliated Nanchong Central Hospital of North Sichuan Medical 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23:19:19","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":110340,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/57f960c164483983048bbfbd.png"},{"id":94048026,"identity":"63b37da8-2e1a-44a0-880b-980b66a3824d","added_by":"auto","created_at":"2025-10-21 23:19:18","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112370,"visible":true,"origin":"","legend":"","description":"","filename":"3b9fb8a2b46749ecb1851538c9be8fa31structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/e0f1b91abb5db58bdc4e896b.xml"},{"id":94048033,"identity":"c67c1aa3-8894-4d30-9f85-ea8703d08151","added_by":"auto","created_at":"2025-10-21 23:19:19","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":118051,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/be536a3dca9883ca03e53475.html"},{"id":94048963,"identity":"0d5d74a4-400d-4c11-a610-2328fd9cc096","added_by":"auto","created_at":"2025-10-21 23:27:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51105,"visible":true,"origin":"","legend":"\u003cp\u003einterleukin-6 (IL-6) level in dysmenorrhea and non-dysmenorrhea group\u003c/p\u003e\n\u003cp\u003eIL-6 levels were significantly higher in patients with dysmenorrhea compared to those without dysmenorrhea in the total cohort (Z = -3.783, P \u0026lt; 0.001), as well as in both the diffuse subtype group (Z = -2.525, P = 0.012) and the focal subtype group (Z = -2.883, P = 0.004).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/7cb12eece332019a929d2cd1.png"},{"id":94048020,"identity":"344e0031-eed6-437e-80ab-0df56faf57a4","added_by":"auto","created_at":"2025-10-21 23:19:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":108773,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curve analysis of IL-6 for dysmenorrhea\u003c/p\u003e\n\u003cp\u003eThe sensitivity and specificity were 71.3% and 47.1% in the total cohort, 65.2% and 59.0% in the diffuse subtype group, and 63.3% and 91.7% in the focal subtype group, respectively. Given that the highest sensitivity was observed in the total cohort, an IL-6 cutoff value of 3.02 pg/ml was chosen (Supplementary Table 1; Figure 2).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/617e3fec7fdf820a459c78a5.png"},{"id":94049405,"identity":"e9d1bb02-d979-4527-9dd4-7ba1608cc6e7","added_by":"auto","created_at":"2025-10-21 23:35:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1163665,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/27461d8c-0147-41f4-8667-88fb25530db1.pdf"},{"id":94048966,"identity":"37693e70-3ffd-4ecd-b31f-2849163402af","added_by":"auto","created_at":"2025-10-21 23:27:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12467,"visible":true,"origin":"","legend":"","description":"","filename":"IL6SupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7472436/v1/44c0080623bda11d94d26a2d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Interleukin-6: A Potential Biomarker for Dysmenorrhea and Disease Severity in Adenomyosis","fulltext":[{"header":"1 Background","content":"\u003cp\u003eAdenomyosis is a common chronic estrogen-dependent disorder, affecting approximately 5\u0026ndash;10% of women of reproductive age, with dysmenorrhea being one of its most frequent symptoms\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The primary pathological features involve cyclic hemorrhage from ectopic endometrial tissue and subsequent fibrosis of surrounding tissues, which collectively contribute to the development of dysmenorrhea\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Nevertheless, the pathogenesis of dysmenorrhea remains inadequately understood\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. One proposed explanation implicates inflammatory processes in its pathogenesis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Previous studies have suggested a significant association between interleukin-6 (IL-6), a key pro-inflammatory cytokine, and pain\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, there are no identified biomarkers associated with the inflammatory mediators for dysmenorrhea in adenomyosis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. IL-6, the pleiotropic cytokine, is predominantly synthesized via monocytes, macrophages, lymphocytes, fibroblasts and endothelial cells\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. It plays a crucial role in mediating inflammatory responses and has been implicated in the pathogenesis of various benign and malignant diseases due to altered expression levels \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Nonetheless, few earlier studies have specifically examined the relationship between IL-6 and dysmenorrhea in adenomyosis patients. Furthermore, the distribution patterns and expression levels of IL-6 in the context of dysmenorrhea pathogenesis remain unclear.\u003c/p\u003e\u003cp\u003eThis retrospective study examined patient data prior to focused ultrasound ablation surgery (FUAS, a common treatment for patients hoping to preserve uterine), aiming to analyze the relation of IL-6 with dysmenorrhea in adenomyosis and investigate factors contributing to dysmenorrhea, thus providing clues for mechanism of dysmenorrhea in adenomyosis.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study design and patients\u003c/h2\u003e\u003cp\u003eThe retrospective study was conducted involving 173 patients diagnosed with adenomyosis at Nanchong Central Hospital between December 3, 2021, and November 30, 2022. Diagnosis was confirmed by magnetic resonance imaging (MRI) or ultrasound, with 51 patients classified as without dysmenorrhea and 122 with dysmenorrhea. Dysmenorrhea and menorrhagia assessments were performed in the context of focused ultrasound ablation surgery (FUAS). The study protocol was approved by the Ethics Committee of the Affiliated Nanchong Central Hospital, North Sichuan Medical College (Approval No: 2021/104). Informed consent was waived due to the retrospective nature of the study and full anonymization of patient data.\u003c/p\u003e\u003cp\u003eInclusion criteria were as follows: female participants of reproductive age (over 18 years old); presence of symptoms suggestive of dysmenorrhea and/or increased menstrual flow; confirmed diagnosis of uterine adenomyosis via MRI, with a single-layer myometrial wall thickness of \u0026ge;\u0026thinsp;2 cm; and absence of gynecological malignancies.\u003c/p\u003e\u003cp\u003eExclusion criteria included: current pregnancy or lactation; acute inflammation; presence of intrapelvic endometriosis; suspicious or confirmed malignant lesions; inability to achieve adequate preoperative acoustic channel positioning; inability to maintain a prone position; refusal to undergo FUAS treatment; and unwillingness to provide peripheral venous blood samples.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Assessments\u003c/h2\u003e\u003cp\u003eAdenomyosis was diagnosed via MRI using the criteria of a junctional zone maximum thickness (JZmax)\u0026thinsp;\u0026ge;\u0026thinsp;12 mm and a JZmax-to-total myometrium ratio exceeding 40% \u003csup\u003e7\u003c/sup\u003e. The diffuse subtype was defined as the widespread distribution of adenomyotic lesions throughout the uterus, while the focal subtype (also referred to as adenomyoma) was characterized by localized lesions [12]. Based on preoperative MRI images, each uterine and adenomyotic lesion was measured three times in the long, right-left, and anteroposterior diameters. The volumes of the uterus and lesions were then calculated using the ellipsoid formula: 0.52 \u0026times; length \u0026times; anteroposterior diameter \u0026times; transverse diameter\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDysmenorrhea was defined as patient-reported menstrual pain documented in medical records during clinical encounters or FUAS consultations prior to follow-up\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Menorrhagia occurring following adenomyosis referred to the clinically-documented elevation of menstrual blood volume\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, reported by the patient, and documented in clinical encounter prior to FUAS and follow-up.\u003c/p\u003e\u003cp\u003ePeripheral venous blood samples were collected from all 173 adenomyosis patients within 24 hours before FUAS. After collection, samples were allowed to coagulate for 30 minutes, then centrifuged at 4000 rpm for 10 minutes, and stored at \u0026minus;\u0026thinsp;80\u0026deg;C until analysis. IL-6 levels were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (eBioscience, Zhuocai Biotechnology, Shanghai, China)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. All procedures were performed in strict accordance with standardized protocols in a single laboratory, with technicians blinded to clinical information.\u003c/p\u003e\u003cp\u003eFor cytokine quantification, flow microsphere array technology\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e was employed using a MAGPIX\u0026reg; flow cytometer. Capture microspheres coated with IL-6-specific antibodies and differentiated by fluorescence intensity were used. Cytokines in the samples bound simultaneously to the capture microspheres and phycoerythrin (PE)-conjugated detection antibodies, forming a sandwich immunocomplex. Cytokine concentrations (pg/mL) were determined based on the fluorescence intensity measured by the flow cytometer. All assays were conducted under standardized operating procedures by personnel blinded to patient group assignments.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical methods\u003c/h2\u003e\u003cp\u003eAnalyses were performed on the total sample and further stratified by adenomyosis subtypes (focal vs. diffuse). Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median with interquartile range (IQR), while categorical variables are expressed as numbers and percentages. Differences in demographic and clinical characteristics between patients with and without dysmenorrhea were assessed using the χ\u0026sup2; test, t-test, or Mann\u0026ndash;Whitney U test, as appropriate.\u003c/p\u003e\u003cp\u003eA logistic regression model was applied to evaluate the association between clinicopathological features (including age, adenomyotic lesion volume, uterine volume, subcutaneous fat thickness, and preoperative IL-6 level) and the presence of dysmenorrhea, with results expressed as odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The optimal cutoff value for IL-6 levels in predicting dysmenorrhea prior to FUAS was determined using receiver operating characteristic (ROC) curve analysis in both the total cohort and subtype subgroups.\u003c/p\u003e\u003cp\u003eAdditionally, logistic regression was used to examine the relationship between elevated IL6 levels and dysmenorrhea before FUAS. A multivariate logistic regression model was employed to identify factors influencing preoperative IL-6 levels, incorporating variables such as age and adenomyotic lesion volume. All figures were prepared using GraphPad Prism 7.0 (La Jolla, CA, USA). Statistical analyses were conducted with SPSS 22.0 (IBM, Armonk, NY), and a two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Clinicopathological features in the total cohort\u003c/h2\u003e\n \u003cp\u003eA total of 122 patients (70.5%) were assigned to the dysmenorrhea group and 51 (29.5%) to the non-dysmenorrhea group. Compared to the non-dysmenorrhea group, patients with dysmenorrhea were significantly younger (42.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 years, P\u0026thinsp;=\u0026thinsp;0.027) and had higher preoperative IL-6 levels (4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 pg/ml, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), larger uterine volumes [median: 209.0, IQR: 115.9\u0026ndash;304.1 cm\u0026sup3;, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001], and greater adenomyotic lesion volumes [median: 106.5, IQR: 29.0\u0026ndash;158.7 cm\u0026sup3;, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001] (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinicopathological features in dysmenorrhea and non-dysmenorrhea\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal cohort (n\u0026thinsp;=\u0026thinsp;173)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDysmenorrhea group (n\u0026thinsp;=\u0026thinsp;122)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-dysmenorrhea group (n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUterus position (n(%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteverted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92(53.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69(56.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23(45.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetroverted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65(37.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40(32.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(49.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16(9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13(10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUterus volume(cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e176.0(103.0-279.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e209.0(115.9-304.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e103.4(69.8-215.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubtype of lesion (n(%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.882\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42(24.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(24.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12(23.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e131(75.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92(75.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39(76.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyosis location (n(%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76(43.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47(38.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29(56.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePosterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53(30.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44(36.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFundus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(20.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24(19.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11(21.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elateral wall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyotic lesions volume (cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.0(23.5-145.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106.5(29.0-158.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.0(13.0-116.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubcutaneous fat thickness (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.706\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDistance (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.304\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum IL-6 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4(2.9\u0026ndash;4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5(3.0-4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0(2.4\u0026ndash;3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMenorrhagia (n(%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.265\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98(59.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74(61.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24(52.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68(41.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46(38.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22(47.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eBMI, body mass index; IL-6, Interleukin-6\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Clinicopathological Features by Lesion Subtype\u003c/h2\u003e\n \u003cp\u003ePatients were classified into diffuse (n\u0026thinsp;=\u0026thinsp;131, 75.7%) or focal (n\u0026thinsp;=\u0026thinsp;42, 24.3%) subtype groups. IL6 levels in patients with dysmenorrhea were higher than those in patients without dysmenorrhea in total cohort (Z=-3.783, P\u0026lt;0.001), diffuse subtype group (Z=--2.525, P\u0026thinsp;=\u0026thinsp;0.012) and focal subtype group (Z=--2.883, P\u0026thinsp;=\u0026thinsp;0.004). In both subtype groups, those with dysmenorrhea exhibited significantly higher uterine volumes, and adenomyotic lesion volumes compared to those without dysmenorrhea (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics in subtype groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDiffuse subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eFocal subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal cohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;131, 75.7%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDysmenorrhea group (n\u0026thinsp;=\u0026thinsp;92, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-dysmenorrhea group (n\u0026thinsp;=\u0026thinsp;39, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal cohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;42,24.3%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDysmenorrhea group (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-dysmenorrhea group (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.925\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.711\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUterus position\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.740\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteverted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66(50.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50(54.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16(41.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(61.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(63.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetroverted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50(38.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20(51.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(41.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12(13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUterus volume(cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e197.5(103.0-260.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e207.9(116.6-281.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e103.4(74.0-220.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135.5(102.0-309.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e232.0(109.1-339.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111.0(54.1-135.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyosis location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58(44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(38.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23(59.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18(42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12(40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePosterior\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42(32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34(37,0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8(20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11(26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFundus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(20.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elateral wall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyotic lesion (cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89.0(23.0-144.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102.0(29.0-150.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0(15.0-132.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.5(22.8-161.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e116.0(29.5-212.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.0(3.2\u0026ndash;30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubcutaneous fat thickness (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.330\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDistance (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.620\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4(2.9\u0026ndash;4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5(3.0-4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0(2.7\u0026ndash;3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.1(2.6\u0026ndash;4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8(2.9\u0026ndash;5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9(1.7\u0026ndash;3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMenorrhagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73(57.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55(61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18(50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(63.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53(42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(38.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18(50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11(36.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003eBMI, body mass index; IL-6, Interleukin-6\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Factors Associated with Dysmenorrhea\u003c/h2\u003e\n \u003cp\u003eMultivariate analysis confirmed that both age (OR\u0026thinsp;=\u0026thinsp;0.914, 95% CI: 0.850\u0026ndash;0.984, P\u0026thinsp;=\u0026thinsp;0.017) and IL-6 level (OR\u0026thinsp;=\u0026thinsp;1.944, 95% CI: 1.291\u0026ndash;2.928, P\u0026thinsp;=\u0026thinsp;0.001) remained independently associated with dysmenorrhea in the total cohort. Similarly, in the diffuse subtype group, age (OR\u0026thinsp;=\u0026thinsp;0.899, 95% CI: 0.821\u0026ndash;0.971, P\u0026thinsp;=\u0026thinsp;0.008) and IL-6 level (OR\u0026thinsp;=\u0026thinsp;1.159, 95% CI: 1.089\u0026ndash;2.563, P\u0026thinsp;=\u0026thinsp;0.019) were also independently associated with dysmenorrhea. In contrast, no significant associations were observed in the focal subtype group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate binary logistic regression analysis of factors for dysmenorrhea in total cohort. IL-6, Interleukin-6\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eTotal cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eDiffuse subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eFocal subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.850\u0026ndash;0.984\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.821\u0026ndash;0.971\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.819\u0026ndash;1.219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.992\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum IL-6 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.944\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.291\u0026ndash;2.928\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.089\u0026ndash;2.563\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.139\u0026ndash;9.660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyotic lesions volume(cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.996\u0026ndash;1.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.995\u0026ndash;1.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.308\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.965\u0026ndash;1.170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.216\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Diagnostic Performance of IL-6 for Dysmenorrhea\u003c/h2\u003e\n \u003cp\u003eROC curve analysis was performed to assess the predictive performance of IL-6 for dysmenorrhea in various patient groups. The sensitivity and specificity were 71.3% and 47.1% in the total cohort, 65.2% and 59.0% in the diffuse subtype group, and 63.3% and 91.7% in the focal subtype group, respectively. Given that the highest sensitivity was observed in the total cohort, an IL-6 cutoff value of 3.02 pg/ml was chosen (Supplementary Table 1; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Factors Influencing Preoperative IL-6 Levels\u003c/h2\u003e\n \u003cp\u003eBinary regression analysis identified preoperative uterine volume (OR\u0026thinsp;=\u0026thinsp;1.028, 95% CI: 1.007\u0026ndash;1.050, P\u0026thinsp;=\u0026thinsp;0.007) as a factor positively associated with elevated IL-6 levels (\u0026ge;\u0026thinsp;3.02 pg/ml) in the total cohort. Subsequent multivariate logistic regression within subtype groups showed that uterine volume was significantly associated with higher IL-6 levels in the diffuse subtype group (OR\u0026thinsp;=\u0026thinsp;1.024, 95% CI: 1.002\u0026ndash;1.046, P\u0026thinsp;=\u0026thinsp;0.028) (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate binary logistic regression analysis of adenomyosis according to IL6 (\u0026ge;\u0026thinsp;3.02 pg / ml vs.\u0026lt;3.02 pg/ml).\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eTotal cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eDiffuse subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eFocal subtype group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.864\u0026ndash;1.148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.776\u0026ndash;1.097\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.531\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.705\u0026ndash;3.323\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUterus volume (cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.007\u0026ndash;1.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.002\u0026ndash;1.046\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.344\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.890\u0026ndash;1.344\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.393\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyotic lesions volume(cm3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.980\u0026ndash;1.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.984\u0026ndash;1.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.847\u0026ndash;1.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\"\u003eIL-6, Interleukin-6; BMI, body mass index\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Summary\u003c/h2\u003e\u003cp\u003eThe pathogenesis of adenomyosis remains incompletely understood, and no well-established biomarkers related to its inflammatory mediators have been identified. This retrospective study aimed to investigate the association between IL-6 and dysmenorrhea in adenomyosis, as well as factors influencing IL-6 levels in patients with adenomyosis. Our study demonstrated that IL-6 levels were significantly elevated in patients with dysmenorrhea compared to those without, a trend consistently observed across total cohort, as well as in both the diffuse subtype group and the focal subtype group. Additionally, we identified preoperative uterine volume as a significant factor associated with increased IL-6 levels in adenomyosis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Comparison with existing literature and clinical implications\u003c/h2\u003e\u003cp\u003eThese findings are consistent with previous studies reporting elevated IL-6 levels in patients with dysmenorrhea\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Elevated IL-6 may contribute to heightened pain perception in adenomyosis through inflammatory mechanisms \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Furthermore, Velascoz et al. discovered that IL-6 was significantly correlated with chronic pelvic pain in individuals with uterine adenomyosis\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Additionally, these findings have been validated in animal models using IL-6 antagonists for the treatment of pelvic pain\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. The findings demonstrate that IL-6 contents are related to the occurrence of dysmenorrhea among patients diagnosed with adenomyosis\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Nevertheless, the aforementioned studies fail to establish an appropriate threshold of IL-6 contents among dysmenorrhea patients. Our research not only revealed distinct serum IL-6 contents among dysmenorrhea patients but also indicated the relatively high sensitivity at the IL-6 threshold of 3.02 pg/mL. Levels above this threshold were significantly associated with increased risk of dysmenorrhea, suggesting its potential utility as a predictive biomarker. Additionally, we observed an association between IL-6 and the increased uterine volume.\u003c/p\u003e\u003cp\u003eAdenomyosis tissues are characterized by the presence of inflammatory immune cells and various cytokines\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, among which IL-6 has been extensively studied for its role in inflammatory processes \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. As a pleiotropic cytokine, IL-6 plays a central role in regulating immune and inflammatory responses \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. On the one hand, IL-6, as a pro-inflammatory factor, heralds the onset of pain and inflammatory response when its serum concentration increases substantially\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Dysmenorrhea is often accompanied by a local inflammatory response, and IL-6 may exacerbate pain by enhancing this inflammatory response\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. On the other hand, IL-6 can affect the synthesis of prostaglandins (such as PGF2α), which are the known mediators of dysmenorrhea and can cause uterine contractions leading to pain\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Thus, IL-6 may influence the severity of dysmenorrhea by regulating the prostaglandin levels. As shown by relevant studies on Chinese medicine, certain medicines can improve the dysmenorrhea symptoms by lowering the serum IL-6 content. For example, Anti-IL-6 drugs can reduce the serum PGF2α and IL-6 levels, thus effectively improving the clinical symptoms of patients with primary dysmenorrhea\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Based on the above studies, IL-6 is associated with dysmenorrhea through a variety of mechanisms, including the promotion of inflammatory responses and the regulation of prostaglandin synthesis. These findings provide potential targets for the future treatment of dysmenorrhea, like alleviating the dysmenorrhea symptoms by inhibiting the activity of IL-6 or blocking those signaling pathway.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e4.3 \u003cb\u003eStrengths and limitations\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eThe primary strength of this retrospective study lies in our identification of an association between IL-6 levels and dysmenorrhea for adenomyosis. This finding provides a potential avenue for researchers to further investigate the relationship between serum IL-6 and the pathogenesis of dysmenorrhea in adenomyosis. Nevertheless, our study has some limitations. Firstly, due to the retrospective nature of this study, we cannot definitively conclude that IL-6 was a risk factor for dysmenorrhea in adenomyosis; however, our results confirmed a significant association between IL-6 and dysmenorrhea in adenomyosis. Secondly, as all data were obtained from patients prior to FUAS, and the retrospective design necessitated the exclusion of some patients due to incomplete records, potential selection bias cannot be ruled out. Nevertheless, the clinicopathological characteristics of our cohort were consistent with established epidemiological profiles of adenomyosis\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Thirdly, although we cannot entirely eliminate potential preanalytical biases related to IL-6 measurement before FUAS, all blood samples were collected and processed within 24 hours before the procedure to minimize confounding factors. Future multicenter studies are planned to provide further evidence and enhance the generalizability of our findings.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, IL-6 was implicated in the dysmenorrhea pathophysiology associated with adenomyosis, underscoring the importance of investigating the underlying mechanisms of dysmenorrhea in adenomyosis. Furthermore, we observed that IL-6 levels were positively related to the disease severity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the faculty at the Department of Medical Records in\u0026nbsp;Nanchong Central Hospital\u0026nbsp;for their diligent clinical work. The authors also sincerely thank all the nurses and staff at the Department of Gynecology for the excellent care they provided patients and precise data recording.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contribution\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYT conceived and designed the study. HNH collected data and wrote the original draft. BS, JW and XC participated in the operations and management of patients. JL and HQH amended the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Key R\u0026amp;D Plan for Intergovernmental Cooperation, the Ministry of Science and Technology of China (Grant No.2022YFE0133100), Foundation of State Key Laboratory of Ultrasound in Medicine and Engineering (Grant No. 2024KFKT016）and the Project of North Sichuan Medical College Youth Program (Grant No. CBY23-QNA19, CBY23-ZDA12, CBY23-QNA11）.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the sensitive nature of the interview scripts and privacy concerns of study participants, we will share qualitative data only upon reasonable request by the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the\u0026nbsp;Ethics Committee of Affiliated Nanchong Central Hospital of North Sichuan Medical College (approval number: 2021/104).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the study was retrospective in nature and fully anonymous, the requirement for written informed consent was waived.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHorne AW, Missmer SA. 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J Cyst Fibros. 2015; 14(6):720-6. doi:10.1016/j.jcf.2015.03.007.\u003c/li\u003e\n\u003cli\u003eAtzeni F, Nucera V, Masala IF, Sarzi-Puttini P, Bonitta G. Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab. Pharmacol Res. 2019; 149:104402. doi:10.1016/j.phrs.2019.104402.\u003c/li\u003e\n\u003cli\u003eYu N, Cui H, Jin S, Liu P, Fang Y, Sun F, et al. IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve. J Neuroinflammation. 2024; 21(1):60. doi:10.1186/s12974-024-03049-z.\u003c/li\u003e\n\u003cli\u003eSvensson CI. Interleukin-6: a local pain trigger? Arthritis Res Ther. 2010; 12(5):145. doi:10.1186/ar3138.\u003c/li\u003e\n\u003cli\u003eTang Y, Ming-Tao Y, Xiang RM, Xu W, Zhang RY, Weng MB, et al. Preoperative CA125 as a risk factor for symptom recurrence of adenomyosis after ultrasound-guided high-intensity focused ultrasound ablation surgery. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2022; 39(1):1164-9. doi:10.1080/02656736.2022.2107716.\u003c/li\u003e\n\u003cli\u003ePandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in Rheumatoid Arthritis. Int J Mol Sci. 2020; 21(15). doi:10.3390/ijms21155238.\u003c/li\u003e\n\u003cli\u003eUpson K, Missmer SA. Epidemiology of Adenomyosis. Seminars in reproductive medicine. 2020; 38(2-03):89-107. doi:10.1055/s-0040-1718920.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Adenomyosis, Serum interleukin 6, Dysmenorrhea, Biomarker, Risk factor","lastPublishedDoi":"10.21203/rs.3.rs-7472436/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7472436/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe pathogenesis of adenomyosis remains incompletely understood, and no well-established biomarkers related to its inflammatory mediators have been identified.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e\u003cp\u003eThis retrospective study aimed to investigate the association between interleukin-6 (IL-6) and dysmenorrhea in adenomyosis, as well as factors influencing IL-6 levels in patients with adenomyosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePatients were categorized based on the presence of dysmenorrhea and lesion subtype. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic utility of IL-6 for dysmenorrhea. Binary logistic regression was employed to identify factors associated with dysmenorrhea and IL-6 levels.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eIL-6 levels were significantly higher in patients with dysmenorrhea compared to those without dysmenorrhea in the total cohort (Z = -3.783, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as well as in both the diffuse subtype group (Z = -2.525, P\u0026thinsp;=\u0026thinsp;0.012) and the focal subtype group (Z = -2.883, P\u0026thinsp;=\u0026thinsp;0.004). An IL-6 level of 3.02 pg/mL was identified as the optimal cutoff value for discriminating dysmenorrhea via ROC analysis. Patients with IL-6 levels\u0026thinsp;\u0026ge;\u0026thinsp;3.02 pg/mL were more likely to experience dysmenorrhea compared to those with IL-6 levels below this threshold. Furthermore, multiple regression analysis revealed a positive correlation between IL-6 levels and uterus volume in both the total cohort and the diffuse subtype group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIL-6 was associated with dysmenorrhea in adenomyosis, and its level correlated positively with disease severity.\u003c/p\u003e","manuscriptTitle":"Interleukin-6: A Potential Biomarker for Dysmenorrhea and Disease Severity in Adenomyosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:19:13","doi":"10.21203/rs.3.rs-7472436/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"163975261719292423888369292506713481425","date":"2025-10-15T23:03:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5155121375562004116024545174561786684","date":"2025-10-10T21:29:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-08T12:14:16+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-05T10:08:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-04T06:23:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-04T06:22:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2025-08-27T14:05:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5c88e1bf-7c82-407a-9b69-1d79adcc9dc1","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-21T23:19:14+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:19:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7472436","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7472436","identity":"rs-7472436","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}