The etiology differs regards to the locations of the lesion: a clinical experience of 1350 patients with adenomyosis confirmed by postoperative pathology

Background Despite proposed mechanisms hypotheses, the etiology of adenomyosis remains unclear. The limited efficacy of current therapeutic approaches may stem from insufficient understanding of its pathobiological underpinnings and the pronounced heterogeneity in clinical presentation and treatment responsiveness among subtypes. This study seeks to compare clinical and sonographic profiles of adenomyosis subtypes to elucidate distinct disease mechanisms and inform subtype-specific management strategies.

In this retrospective cohort of 1,350 surgically treated and pathologically confirmed adenomyosis cases (2017–2022), patients were categorized into diffuse versus focal and anterior versus posterior lesion groups according to sonographic features. Comparative analyses of demographics, symptomatology, concurrent gynecological conditions, and laboratory profiles were conducted to delineate subtype-specific patterns.

1074 (79.56%) had a definitive adenomyotic sonographic signs, with 329 (30.63%) focal adenomyosis and 745 (69.37%) diffuse adenomyosis. Multivariate logistic regression analysis revealed that, compared with focal adenomyosis, diffuse adenomyosis were older (OR, 1.09; 95%CI: 1.06–1.12), had more pregnancies (OR, 1.22; 95%CI: 1.11–1.33), higher BMI (OR, 1.05; 95%CI: 1.00-1.09), long course of disease (OR, 1.06; 95%CI: 1.02–1.11) and higher risk of moderate to severe dysmenorrhea (OR, 1.88; 95%CI: 1.36–2.60). Divided to the location of adenomyosis lesion indicated by sonographic, patients in the posterior wall group (n = 418) have higher risk of moderate to severe dysmenorrhea (OR, 1.88; 95% CI: 1.36–2.60), more endometriosis combination (OR, 3.24; 95%CI: 1.85–5.68) and intraoperative blood loss (OR, 1.001; 95%CI: 1.001–1.003).

By stratifying adenomyosis into diffuse/focal and anterior/posterior subtypes, we identified distinct clinical-pathological profiles: (1) Diffuse adenomyosis was independently associated with older age, higher gravidity, and severe dysmenorrhea, suggesting a progressive phenotype driven by tissue injury mechanisms; (2) Posterior lesions exhibited a 3.24-fold risk of concurrent endometriosis and increased surgical complexity, implicating shared The etiology differs regards to the locations of the lesion: a clinical experience of 1350 patients with adenomyosis confirmed by postoperative pathology Wanqing Li1,2, Yuting Hang1,2, Yunyu Xu1,2, Wen Zhang1, Ye He1, Wei Ye1, Xinyue Hu2 and Zhaolian Wei1* Page 2 of 9 Li et al. BMC Women's Health (2025) 25:268

Adenomyosis is a common gynecological condition in women of reproductive age that is characterized by the presence of ectopic endometrial tissue within the myo - metrium, causing myometrial hypertrophy, hyperplasia, and fibrosis [ 1]. Adenomyosis is clinically characterized by progressive dysmenorrhea, menorrhagia, secondary anemia, infertility, and obstetric complications [2]. While none of the above symptoms are specific to adenomyo - sis, the presence and/or worsening of painful symptoms help identify patients at higher risk of disease progression and is increasingly recognized as a hallmark feature of advanced disease [3]. Similarly, a large percentage of uteri removed at hysterectomies performed because of abnor - mal uterine bleeding (AUB) are reported to have adeno - myosis either as the sole or the main pathology [4]. These symptoms not only compromise patients’ health and quality of life but also serve as critical indicators for early diagnostic suspicion, particularly in women unresponsive to conventional hormonal therapies [ 5]. Although histo - pathological diagnosis following hysterectomy remains the gold standard for adenomyosis confirmation, recent advances in imaging modalities have enabled non-inva - sive diagnostic approaches. Notably, transvaginal pelvic ultrasonography (TVUS) and magnetic resonance imag - ing (MRI) demonstrate promising diagnostic perfor - mance, both achieving sensitivity and specificity rates of 78% [6]. A broader patient populations, including asymptom - atic patients, women undergoing fertility evaluations, and even adolescents, were identified earlier with imag - ing features of adenomyosis. Clinically, the manifesta - tions of adenomyosis exhibit marked heterogeneity, with distinct profiles associated with lesion topography. Kishi et al. classified the lesions according to their location in the myometrium and found that the patients with diffuse internal adenomyosis were older and more often had a history of uterine curettage, while those exhibiting focal - ized adenomyosis of the external myometrium had more often never been pregnant and more often exhibited endometriosis [ 7– 9]. When comparing diffuse and nod - ular adenomyosis, it was found that endometrial lesions were more common in diffuse adenomyosis and nodular adenomyosis was more often associated with AUB [ 10]. These findings collectively suggest that phenotypic vari - ability may reflect distinct adenomyosis entities governed by divergent pathophysiological mechanisms and risk profiles, underscoring the critical role of imaging in both diagnostic stratification and mechanistic investigation of disease progression. However, prior studies remain limited by insuffi - cient histopathological validation, small sample sizes, or incomplete characterization of lesion subtypes. The

obstruct a mechanistic understanding of dis - ease initiation and hinder the creation of etiology-based taxonomies. This ambiguity complicates clinical deci - sion-making, as diffuse and focal subtypes may require divergent management strategies (e.g., hormonal sup - pression vs. surgical excision). To address these chal - lenges, we conducted a large-scale retrospective analysis of 1,350 histologically confirmed adenomyosis cases, sys - tematically integrating demographic, clinical, and comor- bidity data to establish a comprehensive phenotypic framework. By stratifying lesions into diffuse/focal and anterior/posterior subtypes via ultrasound, we dissected etiological divergences, offering mechanistic insights into how anatomical distribution and lesion extent dictate disease behavior. These insights underpin the proposal of subtype-specific management strategies tailored to address divergent pathological pathways.

Population The patients who underwent partial or total hysterec - tomy for various gynecological diseases and diagnosed adenomyosis pathologically between January 2017 and December 2022 at the Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University were included retrospectively. In accordance with the Declaration of Helsinki, the study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Lot No.: FAH.AMU.EC-Fast-PJ 2023-09-15). Data extraction The following data of all eligible patients were detailly collected and compiled from their medical records: (1) demographic characteristics, (2) symptoms presented, (3) the details of preoperative examination and surgical procedures, and (4) pathological reports. The pathologic diagnostic criteria of adenomyosis were the presence of endometrial glands at a distance of 3 mm from the endo - metrial-myometrial junction. Dysmenorrhea severity was classified using a 4-grade Verbal Descriptor Scale (None, Mild, Moderate, Severe) [11, 12]. Full criteria are provided in Supplementary File S1. “ Abnormally heavy or prolonged menstruation (> 7 pathways with deep infiltrating endometriosis. These findings redefine adenomyosis as a heterogeneous disorder with subtype-specific pathophysiology, advocating for tailored therapeutic strategies.

Adenomyosis, Sonographic classification, Pathophysiology, Clinical heterogeneity Page 3 of 9 Li et al. BMC Women's Health (2025) 25:268 days) was considered to be menorrhagia, and irregular uterine bleeding interval time ( 35 days) was supposed to be irregular menstrual cycle. The course of disease namely the duration interval from the occurrence of adenomyosis-related symptoms to the uterine opera - tion, also was recorded. Routine preoperative pelvic ultrasonography was recorded. The presence or absence of the following sono- graphic signs for adenomyosis was evaluated: The uter - ine shape (globular or normal); Symmetry of anterior and posterior wall; Presence of myometrial alterations. Adenomyosis is categorized as focal and diffused. Focal adenomyosis refers to a well-defined area in the myome - trium that presents one or more of the above-mentioned typical adenomyosis ultrasound signs, while diffuse ade - nomyosis refers to adenomyosis signs that extend to the entire myometrium or less than 25% of the lesions are surrounded by the normal myometrium [13]. Patients were stratified into anterior or posterior wall cohorts according to ultrasound-localized pri - mary adenomyotic lesions. Exclusion criteria comprised postmenopausal status, malignancy, acute abdomi - nal pathology, and multifocal leiomyomatosis (≥ 1 lesion ≥ 5 cm in maximum diameter). Unclassifiable cases (e.g., circumferential lesions spanning both uterine walls) were systematically excluded to maintain phenotypic homogeneity. The uterus size was measured and calcu - lated by the prolate ellipse equation: Uterine Vol - ume = D1×D2×D3 × π/6(D1, D2, and D3 represent the vertical, transverse, and anteroposterior diameter of the uterus, respectively) [14]. Blood markers were recorded, such as systemic immu - noinflammatory index (SII = platelet count × neutrophil count / lymphocyte count), D-dime and carbohydrate antigen 125(CA125). The surgery records and pathology reports from hys - terectomies were also reviewed. Postoperative findings, such as leiomyomas, the presence of endometriosis, and other gynecological conditions, were recorded. Statistical analysis Data were coded and entered into a statistical analysis software, Statistical Package for the Social Sciences(SPSS 25.0). Continuous variables were presented as means ± standard deviations, and intragroup differences were investigated using independent sample t-tests. Cat - egorical variables were expressed as the number of cases and percentages. Differences between categorical data were evaluated using the Chi-squared test or Fisher exact test when necessary. Multivariate logistic regression anal- ysis was performed to identify independent predictors of adenomyosis subtypes, adjusting for covariates as previ - ously described with diffuse and posterior adenomyosis presented as odds ratios (ORs) and 95% confidence intervals (CIs). A two-tailed p-value less than 0.05 was accepted as statistically significant.

In the present study we included 1350 patients with a diagnosis of adenomyosis based on histopathologi - cal results from uterine-sparing or non-uterine-sparing specimens. The mean age of patients was 46.67 ± 5.74(23, 81)years old (at the time of operation), 91 (6.7%)of them were post-menopausal, while the remaining 1259 (93.3%) patients were premenopausal. The main indications for operation were treatment- resistant menorrhagia, moderate to severe dysmenor - rhea, abnormal endometrial or cervical pathology, and ovarian neoplasm. A group of 213(15.8%)patients had no typical symptoms and pathologically confirmed adeno - myosis after surgery for other benign or malignant gyne - cological conditions. The characteristics of all patients are listed in Table 1. Of the patients ( n = 1350) who underwent ultrasound scan before surgeries, 1074 (79.56%) with a defini - tive adenomyotic sonographic signs. Among them, 329 cases (30.63%) were focal adenomyosis, while 745 cases (69.37%) had diffuse adenomyosis. There is no statisti - cally significant difference between the diffuse and focal adenomyosis groups regarding the age of first birth, uter - ine operation history, and other gynecological condi - tion. Patients with diffuse adenomyosis tend to be older (46.80 ± 4.30 vs. 44.76 ± 6.56), heavier (24.41 ± 3.29 vs. 23.86 ± 3.18) and have more pregnancies (3.58 ± 1.75 vs. 2.86 ± 1.68) and births (1.58 ± 0.78 vs. 1.40 ± 0.72). On the comparison of clinical symptoms, the propor - tion of patients with moderate to severe dysmenorrhea (66.7% vs. 45.3%) and menorrhagia (65.2% vs. 52%) in the diffuse adenomyosis was higher than that in the focal group. About one-third of the patients in both groups had irregular menstruation. In the diffuse adenomyosis group, 8.3% of the patients had anemia manifestations such as dizziness, weakness, and palpitations, which were significantly higher than the 4.6% in the focal group. There is a higher proportion of patients in the focal ade - nomyosis group combined with lumbosacral pain rather than the diffused group (4.3% vs. 2.0%). Both groups had similar symptoms of bladder compression (4.7% vs. 4.0%) and rectal irritation (1.7% vs. 0.9%). The characteristics of the patients are listed in Table 2. The variables with statistically significant difference between the groups were included in multinomial logis - tic regression analysis for determining independent risk factors of diffuse adenomyosis, using the focal adeno - myosis group as the reference category. After adjusting for confounding factors, the variables age, gravidity, BMI, course of disease, moderate to severe dysmenorrhea, and Page 4 of 9 Li et al. BMC Women's Health (2025) 25:268 asymptomatic were included in the regression model. The results showed that patients in the diffuse adenomy - osis group were older ( OR, 1.09; 95% CI: 1.06–1.12), had more pregnancies ( OR, 1.22; 95% CI: 1.11–1.33), higher BMI (OR, 1.05; 95% CI: 1.00-1.09), long course of disease (OR, 1.06; 95% CI: 1.02–1.11) and higher risk of moder - ate to severe dysmenorrhea ( OR, 1.88; 95%CI: 1.36–2.60) (Table 3). Multinomial logistic regression with focal adenomyosis as the reference group, adjusted for natural labor, parity, abortion, the presence of menorrhagia, and symptoms of anemia. Table 1 Characteristics of the 1350 patients with pathologically diagnosed adenomyosis Variables Results (n = 1350) Age(years) 46.67 ± 5.74(23, 81) <30 7(0.52) 30–40 127(9.41) 40–50 821(60.81) 50–60 378(28) ≥ 60 17(1.26) Gravidity(times) 3.29 ± 1.72(0, 12) Parity(times) 1.55 ± 0.80(0, 6) BMI(kg/m2) 24.21 ± 3.27(15.82, 42.06) Menopause(n,%) Yes 91(6.7) No 1259(93.3) Sonographic Signs(n,%) Yes 1074(79.6) No 276(20.4) Asymptomatic(n,%) 213(15.8) History of Hormone Therapy(n,%) 259(19.2) Surgical Modality(n,%) non-uterine-sparing 1127(83.5) uterine-sparing 223(16.5) Combined Gynecological Conditions(n,%) Uterine Leiomyomas 666(49.3) Endometriosis 224(16.6) Endometrial polyps 177(13.1) Benign ovarian tumor 81(6.0) Ovarian cancer 18(1.3) CIN 52(3.9) Cervical cancer 47(3.5) Endometrial hyperplasia 60(4.4) Endometrial cancer 37(2.7) Other Malignant Gynecological conditions 6(0.4) Education status(n,%) Primary 546(40.4) Secondary 432(32.0) High school 160(11.9) University 212(15.7) For continuous variables, data are presented as means ± the standard deviation and (minimum, maximum) values; and for qualitative variables, the data are reported as number (percentage) BMI, body mass index; CIN, cervical intraepithelial neoplasia Table 2 Comparison between diffuse and focal adenomyosis features Variables Diffuse(n = 745) Focal(n = 329) P Age(year) 46.80 ± 4.30 44.74 ± 6.46 0.000 Age of First Birth(year) 24.16 ± 3.06 24.23 ± 3.17 0.723 Gravidity(times) 3.58 ± 1.75 2.86 ± 1.68 0.000 Parity(times) 1.58 ± 0.78 1.40 ± 0.73 0.000 Natural Labor 1.32 ± 0.91 1.12 ± 0.85 0.001 Cesarean Section 0.26 ± 0.52 0.28 ± 0.56 0.579 Abortion(times) 2.00 ± 1.62 1.46 ± 1.49 0.000 BMI(kg/m²) 24.41 ± 3.29 23.86 ± 3.18 0.012 Course of Disease(year) 4.94 ± 4.25 3.56 ± 3.56 0.000 History of Uterine Operation(n,%) 200(26.8) 92(28.0) 0.704 Clinical Symptom(n,%) Moderate to Severe Dysmenorrhea 497(66.7) 149(45.3) 0.000 Menorrhagia 486(65.2) 171(52.0) 0.000 Irregular Menstrual Cycle 236(33.3) 94(32.8) 0.268 Symptoms of Anemia 62(8.3) 15(4.6) 0.028 Bladder Compression 35(4.7) 13(4.0) 0.597 Rectum Irritation 13(1.7) 3(0.9) 0.227 Lumbosacral Pain 15(2.0) 14(4.3) 0.037 Asymptomatic 40(5.4) 65(19.8) 0.000 Surgical Modality(n,%) 0.000 non-uterine-sparing 722(96.9) 192(58.4) uterine-sparing 23(3.1) 137(41.6) Combined Gynecological Conditions(n,%) Uterine Leiomyomas 269(36.1) 131(39.8) 0.246 Endometrial Polyps 96(12.9) 44(13.4) 0.827 Endometriosis 130(17.4) 74(22.5) 0.052 Benign Ovarian Tumor 37(5.0) 21(6.4) 0.344 Ovarian Cancer 6(0.8) 3(0.9) 1.000 CIN 17(2.3) 11(3.3) 0.314 Cervical Cancer 15(2.0) 6(1.8) 0.836 Endometrial Hyperplasia 38(5.1) 12(3.6) 0.297 Endometrial Cancer 16(2.1) 2(0.6) 0.070 Uterine Malformation 8(1.1) 4(1.2) 0.764 Data are presented as means ± the standard deviation values or n (%) as appropriate BMI, body mass index; CIN, cervical intraepithelial neoplasia Table 3 Risk factors of diffuse and focal adenomyosis Variables Diffuse adenomyosis (versus Focal adenomyosis) OR 95%CI P Age(years) 1.09 1.06–1.12 0.000 Gravidity(times) 1.22 1.11–1.33 0.000 BMI(kg/m2) 1.05 1.00-1.09 0.036 Course of Disease(year) 1.06 1.02–1.11 0.003 Moderate to Severe Dysmenorrhea 1.88 1.36–2.60 0.000 Asymptomatic 0.34 0.21–0.54 0.000 Page 5 of 9 Li et al. BMC Women's Health (2025) 25:268 BMI: body mass index; CI: confidence interval; OR: odds ratio. Following the predefined exclusion criteria, 645 patients were eligible for subgroup analysis, including 227 cases in the anterior wall group and 418 cases in the posterior wall group. There was no difference in the com- parison of age, BMI, uterine operation history, and course of disease between the two groups. The terms of gravidity (3.53 ± 1.82 vs. 3.12 ± 1.65) and abortion (2.00 ± 1.68 vs. 1.67 ± 1.47) were higher in the anterior group than in the posterior group. Still, there was no difference in delivery, either natural labor (1.25 ± 0.90 vs. 1.17 ± 0.84) or cesar - ean Sect. (0.26 ± 0.50 vs. 0.28 ± 0.56). Menorrhagia was significantly more common in the anterior group than the posterior group (67.0% vs. 54.8%, P = 0.003). The rate of moderate to severe dysmenor - rhea in the posterior group was higher than that in the anterior group (70.6% vs. 58%, P = 0.002). The posterior group had a higher proportion of patients with endome - triosis (9.3% vs. 27.8%, P = 0.000) also more intraopera - tive blood loss (68.88 ± 75.53 vs. 95.08 ± 131.97, P = 0.001). No significant difference was observed between the two groups regarding other combined gynecological condi - tions. SII、D-dimer, and uterine volume were not differ - ent between the two groups, and CA125 in the posterior group was significantly higher than in anterior group (Table 4). SII = platelet count × neutrophil count / lymphocyte count; Uterine Volume = vertical diameter × transverse diameter × anteroposterior diameter × π/6. The variables with statistically significant difference between the groups were included in further multinomial logistic regression analysis. Adjusting for gravidity, abor - tion, the presence of menorrhagia, symptoms of anemia, and CA125, the results showed that patients in the poste- rior adenomyosis group have higher risk of moderate to severe dysmenorrhea (OR, 1.88; 95% CI: 1.36–2.60), more endometriosis combination (OR, 3.24; 95%CI: 1.85–5.68) and intraoperative blood loss ( OR, 1.001; 95% CI: 1.001– 1.003) (Table 5).

To our knowledge, this is most significant number of cases to date to investigate clinical differences between diffuse and focal adenomyosis, and it is also a rare study to analyze lesions of the anterior and posterior walls of the uterus. Adenomyosis, characterized by the ectopic presence of endometrial tissue within the myometrium, manifests heterogeneously in terms of lesion distribu - tion (diffuse vs. focal) and anatomical location (anterior vs. posterior uterine walls). While previous studies have highlighted differences in clinical and imaging features between subtypes, our study, encompassing 1,350 histo - logically confirmed cases, provides novel insights into the distinct pathophysiological and clinical profiles of these subtypes, bridging critical gaps in understanding their etiological and therapeutic implications. Based on histologically confirmed cases, we compre - hensively evaluated patients’ medical histories, trans - vaginal ultrasound (TVUS) features, and intraoperative findings. Our results revealed that the “adenomyosis” was incidentally detected in approximately one in six cases during postoperative histopathological examination. Compared to endometriosis, which typically requires 6.7 to 11.7 years for diagnosis [ 15], adenomyosis exhib - ited a shorter symptom-to-diagnosis interval, averaging 4.3 years. Notably, 821 patients (60.81%) were aged 40 to 50 years at the time of surgery, and fewer than 10% were postmenopausal. Consistent with previous studies [ 16, 17], adenomyosis was frequently diagnosed alongside other gynecological comorbidities. In our cohort, 49.3% of cases coexisted with uterine leiomyomas, followed by endometriosis (16.6%) and endometrial polyps (13.1%). The majority of patients presented with prominent symp- toms, including moderate-to-severe dysmenorrhea, menorrhagia, and irregular menstrual cycles. However, approximately 20% of patients had not received hormone therapy, likely due to a prevalent belief among Chinese women that long-term hormonal management is “harm - ful. ” This reluctance may contribute to accelerated disease progression, highlighting the urgent need for enhanced public education and primary care initiatives to improve early symptom recognition and timely medical interven - tion. While some studies suggest that adenomyosis may elevate the risk of gynecological malignancies, such as endometrial or ovarian cancer [18], our data did not sup- port this association. Cervical cancer was observed in 3.5% of adenomyosis patients, followed by endometrial cancer (2.7%) and ovarian cancer (1.3%). These findings align with a prior study of 647 adenomyosis cases [ 19], which also found no significant increase in malignancy risk among affected women. About 80% of patients had at least one definitive ade - nomyotic sonographic signs, with 329 (30.63%) focal ade- nomyosis and 745 (69.37%) diffuse adenomyosis. A study comparing the ultrasound and clinical features of adeno - myosis in early (18–35) and advanced (> 35) reproductive age found that the incidence of severe dysmenorrhea and focal adenomyosis was higher in younger patients, while older women present more frequently menorrhagia, dif - fuse and severe adenomyosis [ 20]. Our findings reinforce that diffuse adenomyosis is associated with more severe symptomatology, including higher rates of moderate- to-severe dysmenorrhea (66.7% vs. 45.3%, P < 0.001) and menorrhagia (65.2% vs. 52.0%, P < 0.001), compared to focal adenomyosis. Notably, our multivariate analy - sis identified older age, higher gravidity, and prolonged disease duration as independent risk factors for diffuse Page 6 of 9 Li et al. BMC Women's Health (2025) 25:268 adenomyosis, suggesting a progressive nature of the dis - ease, possibly evolving from focal lesions over time. As described by Byun et al. [ 21], diffuse adenomyosis typically presents as global junctional zone thickening on MRI, whereas focal lesions appear as circumscribed masses. Our data corroborate these patterns, with dif - fuse cases showing widespread myometrial involvement on preoperative ultrasound, while focal lesions exhib - ited localized hyperechoic islets. The absence of criti - cal quantitative data—including lesion size, thickness of the affected uterine wall, and the number of direct/indi - rect sonographic signs—precluded standardized sever - ity grading of adenomyosis based on established criteria Table 4 Comparison between anterior and posterior adenomyosis features Variables Anterior (n = 227) Posterior (n = 418) P Age(year) 45.52 ± 4.98 45.38 ± 5.24 0.747 Age of First Birth(year) 24.11 ± 3.01 24.11 ± 3.12 0.986 Gravidity(times) 3.53 ± 1.82 3.12 ± 1.65 0.005 Parity(times) 1.52 ± 0.80 1.45 ± 0.72 0.304 Natural Labor 1.25 ± 0.90 1.17 ± 0.84 0.239 Cesarean Section 0.26 ± 0.50 0.28 ± 0.56 0.647 Abortion(times) 2.00 ± 1.68 1.67 ± 1.47 0.010 BMI(kg/m²) 24.20 ± 3.39 23.95 ± 3.07 0.353 Course of Disease(year) 5.45 ± 7.04 5.45 ± 6.48 0.994 History of Uterine Operation(n,%) 65(28.6) 117(28.0) 0.862 Clinical Symptom(n,%) Moderate to Severe Dysmenorrhea 133(58.6) 295(70.6) 0.002 Menorrhagia 152(67.0) 229(54.8) 0.003 Irregular Menstrual Cycle 71(31.3) 149(35.6) 0.264 Symptoms of Anemia 33(14.5) 36(8.6) 0.020 Bladder Compression 12(5.3) 18(4.3) 0.572 Rectum Irritation 3(1.3) 8(1.9) 0.755 Lumbosacral Pain 2(0.9) 9(2.2) 0.344 Asymptomatic 12(5.3) 30(7.2) 0.353 Combined Gynecological Conditions(n,%) Uterine Leiomyomas 80(35.2) 131(31.3) 0.313 Endometriosis 21(9.3) 116(27.8) 0.000 Endometrial polyps 32(14.1) 42(10.0) 0.123 Benign ovarian tumor 16(7.0) 23(5.5) 0.431 Endometrial hyperplasia 11(4.8) 13(3.1) 0.266 CIN 7(3.1) 11(2.6) 0.739 Type of adenomyosis(n,%) 0.637 Diffuse 146(64.3) 261(62.4) Focal 81(35.7) 157(37.6) Surgical Modality(n,%) 0.877 non-uterine-sparing 182(80.2) 333(79.7) uterine-sparing 45(19.8) 85(20.3) Intraoperative Blood Loss(ml) 68.88 ± 75.53 95.08 ± 131.97 0.001 SII 580.34 ± 342.27 580.10 ± 386.91 0.994 D-dimer(ug/ml) 0.29(0.11, 17.89) 0.27(0.10, 15.25) 0.197 CA125(U/ml) 87.96 ± 65.94(171) 112.83 ± 111.97(347) 0.002 Uterine Volume(cm3) 266.18 ± 139.12(168) 265.82 ± 159.08(280) 0.981 Data are presented as means ± the standard deviation values or n (%) as appropriate BMI, body mass index; CIN, cervical intraepithelial neoplasia; SII, systemic immunoinflammatory index Table 5 Risk factors of anterior and posterior adenomyosis Variables Posterior adenomyosis (ver- sus anterior adenomyosis) OR 95%CI P Moderate to Severe Dysmenorrhea 1.58 1.06–2.36 0.026 Combined Endometriosis 3.24 1.85–5.68 0.000 Intraoperative Blood Loss(ml) 1.001 1.001–1.003 0.015 Multinomial logistic regression with anterior adenomyosis as the reference group, adjusted for gravidity, abortion, the presence of menorrhagia, symptoms of anemia, and CA125 CI: confidence interval; OR: odds ratio Page 7 of 9 Li et al. BMC Women's Health (2025) 25:268 (e.g., lesion volume, myometrial infiltration depth). How- ever, studies have indicating that lesion distribution and anatomical location may serve as indirect proxies for dis - ease severity in clinical practice [ 22– 25]. Early diagnosis in young women suffering from focal adenomyosis may help to interrupt the mechanisms that drive the devel - opment of adenomyosis, starting immediately the right treatment. It has been observed that there was no differ - ence in estrogen receptors (ER) /progesterone receptors (PR) expression in gland cells/stromal cells of adenomy - otic lesions on the ipsilateral side of focal adenomyosis and the anterior/posterior walls of diffuse adenomyosis [26]. For diffuse adenomyosis, the severity of symptoms and responsiveness to hormonal therapies may necessi - tate early consideration of uterine-sparing interventions (e.g., gonadotropin-releasing hormone agonists) or hys - terectomy in refractory cases. Conversely, focal adeno - myosis, with its localized pathology, may benefit from targeted surgical excision, particularly in patients desir - ing fertility preservation. The pathogenesis of adenomyosis has not yet been definitively clarified. Two main theories dominate the literature; the widely accepted one involves tissue injury and repair (TIAR) at the endo-myometrial interface, trig- gered by physiological or iatrogenic tissue injury, which facilitates invasion of the endometrial basalis epithelial w/o stromal cells into the myometrium [ 27]. Another one is metaplasia, which means that displaced embryonic pluripotent Müllerian remnants or endometrial stem cells may behave aberrantly for some unknown reason and disintegrate into endometrial tissues [ 28, 29]. When stratifying patients into anterior and posterior uterine wall lesion groups based on adenomyosis lesion indicated via ultrasonography, we observed that patients with ante- rior wall lesions exhibited significantly higher gravidity and abortion frequency compared to the posterior group. Conversely, the posterior wall group demonstrated a markedly higher incidence of coexisting endometrio - sis (27.8% vs. 9.3%, P < 0.001). Furthermore, menorrha - gia was more prevalent in the anterior group, whereas moderate-to-severe dysmenorrhea predominated in the posterior group. These distinct clinical profiles suggest potential etiopathogenetic differences between anterior and posterior lesions. Previous studies have demonstrated that adolescent adenomyosis without a history of pregnancy, is charac - terized by coexisting endometriosis, severe dysmenor - rhea, and a predilection for the posterior uterine wall and extrinsic myometrial layer [22]. Khan et al. [30] proposed another classification of adenomyosis into intrinsic and extrinsic types, in which the extrinsic subtype is char - acterized by its strong association with deep infiltrating endometriosis (DIE), aligns closely with our observations of posterior wall adenomyosis. As a diagnostic parameter and follow-up tool for patients with adenomyosis, the preoperative CA125 levels is significantly correlated with pelvic adhesion [ 31, 32]. Our data also found that, in the absence of differences in uterine volume, patients in the posterior wall group with higher CA125 values also expe- rienced more intraoperative blood loss, possibly related to more severe pelvic adhesions. These findings reflect Khan et al. ‘s report that extrinsic adenomyosis has the same histopathological and molecular features as DIE, including stromal invasion and inflammatory cytokine overexpression, and also suggest that posterior wall ade - nomyosis, which is similar to extrinsic adenomyosis, may have the same metaplasia as endometriosis. In contrast, anterior wall lesions could be linked to physiological or iatrogenic tissue injury—potentially attributed to anterior uterine wall vulnerability during procedures like cesarean sections or curettage. It has already been experimentally confirmed that mechanical or heat-induced disruption of the endometrium-myometrium interface can cause ade - nomyosis in mice, perioperative protective measures can reduce the incidence of adenomyosis [ 33]. Such injury may disrupt endometrial integrity, leading to endometrial cell migration, while simultaneously triggering aberrant tissue repair processes that drive adenomyosis develop - ment. Our data show that patients with anterior lesions were predominantly associated with menorrhagia, possi - bly due to disrupt to endometrial integrity and function. In addition, consistent with observations by Khan et al., it rarely coexists with endometriosis, simplifying treatment options such as hormonal suppression or focal resection. This study elucidates distinct clinical and patho - physiological profiles of adenomyosis subtypes. Diffuse adenomyosis, characterized by older age, higher gravid - ity, prolonged disease duration, and severe dysmenor - rhea, likely represents a progressive phenotype driven by tissue injury and repair mechanisms. In contrast, focal adenomyosis, while associated with milder symp - toms and younger age, exhibited unique features such as higher rates of lumbosacral pain and asymptomatic presentation, suggesting early-stage or localized pathol - ogy. Regarding anatomical localization, posterior wall lesions demonstrated a 3.24-fold increased risk of coex - isting endometriosis and elevated intraoperative blood loss, likely reflecting inflammatory complexity akin to deep infiltrating endometriosis. While these findings highlight the technical challenges of managing posterior lesions, we recommend enhance preoperative screening (CA125, endometriosis) (e.g., preoperative CA125 assess- ment, endometriosis screening). Conversely, anterior wall lesions, linked to menorrhagia and mechanical dis - ruption, may benefit from uterine-sparing interventions targeting focal pathology. This study has several limitations. First, while our findings suggest potential etiopathogenetic distinctions Page 8 of 9 Li et al. BMC Women's Health (2025) 25:268 between anterior and posterior adenomyosis subtypes— whether driven by TIAR (tissue injury and repair) mechanisms in anterior cases or metaplastic processes in posterior cases—remains speculative and require fur - ther validation through rigorously designed studies, ide - ally incorporating molecular profiling and longitudinal cohorts. Second, the retrospective inclusion of only sur - gically confirmed cases of adenomyosis introduced a bias in the selection of symptomatic or treatation-resistant populations, while a majority of cases were combined with uterine leiomyoma, which may confuse the cause of symptoms (e.g., menorrhagia and dysmenorrhea). Third, while we stratified lesions by anterior/posterior location, internal/external myometrial involvement was not sys - tematically evaluated. This limits our ability to correlate symptom severity with specific myometrial layers, an area warranting prospective investigation.

In summary, our data integrated anatomical (anterior/ posterior), distributional (diffuse/focal), and etiological (intrinsic/extrinsic) classifications provides a multidi - mensional view of adenomyosis, providing a framework for subtype-driven management. By evaluating imag - ing, biomarker (e.g., CA125), and symptomatology data, clinicians can better stratify patients for personalized therapeutic strategies, ultimately improving outcomes in this complex patient population. Future studies should focus on molecular subtyping and longitudinal designs to unravel the mechanistic underpinnings of these differences. Supplementary Information The online version contains supplementary material available at h t t p s : / / d o i . o r g / 1 0 . 1 1 8 6 / s 1 2 9 0 5 - 0 2 5 - 0 3 7 5 9 - 3. Supplementary Material 1

We are grateful to our study participants for their detailed medical history. We thank the staff of the Record Room at the First Affiliated Hospital of Anhui Medical University for their support. Authors’ information (optional): ZLW is Director of Obstetrics and Gynaecology, the First Affiliated Hospital of Anhui Medical University (China). Her research interests include endometriosis, adenomyosis, and endometrial injury. Author contributions ZLW and WQL designed the study. WQL was a major contributor in writing the manuscript. YTH and XYH collected, analyzed the data. WY and YYX collected the data and assisted in literature search. YH gave suggestions, and WZ revised the manuscript. All authors contributed to the article and approved the submitted version. Funding This study was supported by“Research Funds of Center for Data and Population Health of IHM”(JKS2022009) and the National Natural Science Foundation of China (No.82171619). Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate In accordance with the Declaration of Helsinki, the study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Lot No.: FAH.AMU.EC-Fast-PJ 2023-09-15). All participants gave informed consent for this study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China 2Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China Received: 25 October 2024 / Accepted: 28 April 2025

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