Phenotypic heterogeneity in adenomyosis: internal and external subtypes

Adenomyosis presents with diverse clinical manifestations. This study reveals that intrinsic and extrinsic adenomyosis subtypes exhibit distinct clinical characteristics and associated risk factors, along with significant differences in perioperative parameters.

A total of 181 women who underwent hysterectomy for AM and had preoperative MRI scans between June 2019 and August 2022 were initially screened. Of these, 50 patients were excluded for the following reasons: 5 patients were over 50 years old, 7 patients had a history of AM lesion excision, 32 patients were classified as the subtype IV of AM, and 6 patients had incomplete clinical data. The remaining 131 women were included in the final analysis, including 77 in the intrinsic group and 54 in the extrinsic group (Fig. 3 ). All surgical procedures were performed by laparoscopy. Fig. 3 Flow chart. AM adenomyosis, MRI magnetic resonance imaging Flow chart. AM adenomyosis, MRI magnetic resonance imaging The demographic characteristics of women between the two groups are shown in Table 1 . There were no differences in terms of age, BMI, duration of menstruation and menstrual cycle. The intrinsic group had a lower education level (P = 0.012), higher gravidity (3.06 ± 1.39 vs 1.78 ± 1.19, P < 0.001), higher parity (1.22 ± 0.64 vs 0.80 ± 0.45, P < 0.001), more abortions (P = 0.001) and more endometrial curettage (P = 0.017) and higher prevalence of anemia (P = 0.002) compared to the extrinsic group. Earlier menarche (13.56 ± 1.08 vs 14.06 ± 1.50 years, P = 0.026), as well as higher unmarried status (P = 0.033), infertility (23.1 vs 6.6%, P = 0.009), especially primary infertility (83.3 vs 60%, P = 0.006), and previous surgery for endometriosis (P = 0.023) were observed in extrinsic group. Table 1 Comparison of demographic characteristics of intrinsic and extrinsic group Intrinsic group Extrinsic group P value Age (years) 44.73 ± 4.16 43.43 ± 4.21 0.08 BMI (kg/m 2 ) 23.69 ± 3.05 23.29 ± 3.17 0.47 Education level 0.01*  Primary school 7.79 (6/77) 1.85 (1/54)  Junior high school 32.46 (25/77) 14.81 (8/54)  High school and above 59.74 (46/77) 83.33 (45/54) Menarche age (years) 14.06 ± 1.50 13.56 ± 1.08 0.02* Duration of menstruation (days) 6.04 ± 1.28 6.43 ± 1.55 0.12 Menstrual cycle (days) 29.08 ± 8.71 28.81 ± 6.66 0.54 Marital status 0.03*  Married 93.51 (72/77) 81.48 (44/54)  Unmarried 6.49 (5/77) 18.52 (10/54) Gravidity  < 0.001*  0 2.59 (2/77) 14.81 (8/54)  1 11.68 (9/77) 22.22 (12/54)  ≥2 85.71 (66/77) 62.96 (34/54) Parity  < 0.001*  0 7.79 (6/77) 22.22 (12/54)  1 66.23 (51/77) 75.92 (41/54)  ≥2 25.97 (20/77) 1.85 (1/54) Cesarean delivery 0.76  0 54.54 (42/77) 53.70 (29/54)  1 41.55 (32/77) 44.44 (24/54)  ≥ 2 3.89 (3/77) 1.85 (1/54) Vaginal delivery 0.002*  0 46.75 (36/77) 68.51 (37/54)  1 38.96 (30/77) 31.48 (17/54)  ≥ 2 14.28 (11/77) 0 (0/54) History of infertility 0.008*  No 92.20 (71/77) 76.92 (40/52)  Yes 7.79 (6/77) 23.07 (12/52) Infertility types 0.006*  Primary 60.0 (3/5) 83.33 (10/12)  Secondary 40.0 (2/5) 16.66 (2/12) Number of abortions 0.001*  0 12.98 (10/77) 38.88 (21/54)  1 28.57 (22/77) 42.59 (23/54)  ≥ 2 58.44 (45/77) 18.51 (10/54) Number of endometrial curettage 0.01*  0 53.24 (41/77) 74.07 (40/54)  1 33.76 (26/77) 22.22 (12/54)  ≥ 2 12.98 (10/77) 3.70 (2/54) Number of previous surgery for endometriosis 0.02*  0 90.90 (70/77) 68.51 (37/54)  1 7.79 (6/77) 24.07 (13/54)  ≥ 2 1.29 (1/77) 7.40 (4/54) Family history of AM 0.71  No 97.40 (75/77) 96.29 (52/54)  Yes 2.59 (2/77) 3.70 (2/54) History of AM treatment 0.61  GnRH-a 18.18 (14/77) 27.77 (15/54)  ING-IUS 19.48 (15/77) 20.37 (11/54)  Progestins 19.48 (15/77) 14.81 (8/54)  Others a 12.98 (10/77) 7.40 (4/54) History of anemia 0.002*  No 19.48 (15/77) 40.74 (22/54)  Yes 80.51 (62/77) 51.85 (28/54) History of blood transfusion 3.89 (3/77) 0 (0/54) 0.38 Values are given as mean ± standard deviation or %(n/N) BMI body mass index, AM adenomyosis, GnRH-a gonadotropin-releasing hormone-antagonist, LNG-IUS levonorgestrel intrauterine system a Others including oral contraceptives, nonsteroidal anti-inflammatory drug, gestrinone * P-value ≤ 0.05 Comparison of demographic characteristics of intrinsic and extrinsic group Values are given as mean ± standard deviation or %(n/N) BMI body mass index, AM adenomyosis, GnRH-a gonadotropin-releasing hormone-antagonist, LNG-IUS levonorgestrel intrauterine system a Others including oral contraceptives, nonsteroidal anti-inflammatory drug, gestrinone * P-value ≤ 0.05 The mean of VAS scores was higher (7.91±1.9 vs 6.00±3.50, P = 0.009) in the extrinsic group. Moreover, the patients with OMA (72.2 vs 2.6%, P = 0.009), DIE (79.6 vs 1.3%, P < 0.001) and stage IV endometriosis (62.3 vs 1.3%, P < 0.001) were significantly higher in the extrinsic group. A sub-analysis within the extrinsic group revealed that patients with concomitant DIE reported significantly higher dysmenorrhea scores compared to those without DIE (mean VAS 8.8.0 vs 6.5-, P = 0.05).Conversely, women in intrinsic group had higher MVJ scores (5.57±1.90 vs 4.70±1.30, P < 0.001) and suffered from endometrial hyperplasia (51.9 vs 27.8%, P = 0.007) more often. This group also presented larger uterine volumes (348.82±155.49 vs 260.30±113.08 cm 3 , P = 0.005). The AM lesions had more diffuse lesions (76.6 vs 14.8%) in intrinsic group while the extrinsic group had more focal lesions (85.2 vs 23.4%). The focal lesions in the posterior wall were more frequently seen in the extrinsic group (95.7 vs 55.6%, P = 0.002) (Table 2 ). In the extrinsic adenomyosis, 34 patients (63%) were found to have concomitant DIE. Among them, the most commonly involved site was the uterosacral ligaments (USLs), affected in 18 cases (52.9%), followed by the rectovaginal septum (RVS) in 11 cases (32.4%), bowel involvement in 2 cases (5.9%), and bladder endometriosis in 3 cases (8.8%). Multiple-site involvement was observed in 10 patients (29.4%). These findings highlight the high prevalence and complex distribution pattern of DIE in patients with extrinsic adenomyosis. Table 2 Comparison of clinical features of intrinsic and extrinsic group Intrinsic group Extrinsic group P value Dysmenorrhea 0.03*  No dysmenorrhea 10.38 (8/77) 3.70 (2/54)  Primary 25.97 (20/77) 46.29 (25/54)  Secondary 63.63 (49/77) 50.0 (27/54) VAS 6.00 ± 3.50 7.91 ± 1.91 0.009* MVJ 5.57 ± 1.90 4.70 ± 1.30  < 0.001* Leiomyoma 0.18  No 36.36 (28/77) 50.0 (27/54)  Yes 63.63 (49/77) 48.14 (26/54) Maximum diameter of leiomyomas (cm) 19.61 ± 16.37 20.78 ± 14.12 0.54 OMA  < 0.001*  No 97.40 (75/77) 27.77 (15/54)  Yes 2.59 (2/77) 72.22 (39/54) DIE  < 0.001*  No 98.70 (76/77) 20.37 (11/54)  Yes 1.30 (1/77) 79.62 (43/54) Stages of endometriosis 0.001*  I 7.79 (6/77) 9.25 (5/54)  II 0 5.55 (3/54)  III 0 9.25 (5/54)  IV 1.29 (1/77) 62.96 (34/54) Endometrial disease 0.007*  No 48.05 (37/77) 72.22 (39/54)  Yes 51.94 (40/77) 27.77 (15/54) Uterine volume (cm 3 ) 348.82 ± 155.49 260.30 ± 113.08 0.005* Uterine position 0.06  Anteversion 79.22 (61/77) 61.11 (33/54)  Axial 5.19 (4/77) 12.96 (7/54)  Retroversion 15.58 (12/77) 25.92 (14/54) Lesion type 0.001*  Focal 23.37 (18/77) 85.18 (46/54)  Diffuse 76.62 (59/77) 14.81 (8/54) Location of focal lesion 0.002*  Anterior 33.33 (6/18) 4.34 (2/46)  Posterior 55.55 (10/18) 95.65 (44/46)  Fundus uteri 11.11 (2/18) 0 (0/46) Ca125 (U/ml) 133.97 ± 124.38 157.33 ± 128.31 0.32 AMH (ng/ml) 0.94 ± 1.09 0.79 ± 0.84 0.61 Values are given as mean ± standard deviation or %(n/N) VAS visual analog scale, MVJ Mansfield–Voda–Jorgensen menstrual bleeding scale, OMA ovarian endometrioma, DIE deep infiltrating endometriosis, r-AFS the revised American Fertility Society (r-AFS) classification for endometriosis, Ca125 carbohydrate antigen 125, AMH anti-Müllerian hormone * P-value ≤ 0.05 Comparison of clinical features of intrinsic and extrinsic group Maximum diameter of leiomyomas (cm) Values are given as mean ± standard deviation or %(n/N) VAS visual analog scale, MVJ Mansfield–Voda–Jorgensen menstrual bleeding scale, OMA ovarian endometrioma, DIE deep infiltrating endometriosis, r-AFS the revised American Fertility Society (r-AFS) classification for endometriosis, Ca125 carbohydrate antigen 125, AMH anti-Müllerian hormone * P-value ≤ 0.05 The perioperative and postoperative data were also studied . Women in the extrinsic group had longer surgical time (185.69 ± 65.40 vs 100.26 ± 22.27 min, P < 0.001), more operative blood loss (12.15 ± 8.68 vs 6.81 ± 7.78 g/L, P = 0.001), higher rate of excision of OMA or/and DIE (63.0 vs 2.6%, P < 0.001), and higher hospitalization cost (23,246.81 ± 3975.89 vs 19,278.01 ± 2241.54 RMB, P < 0.001) compared to intrinsic group. No surgical complications were observed in the intrinsic group, and ureteral injury occurred in only one patient in the extrinsic group which resolved after intraoperative repair. Drug treatment following surgery was significantly more common in the extrinsic group (35.2 vs 2.6%, P = 0.001). The degree satisfaction of treatment was similar between the two groups (Table  3 ). Table 3 Comparison of perioperative and postoperative data of intrinsic and extrinsic group Intrinsic group External group P value Surgical time (min) 100.26 ± 22.27 185.69 ± 65.40  < 0.001* Hb before operation (g/L) 115.17 ± 15.40 116.67 ± 15.78 0.58 Operative blood loss (g/L) 6.81 ± 7.78 12.15 ± 8.68 0.001* Excision of OMA or/and DIE  < 0.001*  No 97.40 (75/77) 37.03 (20/54)  Yes 2.59 (2/77) 62.96 (34/54) Postoperative morbidity 0.06  No 89.61 (69/77) 77.77 (42/54)  Yes 10.38 (8/77) 22.22 (12/54) Length of hospitalization (days) 7.91 ± 1.58 8.15 ± 1.58 0.39 Hospital cost (RMB) 19,278.01 ± 2241.54 23,246.81 ± 3975.89  < 0.001* Postoperative drug treatment 0.001*  No 97.40 (75/77) 64.81 (35/54)  Yes 2.59 (2/77) 35.18 (19/54) Treatment satisfaction 0.97  Very satisfied 74.02 (57/77) 75.93 (41/54)  Satisfied 23.37 (18/77) 22.22 (12/54)  Uncertain 2.59 (2/77) 1.85 (1/54)  Dissatisfied 0 (0/77) 0 (0/77)  Very dissatisfied 0 (0/77) 0 (0/77) Values are given as mean ± standard deviation or %(n/N) RMB RenMinBi, Yuan, Hb hemoglobin, DIE deeply infiltrating endometriosis * P-value ≤ 0.05 Comparison of perioperative and postoperative data of intrinsic and extrinsic group Values are given as mean ± standard deviation or %(n/N) RMB RenMinBi, Yuan, Hb hemoglobin, DIE deeply infiltrating endometriosis * P-value ≤ 0.05 In order to screen potential related factors for intrinsic and extrinsic AM, we conducted a univariate analysis. Education level, age of menarche, gravidity, parity, endometrial curettage, previous endometriosis surgery, OMA, DIE and endometriosis stage were included in the analysis. We then performed logistic regression analysis to adjust for confounding variables. The result showed the following factors to be related to the subtype AM: high school and above (OR 0.62, 95% CI 0.44–0.87), endometrial curettage greater than or equal to 2 (OR 2.23, 95% CI 1.07–4.68) and gravidity greater than or equal to 2 (OR 1.80, 95% CI 1.17–2.76) were remained significantly associated with intrinsic AM. OMA (OR 22.32, 95% CI 2.94–124.42) and DIE (OR 24.22, 95% CI 10.35–149.33) were independently associated with extrinsic AM (Fig. 4 A, B). Fig. 4 Multivariate analysis of related factors in different types of adenomyosis. A in intrinsic adenomyosis; B in extrinsic adenomyosis. OMA ovarian endometrioma, DIE deep infiltrating endometriosis, OR odds ratio, CI confidence interval, a multiple logistic regression analysis Multivariate analysis of related factors in different types of adenomyosis. A in intrinsic adenomyosis; B in extrinsic adenomyosis. OMA ovarian endometrioma, DIE deep infiltrating endometriosis, OR odds ratio, CI confidence interval, a multiple logistic regression analysis

We performed a retrospective observational study recruiting women who underwent hysterectomy as AM treatment at the International Peace Maternity and Child Health Hospital affiliated to the Shanghai Jiao Tong University between June 2019 and August 2022. The study was approved by the institutional ethics committee of the International Peace Maternity and Child Health Hospital (approval No. GKLW 2022-16). Data was fully anonymized. Indications for surgery (possibly more than one per patient) included: 1) medication or other conservative treatment (levonorgestrel intrauterine system (LNG-IUS), uterine artery embolization, etc.) fail to relieve the symptoms, such as dysmenorrhea, menorrhagia, and symptoms caused by compression, which seriously affect the patient's quality of life; 2) patients refuse to conservative treatment; 3) request for hysterectomy due to the severe symptoms caused by AM. The inclusion criteria was as the follow: 1) Age>18 and <50 years, premenopausal; 2) Without any hormone treatment within at least three months before the hysterectomy; 3) Patients were evaluated by MRI examination with T1 and T2-weighted sequences prior to surgery and determined to be intrinsic AM or extrinsic AM; 4) AM diagnosed by pathology after surgery. All MRI images were evaluated independently by two senior radiologists unaware of the clinical data of the patients. When the diagnosis of two radiologists was different, a third senior radiologist was invited to cast the deciding vote. Exclusion criteria included: 1) Subtype III and subtype IV AM; 2) Previous excision of AM lesions; 3) Patients with cancer or infectious disease; 4) Incomplete information. Women were then classified into intrinsic AM group (intrinsic group) and extrinsic AM group (extrinsic group) after enrollment. Data on demographic characteristics, clinical features, and perioperative data were obtained from the internal database of the hospital, while the postoperative information was collected from outpatient interview database. The following demographic data were collected: age, body mass index (BMI), education level, age of menarche, duration of menstruations, menstrual cycle, marital status, gravidity, parity, previous deliveries (cesarean section or vaginal delivery), infertility, number of abortions, number of endometrial curettage and previous endometriosis surgery, drug treatment for AM (gonadotropin-releasing hormone-antagonist (GnRH-a), LNG-IUS, progestins, oral contraceptives, nonsteroidal anti-inflammatory drug, gestrinone), family history of AM, history of anemia and blood transfusion. Clinical features were included: dysmenorrhea, menstrual blood loss, presence of ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE), endometrial disease (nonatypical hyperplasia, atypical hyperplasia, polypoid hyperplasia of endometrium and endometrial polyps), leiomyomas, stage of endometriosis, serum levels of carbohydrate antigen (Ca125), and Anti-Mullerian hormone (AMH). We also recorded uterine volume and position, location of AM lesions based on MRI images if the lesions were focal. Surgical time (minutes), operative blood loss, complications (bowel, ureteral, or bladder injury, large-vessel injury, blood transfusion, conversion to laparotomy), postoperative morbidity, hospital stay (days), hospital cost, and medical treatment after the operation (GnRH-a, progesterone, oral contraceptives) were noted. The degree of satisfaction of treatment was also assessed. The collected data was independently checked by two researchers to ensure that there were no inconsistencies or errors. Pathologic diagnosis for AM according to the criteria [ 13 , 15 ], were: (a) Ectopic endometrial glands and stroma, the ectopic endometrium should be observed at least 2.5-mm from the endometrial-myometrial interface (EMI), (b) Muscular hyperplasia/hypertrophy with a swirl trabeculated pattern, (c) Increased vascularity, (d) Cystic filled with cell debris and/or iron laden macrophages[ 19 ]. All pelvic MRI examinations were performed on a 1.5T MRI machine (Sonata, Siemens; Erlangen, Germany). AM cases were categorized into four subtypes depending on the characteristics of the lesions by MRI images: Subtype I (intrinsic): AM lesions occur in the uterine inner layer without affecting the outer structures. Subtype II (extrinsic): AM lesions occur in the uterine outer layer without affecting the inner structures, with healthy muscular structures between the lesions and the junction zone (JZ). Subtype III (intramural): AM lesions occur solitarily without relationship to structural components. Subtype IV: AM lesions do not meet any criteria listed above. Subtype I (intrinsic): AM lesions occur in the uterine inner layer without affecting the outer structures. Subtype II (extrinsic): AM lesions occur in the uterine outer layer without affecting the inner structures, with healthy muscular structures between the lesions and the junction zone (JZ). Subtype III (intramural): AM lesions occur solitarily without relationship to structural components. Subtype IV: AM lesions do not meet any criteria listed above. T2-weighted MRI images of intrinsic and extrinsic AM are shown in Figs. 1 and 2 . Fig. 1 T2-weighted MRI photograph of intrinsic AM. A and B: the AM lesions in the posterior wall of uterus; C and D: the AM lesion in the anterior wall of the uterus (white arrow) Fig. 2 T2-weighted MRI photograph of extrinsic AM. A , B focal AM lesions (white arrow) in the posterior wall of -uterus combined with DIE (yellow star) and OMA (red triangle); C , D the AM lesion in the posterior wall of the uterus (white arrow) and adhered to the rectum (yellow arrow) T2-weighted MRI photograph of intrinsic AM. A and B: the AM lesions in the posterior wall of uterus; C and D: the AM lesion in the anterior wall of the uterus (white arrow) T2-weighted MRI photograph of extrinsic AM. A , B focal AM lesions (white arrow) in the posterior wall of -uterus combined with DIE (yellow star) and OMA (red triangle); C , D the AM lesion in the posterior wall of the uterus (white arrow) and adhered to the rectum (yellow arrow) Diffuse and focal lesions were classified based on the following criteria: a diffuse lesion is characterized by foci of endometrial mucosa (glands and stroma) scattered throughout the uterine musculature, while a focal lesion is restricted in an area of hypertrophic and distorted endometrium and myometrium [ 16 , 20 , 21 ]. The degree of dysmenorrhea was evaluated with a Visual Analog Scale (VAS) system, using a 10 cm line where 0 represents “no pain” and 10 “maximum pain”. A VAS score ≥ 7 was considered to be severe pain [ 22 , 23 ]. Menstrual blood loss was assessed using the Mansfield-Voda-Jorgensen menstrual bleeding scale (MVJ), ranging from 1 (spotting) to 6 (gushing), and menorrhagia was defined as a MVJ score ≥ 5 [ 24 ]. 12 months or more of unprotected intercourse not resulting in pregnancy was considered as infertility [ 25 ]. The uterine volume was calculated by three-dimensional MRI examination using the following formula: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$volume = A \times B \times C \times 0.52$$\end{document} v o l u m e = A × B × C × 0.52 where A, B and C represent respectively the length, width, and depth of the uterus [ 26 ]. The stage of endometriosis was evaluated according to the revised American Fertility Society classification (r-AFS): score 1–5=stage I; score 6–15=stage II; score 16–40=stage Ⅲ; score>40=stage Ⅳ [ 27 ]. The normal serum levels of Ca125 and AMH were defined respectively as ≤35 U/ml and 2–6.8ng/ml, as usual practice in the clinical laboratory of our hospital. The operative blood loss was assessed based on the difference between pre and postoperative hemoglobin (Hb) levels. Patients were assessed about their degree of satisfaction for the treatment at least three months after surgery through the outpatient interview and were given the following scale: very satisfied, satisfied, uncertain, dissatisfied or very dissatisfied [ 28 ]. Statistical analysis was performed using SPSS version 24.0.0. (SPSS, Chicago, IL, USA) and Graphpad Prism 9.0.0 (Graphpad, San Diego, CA, USA). The normal distribution of continuous variables was tested with the Kolmogorov-Smirnov test. Descriptive statistics are reported as means ± standard deviation (SD) or percentages. Continuous variables were compared using the Student’s t -test. Categorical variables were analyzed by Chi square test and Fisher’s exact test between two groups, while non-parametric variables were compared using Wilcoxon signed-rank test or Kruskal-Wallis test. Logistic regression models were used for multivariate analysis, in which the variables included were those found to have P < 0.05 in the univariate analysis. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Two-sided P < 0.05 was considered statistically significant.

Our findings reveal that there are significant differences between intrinsic and extrinsic AM in terms of clinical manifestations, etiological associations, and perioperative outcomes. The underlying pathogenic mechanisms differentiating these two AM subtypes warrant further investigation.

We found that distinct clinical patterns and related factors between intrinsic and extrinsic AM. Patients with intrinsic AM demonstrated heavier menstrual blood loss (frequently leading to anemia) and showed significant associations with lower education levels, higher gravidity, and history of endometrial curettage. In contrast, extrinsic AM was characterized by more severe dysmenorrhea and stronger correlations with OMA and DIE. Meanwhile, surgery time, operative blood loss, hospital cost and postoperative medication were all significantly higher in the extrinsic group than in the intrinsic group. Despite these differences, treatment satisfaction rates were comparable between the two subtypes. A number of epidemiological studies have shown that both a history of uterine surgery and multiple births are risk factors for AM [ 29 – 31 ]. Our study found that intrinsic AM more often involved women with lower education level, multiparous and history of endometrial curettage. Guo et al. suggested that the trophoblast invasion of the inner myometrium during pregnancy and mechanical factors during curettage can damage the EMI, resulting in inflammation which in turn could perpetuate oxytocin-mediated uterine activity, local estrogen production, and chronic peristaltic myometrial contractions that are exacerbated with repetitive cycles, leading to endometrial cell migration into the myometrium [ 32 ]. We also observed a close relationship between OMA, DIE and extrinsic AM. Comorbidities with DIE and OMA in extrinsic AM cases were 79.6 and 72.2% respectively. Focal lesions mostly occurred in the posterior wall of the uterus (95.7%, 44/46). Previous studies have evaluated the prevalence of DIE in women affected by extrinsic AM to be up to 47–97% [ 33 , 34 ] and observed that in cases where both AM and DIE were present, 50% of endometriosis involving the bladder was associated with AM involving the anterior wall of the uterus [ 35 ]. Distinct expression patterns of fibrosis related proteins between intrinsic and extrinsic AM [ 36 ]. Cao et al. have found that the use of tamoxifen and Diarylpropionitrile (DPN) both caused AM in newborn ICR mice, and the lesions caused resembled those found in extrinsic AM cases [ 37 ]. The lesion’s pattern of gland and stromal cells was the same as in the endometrium in intrinsic AM, the pattern of Ber-EP4-stained glands and CD10-stained stromal cells of extrinsic AM was similar to that of coexistent DIE lesions, the study suggested that extrinsic AM and pelvic endometriosis may share a common epigenetic pathogenesis [ 33 ]. However, whether pelvic endometriotic lesions invading the uterine serous and AM lesion can cause pelvic endometriosis needs to be further investigated. Dysmenorrhea and menorrhagia are considered as common symptoms of AM [ 38 ]. The suggested mechanisms for the occurrence of dysmenorrhea are still poorly elucidated and it could be related to increased levels of oxytocin receptor (OTR), higher intensity and frequency of uterine contractions, neurological overgrowth within the lesion and the endometrium, and central sensitization [ 39 – 41 ]. Several studies reported that intrinsic and extrinsic AM result in pelvic pain and dysmenorrhea and have no difference in intensity [ 6 , 23 ]. However, our study reveals that dysmenorrhea is significantly more severe in extrinsic AM. Furthermore, the results also show that the menstrual blood loss in intrinsic AM cases is heavier than in extrinsic AM ones. This may be due to intrinsic AM lesions are close to endometrium and tend to grow diffusely around to the endometrium, the fibrosis of AM lesions, neighboring EMI and endometrium area accompanied by reduced HIF-1α and PGE2 and possibly signaling, which may result in impaired endometrial repair and subsequent menorrhagia [ 42 ]. In addition, the foci damaged micro-vessels are contiguous with decidualized human endometrial stromal cells at the inner myometrium. Larger uterine volume, diffuse lesions, and a higher rate of comorbidity with other endometrial diseases in intrinsic AM can also be the plausible explanation of menorrhagia [ 9 ]. On the other hand, we demonstrated that extrinsic AM is associated with primary infertility, this result was similar to previously published data [ 43 ]. Intrinsic and extrinsic AM have different clinical profiles, collecting demographic characteristic and clinical features of patients may contribute to the accurate diagnosis of intrinsic and extrinsic AM. Chen et al. have explored the relationship between the subtypes of AM and the effects of LNG-IUS, discovered that the 3-year efficacy rate was 88.52% for subtype I, 81.54% for subtype II and 57.69% for subtype IV, but subtype IV had a high incidence of recurrence [ 24 , 44 , 45 ]. Another study has shown that intrinsic AM is a predictor of serious bleeding risk in patients receiving Dienogest (DNG) therapy [ 46 ]. Our study shows that extrinsic AM generally coexists with OMA, DIE, and stage IV endometriosis. As a result, longer operative time and more blood loss can be observed in the extrinsic group during surgery. We recommend that the AM subtype should be assessment adequately before the surgery, and was performed by skilled surgeons to minimize surgical complications, identify and remove lesions of endometriosis effectively in extrinsic AM. We recognize a few limitations in the study: the present study enrolled women underwent hysterectomy for AM, which does not represent the overall AM population, and excluded especially younger women. In addition, the sample size of study is relatively small and it is a single-center study. Future prospective study with larger sample size is needed to screen the general population across its lifespan by TVUS or MRI, and follow up on clinical features of different subtypes of AM. The strong correlation between severe dysmenorrhea and coexisting DIE in extrinsic AM cases [ 47 ] underscores the clinical importance of a thorough preoperative assessment to anticipate a more complex surgery and to plan for adequate postoperative management, which may include hormonal therapies like GnRH-a to address any residual endometriosis and improve long-term patient outcomes [ 48 ].

Adenomyosis (AM) is a disorder of the uterus which has a substantial impact on physical and psychological health of women. AM is characterized histologically by the presence of endometrial glands and stroma within the myometrium, a phenomenon which is accompanied by hypertrophy and hyperplasia of the surrounding myometrial tissues [ 1 ], causing dysmenorrhea (15–30%), menorrhagia (40–60%) [ 2 ], and in some cases even infertility (7.5–24.4%) [ 3 ]. It is estimated over the last 50 years that the prevalence of AM among women who underwent consecutive hysterectomy has ranged from 8.8 to 61.5% [ 4 ]. Although this feature is well recognized, the underlying pathogenesis remains poorly understood. Two predominant theories have been proposed to explain its origin: one suggests that it results from the invagination of the endometrial basalis into the myometrium, while the other posits a de novo development as a consequence of metaplasia of embryonic Müllerian remnants [ 5 ]. With the advancements in transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI), AM can now be diagnosed based on imaging parameters[ 6 ] and demonstrated a high diagnostic accuracy for AM (sensitivity 70–93%, specificity 86–93%) [ 7 – 9 ]. Yet the classification of AM depending on MRI is considered controversial and there is no universal agreement on it [ 10 , 11 ]. Pistofieis et al. have classified AM into diffuse and focal types or an adenomyoma based on the appearance of the myometrium on MRI [ 12 ]. Depending on the location of AM in relation to other structural components of the uterus on MRI, Kishi et al . have proposed classification of AM in four subtypes [ 13 ]. Among these, intrinsic AM (subtype I: lesions occur in the inner myometrium) and extrinsic AM (subtype II: lesions occur in the outer myometrium) are the most common ones and account respectively for 31.5 and 43.9% of the case [ 6 ]. Meanwhile, subtype III AM is characterized by diffuse infiltration throughout the myometrium, while subtype IV involves a combination of internal and external lesions with extensive, transmurally distributed involvement. Previous studies proposed the following hypothesis: Intrinsic AM is consistent with the “inside-out” theory, suggesting it originates from the direct invagination of the endometrium, while extrinsic AM aligns with the “outside-in” theory [ 14 ], proposing it is caused by the invasion of pelvic endometriosis through the uterine serosa [ 13 , 15 ]. This distinction in pathogenesis provides a theoretical basis for the different clinical associations we investigate in this study. The frequent coexistence of extrinsic AM with endometriosis presents substantial diagnostic and therapeutic challenges. Studies have reported co-occurrence rates as high as 80% [ 16 ], and the overlapping symptomatology such as chronic pelvic pain and dysmenorrhea further complicates clinical management [ 17 , 18 ]. Therefore, a deeper understanding of the clinical characteristics and related factors of different subtypes of AM, especially the potential common epigenetic pathogenesis between extrinsic AM and pelvic endometriosis, is crucial for improving diagnosis and formulating personalized treatment strategies. AM is a heterogeneous disease with diverse clinical manifestations, and the relationship between its subtypes and clinical characteristics remains unclear. Our study aims to compare demographic traits, clinical features, and perioperative and postoperative outcomes in women undergoing hysterectomy for intrinsic versus extrinsic AM, as classified by MRI. A deeper understanding of the clinical profiles associated with different AM subtypes is essential for accurate prevention, diagnosis, and treatment. Such investigations could also provide a clinical foundation for further research into the pathogenesis of AM.