Differences clinical characteristics and factors in intrinsic and extrinsic adenomyosis

doi:10.21203/rs.3.rs-2752816/v1

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Differences clinical characteristics and factors in intrinsic and extrinsic adenomyosis

https://doi.org/10.21203/rs.3.rs-2752816/v1

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Adenomyosis (AM) is a common gynecological condition that can be classified into different subtypes. This study aimed to evaluate the clinical characteristics, factors and treatment effect in women who diagnosed with intrinsic or extrinsic AM by MRI and underwent hysterectomies. A total of 181 women were enrolled in the study. Among these, 77 of which were identified to be in the intrinsic AM group (intrinsic group) and 54 in the extrinsic AM group (extrinsic group). Our results show that gravidity (P < 0.0001), parity (P < 0.0001), number of abortion (P < 0.0013) and endometrial curettage (P = 0.0167) were significantly higher in the intrinsic group, while the education level was lower in the intrinsic group (P = 0.0118). Women in the extrinsic group had earlier menarches (P = 0.0257) and were more coexist with ovarian endometrioma (OMA) (P < 0.0001) and deep infiltrating endometriosis (DIE) (P < 0.0001). In terms of clinical features, dysmenorrhea was more serious in the extrinsic group (P = 0.0091), whereas women in the intrinsic group had heavier menstrual volume (P < 0.0001). Surgery duration (P < 0.0001), surgical bleeding (P < 0.0013), hospitalization cost (P < 0.0001), and postoperative medical therapy (P < 0.001) were significantly higher in the extrinsic group than in the intrinsic group. In the multivariate analysis we performed, education level, gravidity and number of endometrial curettage were significantly associated with intrinsic AM. OMA and DIE were closely related to extrinsic AM. These results suggest that intrinsic and extrinsic AM have specific clinic characteristics, are associated with different factors, and may have different pathogenesis.

Intrinsic adenomyosis

extrinsic adenomyosis

clinical characteristics

factors

Adenomyosis (AM) is a disorder of the uterus which has a substantial impact on both the physical and psychological health of women. AM consists in endometrial glands and stroma invading 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 prevalence of AM among performed hysterectomy women has ranged from 8.8–61.5% [4]. The exact pathogenesis and etiology of AM have not yet been fully understood. There are currently two main theories about the origin of AM: an invagination of the endometrial basalis into the myometrium or a de novo consequence of the 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]. MRI has high sensitivity (70%-93%) and specificity (86%-93%) for the diagnosis of AM [7–9]. Yet the classification of AM is diverse [10,11]. Pistofidis et al. [12] have classified AM into diffuse, focal AM, and cystic adenomyoma, based on the different manifestations of the myometrium in MRI. According to assessment of the positional relationship between the AM lesions and other structural components by MRI, Kishi et al. [13] have proposed the most comprehensive and widely accepted classification of AM in four subtypes. Among these, intrinsic AM (subtype I: lesions occur in the inner myometrium) and extrinsic AM (subtype II: lesions occur in the outer myometrium) account respectively for 31.5% and 43.9% of the cases [6].

Previous studies have suggested hypothesis that intrinsic AM may be a product of direct endometrial invasion involving inner-mid myometrium, while extrinsic AM could be caused by pelvic endometriosis invading the uterine serous and the outer myometrium [13,14]. In addition, AM is a highly heterogeneous disease with several possible clinical manifestations, the relationship between AM subtypes and clinical characteristics is still not clear. The aim of our study is to compare baseline characteristics, clinic features, perioperative and postoperative conditions in women diagnosed with intrinsic or extrinsic AM by MRI, and who underwent hysterectomies as treatment. In-depth research on clinical data of women affected by different subtypes of AM is needed to perform prevention, get accurate diagnoses and treatments. Such research would also provide a clinical basis for further studies on the pathogenic mechanisms underlying the disease.

Study design and ethic

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.

Population study and collected data

The inclusion criteria were the following: 1) age > 18 and < 50 years, premenopausal; 2) did not received any hormone treatment for at least six months before the hysterectomy and condition histopathologically proven to be AM; 3) MRI examination on T1 and T2-weighted sequences prior to surgery and condition determined to be intrinsic or extrinsic AM. All MRI images were evaluated by two senior radiologists unaware of the clinical data of the patients. When the diagnosis of the two radiologists were different, a third senior radiologist was invited to give a further diagnosis. Exclusion criteria were the following: 1) previous excision of an AM lesion; 2) cancer or infectious disease; 3) incomplete information available. Women were then classified into two groups: the intrinsic AM group (intrinsic group) and the extrinsic AM group (extrinsic group).

Data on baseline characteristics, clinical features, and perioperative data were obtained from the internal database of the hospital, while the postoperative of information was collected from outpatient interview data.

The baseline characteristics collected included age, body mass index (BMI), education level, age of menarche, duration of menstruations, menstrual cycle, marital status, gravidity, parity, previous deliveries (cesarean or vaginal delivery), infertility, number of abortions, endometrial curettage, endometriosis surgery, drug therapy for AM (gonadotropin-releasing hormone-antagonist (GnRH-a), levonorgestrel intrauterine system (ING-IUS), progesterone, contraception, nonsteroidal anti-inflammatory drug, gestrinone), family history of AM, history of anemia, history of blood transfusion and presence of comorbidities. Clinical features collected were the intensity of dysmenorrhea, menstrual blood volume, presence of ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE), endometrial hyperplasia, leiomyomas, stage of endometriosis, serum levels of carbohydrate antigen (Ca125), and Anti-Mullerian hormone (AMH). We also recorded uterine volume and position, if the lesions were focal or diffuse, and location of focal lesions based on MRI images. Surgery duration, bleeding, complications (intestinal, ureteral, bladder injury, large vessel injury, blood transfusion, conversion to laparotomy), postoperative morbidity, length of hospitalization, hospital cost, and drug therapy after the operation (GnRH-a, progesterone, contraceptives) were noted. The degree of satisfaction of treatment was also recorded. The collected data was independently checked by two researchers to ensure that there were no inconsistencies or errors.

Criteria of evaluation

AM cases were categorized into four subtypes depending on the characteristics of the lesions and on the MRI images based on Kishi’s criterion [13]:

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 satisfy any previously listed criteria.

T2-weighted MRI images of intrinsic and extrinsic AM are shown in Figs. 1 and 2.

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 [14–16].

Dysmenorrhea intensity 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 [17,18]. Menstrual blood volume 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 [19]. 12 months or more of unprotected intercourse not resulting in pregnancy was considered as infertility [20]. The uterine volume was calculated by three-dimensional MRI examination using the following formula:

volume = A × B × C × 0.52

where A, B and C represent respectively the length, width, and depth of the uterus [21]. 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 [22]. 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 surgical bleeding volume was assessed considering the difference in hemoglobin (Hb) between before surgery and the day after surgery. Patients were surveyed 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 [23].

Statistical analysis

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.

We enrolled in the study 181 women who underwent hysterectomy as treatment for AM after undergoing a pre-surgical MRI between June 2019 and August 2022. We excluded from analyses the women: >50 years (n = 5), with a history of AM lesion excision (n = 7), that were affected by subtype IV AM (n = 32), and patients for which incomplete information were recorded (n = 6). 131 women were considered for further analyses, among them 77 were in the intrinsic group and 54 in the extrinsic group (Fig. 3). All surgical procedures were performed by laparoscopy.

The baseline characteristics of women between the two groups are shown in Table 1. There are no differences between the two groups in terms of age, BMI, duration of menstruation and menstrual cycle. The intrinsic group had a lower education level (p = 0.0118), more gravidity (3.06 ± 1.39 vs 1.78 ± 1.19, P < 0.0001), parity (1.22 ± 0.64 vs 0.80 ± 0.45, P < 0.0001), more abortions (P = 0.0013), endometrial curettage (P = 0.0167) and anemia (P = 0.0015) compared to the extrinsic group. Earlier menarches (13.56 ± 1.08 vs 14.06 ± 1.50 years, P = 0.0257) were observed in extrinsic group, as well as higher likelihood of unmarried status (P = 0.0337), infertility (23.1% vs 6.6%, p = 0.0087), especially primary infertility (83.3% vs 60%, P = 0.006), and previous endometriosis surgery (P = 0.0225).

Table 1

Comparison of baseline characteristics of intrinsic and extrinsic group
	Intrinsic group	Extrinsic group	P value
Age (years)	44.73 ± 4.16	43.43 ± 4.21	0.0823
BMI (kg/m²)	23.69 ± 3.05	23.29 ± 3.17	0.4701
Education level			0.0118*
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	0.0257*
Duration of menstruation (days)	6.04 ± 1.28	6.43 ± 1.55	0.1212
Menstrual cycle (days)	29.08 ± 8.71	28.81 ± 6.66	0.5464
Marital status			0.0337*
Married	93.51 (72/77)	81.48 (44/54)
Unmarried	6.49 (5/77)	18.52 (10/54)
Gravidity			< 0.0001*
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			< 0.0001*
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			0.7695
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			0.0024*
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)
Infertility			0.0087*
No	92.20 (71/77)	76.92 (40/52)
Yes	7.79 (6/77)	23.07 (12/52)
Infertility types			0.0063*
Primary	60.0 (3/5)	83.33 (10/12)
Secondary	40.0 (2/5)	16.66 (2/12)
Number of abortion			0.0013*
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			0.0167*
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 endometriosis surgery			0.0225*
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			0.7174
No	97.40 (75/77)	96.29 (52/54)
Yes	2.59 (2/77)	3.70 (2/54)
History of therapy to AM			0.6061
GnRH-a	18.18 (14/77)	27.77 (15/54)
ING-IUS	19.48 (15/77)	20.37 (11/54)
Progesterone	19.48 (15/77)	14.81 (8/54)
Others^†	12.98 (10/77)	7.40 (4/54)
History of anemia			0.0015*
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)	0.3826
Comorbidities^‡			0.1939
No	81.81 (63/77)	72.22 (39/54)
Yes	12.98 (14/77)	27.77 (15/54)
BMI body mass index (calculated as weight in kilograms divided by the square of height in meters), AM adenomyosis, GnRH-a gonadotropin-releasing hormone-antagonist, LNG-IUS levonorgestrel intrauterine system
Others^†: including contraception, nonsteroidal anti-inflammatory drug, gestrinone
Medicinal comorbidities^‡: including hypertension, arrhythmia, diabetes mellitus, chronic nephritis, hyperthyroidism, rheumatoid arthritis
Values are given as mean ± standard deviation or %(n/N)
*Significant

In terms of clinical feature, VAS scores (7.91 ± 1.9 vs 6.00 ± 3.50, P = 0.009), comorbidity with OMA (72.7% vs 3.9%, P = 0.0091), DIE (81.1% vs 1.3%, P < 0.0001) and stage IV endometriosis (64.2% vs 1.3%, P < 0.0001) were significantly higher in the extrinsic group. Conversely, higher MVJ scores (5.57 ± 1.90 vs 4.70 ± 1.30, P < 0.0001) and more endometrial hyperplasias (51.95% vs 27.8%, P = 0.0074) were significantly associated with the intrinsic group. This group also presented larger uterine volumes (348.82 ± 155.49 vs 260.30 ± 113.08 cm³, P = 0.0054). In terms of AM lesions, the intrinsic group had more diffuse lesions (76.6% vs 14.8%) while the extrinsic group had more focal lesions (85.2% vs 23.4%). The presence of focal lesions in the posterior wall was more frequent in the extrinsic group (95.7% vs 55.6%, P = 0.0023). (Table 2).

Table 2

Comparison of clinical features of intrinsic and extrinsic group
	Intrinsic group	Extrinsic group	P value
Dysmenorrhea			0.0354*
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	0.0091*
MVJ	5.57 ± 1.90	4.70 ± 1.30	< 0.0001*
Leiomyoma			0.1823
No	36.36 (28/77)	50.0 (27/54)
Yes	63.63 (49/77)	48.14 (26/54)
Leiomyomas maximum diameter (cm)	19.61 ± 16.37	20.78 ± 14.12	0.5424
OMA			< 0.0001*
No	97.40 (75/77)	27.77 (15/54)
Yes	2.59 (2/77)	72.22 (39/54)
DIE			< 0.0001*
No	98.70 (76/77)	20.37 (11/54)
Yes	1.30 (1/77)	79.62 (43/54)
Stages of endometriosis			0.0015*
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 hyperplasia			0.0074*
No	48.05 (37/77)	72.22 (39/54)
Yes	51.94 (40/77)	27.77 (15/54)
Uterine volume (cm³)	348.82 ± 155.49	260.30 ± 113.08	0.0054*
Uterine position			0.0673
Anterior	79.22 (61/77)	61.11 (33/54)
Median	5.19 (4/77)	12.96 (7/54)
Posterior	15.58 (12/77)	25.92 (14/54)
Lesion type			0.0016*
Focal	23.37 (18/77)	85.18 (46/54)
Diffuse	76.62 (59/77)	14.81 (8/54)
Location of focal lesion			0.0023*
Anterior	33.33 (6/18)	4.34 (2/46)
Posterior	55.55 (10/18)	95.65 (44/46)
Bottom of uterus	11.11 (2/18)	0 (0/46)
Ca125 (U/ml)	133.97 ± 124.38	157.33 ± 128.31	0.3281
AMH (ng/ml)	0.94 ± 1.09	0.79 ± 0.84	0.6171
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
Values are given as mean ± standard deviation or %(n/N)
*Significant

The perioperative and postoperative situation were also studied. Women in the extrinsic group had longer surgery durations (185.69 ± 65.40 vs 100.26 ± 22.27 min, P < 0.0001), presented more surgical bleeding (12.15 ± 8.68 vs 6.81 ± 7.78 g/L, P = 0.0013), a higher proportion of excision of OMA or/and DIE (63.0% vs 2.6%, P < 0.0001), and had a higher hospitalization cost (23246.81 ± 3975.89 vs 19278.01 ± 2241.54 RMB, P < 0.0001) compared to intrinsic group. No surgical complications were observed in the intrinsic group, and only one case of complications occurred in the extrinsic group, which resolved well after intraoperative repair. There were no significant differences in the periods after surgery (intrinsic group: 13.4 months vs extrinsic group: 12.6 months), while the use of drug therapy after surgery was markedly higher in the extrinsic group (35.2% vs 2.6%, P = 0.0014). The degree of satisfaction reported by the patients was similar between the two groups (Table 3).

Table 3

Comparison of perioperative and postoperative situation of intrinsic and extrinsic group
	Intrinsic group	External group	P value
Surgery duration (min)	100.26 ± 22.27	185.69 ± 65.40	< 0.0001*
Hb before operation (g/L)	115.17 ± 15.40	116.67 ± 15.78	0.5881
Surgical bleeding (g/L)	6.81 ± 7.78	12.15 ± 8.68	0.0013*
Excision of OMA or/and DIE			< 0.0001*
No	97.40 (75/77)	37.03 (20/54)
Yes	2.59 (2/77)	62.96 (34/54)
Postoperative morbidity			0.0644
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	0.3963
Hospital cost (RMB)	19278.01 ± 2241.54	23246.81 ± 3975.89	< 0.0001*
Postoperative drug therapy			0.0014*
No	97.40 (75/77)	64.81 (35/54)
Yes	2.59 (2/77)	35.18 (19/54)
Treatment satisfaction			0.9710
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)
RMB RenMinBi, Yuan, Hb hemoglobin, DIE deeply infiltrating endometriosis
Values are given as mean ± standard deviation or %(n/N)
*Significant

In order to screen potential related factors for intrinsic and extrinsic AM, we conducted a univariate analysis. Education level, age of menarche, gravidity, parity and number of endometrial curettage were included in the analysis of the intrinsic group. Number of endometriosis surgery, OMA, DIE, and endometriosis stage were included in the analysis of the extrinsic group. We then performed logistic regression analysis to adjust for confounding variables. We found that education level, gravidity and number of endometrial curettage remained significantly associated with intrinsic AM. OMA and DIE were independently associated with extrinsic AM (Fig. 4A and 4B).

We found that the women affected by intrinsic AM had a higher menstrual volume, easy to cause anemia, and that AM was closely related to the education level of the patients, gravidity and endometrial curettage. Dysmenorrhea was instead more severe in women with extrinsic AM, which was significantly associated with pelvic OMA and DIE. In addition, we observed that the distribution of AM lesions in the two AM subtypes had different characteristics. Surgery duration, bleeding volume, hospital cost, and drug therapy after surgery were all significantly higher in the extrinsic group than in the intrinsic group. Yet the satisfaction levels of patients reported were no different between two subtypes of AM.

A number of epidemiological studies have shown that both a history of uterine surgery and multiple births are risk factors for AM [24–26]. Another study has suggested macrophage infiltration in the endometrium may be significantly higher in intrinsic AM than in extrinsic AM [27]. Our study found that the education level of the patients, gravidity, and number of endometrial curettage are all factors closely related to intrinsic AM. This may be due to the trophoblast invasion of the inner myometrium during pregnancy and mechanical factors during surgeries that can damage the endometrial-myometrial interface (EMI), resulting in inflammation. Inflammation 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 [28]. We also observed a close relationship between OMA, DIE and extrinsic AM. Comorbidities with DIE and OMA in extrinsic AM cases were respectively 81.1% and 72.7%. 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% [29,30] and observed that 50% of AM lesions of the bladder in cases of AM and DIE were in the anterior wall of the uterus [31]. Data from molecular studies has shown distinct expression patterns of fibrosis related proteins between intrinsic and extrinsic of AM [32]. 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 [29]. Liu et al. have found that the use of tamoxifen and DPN both caused AM in newborn ICR mice, and the lesions caused resembled those found in extrinsic AM cases [33]. We therefore suggest that the origin and pathogenesis of intrinsic and extrinsic AM may differ. We also believe extrinsic AM and pelvic endometriosis, such as OMA or DIE, may share a common epigenetic pathogenesis. Whether pelvic endometriotic lesions invading the uterine serous and AM can cause pelvic endometriosis needs to be further investigated. Meanwhile, subtypes of AM could be possible to prevent by intervening on different factors, for instance, improving the level of education and contraceptive awareness, reducing abortions and curettage may decrease the incidence of intrinsic AM.

Dysmenorrhea and menorrhagia are considered classic symptoms of AM [34]. Dysmenorrhea is associated with increased levels of oxytocin receptor (OTR), higher intensity and frequency of uterine contractions, neurological overgrowth within the lesion and the endometrium, and central sensitization [35–37]. Several studies have investigated how intrinsic and extrinsic AM result in pelvic pain and dysmenorrhea and have no difference in intensity [6,18]. Our study reveals that dysmenorrhea is significantly worse in extrinsic AM. Our results also show that the menstrual volume in intrinsic AM cases is significantly higher than in extrinsic AM ones. This is due to the fact that intrinsic AM lesions are close to each other and tend to grow diffusely around to the endometrium, and fibrosis of these lesions is more likely to involve the endometrium, impairing the endometrial repair function [38]. In addition, the foci damaged microvessels 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 hyperplastic diseases in intrinsic AM can also be the plausible explanation of menorrhagia [39]. In addition, this study we demonstrated that extrinsic AM is associated with primary infertility, consistently with the results of Bourdon et al. [40]. Collecting baseline 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-IUD and 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 [30,41]. Another study has shown that intrinsic AM is a predictor of serious bleeding risk in patients receiving dienogest (DNG) therapy [42]. Our study shows that extrinsic AM generally coexists with OMA, DIE, and stage IV endometriosis. As a result, longer operation duration and more bleeding can be observed in the extrinsic group during surgery. We recommend that an adequate preoperative evaluation is carried out, and that the surgery is performed by experienced surgeons in order to effectively identify and remove lesions of endometriosis, especially in extrinsic AM.

We recognize our study has a few limitations: the participant set consisted of women undergoing hysterectomy, 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 research needs to include a larger population-based prospective study to screen the general population across its lifespan by TVUS or MRI, and follow up on clinical features of different subtypes of AM.

In conclusion, intrinsic AM and extrinsic AM have distinctly different clinical characteristics and are associated with different factors. Interestingly, the plasma layer of the uterus is always intact in intrinsic AM cases regardless of the size of the lesions and of the uterine volume, while the plasma layer of the uterus is always invaded in extrinsic AM. The pathogenesis of these two AM subtypes warrants further investigation.

Funding

This work was supported by Shanghai Municipal Commission of Science and Technology Program [grant 22Y11906400].

Ethics Approval The present study was approved by the institutional ethics committee of the International Peace Maternity and Child Health Hospital (approval No. GKLW 2022-16).

Consent for Publication The authors contributed to the study and consented to its submission after the final review.

Competing Interests The authors declare no competing interests.

Author contributions: Conception and design by Yan Liang and Jian Zhang, administrative support by Wei Shi and Feng Sun, provision of study materials or patients by Yan Liang and Yuan Liu, collection and assembly of data by Yuan Liu and Minjiao Zhu, data analysis and interpretation by Yan Liang and Wei Shi; All authors discussed the results, contributed to the manuscript writing, and approved the version for publication.

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Differences clinical characteristics and factors in intrinsic and extrinsic adenomyosis

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