Mechanisms Underlying Adenomyosis-Related Fibrogenesis.

Adenomyosis is a common gynecologic disorder defined by the presence of endometrial glands and stroma within the uterine myometrium. This review focusses on: (1) current understanding of cellular and molecular mechanisms of adenomyosis-related fibrogenesis, (2) transforming growth factor beta (TGF-ß)-dependent or TGF-ß-independent mediators of fibrogenesis, and (3) the origin of fibrogenic myofibroblasts. We collected a literature search from PubMed and EMBASE database up to December 2018. First, causative factors of adenomyosis are classified into exogenous traumatic damage (surgical interventions, including curettage, normal delivery, or cesarean section) and endogenous traumatic damage (mechanical strain or myometrial hyperperistalsis). The mechanical forces and injury (microdehiscences) are fundamental regulators of cell behavior and central to our understanding of disease pathogenesis. Adenomyosis is characterized by abnormal response to injury and activation of myofibroblasts in the myometrium through altered barrier function of the endometrial-myometrial junctional zone (EMJZ). Second, we summarize recent advances on the molecular mechanism of fibrosis. Two distinct populations of myofibroblasts, highly myogenic cells, and nonmyogenic cells arise possibly through the TGF-ß-dependent and TGF-ß-independent processes. TGF-ß-independent mechanisms are still intriguing and far from clear. Third, the importance and implications of resident fibroblasts, bone-marrow stem cells-derived fibrocytes, and epithelial-mesenchymal transition-derived myofibroblasts in fibrosis remain uncertain. Finally, originally adenomyosis was believed to be the single entity, but this disorder is composed of multiple heterogeneous subtypes. Key mediators of fibrogenesis may vary widely and largely depend on adenomyosis subtype. In conclusion, both cyclic mechanical strain and EMJZ weakness (microdehiscences) may be a prerequisite for adenomyosis fibrogenesis through the mechanotransduction process. Since there are significant molecular variations among affected individuals, the approach to identify key mediators of fibrosis remains challenging.

Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification.

OBJECTIVE: The aim of the present study was to differentiate and specify the subtypes of adenomyosis. STUDY DESIGN: Surgically treated adenomyosis (n = 152) was subcategorized retrospectively into 4 subtypes on the basis of magnetic resonance imaging geography. Subtype I (n = 59) consisted of adenomyosis that occurs in the uterine inner layer without affecting the outer structures. Subtype II (n = 51) consisted of adenomyosis that occurs in the uterine outer layer without affecting the inner structures. Subtype III (n = 22) consisted of adenomyosis that occurs solitarily without relationship to structural components. Adenomyosis that did not satisfy these criteria composed subtype IV (n = 20). Stepwise logistic regression analysis was used for specification of the subtypes. RESULTS: Subtypes I-III were suggested as a product of direct endometrial invasion, endometriotic invasion from the outside, and de novo metaplasia, respectively. Subtype IV was a heterogeneous mixture of far advanced disease. CONCLUSION: Adenomyosis appears to consist of 3 distinct subtypes of different causes and an additional subtype of indeterminate cause.

TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma.

Adenomatoid tumors (ATs) are benign mesothelial tumors with a good prognosis and usually occur in female and male genital tracts, including in the uterus. ATs are genetically defined by tumor necrosis factor receptor-associated factor (TRAF) 7 mutations, and a high number of AT cases show immunosuppression. On the other hand, malignant mesotheliomas (MMs) are malignant mesothelial tumors with a very poor prognosis. Genetic alterations in TRAF, methylthioadenosine phosphorylase(MTAP), and BRCA-associated nuclear protein 1 (BAP1) in ATs derived from the uterus and MMs of pleural or peritoneal origin were compared by gene sequence analysis or immunohistochemical approaches. Formalin-fixed paraffin-embedded tissues derived from patients were used for immunohistochemical staining of L1 cell adhesion molecule (L1CAM), BAP1, MTAP, and sialylated protein HEG homolog 1 (HEG1) in 51 uterine AT cases and 34 pleural or peritoneal MM cases and for next-generation sequencing of the TRAF7 gene in 44 AT cases and 21 MM cases. ATs had a significantly higher rate of L1CAM expression than MMs, whereas MMs had a significantly higher rate of loss of MTAP and BAP1 expression than ATs. There was no difference in the rate of HEG1 expression between the tumor types. Most of the ATs (37/44; 84%) had somatic mutations in TRAF7, but none of the MMs had somatic mutations in TRAF7 (0/21; 0%). In addition, a low number of AT cases were associated with a history of immunosuppression (9/51; 17.6%). TRAF7 mutation is one of the major factors distinguishing the development of AT from MM, and immunosuppression might not be associated with most AT cases.

The benefit of adenomyomectomy on fertility outcomes in women with rectovaginal endometriosis with coexisting adenomyosis.

STUDY OBJECTIVE: To evaluate the effect of removal of coexisting adenomyosis on fertility outcomes in women with rectovaginal endometriosis. DESIGN: A retrospective cohort study. SETTING: A general hospital. PATIENTS: A total of 190 women who underwent laparoscopic nodule excision surgery for rectovaginal endometriosis between April 2007 and December 2012. INTERVENTIONS: Surgical excision of the rectovaginal endometriosis and coexisting uterine adenomyosis. Statistical analysis for fertility outcomes. MEASUREMENT AND MAIN RESULTS: A total of 119 women desired postoperative pregnancy. Coexisting adenomyosis was found in 21% of the women. The overall clinical pregnancy rate was 41.2%. The only determining factor associated with a successful pregnancy was "age at surgery". Clinical pregnancy rates with or without adenomyosis were 36.0% and 42.6%, respectively. We found no significant difference in clinical pregnancy rates between the groups. CONCLUSION: There is a possibility that surgical removal of coexisting adenomyosis positively effects fertility outcomes in women with rectovaginal endometriosis. However, it is also important to note that the age at surgery was a critical factor for successful pregnancy.

Phenotypic characterization of adenomyosis occurring at the inner and outer myometrium.

OBJECTIVE: To estimate the phenotypic characterization of fibrotic process in adenomyosis occurring at the inner or the outer myometrium. METHODS: Eight cases of adenomyosis occurring at the inner myometrium (Subtype I) and 10 cases of adenomyosis occurring at the outer myometrium (Subtype II), and 10 normal counterparts were used in this study. A immunohistochemical study for smooth muscle cells (SMCs) was performed using cytoskeletal proteins, Type I and III collagen, TGF-ß and its signaling molecules. RESULTS: An increased expression of Type I collagen was observed in the extracellular matrix of adenomyotic foci. In normal uteri, immunostaining of SMC differentiation marker proteins (Desmin, Smoothelin, Myosin heavy chain (MHC)) were absent or only found in low numbers at the inner myometrium, while all of these marker proteins were clearly stained at the outer myometrium. In both types of adenomyotic foci, Desmin, Smoothelin, and MHC commonly showed a negative staining at the adjacent area to the glands. A significant staining of Non-muscle myosin IIB, TGF-ß, and phosphorylated TGF-ß type I receptors were found only at the SMCs of Subtype II adenomyosis. The Smad3/2 ratio of Subtype II adenomyosis was significantly higher than that of Subtype I. CONCLUSIONS: The inner myometrium of normal uteri was composed of undifferentiated phenotypes of SMCs, while the outer myometrium was composed of terminally differentiated SMCs. Various fibrotic processes have been suggested in the development of uterine adenomyosis. Distinct expression patterns of fibrosis related proteins have been shown to be implicated with differences in the subtypes of adenomyosis.

Subpopulations of macrophages within eutopic endometrium of endometriosis patients.

PROBLEM: Endometriosis is recognized as a chronic inflammatory disease and is related to immune response. There have been reports that revealed the different distribution of macrophage within the eutopic endometrium of women with endometriosis. Macrophages are functionally polarized into M1 and M2 cell lineages. We studied a difference in the subpopulations of M1 and M2 macrophages within the eutopic endometrium in patients with or without endometriosis to investigate how the eutopic endometrium is stimulated immunologically. METHOD OF STUDY: Thirty-six patients with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group) were analyzed. Paraffin-embedded endometrial specimens were used for the study. Consecutive sections were used for immunostaining of CD68 (pan-macrophage marker) and CD163 (M2 macrophage marker). Cells positive for each marker were quantified, and the ratio of M2 macrophages in pan-macrophages was calculated. RESULT: The endometriosis group had a significantly higher number of pan-macrophages than the control group in all phases (P < 0.05). The ratios of M2 macrophages in pan-macrophages were significantly lower in all phases in the endometriosis group (P < 0.05). CONCLUSION: The macrophage population slants toward M1 in the endometrium of endometriosis patients. The endometrium appeared to be stimulated by some organelles and/or substances that induce M1 in endometriosis patients.

Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility?

OBJECTIVE: To analyze the determinants of successful pregnancy following laparoscopic adenomyomectomy. DESIGN: Retrospective cohort study. SETTING: A general hospital. PATIENT(S): A total of 102 women who had a desire for pregnancy underwent laparoscopic adenomyomectomy from 2007 to 2012. INTERVENTION(S): Surgical excision of the uterine adenomyosis; statistical analysis for fertility outcomes. MAIN OUTCOME MEASURE(S): Pregnancy rates and the results of univariable and multivariable analyses. RESULT(S): When the women were divided into ≤39 years and ≥40 years age groups, clinical pregnancy rates were 41.3% and 3.7%, respectively. Factors associated with clinical pregnancy were: history of IVF treatments, posterior wall involvements, and age, with odds ratios of 6.22, 0.18, and 0.77, respectively. In the younger group, 60.8% of women with history of IVF failure showed successful pregnancy after surgery. We experienced 2 cases of placenta accreta in far advanced cases. CONCLUSION(S): This study demonstrated age as a determinant in fertility outcomes. Surgery could be a beneficial treatment for women who experienced IVF treatment failures, especially at ages of ≤39 years. We could not show a clear benefit of the surgery on fertility outcomes of the group aged ≥40 years. Extremely severe adenomyosis affecting a broad range of the uterine subendomerial myometrium should be treated carefully on a pregnancy course.

Progesterone and synthetic progestin, dienogest, induce apoptosis of human primary cultures of adenomyotic stromal cells.

OBJECTIVES: To investigate the direct effects of progesterone receptor (PR) agonists on proliferation and apoptosis of human adenomyotic cells. STUDY DESIGN: Human primary cultures of adenomyotic stromal cells (ASCs) from 24 patients with adenomyosis were co-treated with estradiol (E2) plus the PR agonists, endogenous progesterone (P) or the synthetic progestin dienogest (DNG), which is used to treat endometriosis. In ASCs, anti-proliferative effects and induction of apoptosis were evaluated in the presence or absence of P (10(-8)-10(-6)M) or DNG (10(-8)-10(-6)M) in culture medium containing E2. Cellular proliferation was analyzed with bromodeoxyuridine incorporation and flow cytometry. Apoptosis was detected with annexin V/7-amino-actinomycin D (7-AAD) staining with flow cytometry and cellular caspase 3/7 activity. RESULTS: P and DNG significantly decreased the proportion of cells in the S phase. In addition, both P and DNG increased apoptosis as measured by annexin V-positive/7-AAD -negative cells and caspase 3/7 activity. CONCLUSIONS: Both endogenous P and synthetic progestin directly inhibited cellular proliferation and induced apoptosis in human ASCs. These pharmacological features of progestational compounds provide insight into the therapeutic strategy for the treatment of adenomyosis.

The association between endometriosis and chronic endometritis.

OBJECTIVE: To evaluate the association between endometriosis and chronic endometritis. METHODS: Endometrial specimens were obtained from 71 patients, 34 with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group), who underwent hysterectomy, and the specimens were immunostained for the plasmacyte marker CD138. The rate of chronic endometritis was compared between the endometriosis group and the non-endometriosis group. Furthermore, the 71 patients were also divided into two groups, 28 with chronic endometritis (chronic endometritis group) and 43 without chronic endometritis (non-chronic endometritis group). Logistic regression analysis was performed with variables including age, body mass index (BMI), gravidity and parity, and diagnoses of leiomyoma, adenomyosis, and endometriosis on pathology to examine the independent effect of each variable on chronic endometritis. Patients suffering from cervical invasive carcinoma, endometrial carcinoma, and endometrial polyps or treated with gonadotropin-releasing hormone agonists, progestins, or oral contraceptives before surgery were excluded. RESULTS: Chronic endometritis was identified in 52.94% of the endometriosis group and 27.02% of the non-endometriosis group (p<0.05). Logistic regression analysis revealed that endometriosis was associated with chronic endometritis. CONCLUSIONS: This result suggests a strong association between endometriosis and chronic endometritis.