The pathogenesis of endometriosis and adenomyosis: insights from single-cell RNA sequencing†.

Endometriosis and adenomyosis are two similar gynecological diseases that are characterized by ectopic implantation and the growth of the endometrial tissue. Previous studies have reported that they share a common pathophysiology in some respects, such as a similar cellular composition and resistance to the progestogen of lesions, but their underlying mechanisms remain elusive. Emerging single-cell ribonucleic acid sequencing (scRNA-seq) technologies allow for the dissection of single-cell transcriptome mapping to reveal the etiology of diseases at the level of the individual cell. In this review, we summarized the published findings in research on scRNA-seq regarding the cellular components and molecular profiles of diverse lesions. They show that epithelial cell clusters may be the vital progenitors of endometriosis and adenomyosis. Subclusters of stromal cells, such as endometrial mesenchymal stem cells and fibroblasts, are also involved in the occurrence of endometriosis and adenomyosis, respectively. Moreover, CD8+ T cells, natural killer cells, and macrophages exhibit a deficiency in clearing the ectopic endometrial cells in the immune microenvironment of endometriosis. It seems that the immune responses are activated in adenomyosis. Understanding the immune characteristics of adenomyosis still needs further exploration. Finally, we discuss the application of findings from scRNA-seq for clinical diagnosis and treatment. This review provides fresh insights into the pathogenesis of endometriosis and adenomyosis as well as the therapeutic targets at the cellular level.

Risk of Recurrence and Reintervention After Uterine-Sparing Interventions for Symptomatic Adenomyosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the risk of recurrence and reintervention after uterine-sparing treatment options for symptomatic adenomyosis, including adenomyomectomy, uterine artery embolization (UAE), and image-guided thermal ablation. DATA SOURCES: We searched electronic databases such as Web of Science, MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov , and Google Scholar from January 2000 to January 2022. The search was conducted using the following search terms: "adenomyosis," "recurrence," "reintervention," "relapse," and "recur." METHODS OF STUDY SELECTION: All studies that described the risk of recurrence or reintervention after uterine-sparing interventions for symptomatic adenomyosis were reviewed and screened according to the eligibility criteria. Recurrence was defined as the reappearance of symptoms (painful menses or heavy menstrual bleeding) after significant or complete remission, or the reappearance of adenomyotic lesions confirmed by ultrasonography or magnetic resonance imaging. TABULATION, INTEGRATION, AND RESULTS: The outcome measures were presented as the frequency with percentage and pooled with 95% CI. A total of 42 studies (single-arm retrospective and prospective studies) that represented 5,877 patients were included. The recurrence rates after adenomyomectomy, UAE, and image-guided thermal ablation were 12.6% (95% CI 8.9-16.4%), 29.5% (95% CI 17.4-41.5%), and 10.0% (95% CI 5.6-14.4%), respectively. The reintervention rates were 2.6% (95% CI 0.9-4.3%), 12.8% (95% CI 7.2-18.4%), and 8.2% (95% CI 4.6-11.9%) after adenomyomectomy, UAE, and image-guided thermal ablation, respectively. Subgroup analysis and sensitivity analysis were performed, and the heterogeneity was reduced in several analyses. CONCLUSION: Uterine-sparing techniques were successful in treating adenomyosis with low reintervention rates. Uterine artery embolization had higher recurrence and reintervention rates than other techniques; however, patients treated with UAE had larger uteri and larger adenomyosis, indicating that selection bias may influence these results. More randomized controlled trials with a larger population are needed in the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021261289.

Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology.

In brief: Traditionally viewed as enigmatic and elusive, adenomyosis is a fairly common gynecological disease but is under-recognized and under-researched. This review summarizes the latest development on the pathogenesis and pathophysiology of adenomyosis, which have important implications for imaging diagnosis of the disease and for the development of non-hormonal therapeutics. Abstract: Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development in the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress in our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial-myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain are less understood but presumably involve increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, a new imaging technique can be used to diagnose adenomyosis more accurately and informatively and possibly help to choose the best treatment modality.

Investigation of the role of platelets in the aetiopathogenesis of adenomyosis.

RESEARCH QUESTION: Do platelets aggregate in adenomyotic lesions and participate in adenomyosis pathogenesis and related fibrosis? DESIGN: Eutopic and ectopic endometrium from 17 patients with adenomyosis and endometrium from 23 healthy controls were collected. Immunohistochemical analyses of platelet marker CD41, transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF) were performed to investigate aggregation and activation of platelets in the stroma. Picrosirius staining was carried out to evaluate the extent of fibrotic tissue. RESULTS: Stroma in the control group showed higher CD41 staining levels than ectopic stroma from patients with adenomyosis (P < 0.001). In patients with adenomyosis, eutopic stroma expressed more extensive CD41 staining than ectopic stroma (P < 0.0001). Stroma in the control group exhibited higher TGF-ß1 expression than eutopic and ectopic stroma from adenomyosis patients (P = 0.009 and P < 0.0001). Stroma in the control group also expressed higher VEGF levels than ectopic stroma from patients with adenomyosis (P < 0.001). In patients with adenomyosis, eutopic stroma showed higher VEGF expression than ectopic stroma (P = 0.021). Stroma in ectopic endometrium from adenomyosis patients displayed greater Picrosirius staining compared with both eutopic stroma from adenomyosis patients and stroma in the control group (P < 0.0001). CONCLUSION: The results of this study did not detect a primary role for platelet activation or aggregation in the pathophysiological process of adenomyosis. Higher rates of collagen fibres were found in adenomyotic lesions, likely to be related to a TGF-ß1-independent pathway. Collagen fibre deposition was more extensive in adenomyotic lesions, consistent with fibrosis.

Possible involvement of neuropeptide and neurotransmitter receptors in Adenomyosis.

BACKGROUND: Accumulating data indicate that sensory nerve derived neuropeptides such as substance P and calcitonin gene related-protein (CGRP) can accelerate the progression of endometriosis via their respective receptors, so can agonists to their respective receptors receptor 1 (NK1R), receptor activity modifying protein 1 (RAMP-1) and calcitonin receptor-like receptor (CRLR). Adrenergic ß2 receptor (ADRB2) agonists also can facilitate lesional progression. In contrast, women with endometriosis appear to have depressed vagal activity, concordant with reduced expression of α7 nicotinic acetylcholine receptor (α7nAChR). The roles of these receptors in adenomyosis are completely unknown. METHODS: Adenomyotic tissue samples from 30 women with adenomyosis and control endometrial tissue samples from 24 women without adenomyosis were collected and subjected to immunohistochemistry analysis of RAMP1, CRLR, NK1R, ADRB2 and α7nAChR, along with their demographic and clinical information. The extent of tissue fibrosis was evaluated by Masson trichrome staining. RESULTS: We found that the staining levels of NK1R, CRLR, RAMP1 and ADRB2 were all significantly elevated in adenomyotic lesions as compared with control endometrium. In contrast, α7nAChR staining levels were significantly reduced. The severity of dysmenorrhea correlated positively with lesional ADRB2 staining levels. CONCLUSIONS: Our results suggest that SP, CGRP and noradrenaline may promote, while acetylcholine may stall, the progression of adenomyosis through their respective receptors on adenomyotic lesions. Additionally, through the activation of the hypothalamic-pituitary-adrenal (HPA)-sympatho-adrenal-medullary (SAM) axes and the lesional overexpression of ADRB2, adenomyosis-associated dysmenorrhea and adenomyotic lesions may be mutually promotional, forming a viscous feed-forward cycle.

Origin and Pathogenic Mechanisms of Uterine Adenomyosis: What Is Known So Far.

Uterine adenomyosis is a benign disease, commonly encountered in reproductive-age women and responsible for chronic pelvic pain, abnormal uterine bleeding, and infertility. Although the exact origin and pathogenic mechanisms involved in adenomyosis still need to be elucidated, significant progress has been made over recent years. Ever since the theory of endometrium invaginating the myometrium via a traumatized interface was first proposed, numerous molecular mechanisms have been reported to participate in this process. At the same time, an alternative theory has suggested de novo development of adenomyotic lesions from metaplasia of Müllerian remnants or adult stem cells. Hence, our understanding of the pathogenesis of adenomyosis has been greatly enhanced and is anticipated to pave the way for development of an effective and safe treatment. The goal of this review is to analyze current knowledge on the origin and pathogenic mechanisms of adenomyosis, ranging from the most widely accepted theories to newly reported data.

Dysmenorrhea in patients with adenomyosis: A clinical and demographic study.

OBJECTIVE: To identify the risk factors associated with dysmenorrhea in adenomyosis and to discuss the potential hormone-based understanding of pain mechanisms. STUDY DESIGN: Adenomyosis patients with mild or no dysmenorrhea (n = 40, Group 1) and moderate-to-severe dysmenorrhea (n = 80, Group 2) were recruited. Charts of all patients were recorded. An immunohistochemistry (IHC) analysis was performed to detect the cellular levels of estrogen receptor-α (ER-α), estrogen receptor-ß (ER-ß), gonadotropin-releasing hormone receptor (GnRH-R), and neurofilaments (NFs) in 60 cases. RESULTS: A history of cesarean section (CS) was positively related to the degree of dysmenorrhea in adenomyosis (OR (95 % CI): 4.397 (1.371-14.104)). The ER-α levels in the eutopic endometrium (EUE) of Group 2 were higher than those in the ectopic endometrium (ECE) of Group 1. Group 2 had higher NF levels in the ECE than in the EUE. CONCLUSION: A history of CS is a risk factor for adenomyosis with moderate-to-severe dysmenorrhea. For patients with adenomyosis, high ER-α levels in the EUE and high NF levels in the ECE may be related to moderate-to-severe dysmenorrhea. These hormone-based mechanisms may contribute to our understanding of the pathogenesis of dysmenorrhea in adenomyosis.

ß-catenin activates TGF-ß-induced epithelial-mesenchymal transition in adenomyosis.

Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma within the myometrium. Adenomyosis is a common cause of dysmenorrhea, menorrhagia, and chronic pelvic pain but is often underdiagnosed. Despite its prevalence and severity of symptoms, its pathogenesis and etiology are poorly understood. Our previous study showed that aberrant activation of ß-catenin results in adenomyosis through epithelial-mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-ß signaling in the uteri of mutant mice that expressed dominant stabilized ß-catenin in the uterus. There was a strong positive correlation between ß-catenin and TGF-ß2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-ß inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear ß-catenin. Our results suggest that ß-catenin activates TGF-ß-induced epithelial-mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-ß as a potential therapeutic target for adenomyosis.

Differential expression and inhibitory effects of aquaporins on the development of adenomyosis.

Aquaporin 2 (AQP2), AQP5 and AQP8 participate in adenomyosis (AM). Ηowever, the roles of these three molecules in AM have not been fully elucidated. In the present study, Institute of Cancer Research female mice were used to establish a model of AM. Subsequently, the endometrial tissues of the mice were observed by hematoxylin­eosin staining, and AM severity, uterus diameter, uterus index, ovary index and numbers of nodules on the uterine surface were evaluated and counted. In addition, eutopic and ectopic endometrial stromal cells (ESCs) were isolated from eutopic and ectopic endometrial samples derived from patients with AM and were then identified by immunofluorescence. The viability, and migratory and invasive ability of ESCs transfected with small interfering RNA targeting AQP5 (siAQP5) were determined by Cell Counting Κit­8, scratch wound­healing and Transwell assays, respectively. Reverse transcription­quantitative polymerase chain reaction was performed to determine the mRNA expression levels of AQP5, epithelial­mesenchymal transition (EMT)­related genes (E­and N­cadherin), matrix metalloproteinase (MMP)­2 and ­9. Protein expression levels of AQP2, AQP5, AQP8, E­, N­cadherin, MMP­2 and ­9 were detected by western blotting. AM severity and uterus index were higher, and there were a greater number of nodules on the uterine surface in the AM group compared with the sham group. AQP2, AQP5 and AQP8 proteins were highly expressed in eutopic and ectopic endometrium of the AM group, and AQP5 was more highly expressed than AQP2 or AQP8. In addition, the data showed that Vimentin was positively expressed in ESCs, and that siAQP5 suppressed the mRNA expression levels of AQP5, cell viability, migration, invasion, EMT and MMP­2 and ­9 expression in ESCs. In conclusion, AQP2, AQP5 and AQP8 were highly expressed in eutopic and ectopic endometrium. Notably, AQP5 silencing may suppress AM by inhibiting viability, migration, invasion, EMT, and MMP­2 and ­9 expression in ESCs.

Birth weight, childhood body mass index and height and risks of endometriosis and adenomyosis.

Background: Body size in adult life is likely associated with risks of endometriosis and adenomyosis, yet little is known about associations with body size earlier in life.Aim: To examine whether birth weight, childhood body mass index (BMI) and height are associated with risks of endometriosis and adenomyosis.Subjects and methods: From the Copenhagen School Health Records Register, 171,447 girls born 1930-1996, with measured weights and heights at ages 7-13 were included. Outcomes were obtained from health registers. Cox regressions were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI).Results: During follow-up, 2149 endometriosis cases and 1410 adenomyosis cases were diagnosed. Childhood BMI was inversely associated with endometriosis (HR = 0.92 [95% CI: 0.88-0.96] per z-score at age 7). In contrast, childhood height was positively associated with endometriosis (HR = 1.09 [95% CI: 1.05-1.14] per z-score at age 7). Associations with childhood body size did not differ by endometriosis location. Childhood BMI and height had limited associations with adenomyosis. Birth weight was not associated with endometriosis or adenomyosis.Conclusion: Lean and tall girls are more often diagnosed with endometriosis, but not adenomyosis. These findings suggest that indicators of endometriosis risk are already apparent at early ages.

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.

Uterine Artery Embolization for Leiomyomas and Adenomyosis: A Pictorial Essay Based on Our Experience from 1300 Cases.

Since its introduction in 1995, uterine artery embolization (UAE) has become an established option for the treatment of leiomyomas. Identification of a leiomyoma using arteriography improves the ability to perform effective UAE. UAE is not contraindicated in a pedunculated subserosal leiomyoma. UAE in a cervical leiomyoma remains a challenging procedure. A leiomyoma with high signal intensity on T2-weighted imaging responds well to UAE, but a malignancy with similar radiological features should not be misdiagnosed as a leiomyoma. Administration of gonadotropin-releasing hormone agonists before UAE is useful in selected patients and is not a contraindication for the procedure. The risk of subsequent re-intervention 5 years after UAE is approximately 10%, which represents an acceptable profile. UAE for adenomyosis is challenging; initial embolization using small particles can achieve better success than that by using larger particles. An intravenous injection of dexamethasone prior to UAE, followed by a patient-controlled analgesia pump and intra-arterial administration of lidocaine after the procedure, are useful techniques to control pain. Dexmedetomidine is an excellent supplemental sedative, showing a fentanyl-sparing effect without causing respiratory depression. UAE for symptomatic leiomyoma is safe and can be an alternative to surgery in most patients with a low risk of re-intervention.

Current facts constituting an understanding of the nature of adenomyosis.

Adenomyosis seems to be the most widespread coexistent pathology included under the umbrella of common benign disorders of the human uterus. The incidence of adenomyosis is under discussion since different imaging criteria are used. In the majority of cases, prevalence is determined among women with uterine fibroids and endometriosis or severe gynecological symptoms. This common benign pathology is asymptomatic in 1/3 of cases. Up to 50% of women with infertility are affected by adenomyosis. It seems to be an important risk factor for spontaneous pre-term delivery and pre-term premature rupture of the membranes. Nowadays, the etiology of adenomyosis is still unclear and requires deeper investigation. This review summarizes the aspects of prevalence, co-existence, risk factors, classification, mechanisms of pathogenesis, genes and immunological features, main histological features, animal models, and clinical manifestation of adenomyosis. It might facilitate understanding of the independent nature of such a dual enigma as adenomyosis.

FAK regulates epithelial­mesenchymal transition in adenomyosis.

Epithelial­mesenchymal transition (EMT) has been associated with the pathogenesis of adenomyosis; focal adhesion kinase (FAK) serves an important role in the EMT process. The aim of the present study was to determine whether FAK regulates EMT in adenomyosis and to investigate the potential pathway in this process. The expression of FAK and EMT­associated molecules in adenomyosis and control cells were determined by immunohistochemical staining and immunofluorescence at the protein level, and at the mRNA level by reverse transcription­quantitative polymerase chain reaction (RT­qPCR). Small interfering RNAs were designed to knock down FAK expression. Subsequently, molecular expression was detected by immunofluorescence, RT­qPCR and western blotting; cell migration was investigated via Transwell assays. In addition, the expression levels of members of the phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT) signaling pathway was also analyzed by RT­qPCR and western blotting to determine the association between these members and EMT in adenomyosis. The results of the present study revealed that FAK was upregulated and the expression levels of EMT­associated molecules were altered in adenomyosis. Silencing FAK expression inhibited adenomyosis cell migration in vitro and the expression of EMT­promoting molecules, suggesting that the FAK/PI3K/AKT signaling pathway may participate in the EMT of endometrial cells in adenomyosis. In conclusion, FAK may regulate EMT in adenomyosis, and this process may be associated with the PI3K/AKT signaling pathway.

Adenomyosis: A Sonographic Diagnosis.

Adenomyosis is a common benign uterine condition and a frequent cause of pelvic pain in premenopausal women. Transvaginal US is now considered the primary imaging modality for the diagnosis of adenomyosis, and thus radiologists should be familiar with its sonographic appearance. US findings can be divided into three categories, which parallel the histology of adenomyosis: (a) ectopic endometrial glands and stroma, (b) muscular hyperplasia/hypertrophy, and (c) increased vascularity. Ectopic endometrial glands manifest as echogenic nodules and striations, radiating from the endometrium into the myometrium. When the glands contain fluid, myometrial cysts and fluid-filled striations may be visible at US. Muscular hyperplasia and hypertrophy cause focal or diffuse myometrial thickening and globular uterine enlargement, often with thin "venetian blind" shadows. The combination of these findings results in a heterogeneous myometrium, with blurring of the endometrial border. Adenomyosis increases uterine vascularity, depicted as a pattern of penetrating vessels at color Doppler US. Other US techniques that are helpful in the diagnosis of adenomyosis include obtaining cine clips and coronal reformatted images, both of which can survey the entire endometrial-myometrial border, and performing saline-infusion sonohysterography, during which ectopic glands frequently fill with either air or fluid. While most cases of adenomyosis develop spontaneously, there are specific inciting causes that include tamoxifen use, postendometrial ablation syndrome, and deep-infiltrating endometriosis. Mimics of adenomyosis include leiomyomas, uterine contractions, neoplasms, and vascular malformations. This article reviews the pathophysiology of adenomyosis and correlates it with the US findings, highlights specific causes of adenomyosis, and describes how to distinguish this common diagnosis from a variety of mimics. Online supplemental material is available for this article. ©RSNA, 2018.

ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis.

OBJECTIVE: Adenomyosis is a benign gynecological disease, characterized by the malignant biological behaviors of invasion and metastasis. ILK plays an important role in intercellular adhesion and triggers the process of EMT. In this study, we investigated the role of ILK-induced EMT in the pathogenesis of adenomyosis. METHODS: ILK and EMT markers including E-cadherin, N-cadherin and Vimentin have been detected with Immunohistochemistry(IHC), RT-PCR and Western Blot, in normal endometrium, matched eutopic and ectopic endometrium respectively. Primary endometrial cells were isolated in order to observed the morphology features, as well as the change of invasiveness. RESULTS: Hyper-activation of ILK were detected in the adenomyosis lesions, along with the typical aberrant expression of EMT markers. Furthermore, comparing with ESCs, the EuSCs showed a more invasive and dynamic phenotype. CONCLUSIONS: ILK-induced EMT is a novel mechanism in the pathogenesis of adenomyosis and may be a potential therapeutic agent for adenomyosis.

Sonographic Signs of Adenomyosis Are Prevalent in Women Undergoing Surgery for Endometriosis and May Suggest a Higher Risk of Infertility.

OBJECTIVES: To determine the prevalence of ultrasound features suggestive of adenomyosis in women undergoing surgery for endometriosis compared with a control group of healthy women without endometriosis. METHODS: Retrospective case-control study comparing women with intractable pain or infertility, who underwent transvaginal ultrasound and subsequent laparoscopic surgery, with a control group of healthy women without a previous history of endometriosis. A diagnosis of adenomyosis on TVUS was made based on asymmetrical myometrial thickening, linear striations, myometrial cysts, hyperechoic islands, irregular endometrial-myometrial junction, parallel shadowing, and localized adenomyomas and analyzed for one sign and for three or more signs. RESULTS: The study and control groups included 94 and 60 women, respectively. In the study group, women were younger and had more dysmenorrhea and infertility symptoms. The presence of any sonographic feature of adenomyosis, as well as three or more signs, was found to be more prevalent in the study group, which persisted after controlling for age, for all features but linear striations. Women in the study group who had five or more sonographic features of adenomyosis had more than a threefold risk of suffering from infertility (OR = 3.19, p = 0.015, 95% CI; 1.25-8.17). There was no association with disease severity at surgery. CONCLUSIONS: Sonographic features of adenomyosis are more prevalent in women undergoing surgery for endometriosis compared to healthy controls. Women with more than five features had an increased risk of infertility.

Different macrophages equally induce EMT in endometria of adenomyosis and normal.

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial-mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-ß1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of CD163, IL10 and MMP12 using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

Down-regulation of tumor suppressor PDCD4 expression in endometrium of adenomyosis patients.

OBJECTIVE: Adenomyosis is a common benign gynecological disease which has some malignant behaviors. Programmed cell death 4 (PDCD4) is a newly identified tumor suppressor gene which lowly expresses in various cancers. However, the expression status of PDCD4 in endometrium of adenomyosis patients has not been investigated. The aim of this study is to assess the expression levels of PDCD4 in endometrium of normal controls and adenomyosis patients. METHODS: The expression of PDCD4 in endometrium of normal controls and eutopic or ectopic endometrium of patients with adenomyosis was evaluated with quantitative real-time PCR, western blot and immunohistochemistry. In addition, the levels of serum estradiol and progesterone in normal controls and adenomyosis patients were detected using electrochemiluminescence immunoassay. RESULTS: The results showed that PDCD4 mainly expressed in the cytoplasma of glandular epithelium of control endometrium and varied during the cycle changes of endometrium, which may be regulated by changing concentrations of progesterone in the menstrual cycle. Compared with the proliferative phase of control endometrium, PDCD4 expression was down-regulated in proliferative phase of eutopic endometrium or ectopic endometrium, and there was no cyclic variation of PDCD4 expression in eutopic endometrium of adenomyosis patients due to progesterone resistance. CONCLUSION: These results suggest that PDCD4 may be involved in the pathogenesis of adenomyosis, which will provide a novel strategy for the early diagnosis and new therapeutic target of adenomyosis.

The role of pathologic evaluation of endometrial ablation resections in predicting ablation failure and adenomyosis in hysterectomy.

Endometrial ablation is commonly performed to manage heavy menstrual bleeding. However, failure in symptom control eventually requiring hysterectomy is frequent. Adenomyosis is common in such failure cases. Ablations using a resectoscope will produce an Endo-Myometrial Resection (EMR) specimen. The value of histopathologic examination of EMRs in predicting treatment failure and adenomyosis has not been addressed. We retrieved histologic material from subjects with failed ablation (persistent symptoms requiring hysterectomy) and subjects with ablation followed by clinical improvement and no hysterectomy (control group). Material was evaluated for features of an abnormal endometrial distribution suggestive of adenomyosis: myometrial fragments with endometrium on opposite edges, myometrium with endometrium in ≥3 edges and areas of endometrium completely surrounded by myometrium (endometrial islands). Hysterectomy specimens from the study group were evaluated for the presence of adenomyosis and its distribution (superficial/deep). Both study and control groups consisted of 18 patients each. The number of fragments with endometrium on opposite sides was significantly higher in the study group: 2.11 vs 0.94 in the control group (p=0.005). Conversely, maximum aggregate dimension (2.3cm vs 2.79cm), number of fragments with endometrium on three sides (4.5 vs 2.78) and number of fragments with endometrial islands (4.5 vs 4.11) did not significantly differ between groups. Adenomyosis was seen in 72.2% hysterectomies from the study group; 27.8% involved deep myometrium. None of the EMR features were statistically associated with adenomyosis. Certain endomyometrial distribution patterns in EMR specimens correlate with future ablation failure and need for definitive surgery. This may be explained by residual endometrial tissue not resected due to a markedly irregular endomyometrial interface. Adenomyosis is frequent in cases of ablation failure. However, a significant association between EMR patterns studied and adenomyosis was not observed.