Growth Of Ectopic Endometrial Tissue Research Articles

NOTCH1- and CD117-Positive Stem Cells in Human Endometriosis and Adenomyosis Lesions.

Adenomyosis and endometriosis are distinct gynecological disorders characterized by ectopic growth of endometrial tissue. Their etiology remains unclear, but stem cells have been implicated in both. The aim of this study was to investigate and compare the quantity of NOTCH1+ and CD117+ stem cells in endometriosis and adenomyosis lesions. Immunohistochemical staining of ectopic endometrium biopsies using antibodies against NOTCH1 and CD117 was performed. The quantity and spatial distribution of endometrial stromal cells positive for these markers were determined and compared between endometriosis and adenomyosis lesions. Additionally, their quantities were compared between endometriosis lesion types. Mann-Whitney U test showed that the median percentages of both NOTCH1+ and CD117+ cells in the endometriosis lesions were significantly higher than those in the adenomyosis lesions (2.26% vs. 0.13%, p = 0.002 and 0.44% vs. 0.26%, p = 0.016, respectively). Spearman's test showed a positive correlation between NOTCH1+ and CD117+ cells in endometriosis lesions (R = 0.45, p = 0.027) but no significant correlation in adenomyosis lesions (R = -0.11, p = 0.69). The quantity of both stem cell types was highest in extragenital endometriotic lesions. Unlike adenomyosis, endometriosis lesions are associated with higher quantities of NOTCH1+ and CD117+ stem cells and a coordinated increase in their number. These findings support the distinct origin of the two conditions.

P-291 In women with endometriosis, effective treatment of chronic endometritis with antibiotics lowers serum CA-125 levels

Abstract Study question To evaluate the effect of chronic endometritis treatment on serum CA-125 levels in women with endometriosis. Summary answer Cure of chronic endometritis leads to a reduction in serum Ca-125 levels in women with endometriosis. What is known already Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is hypothesized that the disease exerts direct inflammatory effects on the ovaries, fallopian tubes, and the eutopic endometrium. In endometriosis, CA-125 levels are often elevated. Literature reports a frequent coexistence of endometriosis and chronic endometritis (CE) in women undergoing hysterectomy for benign indications. CE, characterized by macroscopic and histological alterations of the endometrium, was present in 38.5%-42.3% of women with endometriosis, compared to lower prevalence rates in controls infertile patients without endometriosis, supporting a potential etiopathogenic link between endometriosis and CE. Study design, size, duration This retrospective case-control study was conducted at the Department of Obstetrics and Gynecology, University of Bari. The study included 51 patients suffering of both ovarian endometriosis and CE. The primary objective was to investigate whether CE cure modifies serum CA-125 levels among women with ovarian endometriosis. The secondary objective was to assess any modifications in the size of endometriotic cysts following the cure of CE. Recruitment period was from September 2021 to February 2023. Participants/materials, setting, methods All patients received antibiotic therapy (100 mg of doxycycline, twice daily for ten days) and, the following month, hysteroscopy with control biopsy. Of these, 36 women were cured of chronic endometritis (Group A), while 15 women showed persistent disease (Group B). Endometriosis was diagnosed by transvaginal ultrasound and chronic endometritis through hysteroscopy, histology, and immunohistochemistry for CD138. Serum CA-125 levels were measured before antibiotic therapy and approximately 3 months later. Main results and the role of chance The primary outcome was to compare the change in CA-125 values between women cured of chronic endometritis and women with persistent disease. There were no statistically significant differences in baseline characteristics between the groups (p=ns). The majority of patients in both groups had a single ovarian endometrioma and the micropolypoid endometrial appearance was the predominant finding of chronic endometritis observed during hysteroscopy in both Groups. In Group A, the mean CA-125 value significantly decreased after antibiotic therapy from 58.56 U/mL (± 32.45) to 38.25 U/mL (± 17.31) (p < 0.001). No significant changes in CA-125 values were observed in Group B before and after antibiotic therapy (69.70 ± 27.42 versus 67.47 ± 24.52 U/mL, p=ns). The absolute change in CA-125 values was significantly greater in terms of reduction in Group A compared to Group B (-20.31 ± 27.09 versus -2.13 ± 12.51 U/mL; p = 0.02). Adjustment for confounders in a multivariable regression model revealed that the cure of chronic endometritis was independently associated with a significant decrease in absolute serum CA-125 levels (p = 0.006). Cyst size did not significantly change after antibiotic therapy in both groups (p=ns). Limitations, reasons for caution The main weakness of our study is that CA-125 was only measured once before and once after treatment of CE with a course of antibiotics. Moreover, our study does not allow for inferences regarding the impact of the observed reduction in serum CA-125 on the subjective symptoms related to endometriosis. Wider implications of the findings Our study constitutes the first demonstration that effective treatment of CE results in a significant decrease in a non-invasive marker of endometriosis, CA-125 supporting the emerging concept that the endometriosis might have an infectious origin. Trial registration number not applicable

Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance.

Endometriosis is a chronic condition affecting reproductive-aged women, characterized by the growth of ectopic endometrial tissue. Despite being benign, endometriosis is associated with an increased risk of certain cancers, including endometriosis-associated ovarian cancer (EAOC). Ovarian cancer is rare, but more common in women with endometriosis, particularly endometrioid and clear-cell carcinomas. Factors such as hormonal imbalance, reproductive history, environmental exposures, and genetic predisposition contribute to the malignant transformation of endometriosis. Thus, understanding potential risk factors causing malignancy is crucial. Over the past few decades, various genetic mutations, microRNAs, as well as tumor microenvironmental factors have been identified, impacting pathways like PI3K/AKT/mTOR, DNA repair mechanisms, oxidative stress, and inflammation. Thus, this review aims to summarize molecular studies involved in EAOC pathogenesis as potential therapeutic targets. However, further research is needed to better understand the molecular and environmental factors driving EAOC development, to target the susceptibility of endometriotic lesions to malignant progression, and to identify effective therapeutic strategies.

Understanding the Molecular Landscape of Endometriosis: A Bioinformatics Approach to Uncover Signaling Pathways and Hub Genes.

Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial tissue outside the uterus, leading to debilitating pain and infertility in affected women. Despite its prevalence and clinical significance, the molecular mechanisms underlying the progression of endometriosis remain poorly understood. This study employs bioinformatics tools and molecular docking simulations to unravel the intricate genetic and molecular networks associated with endometriosis progression. The primary objectives of this research are to identify differentially expressed genes (DEGs) linked to endometriosis, elucidate associated biological pathways using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), construct a Protein-Protein Interaction (PPI) network to identify hub genes, and perform molecular docking simulations to explore potential ligand-protein interactions associated with endometriosis. Microarray data from Homo sapiens, specifically Accession: GDS3092 Series = GSE5108 (Platform: GPL2895), were retrieved from the NCBI Gene Expression Omnibus (GEO). The data underwent rigorous preprocessing and DEG analysis using NCBI GEO2. Database for Annotation, Visualization, and Integrated Discovery analysis was employed for functional annotation, and a PPI network was constructed using the STITCH database and Cytoscape 3.8.2. Molecular docking simulations against target proteins associated with endometriosis were conducted using MVD 7.0. A total of 1 911 unique elements were identified as DEGs associated with endometriosis from the microarray data. Database for Annotation, Visualization, and Integrated Discovery analysis revealed pathways and biological characteristics positively and negatively correlated with endometriosis. Hub genes, including BCL2, CCNA2, CDK7, EGF, GAS6, MAP3K7, and TAB2, were identified through PPI network analysis. Molecular docking simulations highlighted potential ligands, such as Quercetin-3-o-galactopyranoside and Kushenol E, exhibiting favorable interactions with target proteins associated with endometriosis. This study provides insights into the molecular signatures, pathways, and hub genes associated with endometriosis. Utilizing DAVID in this study clarifies biological pathways associated with endometriosis, revealing insights into intricate genetic networks. Molecular docking simulations identified ligands for further exploration in therapeutic interventions. The consistent efficacy of these ligands across diverse targets suggests broad-spectrum effectiveness, encouraging further exploration for potential therapeutic interventions. The study contributes to a deeper understanding of endometriosis pathogenesis, paving the way for targeted therapies and precision medicine approaches to improve patient outcomes. These findings advance our understanding of the molecular mechanisms in endometriosis (EMS), offering promising avenues for future research and therapeutic development in addressing this complex condition.

The Role of Herbal Medicine as An Alternative Treatment Option for Endometriosis: A Literature Review

Introduction: Endometriosis is a benign gynecological disorder characterized by ectopic growth of endometrial tissue. This condition may deteriorate patient’s quality of life due to pain as its main manifestation and its complications, including impaired fertility and risk of ovarian cancer. Current standard endometriosis treatment still yields numerous side effects and controversy. Thus, herbal medicine is hoped to be the safer alternative treatment with excellent efficacy for endometriosis. Methods: The search of literature published in English or Bahasa Indonesia was performed by incorporating the search queries “endometriosis”, “herbal therapy”, “silymarin”, “curcumin”, “Viburnum opulus”, “Pueraria”, “Allium sativum”, “black garlic”, “naringenin” on databases including PubMed, Cochrane, Springer, Science Direct, Nature, and Google Scholar. The studies included were in vitro studies, in vivo studies, and clinical trials. Results: Various herbal treatments have been widely studied regarding their anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, cardioprotective, antiallergy, and immunomodulatory capacity. A lot of herbal compounds have the potential to suppress and manage endometriosis through various mechanisms, such as inhibiting the migration and adhesion of endometriosis to other tissues, suppressing inflammatory response in endometriosis pathogenesis, generating antioxidant, inhibiting estrogen activity, and inducing apoptosis of endometriosis cell through a number of signaling pathways. Conclusion: Herbal medicine has the potential to manage endometriosis through various mechanisms. Further research is needed regarding the efficacy of herbal therapy in managing endometriosis.

Endometriosis Induces Colonic Inflammation and Reactive Gliosis in an Animal Model

IntroductionEndometriosis is a complex gynecological disorder characterized by the ectopic growth of endometrial tissue. Symptoms of endometriosis are known to impair the quality of life of patients, among these symptoms are dysmenorrhea, chronic pelvic pain, and gastrointestinal (GI) issues. These GI issues are one of the common reasons for misdiagnosis with irritable bowel syndrome (IBS), a pain syndrome characterized by abdominal pain, painful bowel movements, diarrhea, and constipation, all of which are often present in endometriosis and persist even after treatment. Enteric glial cells (EGC) are known to play a role in pain associated with IBS, and reactive gliosis has been reported in patients with IBS, but the role of EGC in endometriosis has yet to be elucidated.HypothesisWe hypothesize that endometriosis will induce reactive gliosis, with increased expression of the glial fibrillary acidic protein (GFAP) and S100B, in the myenteric plexus of colonic sections in an animal model of endometriosis.MethodsWe used 15 female Sprague Dawley rats and divided them into three groups (n=5 per group): Naïve, Sham, and Endo. Endometriosis was induced in the Endo group by suturing 4 pieces of autologous uterine tissue in the intestinal mesentery, while the Sham group received only sutures without tissue. Von Frey and Hot Plate tests were done the day before surgery, two weeks after surgery, and before sacrifice to assess pain behavior. 21 days after surgery, animals were sacrificed, and endometriosis development and colonic macroscopic inflammation were assessed. Colonic tissue was collected to assess GFAP and S100B immunoreactivity, microscopic damage, and mast cell whole‐tissue cell count.ResultsWe found Endo animals showed a decrease in allodynia threshold, but no hyperalgesia. All Endo animals developed endometriosis with an average area per vesicle of 13.89±1.43mm2, and we found Endo animals had a significant increase in the colonic macroscopic score (3.01±0.22;p<0.001) compared to Sham (0.35±0.12) and Naïve (0.47±0.20). Paraffin‐embedded colon sections stained with H&E didn’t show statistical differences in microscopic damage between groups, yet toluidine blue staining for mast cells showed a 36% increase in the mean number of cells in Endo compared to Naïve but didn’t reach statistical difference. GFAP whole‐mount immunostaining showed significantly increased integrated density in Endo (25655.00±2395.00) when compared to Sham (13558.00±719.80;p<0.001) or Naïve (9035.00±1362.00;p<0.001), while no statistical difference was found in S100B integrated density between groups.ConclusionEndometriosis can alter GI homeostasis by inducing macroscopic inflammation, reactive gliosis, and some mast cell infiltration. Taken together these suggest endometriosis can mimic IBS histopathology beyond the symptomatology, reinforcing this disease’s complexity and the need to treat it beyond the gynecological setting.

Role of repressed microRNAs in endometriosis.

Endometriosis is a common, estrogen-dependent benign tumor that affect 3-10% women of reproductive age, and is characterized by the ectopic growth of endometrial tissue, which is found primarily in the rectovaginal septum, ovaries, and pelvic peritoneum. To date, accumulating evidence suggests that various epigenetic aberrations, including the expression of aberrant microRNAs (miRNAs), play definite roles in the pathogenesis of endometriosis. This review summarizes the recent findings on the aberrantly repressed miRNAs, as well as their potential roles regarding the pathogenesis of endometriosis.

Peritoneal Fluid from Patients with Ovarian Endometriosis Displays Immunosuppressive Potential and Stimulates Th2 Response.

Endometriosis is a common gynaecological disorder characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is associated with chronic pelvic inflammation and autoimmune reactivity manifesting by autoantibody production and abrogated cellular immune responses. Endometriotic peritoneal fluid contains various infiltrating leucocyte populations and a bulk of proinflammatory and immunoregulatory cytokines. However, the nature and significance of the peritoneal milieu in women with endometriosis still remains obscure. Therefore, the aim of the present study was to investigate the immunoregulatory activity of the peritoneal fluid (PF) from women with endometriosis. The peritoneal fluid samples were collected during laparoscopic surgery from 30 women with and without endometriosis. Immunoregulatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) and chemokines (CCL2, CCL5, CXCL8 and CXCL9) were evaluated in PF and culture supernatants generated by unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells cultured in the presence of PF. The effect of PF on the generation of Treg and Th17 cells in CD4+ T cell cultures, as well as the natural cytotoxic activity of peripheral blood mononuclear cells, was also investigated. Concentrations of IL-6, IL-10, CCL2, CXCL8 and CXCL9 were significantly upregulated in the PF from women with endometriosis when compared to control women, whereas concentrations of other cytokines and chemokines were unaffected. The culturing of unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells in the presence of endometriotic PF resulted in the downregulation of their IL-2, IFN-γ, IL-17A and TNF production as compared to culture medium alone. On the other side, endometriotic PF significantly stimulated the production of IL-4 and IL-10. Endometriotic PF also stimulated the release of CCL2 and CXCL8, whereas the production of CCL5 and CXCL9 was downregulated. Endometriotic PF stimulated the generation of Treg cells and had an inhibitory effect on the generation of Th17 cells in cultures of CD4+ T cells. It also inhibited the NK cell cytotoxic activity of the peripheral blood lymphocytes. These results strongly imply that the PF from patients with endometriosis has immunoregulatory/immunosuppressive activity and shifts the Th1/Th2 cytokine balance toward the Th2 response, which may account for deviation of local and systemic immune responses. However, a similar trend, albeit not a statistically significant one, was also observed in case of PF from women without endometriosis, thus suggesting that peritoneal milieu may in general display some immunoregulatory/immunosuppressive properties. It should be stressed, however, that our present observations were made on a relatively small number of PF samples and further studies are needed to reveal possible mechanism(s) responsible for this phenomenon.

Renal Endometriosis Mimicking a Malignancy—a Rare Case of Reno-Mullerian Fusion?

Endometriosis is a common gynaecological condition characterised by ectopic endometrial tissue growth beyond the uterine cavity. Urinary tract endometriosis represents only 1.2% of all cases, with renal endometriosis accounting for less than 1% of urinary tract involvement. An asymptomatic, 49-year-old, perimenopausal Irish female was found to have an incidental mass at the upper pole of the right kidney on imaging studies. Histological analysis was recommended to outrule a renal malignancy and an open radical nephrectomy was performed following multidisciplinary input. Histological analysis surprisingly revealed the presence of endometriosis and endosalpingiosis, accompanied by a significant smooth muscle component, which mimicked a renal neoplasm. The aetiology of renal endometriosis remains unclear. However, given the lack of a history of endometriosis and the absence of other foci of disease in this patient, together with the smooth muscle predominant phenotype, this may represent a case of reno-mullerian fusion or endometrial displacement during gestational development.

Luteolin Promotes Apoptosis of Endometriotic Cells and Inhibits the Alternative Activation of Endometriosis-Associated Macrophages.

Luteolin, a flavonoid present in several fruits, vegetables, nuts, and herbs reportedly exhibits anti-cancer and anti-inflammatory properties. However, the effect of luteolin on endometriosis, a painful condition characterized by the ectopic growth of endometrial tissue and pelvic inflammation, remains elusive. Herein, we observed that luteolin inhibited cell growth and induced apoptosis of 12Z human endometriotic cells by activating caspase-3, -8, and -9. Additionally, luteolin significantly inhibited the expression of key chemokines, C-C motif chemokine ligand 2 (CCL2) and CCL5, required for monocyte/macrophage influx at endometriotic sites. In macrophages stimulated by endometriotic cells, luteolin treatment suppressed the intracellular expression of M2 markers and endometriosis-promoting factors. Collectively, our data suggest that luteolin exerts anti-endometriotic effects by stimulating endometriotic cell apoptosis and hindering the alternative activation of macrophages.

Sciatic endometriosis: A narrative review of an unusual neurogynecologic condition

Endometriosis is a condition in which there is an ectopic growth of endometrial tissue. Sciatic endometriosis, otherwise known as catamenial sciatica, is a rare but exceedingly significant presentation of endometriosis. Symptoms include cyclic sciatic pain that peaks during the menstrual period; additionally, paresthesia, paresis, and areflexia may occur with this condition. Sciatic endometriosis can be presumptively diagnosed in response to empiric treatment (e.g. gonadotropin-releasing hormone analogs) or imaging studies, but a definitive diagnosis of sciatic endometriosis may occur from examining tissue obtained during surgery. Surgical removal of endometriosis from the sciatic nerve root can potentially eliminate symptoms while maintaining normal reproductive function, though poses particular surgical risks. Familiarity with this rare condition is paramount to making this diagnosis and the initiation of earlier treatment.

Anti-nociceptive and anti-inflammatory effects of sulforaphane on sciatic endometriosis in a rat model

Endometriosis of sciatic nerve is a common gynecological disease. Here we aimed to study the anti-inflammatory and anti-nociceptive role of sulforaphane on sciatic nerve endometriosis. The sciatic nerve endometriosis rat model was constructed by autologous implantation of uterine tissue. Sulforaphane was administered intraperitoneally at the dose of 5, 15, 30 and 60 mg/kg/day for 28 days. Behavioral testing was performed at day 7, 14, 21 and 28. At day 28, rats were sacrificed, followed by collecting superficial dorsal horn tissues and lesions. Quantitative real-time PCR and Western blot were performed to assess COX2, Keap1, Nrf2 expression in collected tissues. Enzyme-linked immunosorbent assay was conducted to assess the expression of pro-inflammatory cytokines. Sulforaphane alleviated pain of sciatic endometriosis as evidenced by the increase in paw withdrawal threshold and paw withdrawal latency. Sulforaphane also inhibited ectopic endometrial tissue growth in sciatic endometriosis rat, shown as the shrinkage of lesion size and decreased VEGF levels. IL6, IL-1β and TNF-α levels were decreased by sulforaphane. Sulforaphane induced DOX2 and INOS suppression and Keap1 and Nrf2 upregulation. Sulforaphane alleviates pain induced by sciatic endometriosis, which is mediated by inhibiting inflammation.

Endomeriosis of Cesarean Section Why on Leet side?

Background: Endometriosis is defined as the presence or growth of ectopic endometrial tissue outside their usual site ( the uterus). It is a common condition in women. It may occur in the ovaries, fallopian tubes, vagina and rarely, endometriosis may occur in the abdomen and lungs. Endometriosis is common among women of reproductive age. It is either primary or secondary. The triad of diagnosis is a pain with menstruation, cesarean scar and a mass in the scar. Methods: A report a series of 65 patients in the period from 1st Jan 2013 to 31st Dec 2017. The study was performed in Al-Kindi Teaching Hospital and a private hospital. The mean age was 35 years (range 20-45).All patients were treated surgically i.e. excision of the tumor and old surgical scar in the lower abdomen.
 Result: mean age was 35 years (range 20-45). Thirty patients (46.15%) were housewives while 35(53.84%) were officers. The interesting finding is that 52 patients had the mass in the left side, 10 in the middle and only 3 in the right side of the scar respectively.
 Conclusion: Our study demonstrated a lateral asymmetry in the location of scar endometriosis i.e. mostly on the left side. The prevalence on left side of scar can be added to the triad of diagnosis mentioned above I.e. cyclical pain, cesarean scar and mass mostly in left side of the scar.

The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review).

Aberrant regulation of matrix metalloproteinases (MMPs) may be the primary cause of endometrial lesion formation in a group of predisposed women. Prospect for the genuine origin of endometriosis is ongoing, since retrograde menstruation leads to presence of endometrial debris in peritoneal cavity of many women, which do not experience endometriosis. Tissue remodeling is regulated precisely by a balance of MMPs and their inhibitors. Interplay between factors enhancing and suppressing matrix turnover is crucial for cyclic preparation of endometrium for embryo implantation, and endometrial shedding and renewal in physiology of primates. Disorders of the regulation of matrix remodeling leads to augmentation of implantation and invasive growth of ectopic endometrial tissue. Moreover, endometriosis-induced changes in the matrix balance leads to adhesion formation, ovulatory dysfunction and fertility impairment. The review summarizes the current knowledge regarding the regulation of extracellular matrix turnover in the physiology of the endometrial cycle and in the development of endometriosis, as well as the pathophysiology of ovulatory dysfunction in endometriotic women. Therapeutic modalities utilizing modulation of tissue remodeling were discussed.

Hematogenous Dissemination of Mesenchymal Stem Cells from Endometriosis.

Endometriosis is ectopic growth of endometrial tissue traditionally thought to arise through retrograde menstruation. We aimed to determine if cells derived from endometriosis could enter vascular circulation and lead to hematogenous dissemination. Experimental endometriosis was established by transplanting endometrial tissue from DsRed+ mice into the peritoneal cavity of DsRed- mice. Using flow cytometry, we identified DsRed+ cells in blood of animals with endometriosis. The circulating donor cells expressed CXCR4 and mesenchymal stem cell (MSC) biomarkers, but not hematopoietic stem cell markers. Nearly all the circulating endometrial stem cells originated from endometriosis rather than from the uterus. Cells expressing DsRed, CXCR4, and MSCs markers were identified in the peritoneal wall and surrounding vessels of recipient mice, contributing to both endometriosis and angiogenesis. Cells originating in endometriosis lesions migrated and implanted in lung tissue and displayed makers of differentiation, indicating retained multipotency. In vitro these cells demonstrated multipotency and were able to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Endometriosis lesions also expressed high levels of CXCL12, the CXCR4 receptor ligand. Serum CXCL12 levels were greater than in sham control mice. In humans with endometriosis, serum CXCL12 levels were significantly higher than controls, suggesting that the CXCL12/CXCR4 axis is operational in women with spontaneous endometriosis as well. Stem cells, rather than differentiated cells from endometriosis, enter the circulation in response to CXCL12. We identify an endometriosis-derived stem cell population, a potential mechanism of dissemination of this disease and a potential target for treatment of endometriosis. Stem Cells 2018;36:881-890.

Mesenchymal Stromal Cells Support Endometriotic Stromal Cells In Vitro.

Endometriosis is an inflammatory disease marked by ectopic growth of endometrial cells. Mesenchymal stromal cells (MSC) have immunosuppressive properties that have been suggested as a treatment for inflammatory diseases. Therefore, the aim herein was to examine effects of allogeneic MSC on endometriosis-derived cells in vitro as a potential therapy for endometriosis. MSC from allogeneic adipose tissue (Ad-MSC) and stromal cells from endometrium (ESCendo) and endometriotic ovarian cysts (ESCcyst) from women with endometriosis were isolated. The effects of Ad-MSC on ESCendo and ESCcyst were investigated using in vitro proliferation, apoptosis, adhesion, tube formation, migration, and invasion assays. Ad-MSC significantly increased proliferation of ESC compared to untreated controls. Moreover, Ad-MSC significantly decreased apoptosis and increased survival of ESC. Ad-MSC significantly increased adhesion of ESCendo and not ESCcyst on fibronectin. Conditioned medium from cocultures of Ad-MSC and ESC significantly increased tube formation of human umbilical vein endothelial cells on matrigel. Ad-MSC may significantly increase migration of ESCcyst and did not increase invasion of both cell types. The data suggest that allogeneic Ad-MSC should not be considered as a potential therapy for endometriosis, because they may support the pathology by maintaining and increasing growth of ectopic endometrial tissue.

Differentiating mouse embryonic stem cells express markers of human endometrium

BackgroundModeling early endometrial differentiation is a crucial step towards understanding the divergent pathways between normal and ectopic endometrial development as seen in endometriosis.MethodsTo investigate these pathways, mouse embryonic stem cells (mESCs) and embryoid bodies (EBs) were differentiated in standard EB medium (EBM). Immunofluorescence (IF) staining and reverse-transcription polymerase chain reaction (RT-PCR) were used to detect expression of human endometrial cell markers on differentiating cells, which were sorted into distinct populations using fluorescence-activated cell sorting (FACS).ResultsA subpopulation (50%) of early differentiating mESCs expressed both glandular (CD9) and stromal (CD13) markers of human endometrium, suggestive of a novel endometrial precursor cell population. We further isolated a small population of endometrial mesenchymal stem cells, CD45−/CD146+/PDGFR-β+, from differentiating EBs, representing 0.7% of total cells. Finally, quantitative PCR demonstrated significantly amplified expression of transcription factors Hoxa10 and Foxa2 in CD13+ EBs isolated by FACS (p = 0.03).ConclusionsThese findings demonstrate that mESCs have the capacity to express human endometrial cell markers and demonstrate potential differentiation pathways of endometrial precursor and mesenchymal stem cells, providing an in vitro system to model early endometrial tissue development. This model represents a key step in elucidating the mechanisms of ectopic endometrial tissue growth. Such a system could enable the development of strategies to prevent endometriosis and identify approaches for non-invasive monitoring of disease progression.

Endocannabinoids modulate apoptosis in endometriosis and adenomyosis

Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p = 0,001 and p = 0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p = 0,001, p = 0,001, p = 0,001 and p = 0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p = 0,001 and p = 0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis.

Spontaneous Cutaneous Endometriosis of the Umbilicus: A Case Report

Cutaneous endometriosis represents an unusual ectopic growth of endometrial tissue outside the uterine cavity. We present a case of spontaneous (primary) cutaneous endometriosis of the umbilicus with review of the appropriate literature. Our patient is a 30-year-old African American female, with no previous surgical history, who presented to our dermatology clinic with concern regarding nodules in her umbilicus. According to the patient, the nodules were associated with cyclical pain, episodic bleeding and fluctuation in size. Dermatological examination revealed multiple 5-6 mm reddish-blue, dome shaped papules within the umbilicus. Following shave biopsy, histological examination revealed endometrial glands surrounded by fibrotic, mucinous stroma and erythrocyte extravasation with hemosiderin deposition. Also identified, were ductal structures with cilia on the internal lining. The lesions were diagnosed as cutaneous endometriosis with cilia. The patient was referred to plastic surgery for local excision and gynecology for assessment of endometriosis in the pelvic cavity.

Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis.

Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F2α (PGF2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF2α is a potent angiogenic factor in endothelial cells. We sought to determine whether or not the F-prostanoid receptor modulates angiogenesis in ectopic stromal cells. Release of angiogenic factors by ectopic endometrial stromal cell primary cultures stimulated with PGF2αand exposed to agents that target PGF2α signaling was assessed. The study was conducted in an immunology laboratory at the Centre Hospitalier Universitaire (Québec City) medical research center. Women found to have peritoneal endometriosis during laparoscopy were included in this study. Prostaglandin E2, PGF2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression. PGF2α markedly up-regulated prostaglandin E2, CXC chemokine ligand 8 and vascular endothelial cell growth factor secretion in endometriotic cells. This effect was suppressed in the presence of a specific F-prostanoid antagonist (AL8810) and its signaling pathway was dependent on F-prostanoid receptor variant. PGF2α can exert its proliferative and angiogenic activities either directly by stimulating endothelial cell proliferation, migration and angiogenesis through F-prostanoid receptor, or indirectly, by stimulating endometriotic stromal cells to produce potent angiogenic factors through either receptor variant. These results show for the first time that PGF2α exerts an angiogenic effect on ectopic stromal cells, inducing the secretion of major angiogenic factors via different F-prostanoid signaling pathways. This study suggests a new interpretation of the mechanism underlying endometriosis development involving PGF2α in endometriosis-associated angio-inflammatory changes.