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Objectives: To validate probe-based Confocal Laser Endomicroscopy (pCLE) as a method in assessing endometriosis during conventional and robot-assisted laparoscopy., Study Design: Pilot study, including five women in Hospital Moriah, São Paulo, Brazil. During laparoscopic procedures, pCLE was used to assess endometriosis lesions, complemented by subsequent histological evaluations. 214 optical biopsies were performed. These assessments contributed to the development of a comparative atlas, which was used by surgeons to respond to a questionnaire to identify specific cellular structures related to endometriosis in selected confocal images., Results: The patients had an average age of 35, exhibiting predominant symptoms like dysmenorrhea and dyspareunia. Despite varied familiarity with pCLE, surgeons demonstrated positive acceptance of the method, with 63.1% recommending its use for intraoperative diagnosis. The technique was particularly noted for its ability to provide real-time, detailed images aiding the identification of endometriosis and associated structures like adipocytes and vascularization, with average evaluation scores exceeding 8 of 10., Conclusions: This study underscores pCLE's potential as a transformative diagnostic tool in minimally invasive gynecological surgery. It highlights the feasibility and initial acceptance among surgeons, emphasizing the need for further improvements in device durability and cost-effectiveness. pCLE promises significant advancements in the diagnosis and management of endometriosis, suggesting a future direction for clinical applications and technological refinement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32‒18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Objective: To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women., Method: A retrospective cross-sectional study, was conducted in a Tertiary hospital., Patients: Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis., Intervention: The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers., Results: A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location., Conclusion: Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Endometriosis can be classified into three phenotypes: superficial, ovarian, and deep. Deep endometriosis (DE) has been associated with more severe pain symptoms, although no large-scale studies have evaluated the association between pain intensity and infertility and the different compartments of the pelvis affected by superficial and DE. This retrospective study included 1116 women who underwent laparoscopy for endometriosis treatment at two referral centers between 2009 and 2019. For the evaluation of each symptom, patients were divided according to their visual analog scale score (< 7 and ≥ 7) and fertility status. On multiple logistic regression, severe dysmenorrhea and dyschezia were correlated with DE of the posterior compartment alone (odds ratio (OR) = 1.6, confidence interval (CI) 1.09-2.34, and p = 0.02 and OR = 2.09, CI 1.36-3.23, and p < 0.01, respectively) and in combination with other compartments. DE of the posterior and lateral compartments had the most consistent statistical power (OR = 3.55 for dysmenorrhea and OR = 4.4 for dyschezia). Infertility was associated with DE of the posterior compartment alone (OR = 1.6, CI 1.06-2.54, p = 0.04) and in combination with the anterior compartment (OR = 2.62, CI 1.29-5.29, p < 0.01), with the combination of posterior and anterior compartment having the highest OR value. Severe dyschezia and infertility were also correlated with the presence of multiple localizations of DE (p = 0.04 and p < 0.01). This study confirms the association between DE and severe pain symptoms as well as the influence of the number of DE compartments on the severity of symptoms and the chance of infertility., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Deep endometriosis (DE) surgery often requires advanced knowledge in laparoscopic surgery due to the location of affected organs such as the bowel, vagina, rectovaginal space including adjacent nerve structures, ureters and urinary bladder. Patients are at risk of serious complications and sequelae like anastomotic leakage, rectovaginal fistula and voiding dysfunction. Detailed knowledge of disease extent and location by transvaginal sonography (TVS) can aid the clinician to pre-operatively plan complex surgeries and estimate associated risks. Classification systems like #Enzian can be used in combination with TVS to assess surgical risk factors., (Copyright © 2022. Published by Elsevier B.V.)

Competing Interests: None to declare.

Objective: To evaluate the expression of Ezrin and Phosphorylated Ezrin (Phospho-Ezrin) in endometriosis lesions and its relation to the menstrual cycle phase, stage of endometriosis, histological classification, and clinical symptoms., Material and Methods: The authors conducted a retrospective study, with endometriotic lesions collected from women with endometriosis (n = 57) who underwent laparoscopy from 2017 to 2018. The expression of Ezrin and Phosphorylated Ezrin proteins was analyzed by immunohistochemistry., Results: All the endometriotic lesions contained immunostaining for Ezrin in the glands. Phosphorylated Ezrin was expressed in the stroma of all endometriotic lesions. There was no difference in the Ezrin and Phosphorylated Ezrin's expression in the retrocervical, ovarian, superficial, and intestinal lesions in the same patient. Dysmenorrhea, dyspareunia, acyclic pain, infertility, and dysuria were similar in the three groups of Ezrin staining. There was an inversely proportional relationship between severe dyschezia and Ezrin's intensity, being 66.7% of Ezrin 1 (weak intensity), 36.7 Ezrin 2 (moderate intensity), and 10.0% of Ezrin 3 (p = 0.013). Regarding Phospho-Ezrin there wasn't a significant difference between all the analyzed variables. Histological classification and menstrual cycle phase had also no significant difference between Ezrin and Phospho-Ezrin immunostaining., Conclusion: Ezrin protein and Phospho-Ezrin can be considered important markers to elucidate the mechanisms related to migration and attachment of endometriotic lesions. It is still unclear if Ezrin and Phospho-Ezrin are a cause or consequence of endometriosis. Further studies comparing different types of lesions and eutopic endometrium are necessary to elucidate the role of these proteins in the pathogenesis of endometriosis., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Objective: To evaluate the frequencies of iNKT cells and their subsets in patients with deep endometriosis., Methods: A case-control study was conducted between 2013 and 2015, with 73 patients distributed into two groups: 47 women with a histological diagnosis of endometriosis and 26 controls. Peripheral blood, endometriosis lesions, and healthy peritoneal samples were collected on the day of surgery to determine the frequencies of iNKT cells and subtypes via flow cytometry analysis., Results: The authors observed a lower number of iNKT (p = 0.01) and Double-Negative (DN) iNKT cells (p = 0.02) in the blood of patients with endometriosis than in the control group. The number of DN iNKT IL-17 + cells in the secretory phase was lower in the endometriosis group (p = 0.049). There was an increase in the secretion of IL-17 by CD4 + iNKT cells in the blood of patients with endometriosis and severe dysmenorrhea (p = 0.038), and severe acyclic pelvic pain (p = 0.048). Patients with severe dysmenorrhea also had a decreased number of CD4 + CCR7 + cells (p = 0.022)., Conclusion: The decreased number of total iNKT and DN iNKT cells in patients with endometriosis suggests that iNKT cells play a role in the pathogenesis of endometriosis and can be used to develop new diagnostic and therapeutic agents., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Endometriosis (EDT), a common estrogen-dependent inflammatory disorder, is characterized by endometrial-like tissue outside the uterus. While its pathogenesis is poorly understood, it is supposed that the immune system plays a role in its pathophysiology, and increased number of immune cells and changes in both cell-mediated and humoral immunity have been described. Dendritic cells (DCs) are antigen-presenting cells (APC) of the immune system that recognize, capture, and process complex antigens and present them to T cells, conferring them a unique ability as mediators between the innate and adaptive immune systems. This systematic review aims to enlighten possible disturbances (systemically and locally) of DCs in the development and progression of endometriosis. A search using the strategy: ("dendritic cells" AND "immunology" AND "endometriosis") in databases resulted in 490 citations; after applying inclusion and exclusion criteria, a total of 13 studies were assessed. The evaluated studies demonstrated that DCs are susceptible to pro-endometriotic changes which could inhibit immature DCs (imDCs) from their maturation and induce imDCs into a macrophage phenotype. In addition, the growth and vascularization of endometriosis requires the presence of endogenous DC, which infiltrate endometriotic lesions and enhance endothelial cell migration by secreting proangiogenic factors. Whereas DC maturation suppresses this response, imDC actively promote angiogenesis and growth, leading to a switch in their immunologic role from presenting antigens to support angiogenesis and EDT progression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Inhibins and their co-receptor betaglycan are members of the transforming growth factor β superfamily, a group of signaling molecules that control the differentiation of human endometrium in the secretory phase of the menstrual cycle., Objective: Since endometriosis is associated with endometrial dysfunction and infertility, this study aimed at evaluating the expression of α-inhibin and betaglycan mRNA and proteins in endometrial samples of infertile women with and without endometriosis., Design: This was a cross-sectional study. Participants/Materials: Endometrial samples of women with (n = 17) and without (n = 22) endometriosis were subdivided according to the menstrual cycle phase into proliferative and secretory., Setting: University hospital., Methods: We used real-time RT-PCR to quantify mRNA levels and immunohistochemistry to localize the proteins., Results: α-inhibin mRNA levels were significantly increased in the secretory phase (p < 0.01 vs. proliferative phase) only among women with endometriosis. Conversely, betaglycan mRNA levels were downregulated in the secretory endometrium of controls (p < 0.01 vs. proliferative) but failed to change between cycle phases of patients with endometriosis. Both proteins were present in the glandular epithelium and stroma in the endometrium of women with and without endometriosis. Immunostaining analysis showed that while α-inhibin protein expression did not vary significantly, the intensity of betaglycan immunostaining decreased in the secretory phase in the control group (p = 0.038 vs. proliferative phase) but not in the endometriosis group., Limitations: We cannot determine whether endometriosis causes the abnormal expression of α-inhibin and betaglycan in the eutopic endometrium or if this alteration already existed before the establishment of endometriotic lesions., Conclusion: Our findings suggest an abnormally increased expression of α-inhibin mRNA (not protein) and betaglycan (mRNA and protein) in the secretory-phase endometrium of women with endometriosis., (© 2022 S. Karger AG, Basel.)

Introduction: The prevalence of appendiceal endometriosis ranges from 0.4% to 22%. The carcinoid tumor is the most common neoplasm of the appendix, with incidence ranging from 0.3% to 0.9%. Appendix lesions develop in up to 22% of women with deep infiltrative endometriosis. Even though these are most likely endometriosis, carcinoid tumors should always be considered. The aim of this review was to assess the prevalence of appendiceal carcinoid tumors and appendiceal endometriosis in patients undergoing gynecologic surgery, its association with endometriosis, and related symptoms., Evidence Acquisition: We included retrospective and prospective studies that assessed women who underwent appendicectomy in the past 20 years for appendiceal endometriosis and/or appendix carcinoid tumor confirmed by histological analysis. Results were reported as relative and absolute frequencies. Due to the heterogeneity of included studies, a statistical analysis (meta-analysis) was not performed., Evidence Synthesis: The prevalence of appendiceal endometriosis was 15.2% in patients who underwent surgery for pelvic endometriosis and 11.4% in those who underwent benign gynecological surgery. Conversely, carcinoid tumors of the appendix were present in 2.4% of endometriosis patients and 1.3% of other benign gynecological surgeries., Conclusions: The rates of carcinoid tumors in patients with endometriosis are the same as in the general population. Given the risk of a malignant appendiceal tumor, in all gynecological surgeries, especially those for endometriosis, the appendix should be inspected and removed if it has an abnormal appearance.

Background: Human endometrium harbors stem/progenitor cells (SPCs) that may contribute to the establishment of endometriosis when seeded outside the uterus. Oct-4, C-kit and Musashi-1 are some of the many proteins used to characterize SPCs, but their association with endometriosis is uncertain., Objective and Design: In this study, specimens of normal endometrium (n = 12), eutopic endometrium from women with endometriosis (n = 9), superficial peritoneal endometriosis (SUP, n = 12) and deep endometriosis (DE, n = 13) lesions were evaluated for localization and intensity of immunostaining for Oct-4, C-kit and Musashi-1., Results: The three markers were abundantly expressed in normal endometrium, eutopic endometrium from endometriosis patients, SUP and DE specimens. Oct-4 and C-kit expression did not vary across groups as regards intensity or frequency. C-kit staining signal was seldom detected in vascular endothelium of normal or eutopic endometrium from endometriosis patients; however, it was positive in 67% of the SUP lesions and in 25% of the DE lesions (p = 0.042). Musashi-1 was expressed in some endometriotic glands as cell clusters, but its signal was similar between the four types of tissue (p = 0.971) CONCLUSION: The wide distribution of Oct-4, C-kit and Musashi-1 in endometria of patients with and without endometriosis and in SUP and DE endometriotic lesions suggests that these markers are not suitable for the in situ characterization of endometrial SPCs and should not be taken as surrogates for the study of SPCs in the pathogenesis of endometriosis., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Competing Interests: None to declare.

Objective: To evaluate the association of two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound (TVUS) findings with adenomyosis symptoms., Methods: This prospective study conducted between January and December 2018 enrolled 78 women aged 18 to 40 years with abnormal uterine bleeding (AUB), infertility, and/or pelvic pain. All patients underwent 2D and 3D TVUS. Signs of adenomyosis on TVUS were identified according to the consensus of the Morphological Uterus Sonographic Assessment group., Results: The prevalence of adenomyosis on TVUS was 55.12%. Patients with adenomyosis were older (p=0.002) and had more dysmenorrhea, AUB, and endometriosis than those without adenomyosis. When comparing the presence of symptoms with each adenomyosis feature, on 2D TVUS, severe dyspareunia was significantly associated with the presence of a poorly defined junctional zone (JZ) (p=0.023) and on 3D TVUS, patients with AUB had a more irregular (p=0.003), poorly defined (p=0.028), and interrupted JZ (p=0.011). After logistic regression analysis, signs of adenomyosis on TVUS remained significantly associated only with age over 30 years (OR: 1.2; 95% CI: 1.0-1.2) and AUB (OR: 7.65; 95% CI: 2-29). Patients with diffuse adenomyosis were older and presented with more infertility and AUB than patients with focal or no adenomyosis., Conclusion: The findings of adenomyosis by 2D and 3D TVUS showed association with age and AUB. 3D TVUS alterations in the JZ were associated with AUB and dyspareunia. Diffuse adenomyosis was associated with older age, a greater prevalence of infertility, and AUB.

Objective: The aims of this systematic review and meta-analysis were to compare reproductive outcomes in patients who underwent surgery for deep infiltrative endometriosis (DIE) before in vitro fertilization (IVF) with those in patients who underwent IVF without a previous surgery for DIE, to analyze data according to different types of surgery (complete or incomplete) or subgroups of patients (DIE with or without bowel involvement), and to assess surgical and IVF complications and data regarding safety concerns., Data Sources: A systematic literature search from January 1980 to November 2019 with no language restriction was performed in PubMed, MEDLINE, Embase, and Web of Science. The search strategy used the following Medical Subject Headings terms: "in vitro," "fertilization," "IVF," "assisted reproduction," "colorectal," "endometriosis," "deep," "infiltrating," "deep infiltrative endometriosis," "intestinal," "bowel," "rectovaginal," "uterosacral," "vaginal," and "bladder.", Methods of Study Selection: We included studies that compared reproductive outcomes in women with infertility with DIE who received IVF with or without a previous surgery for DIE lesions. Meta-analysis was performed using Review Manager (RevMan v.5.3; Cochrane Training, London, United Kingdom). The risk of bias of the included studies was assessed using the method recommended by Cochrane Collaboration., Tabulation, Integration, and Results: The systematic search retrieved 150 articles; 98 studies were potentially eligible, and their full texts were reviewed. Of these, 12 studies met our inclusion criteria, and 5 presented data suitable for inclusion in a meta-analysis; however, 2 of the studies provided overlapping data, and only the larger study was finally included. No randomized controlled trials (RCTs) were found. The pregnancy rate per patient was 1.84 (95% confidence interval [CI], 1.28-2.64), the pregnancy rate per cycle was 1.84 (95% CI, 1.26-2.70), and the live birth rate per patient was 2.22 (95% CI, 1.42-3.46) times more likely for operated patients than for nonoperated ones. The addition of data from the incomplete surgery groups also showed a higher pregnancy rate per patient for surgery before IVF (odds ratio [OR] 1.63; 95% CI, 1.16-2.28). The results favor previous surgery in DIE with digestive involvement (OR 2.43; 95% CI, 1.13-5.22) and also in DIE without digestive involvement (OR 1.55; 95% CI, 0.61-3.95). A qualitative analysis of the complications of surgery and IVF showed a partial or complete lack of information on these issues as well as high heterogeneity in the reported data. None of these studies is an RCT; therefore, all have a high risk of selection and allocation bias, except for 1 study that statistically controlled the latter risk by using propensity scores. Funnel plots showed no asymmetry., Conclusion: The results were very consistent for all the studied outcomes, showing a statistically significant benefit for surgery before IVF, although they should be confirmed with RCTs. In addition to the reproductive outcomes, safety data should also be reported to obtain a complete assessment of the risks and benefits., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Objective: To compare the sensitivity and specificity of the transvaginal ultrasonography (TVUS) narrative report with those of the structured report for the diagnosis of adenomyosis., Design: Retrospective study., Setting: A tertiary teaching hospital., Patients: One hundred ninety-two patients (45 with adenomyosis and 147 controls) who underwent hysterectomy between 2012 and 2016 and were aged 30 years to 55 years, with available preoperative TVUS images, were included., Interventions: To compare preoperative TVUS with histologic analysis of the uterus after hysterectomy for the diagnostic of adenomyosis., Measurements and Main Results: Data regarding the presence of the ultrasonographic characteristics previously described for the diagnosis of adenomyosis were obtained from the original TVUS report (narrative report) and the structured report from 2 blinded radiologists (R1 and R2). Histologic analysis is defined as the gold standard for the diagnosis of adenomyosis. The mean age (45.4 ± 5.3 years vs 44.9 ± 4.8 years; p = .496) and clinical symptoms were similar between the adenomyosis and control groups, except for dyspareunia, which was more frequently reported in the patients with adenomyosis (25.6% vs 9.4%; p = .006). Most of TVUS characteristics were more frequently observed in the structured reports than in the narrative reports. The structured report presented higher sensitivity (R1: 84.4%, R2: 69.1%; narrative report: 31.1%; p <.05) and lower specificity (R1: 28.0%, R2: 31.2%; narrative report: 90.5%; p <.05) for adenomyosis. The structured report presented higher sensitivity and lower specificity for most of sonographic characteristics evaluated. After logistic regression analysis, no sonographic characteristics presented with statistical significance for the diagnosis of adenomyosis on R1's structured report, while globular uterus (odds ratio [OR] 0.276; p = .006; 95% CI, 0.11-0.697) and poorly defined junctional zone (OR 3.6; p = .007; 95% CI, 1.4-9.2) were significantly associated with adenomyosis. In the narrative report, a myometrial cyst was associated with a higher risk of adenomyosis (odds ratio 9.486, p =.002; CI, 2.359-38.149)., Conclusion: The narrative reports were more specific, whereas the structured reports were more sensitive for the diagnosis of adenomyosis. In addition, the sensitivity of most of sonographic feature of adenomyosis was higher and the specificity was lower in the structured report. Future prospective studies comparing both reports are needed to validate the current findings., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Deep endometriosis (DE) is classically defined as disease that infiltrates structures by more than 5 mm, such as bowel, ureters, bladder and vagina. The two major symptoms related to DE are pain and infertility. A lot of debate goes on upon the best treatment choice for DE. Treatments include medical therapy with oral progestins or combined contraceptives, and surgery for resection of DE nodules. In this review we focus on the best option treatment for the symptomatic patients with DE not seeking conception. We performed a narrative review of literature searching for the latest evidence on efficacy and outcomes of medical and surgical treatment of DE patients. Results showed that 2/3 of patients with DE will be satisfied with hormonal treatment, and surgery will be effective in improving QoL in most patients with DE. Most studies published regarding surgical outcomes involve bowel endometriosis, and their complication rates should not be extrapolated to all DE. DE that does not infiltrate pelvic viscera accounts for most cases of DE. Together with DE affecting the urinary tract, a much lower rate of severe complications is reported when compared to bowel endometriosis. This distinction should influence decision making. Medical treatment should be first option for non-complicated DE patients not seeking conception. Surgery should be indicated for those who do not tolerate nor improve with medical treatment, as well as those cases complicated by visceral impairment.

Endometriosis (EDT) is an inflammatory disease characterized by implantation/growth of endometrial tissue, glands, and/or stroma, outside the uterus. Reduced NK cell cytotoxic activity has been implicated in its pathogenesis, together with other immunologic alterations. We investigated the influence of KIR gene polymorphisms and their HLA ligand combinations in deep endometriosis (DE) susceptibility. One hundred sixty women with a histological diagnosis of DE and 202 control women without the disease, who underwent laparoscopy, were enrolled. The DE group was subdivided into initial (I/II; n = 60) and advanced stages (III/IV, n = 100). KIR and HLA class I gene polymorphisms were typed by PCR-SSP and sequence-based-typing (SBT), respectively. We observed a significant association of KIR2DL2, an inhibitory gene of B haplotype, conferring risk for DE in Euro-descendants. Positive associations of Bx haplotype and centromeric AB segments were also found. However, no association with KIR-HLA ligand combination was observed. Our data suggest KIR2DL2 gene to be a relevant factor favoring NK inhibition in DE in Euro-descendants, contributing to the defective NK cytotoxic activity and impaired clearance of ectopic endometrial cells in the disease.

Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed "trained immunity." Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPS low ) or adoptive transfer of LPS low -tolerized macrophages elicits a suppressor effect. LPS low -tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: To evaluate bowel function (changes in stool caliber, sensation of incomplete evacuation, stooling frequency, and rectal bleeding) and urinary function (dysuria and retention) after segmental resection in patients with bowel endometriosis., Design: Retrospective study., Setting: Tertiary hospital., Patients: A total of 413 (mean age = 33.6 ± 5.1 years) of reproductive aged women, with bowel endometriosis that underwent segmental bowel resection of the rectosigmoid from 2005 to 2018, without history of prior bowel surgery, without existing or history of malignancy., Interventions: Laparoscopic segmental bowel resection performed by the same team and with the same technique., Measurements and Main Results: Data collected from the patients' records included length of resected segment, distance of the lesion from the anal verge, and complications. Information on intestinal and urinary function was obtained from a questionnaire applied before the surgery and at 2, 6, and 12 months after the surgery. There was a significant increase in the incidence of stool thinning and rectal bleeding 2 months after surgical procedure; these symptoms decreased significantly over time. The incidence of urinary symptoms decreased significantly over time after surgery. The length of the bowel segment resected was not associated with the postoperative symptoms, but the rectosigmoid lesion was significantly closer to the anal verge in patients with rectal bleeding and urinary symptoms. There was no association between the length of intestinal segment resected and the frequency of stooling. At 6 months, patients who had a decreased frequency of stooling underwent a resection closer to the anal verge (9.7 cm) in comparison with the ones with unchanged or increase frequency of stooling (10.1 cm and 10.7 cm, respectively; p <.05)., Conclusion: Patient complaints on bowel and urinary alterations after segmental resection were transient with significant improvement over time up to 12 months. Bowel and urinary symptoms were not associated with the size of the bowel segment resected, whereas rectal bleeding at 2 months after surgery was significantly associated with the distance from anal verge. Segmental resection was also associated with a great improvement in constipation at 12 months postoperative., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Objective: To validate the algorithm for selective bowel surgery based on preoperative imaging by comparing the perioperative outcomes of patients who undergo each type of bowel surgery for deep bowel disease, and secondarily to evaluate the incidence, factors, and subsequent outcomes when the actual procedure performed deviated from the preoperative surgical plan., Design: Retrospective study comparing 3 surgical interventions in an intention-to-treat analysis., Setting: Tertiary care hospital., Patients: Women with significant pain (visual analog scale [VAS] >7) who were diagnosed with bowel endometriosis from preoperative imaging and underwent laparoscopic surgery for bowel endometriosis at a large referral center between 2014 and 2017., Intervention: Laparoscopic shaving, disc resection, or full-segment resection and reanastomosis of bowel endometriosis., Measurements and Main Results: A total of 172 patients (mean age, 36.6 ± 5.2 years) underwent bowel surgery for endometriosis (n = 30 shaving, 71 disc, and 71 segmental resection). Total operative time was similar in the 3 group, but the mean length of hospital stay was longer in the segmental group (5.3 ± 1.0 days) compared with the disc group (4.6 ± 0.9 days) and the shaving group (3.8 ± 1.5 days) (p = .001). The surgical procedure was performed as planned according to the clinical algorithm in 86.5% of patients. Adherence to the proposed clinical algorithm resulted in a low incidence of overall complications (8.7% of total complications, 4.6% of minor complications, and 3.5% of major complications). The incidence of minor complications was higher in the segmental group (9.9%) compared with the discoid group (1.4%) and the shaving group (0%) (p = .0236), whereas the incidence of major complications were similar across the 3 groups (3.3%, 2.8%, and 4.2%, respectively; p = .899). There was a significantly higher frequency of pseudomembranous colitis in the segmental resection group (7 patients; 9.9%) compared with the discoid group (n = 1; 1.4%) and shaving group (0%) (p = .04). Owing to discrepancies between preoperative imaging and intraoperative findings after dissection and mobilization, deviation from the planned procedure occurred in a total of 25 of 172 cases (14.5%), with a less extensive procedure actually performed in 21 of 25 (84%) of the deviated cases. One of the 4 cases (25%) that involved a more extensive procedure resulted in a major complication of rectovaginal fistula., Conclusion: Selective bowel resection algorithm provides a systematic approach to the surgical management of patients with bowel endometriosis. Adherence to the surgical plan according to the preoperative imaging and criteria outlined in the algorithm can be accomplished in the majority of patients; however, the surgical team should be aware that upstaging or downstaging may be required, depending on the intraoperative findings. When feasible, the team should opt for a less extensive procedure to avoid complications associated with more radical surgery., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

We are proposing a shift in mindset in the field of endometriosis, whereby care for patients with endometriosis mirrors that of patients with gynaecological cancer. To achieve this, we advocate for the recognition of complex benign gynaecology as a subspecialty. Since the establishment of gynaecological oncology as a subspecialty, outcomes for patients with ovarian cancer have improved, with their care managed by multidisciplinary teams in specialized units. Despite the marked difference in the primary treatment goal between these two conditions, they share common diagnostic and therapeutic challenges. We believe that care management by a multidisciplinary team of dedicated and specialized health care professionals will lead to improved outcomes, including improved quality of life, for people living with endometriosis., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Research Question: What is the association between endometrioma-affected ovaries, their follicular fluid inflammatory microenvironment, and ovary-specific oocyte and embryo yield and quality?, Design: Exposure-matched prospective cohort study conducted at a university-affiliated infertility clinic. Thirty-four women presenting for oocyte retrieval were enrolled between 2012 and 2013: women with unilateral endometrioma and no other observed peritoneal or deep lesions (n = 10) and women with no signs or symptoms of endometriosis (n = 24). Follicular fluid was aspirated at the time of oocyte retrieval. Samples from each ovary were analysed using a 27-plex immunoassay panel. The associations were evaluated by ovary-specific endometrioma exposure status (affected, unaffected, unexposed) with cytokine levels, oocyte yield and embryo quality., Results: Levels of interleukin (IL)-8 and monocyte chemoattractant protein-1 were higher in fluid obtained from endometrioma-affected ovaries compared with the unexposed ovaries from women without endometriosis, with intermediate levels observed in the contralateral unaffected ovaries. More modest differences were observed for IL-1β and IL-6. The affected ovaries of women with endometriosis yielded fewer oocytes (mean ± SD = 4.6 ± 2.3) compared with both the unaffected (6.0 ± 3.8) and unexposed (7.9 ± 5.6) ovaries. After adjusting for potential confounders and variables generated in a cytokine principal components analysis, oocyte yield remained slightly lower for the endometrioma-affected ovaries compared with unexposed ovaries. No informative differences among ovary groups for embryo quality parameters were observed., Conclusions: The results suggest that the inflammatory milieu of ovarian endometriosis is strongly localized and has a more modestly systemic effect. The effect of endometriomas on infertility, however, cannot be entirely explained by increased inflammation., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To conduct a systematic review of the literature on patients with extrapelvic deep endometriosis., Data Sources: A thorough search of the PubMed/Medline, Embase, and Cochrane databases was performed., Methods of Study Selection: Studies in the last 20 years that reported on primary extrapelvic endometriosis were included (PROSPERO registration number CRD42019125370)., Tabulation, Integration, and Results: The initial search identified 5465 articles, and 179 articles, mostly case reports and series, were included. A total of 230 parietal (PE), 43 visceral (VE), 628 thoracic (TE), 6 central nerve system, 12 extrapelvic muscle or nerve, and 1 nasal endometriosis articles were identified. Abdominal endometriosis was divided into PE and VE. PE lesions involved primary lesions of the abdominal wall, groin, and perineum. When present, symptoms included a palpable mass (99%), cyclic pain (71%) and cyclic bleeding (48%). Preoperative clinical suspicion was low, the use of tissue diagnosis was indeterminate (25%), and a few (8%) malignancies were suspected. Surgical treatment for PE included wide local excision (97%), with 5% recurrence and no complications. Patients with VE involving abdominal organs - kidneys, liver, pancreas, and biliary tract - were treated surgically (86%) with both conservative (51%) and radical resection (49%), with 15% recurrence and 2 major complications reported. In patients with TE involving the diaphragm, pleura, and lung, isolated and concomitant lesions occurred and favored the right side (80%). Patients with TE presented with the triad of catamenial pain, pneumothorax, and hemoptysis. Thoracoscopy with resection followed by pleurodesis was the most common procedure performed, with 29% recurrence. Adjuvant medical therapy with gonadotropin-releasing hormone was administered in 15% of cases. Preoperative magnetic resonance imaging was performed in all cases of nonthoracic and nonabdominal endometriosis. Common symptoms were paresthesia and cyclic pain with radiation. Surgical resection was reported in 84%, with improvement of symptoms., Conclusion: Extrapelvic endometriosis, traditionally thought to be rare, has been reported in a considerable number of cases. Heightened awareness and clinical suspicion of the disease and a multidisciplinary approach are recommended to achieve a prompt diagnosis and optimize patient outcomes. Currently, there are no comparative studies to provide recommendations regarding optimal diagnostic methods, treatment options, and outcomes for endometriosis involving extrapelvic sites., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: Colorectal involvement represents 90% of bowel endometriosis. The best surgical approach must consider the patient's clinical symptoms, preoperative imaging, and correlation with surgical findings. For patients with severe pain who either have failed medical treatment or contraindications to hormonal treatment and have a single bowel lesion <3 cm that involves the inner muscularis, disc resection is the preferred approach to treat bowel endometriosis [1,2]. Therefore, here we describe the surgical principles for disc resection for deep bowel endometriosis., Design: Step-by-step video illustration of our surgical technique with clarification of surgical principles., Setting: Tertiary care center., Intervention: A mechanical bowel preparation is given before surgery. A 10-mm port is placed in the umbilicus, and 3 other 5-mm auxiliary ports are placed in the right and left iliac fossa and in the suprapubic region. Dissection starts with development of both medial pararectal spaces. The retrocervical region is approached, and the bowel lesion is isolated. A suture is placed into the endometriosis bowel lesion to facilitate invagination into the stapler. A circular stapler is inserted into the rectum, and the anvil is opened at the level of the endometriosis lesion. Each end of the suture held by 2 graspers are pushed dorsally, whereas the stapling device is gently pushed ventrally, imbricating the delineated area. The stapler is closed, including the endometriosis area. After reassuring that the posterior part of the mesentery is free, the device is fired, excising only the anterior wall of the rectum., Conclusion: Disc resection is the technique of choice to treat a focal bowel endometriosis lesion <3 cm., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

Study Question: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis?, Summary Answer: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect., What Is Known Already: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear., Study Design, Size, Duration: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation., Participants/materials, Setting, Methods: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA., Main Results and the Role of Chance: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice., Large Scale Data: N/A., Limitations, Reasons for Caution: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans., Wider Implications of the Findings: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis., Study Funding/competing Interest(s): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess whether the HLA-G immunomodulatory protein is potentially involved in the pathophysiology of endometriosis or disease progression., Study Design: Cross-sectional observational study of 227 women who underwent laparoscopy, being 146 for endometriosis excision and 81 for elective tubal ligation (control group). Soluble HLA-G (sHLA-G) levels in the serum and peritoneal fluid (PF), as well as the HLA-G protein expression in matched eutopic and ectopic endometrium of women with and without endometriosis were evaluated by ELISA and immunohistochemistry assays, respectively. Women with endometriosis were separated into groups according to the initial (I/II, n = 60) and advanced (III/IV, n = 86) stages of disease. sHLA-G measurement was performed only in women with matched serum and PF samples in both the control (CTRL; n = 77) and endometriosis (EDT; I-II, n = 60; III-IV, n = 83) groups. HLA-G protein expression was evaluated in 26 women with deep endometriosis (I-II, n = 12; III-IV, n = 14) and 22 controls., Results: Higher concentrations of sHLA-G (P = 0.013) in the serum but not in the PF were observed in women with advanced endometriosis compared to the control group. In situ expression of HLA-G protein was also higher in ectopic (P = 0.018) but not in eutopic endometrium of women with advanced endometriosis compared to control group., Conclusion: Our findings suggest that HLA-G upregulation in advanced stages may contribute to the state of immunosuppression in endometriosis as disease progresses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Because surgery for endometriosis can involve severe complications, it is important to determine if the patient's quality of life (QOL) is indeed improved after surgery. A systematic review and meta-analysis, when appropriate, was conducted and included 38 studies that assessed the QOL using validated questionnaires administered before and after surgery. Results were grouped according to the type of endometriosis reported: all types endometriosis, deep infiltrative endometriosis (DIE), and bowel endometriosis. Quantitative analysis was performed on 17 homogeneous studies. Pooled response mean differences between the 36-Item and 12-Item Short Form Survey (SF-36 and SF-12) showed significant improvement in Mental Component Score (MCS) after surgery for all types of endometriosis (.21; 95% confidence interval [CI], .04-.38); significant improvement after surgical treatment for DIE in Vitality (.67; 95% CI, .41-.94), Social Functioning (.59; 95% CI, .18-.99), Role Emotional .49; 95% CI, .02-.97), Mental Health (.39; 95% CI, .03-.74), Physical Functioning (.93; 95% CI, .49-1.38), Bodily Pain (1.23; 95% CI, .47-1.99), General Health (.57; 95% CI, .02-1.12), MCS (.55; 95% CI, .10-1.00), and Physical Component Score (PCS; .73; 95% CI, .27-1.18); and significant improvement after surgery for bowel endometriosis for all 8 domains (Vitality [1.00; 95% CI, .56-1.43], Social Functioning [.97; 95% CI, .57-1.37], Role Emotional [1.17; 95% CI, .7-1.63], Mental Health [.94; 95% CI, .5-1.38], Physical Functioning [.74; 95% CI, .3-1.18], Role Physical [1.25; 95% CI, .75-1.76], Bodily Pain [1.39; 95% CI, .79-1.98], General Health [.84; 95% CI, 1.46-1.22]), MCS (.93; 95% CI, .47-1.40), PCS (.82; 95% CI, .40-1.23), and total score (1.15; 95% CI, .48-1.83). Only 1 study assessed patients with minimal disease and showed significant improvement in PCS (p = .002) and MCS (p <.001). This systematic review reveals that surgery for endometriosis resulted in overall improvement in most health domains of health-related QOL, with the greatest improvement found in the Bodily Pain domain., (Copyright © 2018. Published by Elsevier Inc.)

Objective: The objective of this study was to evaluate cytokines related to natural killer and T-regulatory cells in endometriotic lesions, peritoneal fluid (PF) and the peripheral blood (PB) of patients with deep infiltrative endometriosis., Study Design: A case-control study was conducted in a tertiary referral hospital. Sixty-four consecutive patients after laparoscopy were divided into 2 groups: with endometriosis (Group A - n = 32) and without endometriosis (Group B - n = 32)., Main Outcome Measures: Interleukin (IL)-2, IL-4, IL-7, IL-10, IL-12, IL-15, transforming growth factor β1, and IFNγ concentration was measured using a LuminexTM multiplex suspension bead array. Tissues from endometriotic lesions of patients with endometriosis and from eutopic endometrium were evaluated, as well as PF and PB of all patients., Results: Compared to the other analyzed groups, IL-15 concentration was significantly higher in the ectopic endometrium and IL-7 in the eutopic endometrium of the endometriosis group (p < 0.05). Compared to endometriosis group, IFNγ, IL-7, and IL-15 were observed to be significantly higher in the PF of the control group, and IL-10 was lower in the control group (p < 0.05). In PB, compared to endometriosis group, IL-4, IL-10, IL-12, IL-15, and IFNγ concentrations were significantly higher in the control group (p < 0.05)., Conclusions: Our hypothesis is that deep endometriosis is a disease out of control. This disease's nature is of progression and invasion of adjacent structures, and proof of this disease state is the disorganized secretion of cytokine regulation and inflammation, which seem to be among the factors responsible for the maintenance of the disease., (© 2019 S. Karger AG, Basel.)

Endometriosis is a chronic disease that affects 5-15% of women of the reproductive age. Different classifications systems have been proposed to categorize endometriosis. In 1979, the American Fertility Society proposed a new system for the classification of endometriosis to correlate surgical findings of endometriosis with fertility, and this system was revised in 1996 (rASRM). Despite the fact that the rASRM classification system is widely used and accepted worldwide, it has limitations. The objectives of this study were to critically assess and discuss the current classification of endometriosis according to pain., (Copyright © 2018. Published by Elsevier Ltd.)

Treatment options for patients with different types of endometriosis - superficial, ovarian, or deep - vary depending on the clinical presentation. New findings in the recent years regarding the role of preoperative imaging, efficacy of medical therapy, and effect of surgery on ovarian reserve have changed the way we understand the disease and subsequently the way we treat our patients. Practicing clinicians frequently refer to published recommendations from major societies for treatment guidelines. This paper aims to present and compare the varying major society guidelines on the indications and best surgical treatment approach for the management of the different types of endometriosis. We also present our preferred surgical treatment algorithm given the evidence in the literature and our cumulative 30-year clinical experience in a large tertiary referral center., (Copyright © 2018. Published by Elsevier Ltd.)

The pathophysiology of endometriosis is not completely understood, but an aberrant immune response in the peritoneal environment seems to be crucial for the proliferation of ectopic endometrial cells - as those cells escape apoptosis and peritoneal cavity immunosurveillance. The growth of endometrial implants leads to the recruitment of a large number and diversity of immune cells and intense inflammation with increased pro-inflammatory cytokines, growth factors, and angiogenesis. There is substantial evidence of aberrant function of almost all types of immune cells in women with endometriosis: decreased T cell reactivity and NK cytotoxicity, polyclonal activation of B cells and increased antibody production, increased number and activation of peritoneal macrophages, and changes in inflammatory mediators. New clinical treatments for endometriosis are an urgent need, especially nonhormonal drugs. The study of immunology may clarify its role in the pathogenesis of endometriosis and contribute to the development of new therapeutic strategies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To detect Mollicutes in women with endometriosis and healthy peritoneal tissues and evaluate the participation of these bacteria in the immune response during endometriosis., Design: Cross-sectional study., Setting: University hospitals., Patient (s): Women with endometriosis (n = 73) and without endometriosis (n = 31)., Intervention(s): Endocervical swabs, peritoneal fluid, and biopsied lesions of endometriosis of women with endometriosis (study group) and healthy peritoneal tissues (control group) were collected during surgery. Clinical characteristics were registered before surgery., Main Outcome Measure(s): We determined the infectious agents with the use of quantitative polymerase chain reaction (PCR). The cytokine secretion profile was determined with the use of Luminex. The expression of immune response related genes was determined with the use of a PCR array kit., Result(s): All target microorganisms were detected at least once in the swab samples analyzed. It was possible to observe higher diversity of microorganisms in the samples of swab and peritoneal fluid in the study group compared with the control. Ureaplasma parvum was associated with the severity of the symptom dyspareunia. Mycoplasma genitalium was associated with higher production of interferon-γ and interleukin-1β. Genes of inflammatory response activation and antigen presentation were up-regulated in biopsied tissue of women with endometriosis. In women with endometriosis, peritoneal fluid cells showed a down-regulation of genes associated with the inflammatory response. This down-regulation profile was higher in presence of M. genitalium., Conclusion(s): Mycoplasma genitalium may play a key role in the immune tolerance process and, especially, the aggravation of this profile. More studies are needed to understand this immune tolerance profile of bacterial infections., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the contribution of CYP2C19 polymorphisms and body mass index (BMI) in the development of endometriosis., Study Design: This is a case-control study that includes 356 women (187 cases and 169 controls) recruited from two hospitals in the Brazilian public health system. The genotyping analyses of the CYP2C19*2 and CYP2C19*17 polymorphisms were performed using TaqMan allelic discrimination assays, and the association of the studied polymorphisms with endometriosis was evaluated by multivariate logistic regression. Pearson correlation coefficients were used to investigate the interaction between BMI and CYP2C19 polymorphisms., Results: The variant allele frequencies of CYP2C19*2 were significantly different between cases and controls, and after adjusting for confounding factors, the CYP2C19*2 polymorphism was more frequent in women with endometriosis, considering all cases (CYP2C19*2: OR=1.83; 95% CI=1.17-2.85) and only deeply infiltrating endometriosis (DIE) cases (CYP2C19*2: OR=2.32; 95% CI=1.42-3.77). BMI was significantly lower in endometriosis patients (26.5±4.68) than in controls (27.8±5.65, P<0.02). Among obese women (BMI 30-40), the CYP2C19*2 polymorphism had a greater association with endometriosis (CYP2C19*2: OR=3.27; 95% CI=1.55-6.89). There was a positive correlation between CYP2C19*2 and BMI 30-40 (P=0.004)., Conclusions: The findings of our study suggest that CYP2C19*2 is positively associated with endometriosis and that BMI may have a significant interaction with CYP2C19*2 and the risk of endometriosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Endometriosis is a chronic inflammatory disease that affects young women in reproductive age. It has mainly three different clinical presentations: superficial (peritoneal), ovarian (endometriomas) and deep endometriosis (DE). The last one is the most advanced form of the disease, frequently impairing fertility and harming women's quality of life (QoL)., Evidence Acquisition: We conducted a systematic review on the surgical treatment of DE in the last ten years focusing on its benefits to improve QoL and for pain relief as well as related surgical complications., Evidence Synthesis: Twenty-three studies were included for qualitative analysis. Overall, included studies showed a relevant improvement in QoL as well as in pain scores using specific questionnaires and the ten-point Visual Analogue Scale (VAS) for pain., Conclusions: Until further comparative studies regarding medical versus surgical treatment for DE are concluded, currently, surgery is the best option for patients with DE and severe pain (VAS>7).

The physiopathology of endometriosis is not completely understood and its progression is associated with a local and systemic inflammatory reaction. It is important to clarify the potential role of the immune system to better understand its implication in the pathogenesis of endometriosis, which includes the study of the role of B cells and antibodies. The aim of this study was to review the literature about the role of B lymphocytes in endometriosis. A search for "endometriosis", "B cells" and "B lymphocytes" in databases resulted in 140 citations; after applying inclusion and exclusion criteria, a total of 22 studies were assessed. The analyzed samples in the studies varied and different markers and techniques were used by the authors to evaluate the direct or indirect role of B lymphocytes in endometriosis. Most studies demonstrated increased number and/or activation of B cells while seven studies found no difference and two studies showed decreased number of B cells. Increased B lymphocytes and excessive production of autoantibodies in endometriosis have been described in the literature, but their role in the development of the disease is not well understood. Moreover, the association of these factors with clinical symptoms, location and severity of the disease has not been investigated. Further studies are necessary to clarify the role of B cells in the development of endometriosis and propose new therapeutic strategies such as the use of drugs that target these cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Question: Is mRNA expression of LDL receptors altered in deep bowel endometriotic foci? SUMMARY ANSWER: mRNA expression of LDL receptors is up-regulated in deep bowel endometriotic foci of patients with endometriosis., What Is Known Already: Several studies have demonstrated the overexpression of low-density lipoprotein receptors in various tumour cell lines and endometriosis has similar aspects to cancer, mainly concerning the pathogenesis of both diseases. This is the first study we know of to investigate lipoprotein receptors expression in deep endometriosis with bowel involvement., Study Design, Size, Duration: During 2014-2015, an exploratory case-control study was conducted with 39 patients, including 20 women with a histological diagnosis of deep endometriosis compromising the bowel and 19 women without endometriosis who underwent laparoscopic tubal ligation., Participants/materials, Setting, Methods: Peripheral blood samples were collected on the day of surgery for lipid profile analysis, and samples of endometrial tissue and of bowel endometriotic lesions were also collected. The tissue samples were sent for histopathological analysis and for LDL-R and LRP-1 gene expression screening using quantitative real-time PCR., Main Results and the Role of Chance: Patients with deep endometriosis had lower LDL-cholesterol than patients without the disease (119 ± 23 versus 156 ± 35; P = 0.001). Gene expression analysis of LDL receptors revealed that LDL-R was more highly expressed in endometriotic lesions when compared to the endometrium of the same patient but not more than in the endometrium of women without endometriosis (0.027 ± 0.022 versus 0.012 ± 0.009 versus 0.019 ± 0.01, respectively; P < 0.001). LRP-1 was more highly expressed in endometriotic lesions, both when compared with the endometrium of the same patient and when compared with the endometrium of patients without the disease (0.307 ± 0.207 versus 0.089 ± 0.076 and versus 0.126 ± 0.072, respectively; P < 0.001). The study also showed that LDL-R gene expression in the endometrium of women with endometriosis was higher during the secretory phase of the menstrual cycle (P = 0.001). LRP-1 gene expression was increased during the secretory phase in the endometrium of women without the disease (P = 0.008)., Limitations, Reasons for Caution: In the endometriotic lesions, the presence of fibrosis is substantial, restricting access to the stromal and glandular components of the lesion. Despite that, we found that LDL receptor mRNA was overexpressed. Future studies may perform laser microdissection to isolate the area of interest in the target tissue, excluding fibrosis contamination., Wider Implications of the Findings: This study supports the feasibility of LDL-R targeted therapy in the treatment of deep endometriosis., Study Funding/competing Interests: This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2011/17245-0). The authors have no conflicts of interest to declare., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Endometriosis is a multifactorial gynecological disease, whose pathogenesis is crucially dependent on angiogenesis, which is signaled via vascular endothelial growth factor (VEGF) and its receptor (VEGFR2). We hypothesize that single nucleotide polymorphisms (SNPs) in VEGF and VEGFR2 genes may influence the onset and/or the progression of endometriosis. The main aim of this study was to investigate the contribution of VEGF and VEGFR2 SNPs as risk factors for endometriosis, as well as their association with endometriosis symptoms., Study Design: A case-control study was conducted, involving 293 endometriosis patients and 223 controls, who were submitted to laparoscopic or laparotomy surgery at hospitals from the Brazilian public health system. Genotyping of VEGF (-2578C>A, -460T>C, -1154G>A, +405G>C and +936C>T) and VEGFR2 (-604T>C, 1192C>T) SNPs was performed by TaqMan real-time polymerase chain reaction. The association between SNPs and endometriosis, deep infiltrating endometriosis (DIE) or endometriosis symptoms was estimated by odds ratios (OR) with their 95% confidence intervals (CI), which were calculated using multivariate logistic regression models., Results: VEGF variant alleles -2578A and -1154A were associated with increased endometriosis risk (OR: 1.39, 95% CI: 1.04-1.87 and OR: 1.63, 95% CI: 1.12-2.37, respectively), whereas VEGF 405C and VEGFR2 1192T were associated with lower risk of endometriosis (OR: 0.66, 95% CI: 0.43-1.00 and OR: 0.58, 95% CI: 0.40-0.84, respectively). The combination of wild-type genotypes of both VEGF -2578C>A and -1154G>A with variant genotypes of both VEGF +405G>C and VEGFR2 1192C>T showed the best protective effect against the development of endometriosis, either considering all cases (OR: 0.33, 95% CI: 0.12-0.89) or only DIE (OR: 0.30, 95% CI: 0.10-0.87). The combination of variant genotypes of VEGF -2578C>A, -1154G>A, +405G>C and VEGFR2 1192C>T was also protective against DIE (OR: 0.67, 95% CI: 0.46-0.96). VEGFR2 1192C>T were associated with reduced cyclical urinary complaints (OR: 0.40, 95% CI: 0.18-0.88)., Conclusions: Our results indicate that VEGF SNPs -2578C>A and -1154G>A increase endometriosis risk, whereas VEGF +405G>C and VEGFR2 1192C>T are protective against disease development, with VEGFR2 1192C>T also reducing cyclical urinary symptoms. The combined analysis of VEGF-VEGFR2 genotypes suggests a gene-gene interaction in endometriosis susceptibility., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Endometriosis has clearly three distinct clinical presentations and deep endometriosis, especially compromising the rectosigmoid is probably the most concerning one for both patients and surgeons. Currently, with the available tools, it is mandatory to have a precise diagnostic of this type of disease prior to indication of treatment. Strategies to manage this form of endometriosis will take into account several involved aspects, such as age of the patient, reproductive desire or infertility, clinical symptoms, as well as the extension and localization of the disease. Treatment could vary from more conservative to more radical depending on those aspects. As we pointed out in this article, the key to manage colorectal endometriosis is to start with a good diagnosis. Knowing exactly what is the extension and localization of the disease and knowing the patient's wishes as well as the clinical complaints, surgeons are able to define the best option for each patient. Critical points should always be discussed; for example, patients chosen to have clinical treatment should be aware of important issues regarding the follow-up, while patients undergoing surgery must be advised about all surgical possibilities and related complications., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Study Hypothesis: Loss of protein BAF250a (ARID1A) expression is present in women with rectovaginal deep-infiltrating endometriosis (DIE) and endometriosis affecting the pelvic sentinel lymph nodes (PSLN)., Study Finding: Partial loss of protein BAF250a was found in some of our patient samples, comprising all endometriosis entities, including rectovaginal DIE and endometriosis affecting the PSLN., What Is Known Already: Loss of BAF250a (BRG-associated factor 250a)/ARIDIA (AT-rich interactive domain 1A) protein expression was identified among endometriosis-associated ovarian carcinomas and ovarian endometriosis, and this phenomenon was described as a possible early event in the transformation of endometriosis into cancer. DIE affecting the bowel/rectovaginal site is the most aggressive presentation of endometriosis and its 'risk' of malignant transformation has not been studied so far., Study Design, Samples/materials, Methods: We evaluated the immunohistochemical expression of BAF250a protein in 70 samples from patients enrolled in this study who were surgically treated at a tertiary center, university Hospital. The samples submitted to investigation were from rectovaginal DIE (n= 25/30), endometriosis affecting the PSLN (n= 5/7), ovarian endometriosis (n= 20/20) and endometrium from patients without endometriosis used as controls (n= 20/20)., Main Results and the Role of Chance: Partial loss (i.e. in one tissue section some cells stained positive for BAF250a while other cells, usually an adjacent group, were negative) of BAF250a protein was identified in 36% (9/25) of rectovaginal DIE samples, 40% (2/5) of endometriosis lesions involving the PSLN, 30% (6/20) of endometriomas, and also in 25% (5/20) of endometrium from controls. We found no statistical correlation between occurrence of partial loss of BAF250a protein and the use or not of hormone medications (P = 0.106), cycle phase (P = 0.917) and stage of disease (P = 0.717)., Limitations, Reasons for Caution: We only found partial loss of BAF250a protein expression, and in a small population of women, with relatively high frequency in all benign tissues assessed in the present analysis. Therefore, this finding alone should not be correlated directly with the risk of malignant transformation in these lesions., Wider Implications of the Findings: The occurrence of partial loss of BAF250a protein expression in women with rectovaginal DIE and endometriosis affecting the PSLN is described for the first time. The value of this finding as a predictor of malignant transformation in endometriosis must still be clarified and further studied in association with other molecular events, such as PTEN (phosphatase and tensin homolog) deletion and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. We might then be able to identify in the future which patients with endometriosis are at higher risk of cancer., Study Funding and Competing Interests: This study was supported by an internal Charité grant to the Endometriosis Research Center and the authors declare no conflicts of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated., (© The Author(s) 2015.)

Introduction: Environmental toxicants can act as endocrine disrupters on the female reproductive system. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is resistant to degradation and due to its lipophilic nature, accumulates in the fat tissue and in the food chain. Human and animal exposure to TCDD affects levels of the steroid receptors and steroid-responsive gene expression and has an impact on metabolism and serum transport of steroids. Gene expression is commonly altered in endometriosis and in the eutopic endometrium of women with the disease. Aberrantly expressed genes include those associated with the regulation of transcription, proliferation, sex steroid metabolism, apoptosis, cell cycle, the immune response and cell adhesion., Methods: In this paper, we review the evidence about TCDD's effect on eutopic and ectopic endometrium, in order to unravel the machinery behind the dysregulation of immune and hormonal homeostasis caused by this environmental toxicant., Conclusion: The evidence collected in this review suggests that TCDD could modulate transcription at multiple levels, including the epigenetic level, and via microRNAs, thus disturbing the physiologic processes mediated through the aryl hydrocarbon receptor pathways. Exposure to TCDD also modulates the immune response by influencing the production and action of endometrial cytokines and chemokines, destroying mucosal immunity of the reproductive tract and re-directing the tissue distribution and behavior of leukocytes. Despite this large body of evidence, current human-based epidemiological studies on the association between TCDD and endometriosis remain controversial.

Chemokines have been associated with endometriosis. Our study was aimed at evaluating the levels of six chemokines--CXCL8 (IL-8), CXCL12 (SDF-1), CCL2 (MCP-1), CCL5 (RANTES), CCL19 (MIP-3β), and CCL21 (6-Ckine)--in the peritoneal fluid (PF) of patients with and controls without endometriosis by multiplexed cytokine assay. In this retrospective case-control study conducted at the Charité University Hospital, patients (n = 36) and controls (n = 27) were enrolled. The patients were separated into groups according to stage of the disease: I-II (n = 21), III-IV (n = 1 5), and according to clinical findings: peritoneal endometriosis (PE; n = 7), deep-infiltrating endometriosis (DIE) affecting the retrocervical area (n = 13) or the bowel/rectovaginal site (n = 14). The subjects were also separated according to the cycle phase: follicular (n = 14) or luteal (n = 8) and the previous use (n = 25) or not (n = 38) of hormones. PF was collected from all subjects (n = 63) consecutively during laparoscopy. The concentration of chemokines in the PF was assessed using Luminex(®) x-MAP(®) technology. Sensitivity and specificity were calculated. A model of multiple logistic regressions estimated the odds of endometriosis for each combination of the chemokines detected. We observed significantly higher concentrations of IL-8 (p < 0.001), MCP-1 (p = 0.014), and MIP-3β (p = 0.022) in the PF of women with endometriosis than in the controls. A joint evaluation revealed that elevated levels of the three chemokines had a positive endometriosis prediction value of 89.1%. The combined assessment of MCP-1, MIP-3β, and IL-8 concentration in PF improved the likelihood of identifying patients with endometriosis. Future studies should investigate this panel in peripheral blood samples., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Deep endometriosis invading the bowel constitutes a major challenge for the gynecologist. In addition to the greater impact on pain, the high incidence of surgical morbidity involved with bowel endometriosis poses a therapeutic dilemma for the surgeon. Intestinal involvement by deep endometriotic nodules has been estimated to occur in 8-12% of women with endometriosis. Individual and clinical factors, pre-operative morphologic characteristics from imaging, surgical considerations and impact on quality of life are critical variables that should be considered in determining the best therapeutic strategy for a patient with deep endometriosis involving the sigmoid and/or the rectum. Pre-operative planning is fundamental for defining the optimal therapeutic strategy; patient counseling of treatment options, and when surgery is indicated, involvement of a multidisciplinary surgical team is required., Methods: The PubMed and Cochrane database were searched for all original and review articles published in English, French and Italian, until June 2014. Search terms included 'deep endometriosis', 'surgical and clinical approach', 'bowel disease', 'quality of life', 'management of deep endometriosis'. Special attention was paid to articles comparing features of discoid and segmental resection., Results: The rationale for the best therapeutic options for patients with deep endometriosis has been shown and an evidence-based treatment algorithm for determining when and which surgical intervention may be required is proposed. In deciding the best treatment option for patients with deep endometriosis involving the sigmoid and rectum, it is important to understand how the different clinical factors and pre-operative morphologic imaging affect the algorithm. Surgery is not indicated in all patients with deep endometriosis, but, when surgery is chosen, a complete resection by the most appropriate surgical team is required in order to achieve the best patient outcome., Conclusion: In women with deep endometriosis, surgery is the therapy of choice for symptomatic patients when deep lesions do not improve with a medical treatment., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Objective: To evaluate the external validity of the validated French model of the quality-of-life questionnaire (QOL) SF-36 in predicting improvement after colorectal resection for endometriosis., Design: Italian and Brazilian cohort studies (Canadian Task Force classification II-3)., Setting: Tertiary referral university hospital in Brazil and expert center in endometriosis in Italy., Patients: Patients with colorectal endometriosis from an Italian population (n = 63) and a Brazilian population (n = 151)., Intervention: Laparoscopic colorectal resection for treatment of endometriosis., Measurements and Main Results: Preoperative and postoperative evaluations of the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of the SF-36 were performed. Substantial improvement in PCS and MCS was observed after colorectal resection in both populations. In the Brazilian population, the receiver operating curve (ROC) (area under the curve [AUC]) was 0.83 (95% confidence interval [CI], 0.77-0.89) for MCS and 0.78 (95% CI, 0.71-0.83) for PCS, demonstrating good discrimination performance. The mean difference between the predicted and calibrated probabilities was 19.6% for MCS and 32.8% for PCS. In the Italian population, the ROC curve (AUC) was 0.65 (95% CI, 0.52-0.78) for PCS and 0.67 (95% CI, 0.55-0.78) for MCS. The model demonstrated poor discrimination and calibration performance for PCS (p < .001) and MCS (p = .003). The mean difference between the predicted and calibrated probabilities was 17.5% for MCS and 21.8% for PCS., Conclusion: Despite the use of validated translations of the SF-36, our results underline the limits of this tool in selection of patients for colorectal resection due to underestimation of predicted quality of life, possibly because of variations in epidemiologic characteristics of the populations., (Copyright © 2015. Published by Elsevier Inc.)

Endometriosis is a benign gynecological disease that is related to immune response alterations. T regulatory cells modulate immune response, and Foxp3 seems to be the best marker of these cells. This study evaluated Foxp3 mRNA expression in eutopic endometrium from women with endometriosis and healthy controls, and its expression in deep rectosigmoid endometriosis lesions, one of the more aggressive types of the disease. Foxp3 expression was higher in lesions than in eutopic endometrium in the two groups. Moreover, eutopic endometrium Foxp3 expression of women with endometriosis was associated with chronic pelvic pain and cyclic urinary pain., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)