Advanced Stage Endometriosis Research Articles

12329 Effectiveness of Surgery for Infertile Women With Advanced Stage Endometriosis: A Systematic Review and Meta-Analysis

12329 Effectiveness of Surgery for Infertile Women With Advanced Stage Endometriosis: A Systematic Review and Meta-Analysis

Comparison of ovarian preservation versus oophorectomy on fertility outcomes in patients with endometriosis post-laparoscopic surgery: A prospective study.

Endometriosis is a chronic inflammatory condition affecting a significant proportion of women of reproductive age. Although laparoscopic surgery is commonly the preferred treatment, the decision to preserve or remove the ovaries remains controversial. Previous studies have yielded inconsistent results regarding the impact of ovarian preservation vs oophorectomy on fertility outcomes and disease recurrence. This prospective study aimed to address this knowledge gap by comparing the effects of these surgical approaches on spontaneous pregnancy rates, time to pregnancy, recurrence rates, and postoperative pain in patients with endometriosis. To compare the reproductive outcomes and recurrence rates between ovarian preservation and oophorectomy in women undergoing laparoscopic surgery for endometriosis. This study was conducted at a tertiary care hospital between January 2019 and December 2023. A total of 312 women aged 18 to 40 years, diagnosed with endometriosis and undergoing laparoscopic surgery, were included. The patients were categorized into the ovarian preservation group (n = 204) and the oophorectomy group (n = 108). The primary outcome measure was the achievement of spontaneous pregnancy within 24 months post-surgery. Secondary outcomes included time to spontaneous pregnancy, recurrence rates, and postoperative pain scores. The ovarian preservation group exhibited a significantly higher spontaneous pregnancy rate than that in the oophorectomy group (43.6% vs 28.7%, P = 0.006). Moreover, the median time to spontaneous pregnancy was shorter in the ovarian preservation group (8.2 months vs 11.4 months, P = 0.018). Nonetheless, endometriosis recurrence was more prevalent in the ovarian preservation group (22.1% vs 11.1%, P = 0.014). The postoperative pain scores demonstrated similar improvements in both groups, with no significant differences observed. Subgroup analyses indicated that the benefit of ovarian preservation on spontaneous pregnancy rates was more evident among younger women (≤ 35 years) and those with advanced-stage endometriosis. Ovarian preservation is associated with a high spontaneous pregnancy rate and a short time to pregnancy. However, because of the increased risk of recurrence, the decision should be based on age, fertility aspirations, and disease severity.

Diagnostic delay and health-related quality of life in Egyptian women with endometriosis

BackgroundFirstly, to measure indicators of health-related quality of life (HRQoL) in Egyptian women with endometriosis; and secondly, to estimate time interval from start of symptoms until endometriosis diagnosis is made (diagnostic delay) in Egyptian women with the disease.Material and methodsBefore laparoscopy for pelvic pain and/or infertility, eligible Egyptian women completed Global Study of Women’s Health (GSWH) questionnaire and validated Arabic version of Rand SF 36 (SF-36). According to laparoscopic findings, participants were divided to endometriosis group and control women with no pelvic abnormalities.ResultsSeventy women with endometriosis and 57 symptomatic controls without endometriosis were enrolled. A diagnostic delay of 36 months (IQR 22.5–60) was observed in women with endometriosis while symptomatic controls had a delay of 48 months (IQR 24–84). The difference was not statistically significant (P = 0.08). Bodily pain (BP) scores were significantly lower in women with endometriosis than controls [80.0 (45.0–100.0) versus 100.0 (68.75–100.0) respectively, P is 0.01]. Women with advanced endometriosis had significantly lower scores for physical functioning (PF), role limitation due to physical function (RP), and BP compared to women with mild endometriosis, and to controls. Physical component summary (PCS) scores were significantly lower in women with advanced stage endometriosis [41.51 (34.19–51.54] compared to women with early-stage disease [58.33 (50.98–60.37)] or control group [54.72 (48.81–59.58)]. Patient’s age, intensity of noncyclical pelvic pain, and disease stage are determining factors of HRQoL in women with endometriosis.ConclusionsEgyptian women with endometriosis experience relatively short diagnostic delay, poor bodily pain scores, and impaired physical health for which age, disease stage, and non-cyclic pain are determinants. Multi-disciplinary endometriosis centers, educational programs, and patient support groups are needed in Egypt.

MLLT11 Regulates Endometrial Stroma Cell Adhesion, Proliferation and Survival in Ectopic Lesions of Women with Advanced Endometriosis.

MLLT11 is a gene implicated in cell differentiation and the development and progression of human cancers, but whose role in the pathogenesis of endometriosis is still unknown. Using quantitative RT-PCR and immunohistochemistry, we analyzed 37 women with and 33 women without endometriosis for differences in MLLT11 expression. We found that MLLT11 is reduced in the ectopic stroma cells of women with advanced stage endometriosis compared to women without endometriosis. MLLT11 knockdown in control stroma cells resulted in the downregulation of their proliferation accompanied by G1 cell arrest and an increase in the expression of p21 and p27. Furthermore, the knockdown of MLLT11 was associated with increased apoptosis resistance to camptothecin associated with changes in BCL2/BAX signaling. Finally, MLLT11 siRNA knockdown in the control primary stroma cells led to an increase in cell adhesion associated with the transcriptional activation of ACTA2 and TGFB2. We found that the cellular phenotype of MLLT11 knockdown cells resembled the phenotype of the primary endometriosis stroma cells of the lesion, where the levels of MLLT11 are significantly reduced compared to the eutopic stroma cells of women without the disease. Overall, our results indicate that MLLT11 may be a new clinically relevant player in the pathogenesis of endometriosis.

MiRNA Expression Profiles in an Ectopic Endometrium of Patients at Different Stage of Endometriosis

Endometriosis is a debilitating disease that affects up to 15% of women worldwide. Delayed diagnosis, lack of noninvasive biomarker and unexplained pathogenesis are key problems for specialists and patients alike. MiRNAs are a class of noncoding RNAs that regulate myriad of cellular functions. These gene expression regulators may prove to be attractive biomarkers with diagnostic and prognostic value for endometriosis.
 Tissue samples were collected from the participants enrolled in the study during laparoscopy (patients) and hysteroscopy (control group). After RNA isolation (miRNeasy MiniKit, Qiagen) based on the disease stage, three pools – each containing 15 RNA samples, were constructed: 1) early stage endometriosis, 2) late stage endometriosis, and 3) healthy controls. Each pool sample was subjected to reverse transcription via miScript II RT Kit, Qiagen to obtain cDNA. SYBR Green based Real-time PCR assay was used to determine the expression profile of 84 miRNAs (Human miFinder miRNA PCR Array, Qiagen).
 We detected 32 differently expressed miRNAs between early stage endometriosis and control group, and 51 differently expressed miRNAs between advanced stage endometriosis and control group. Three miRNAs were differentially expressed with more than 10-fold change in the early stage group and thn miRNAs showed more than 10-fold change in the advanced stages group. The three miRNAs with the highest fold change in the expression levels in both case groups were nominated as potential biomarkers for endometriosis. The results of the analysis of their target genes supports the role of deregulation of apoptosis, angiogenesis, epithelial-mesenchymal transition, and various other cellular signalling pathways in endometriosis development.

The efficacy of GnRH-a followed by SanJieZhenTong capsules in long-term management of endometriosis: Study protocol for a multicenter, double-blinded, double-dummy randomized clinical trial

BackgroundEndometriosis is a common benign gynecological disorder with high risk of recurrence and adverse impact on fertility-sparing. This study aims to evaluate the effectiveness and safety of SanJieZhenTong Capsules, a traditional Chinese medicine, in the long-term management of endometriosis postoperatively. Methodsand analysis: A prospective, double-blinded, double-dummy parallel-group randomized controlled trial will be conducted at three university-based medical centers in China. A total of 600 patients with rAFS III-IV endometriosis diagnosed by laparoscopy will be enrolled. After fundamental treatment (gonadotropin-releasing hormone agonists injection starts on the first day of menstruation postoperatively, and repeats 3 times every 28 days), participants will be randomly allocated to the oral contraceptive group (oral contraceptive + dummy A) or SanJieZhenTong Capsules group (SanJieZhenTong Capsules + dummy B) in a 1:1 ratio. All participants will be treated and followed up for 52 weeks. The primary outcome is a recurrence rate based on endometriosis-related symptoms, physical examination, and/or ultrasound/MRI findings. The secondary outcome includes changes in quality of life and organic function outcome via the 36-item Short-Form scores and gastrointestinal function score. ConclusionThe current trial could provide rigorous evidence on SanJieZhenTong Capsules application in the long-term management of advanced-stage endometriosis.

Migraine Is More Prevalent in Advanced-Stage Endometriosis, Especially When Co-Occuring with Adenomoysis.

BackgroundEmerging data suggest a significant association between migraine and endometriosis, however the relationship between migraine and endometriosis severity or adenomyosis is unclear. Our objectives were to explore the relationship between migraine and endometriosis, according to the endometriosis severity and co-exist with adenomyosis or not.MethodsThis case-control study of 167 endometriosis patients verified by surgery and 190 patients for other benign gynecological conditions (control subjects) was performed from September 2017 and January 2021. There is 49 adenomyosis detected by transvaginal ultrasound or histologic diagnosis among the endometriosis patients. Besides, we also included 41 adenomyosis but without endometriosis patients as a subgroup. All women completed a self-administered headache questionnaire and diagnosed as migraine according to the International Headache Society classification. The severity and stage of endometriosis was evaluated with revised American Society of Reproductive Medicine (rASRM) score. We used logistic regression to estimate the association between the presence of migraine and endometriosis severity while accounting for important confounders, including age, body mass index (BMI) and family history of migraine. We also estimate the risk of adenomyosis alone and adenomyosis with co-occurring endometriosis in migrainous women.ResultsMigraine was significantly more prevalent in endometriosis patients compared with controls (29.9% vs. 12.1%, p<0.05), but the prevalence was similar between isolated adenomyosis patients and controls (9.8% vs.12.1%, p>0.05). For all endometriosis and control participants, migraineurs were 4.6-times (OR=4.6; 95% CI 2.7-8.1) more likely to have severe endometriosis. However, the strength of the association decreased when the analysis examined in moderate stage (OR=3.6, 95% CI 2.1-6.2). The risk of mild and minimal endometriosis was not significant (OR=1.9, 95%CI 0.9-4.0; OR=1.6, 95% CI 0.8-3.4; respectively). When we divided the endometriosis patients according to whether co-occurring with adenomyosis. We found in migrainous women, the risk of endometriosis co-exist with adenomyosis increased, with nearly fivefold greater odds compared with control (OR=5.4;95% CI 3.0-9.5), and nearly two times higher than the risk of endometriosis without co-exist adenomyosis patients (OR=2.2; 95% CI 1.2-3.8).ConclusionOur study supports the strong association between migraine and endometriosis. We found migrainous women suffer more frequently from sever endometriosis, especially endometriosis with co-occurring adenomyosis. It is advisable to heighten suspicion for patients who presenting with either these conditions in order to optimize therapy.

The pro-inflammatory and anti-inflammatory role of hyaluronic acid in endometriosis

ObjectiveEndometriosis is a bothersome disease affected women worldwide, the mechanism of disease development is still under investigation. Several inflammatory responses after clinical hyaluronic acid (HA) use were reported. Cyclooxygenase (COX)-2 mediated inflammation pathway is involved in the pathogenesis of endometriosis. Thus, we tried to investigate the inflammatory role of hyaluronic acid in endometriosis. Materials and methodsPeritoneal fluid was collected in endometriosis and disease-free patients for the measurement of HA. Endometriotic stromal cells were treated with IL-1β and HA and expression of COX-2 was evaluated. Mice model of endometriosis was established and treated with fluid or gel form of HA. Endometriotic lesion size and weight were recorded and level of COX-2 was evaluated by immunohistochemistry staining. ResultsThe level of HA in the peritoneal fluid had no statistically significant difference between normal, early and advanced stage endometriosis patients. The overexpression of COX-2 protein was detected when treating endometriotic stromal cell with HA in the presence of IL-1β (P < 0.001). The endometriotic lesion size was reduced in mice model when treated with higher concentration gel form HA. It further showed less proportion of strong COX-2 expression compare of gel form HA to fluid form treatment in COX-2 expression score of endometriosis lesion. ConclusionBoth proinflammatory evidence, elevated COX-2 expression, and anti-inflammatory result, reduced endometriosis lesion size and COX-2 expression score, were noted in our study after treating HA in in vivo and in vitro models. We hypothesized it is possible that HA may induce an acute proinflammatory response followed by chronic anti-inflammatory reaction in the formation of endometriosis.

Increased Expression of Retinol-Binding Protein 4 in Ovarian Endometrioma and Its Possible Role in the Pathogenesis of Endometriosis.

Although endometriosis is a benign disease characterized by the presence of endometrial tissues outside the uterus, ectopic endometrial cells can exhibit malignant biological behaviors. Retinol-binding protein4 (RBP4) is a novel adipocyte-derived cytokine, which has important roles in regulating insulin sensitivity and energy metabolism. RBP4 is a potent modulator of gene transcription, and acts by directly controlling cell growth, invasiveness, proliferation and differentiation. Here, we evaluated the possible role of RBP4 in the pathogenesis of endometriosis. We compared the levels of RBP4 in the tissues and peritoneal fluid (PF) of women with and without endometriosis and evaluated the in vitro effects of RBP4 on the viability, invasiveness, and proliferation of endometrial stromal cells (ESCs). RBP4 levels were significantly higher in the PF of the women in the endometriosis group than in the controls. RBP4 immunoreactivity was significantly higher in the ovarian endometriomas of women with advanced stage endometriosis than those of controls. In vitro treatment with human recombinant-RBP4 significantly increased the viability, bromodeoxyuridine expression, and invasiveness of ESCs. Transfection with RBP4 siRNA significantly reduced ESC viability and invasiveness. These findings suggest that RBP4 partakes in the pathogenesis of endometriosis by increasing the viability, proliferation and invasion of endometrial cells.

Association between the Genetic Variants of Glutathione Peroxidase 4 and Severity of Endometriosis.

It has been reported that oxidative and nitrative stress might be the pathogenesis of endometriosis. This prospective case-control study attempted to check the connection between single nucleotide polymorphism (SNP) of three antioxidant enzymes (glutathione peroxidase 4 (GPX4), thioredoxin 2 (TXN2), thioredoxin reductase 1 (TXNRD1)) and endometriosis. We recruited 90 patients with histology-approved endometriosis as the case group and 130 age-matched women for an annual pap smear examination as the control group. The stage of endometriosis was evaluated with revised ASRM score. Both groups were genotyped in the peripheral leukocytes for the SNP of GPX4 (rs713041), TXN2 (rs4821494) and TXNRD1 (rs1128446) by PCR-based methods. An X2 test was used to analysis of the difference of allele frequency and SNP distribution between two groups. The results revealed GPX4 (rs713041) has a significantly different distribution between two groups (C:T = 116 (44.6%):144 (55.4%) in control and C:T = 104 (57.8%): 76 (42.2%) in endometriosis groups, p = 0.007). The SNP in TXN2 (rs4821494) also showed a difference in allele frequency (G:T = 180 (69.2%):80 (30.8%) in control and G:T = 141 (78.3%):39 (21.6%) in endometriosis group, p = 0.030). In addition, the SNP GPX4 (rs713041) was associated with the severity of the endometriosis. Women who have advanced stage endometriosis were different from mild endometriosis in genetic variants of GPX4 gene (p = 0.001). In conclusion, the relationship between endometriosis and SNP of antioxidant enzymes, GPX4 and TXN2, was confirmed by the present study. According to the result, we suggested that the GPX4 might contribute to the pathogenesis of endometriosis.

Understanding pre-operative staging and surgical practice in advanced endometriosis: A survey of Canadian gynaecologists

Study objective: To determine the pre-operative evaluation, surgical management and referral practices in patients with advanced stage endometriosis by Canadian gynaecologists. Design: A survey of obstetricians and gynaecologists. Setting: The survey was initiated and piloted at an academic centre by general gynaecologists and endometriosis specialists. Intervention: Electronically distributed to 733 individuals by the Society of Obstetricians and Gynaecologists of Canada. This included all members, irrespective of subspecialty and practice patterns. Measurement: Responses were collected using a web-based survey tool and analysed using Excel. Results: The response rate was 15.7% (115 respondents). Pre-operatively, 62.2% of respondents perform a transvaginal ultrasound on all of their patients, while magnetic resonance imaging is reserved for patients with physical exam findings suspicious for advanced endometriosis (26.7%) or in whom the surgeons suspect deep infiltrating endometriosis, bowel, bladder or uterosacral disease (54.4%). Most surgeons (81.4%) report encountering advanced disease that they did not suspect pre-operatively &lt;10% of the time. Although 40% of respondents would refer their patients in whom they suspected deep infiltrating endometriosis, endometriomas, bowel, bladder or uterosacral ligament involvement to an endometriosis specialist prior to any attempted surgery, 54.4% would never refer without previously confirming the diagnosis at laparoscopy. In contrast, only 15% felt comfortable treating advanced endometriosis completely at time of laparoscopy (including deep infiltrating endometriosis, bladder and bowel disease). Post-operatively, 67.8% of respondents refer patients to an endometriosis specialist only if their disease was not appropriately treated surgically, while 23.3% do not refer any of their patients. Conclusion: Our study identified significant variability in the management of advanced endometriosis in Canada. Understanding these patterns will help us formulate a more universal investigation and management plan, which may improve the identification of patients pre-operatively with advanced stage endometriosis that could benefit from treatment by an endometriosis specialist.

Clinical management of endometriosis.

Endometriosis is a disease of reproductive age women that is commonly characterized by symptoms that often negatively impact quality of life. The clinical management of endometriosis remains highly variable and mostly influenced by geographic location, practice patterns, and breadth of clinician experience. This variability in treatment has inspired a trend towards multidisciplinary and specialized care of patients suffering from this disease. Surgical sampling, followed by histologic confirmation of endometrial-like tissue, remains the standard for the definitive diagnosis of endometriosis. However, the high sensitivity and specificity of MRI and ultrasound has shed light on the path towards non-surgical diagnosis of deep infiltrating endometriosis. Molecular variability and intricacy of this disease has limited the development of biologic markers to target for non-invasive diagnosis and pharmacologic therapies. Surgical management of advanced-stage endometriosis can be difficult, mostly secondary to the invasive nature of the disease, and anatomical distortion requiring advanced surgical skills to manage. The high prevalence of chronic pelvic pain and other complex pain syndromes in patients with endometriosis also requires knowledge in the management of these types of issues in order to provide comprehensive care. Menopausal endometriosis, extrapelvic presentation, and potential malignant transformation of lesions are infrequent, requiring a high index of suspicion for timely diagnosis and treatment.

Plasma levels of polychlorinated biphenyl, genetic polymorphisms, and the risk of advanced stage endometriosis

Both environmental and genetic factors interact and play a critical role in the pathogenesis of endometriosis. We analyzed the plasma levels of 12 polychlorinated biphenyl (PCB) congeners with genetic polymorphisms of glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and aryl hydrocarbon receptor repressor (AhRR) codon 185. Total sum of the 12 congeners was significantly higher in the controls compared with endometriosis group. Women without C/C genotype in AhRR codon 185 had a significantly increased risk of endometriosis compared with those with C/C genotype. Total sum of the 12 congeners was significantly higher in women without C/C genotype compared with those with C/C genotype. Adjusting for age and AhRR codon 185 genotype, there was no significant association between exposure to PCBs and the risk of endometriosis. These findings suggest a possible presence of gene-environment interaction, however, we could not see any clear association between exposure to PCBs and the risk of endometriosis.

Transvaginal Ultrasound Can Accurately Predict the American Society of Reproductive Medicine Stage of Endometriosis Assigned at Laparoscopy

To evaluate the diagnostic accuracy of transvaginal ultrasound in predicting a laparoscopic, surgically assigned, revised American Society of Reproductive Medicine (ASRM) endometriosis stage. A multicenter, retrospective, diagnostic accuracy study. The patients visited 1 of 2 academic gynecologic ultrasound units and underwent laparoscopy led by 1 of 6 surgeons in metropolitan Sydney, Australia, between 2016 and 2018. Patients with suspected endometriosis (n = 204). Ultrasound followed by laparoscopy. Surgical cases were identified. The preoperative ultrasound report and surgical operative notes were each used to retrospectively assign an ASRM score and stage. The breakdown of surgical findings was as follows: ASRM 0 (i.e., no endometriosis), 24/204 (11.8%); ASRM 1, 110/204 (53.9%); ASRM 2, 22/204 (10.8%); ASRM 3, 16/204 (7.8%); ASRM 4, 32 204 (15.7%). The overall accuracy of ultrasound in predicting the surgical ASRM stage was as follows: ASRM 1, 53.4%; ASRM 2, 93.8%; ASRM 3, 89.7%; ASRM 4, 93.1%; grouped ASRM 0, 1, and 2, 94.6%; and grouped ASRM 3 and 4 of 94.6%. Ultrasound had better test performance in higher disease stages. When the ASRM stages were dichotomized, ultrasound had sensitivity and specificity of 94.9% and 93.8%, respectively, for ASRM 0, 1, and 2 and of 93.8% and 94.9%, respectively, for ASRM 3 and 4. Ultrasound has high accuracy in predicting the mild, moderate, and severe ASRM stages of endometriosis and can accurately differentiate between stages when ASRM stages are dichotomized (nil/minimal/mild vs moderate/severe). This can have major positive implications on patient triaging at centers of excellence in minimally invasive gynecology for advanced-stage endometriosis.

36: Correlation of endometriosis on preoperative MRI and surgical pathology

The aim of this study is to assess whether the use of MRI as part of preoperative workup in the setting of patients with chronic pelvic pain and presumed diagnosis of endometriosis is predictive of pathology-proven endometriosis. Retrospective chart review of patients operated on by one fellowship trained minimally invasive gynecologist over the course of 16 months was completed. All surgical cases performed at one of two tertiary hospitals between November 2017 and February 2019 were reviewed and laparoscopic cases were identified. Laparoscopic cases in which a preoperative MRI was performed were then identified. These cases were reviewed to assess for presence or absence of: (1) a preoperative prediction of endometriosis, (2) identification of endometriosis on preoperative MRI, and (3) surgical diagnosis of endometriosis based on intraoperative findings or surgical pathology. 25 surgical cases had MRI performed preoperatively. 10 predicted endometriosis preoperatively and all had pathology confirmed endometriosis. Of the patients with positive MRIs and positive pathology for endometriosis, 5(50%) were stage 4, 3(30%) stage 3, 1(10%) stage 2, and 1(10%) stage 1. Of the 15 of the preoperative MRIs that did not predict endometriosis, 7 had pathology confirmed endometriosis and 8 were pathology confirmed negative for endometriosis. Of the patients with negative MRIs and positive pathology for endometriosis, 4(57.1%) were stage 1, 2(28.6%) stage 2, and 1(14.3%) stage 3. A Fisher exact test for equality of accuracy in the patients showed that patients who had a positive MRI had a significantly higher endometriosis pathologic diagnosis accuracy than patients who had a negative MRI (p<0.05). Ultrasound is the most common form of imaging done in the setting of suspected endometriosis. The advanced dynamic ultrasound techniques in the literature for endometriosis assessment is not universally available in the US. Preoperative MRI may be used as part of the workup of patients with presumed endometriosis because it allows for evaluation of all pelvic compartments as well as increased accuracy in suspected diagnosis. MRI is also less susceptible to interobserver variability that can be associated with ultrasound, which is dependent on the technician and the radiologist. Preoperative MRI was predictive for both presence and absence of endometriosis. The MRI was more predictive of advanced stage endometriosis. Advanced disease endometriosis is best treated by a surgeon with advanced surgical skills and experience with endometriosis so that the patient has clear expectations of outcomes and recurrence, to optimize resection, to minimize complications, and to reduce need for repeat surgery due to inadequate resection.

Ultrasound is Highly Accurate at Predicting the American Society of Reproductive Medicine (AARM) Stage of Endometriosis

Study Objective We aimed to evaluate the diagnostic accuracy of deep endometriosis transvaginal ultrasound (DE TVS) in predicting a surgically-apportioned ASRM endometriosis stage. Design Multicenter retrospective diagnostic accuracy study. Setting Patients attended one of two gynecology-focused ultrasound practices and underwent laparoscopy by one of six surgeons in the Sydney metropolitan area between 2016 and 2018. Patients or Participants Patients with suspected endometriosis. Interventions DE TVS followed by laparoscopy. Measurements and Main Results An ASRM stage was apportioned to each patient based on the surgical report. An ultrasound-based ASRM stage was also apportioned using the preoperative DE TVS report. Where details on size of lesions was missing, the range of possible points for that region was used to calculate a minimum and maximum ASRM stage. The diagnostic accuracy (accuracy, sensitivity, specificity, positive predictive value, negative predictive value and positive and negative likelihood ratios) was calculated for each ASRM stage and dichotomized ASRM stages (0/1/2 and 3/4) at the minimal and maximum ASRM stages. An advanced ASRM stage, called ASRM +, was allocated when rectal, vaginal, or ureteral endometriosis was noted and combined with the base ASRM stage (1-4). 204 patients were included. The breakdown of surgical findings is as follows: normal (i.e. no endometriosis, referred to as ASRM 0) 24/204 (11.8%), ASRM 1 110-127/204 (53.9-62.3%), ASRM 2 8-22/204 (3.9-10.8%), ASRM 3 15-16/204(7.4-7.8%), ASRM 4 30-32/204 (14.7-15.7%). Overall, DE TVS had better test performance in higher disease stages. When the ASRM stages are dichotomized, DE TVS has sensitivity/specificity for ASRM 3/4 of 96.2%/93.4% and ASRM 0/1/2 of 94.9%/93.8%. Conclusion Ultrasound has excellent test performance in predicting a dichotomized ASRM stage state, which can have major positive implications on patient triaging to centers of excellence in minimally-invasive gynecology for advanced stage endometriosis. This may have a downstream positive effect on patient outcomes. We aimed to evaluate the diagnostic accuracy of deep endometriosis transvaginal ultrasound (DE TVS) in predicting a surgically-apportioned ASRM endometriosis stage. Multicenter retrospective diagnostic accuracy study. Patients attended one of two gynecology-focused ultrasound practices and underwent laparoscopy by one of six surgeons in the Sydney metropolitan area between 2016 and 2018. Patients with suspected endometriosis. DE TVS followed by laparoscopy. An ASRM stage was apportioned to each patient based on the surgical report. An ultrasound-based ASRM stage was also apportioned using the preoperative DE TVS report. Where details on size of lesions was missing, the range of possible points for that region was used to calculate a minimum and maximum ASRM stage. The diagnostic accuracy (accuracy, sensitivity, specificity, positive predictive value, negative predictive value and positive and negative likelihood ratios) was calculated for each ASRM stage and dichotomized ASRM stages (0/1/2 and 3/4) at the minimal and maximum ASRM stages. An advanced ASRM stage, called ASRM +, was allocated when rectal, vaginal, or ureteral endometriosis was noted and combined with the base ASRM stage (1-4). 204 patients were included. The breakdown of surgical findings is as follows: normal (i.e. no endometriosis, referred to as ASRM 0) 24/204 (11.8%), ASRM 1 110-127/204 (53.9-62.3%), ASRM 2 8-22/204 (3.9-10.8%), ASRM 3 15-16/204(7.4-7.8%), ASRM 4 30-32/204 (14.7-15.7%). Overall, DE TVS had better test performance in higher disease stages. When the ASRM stages are dichotomized, DE TVS has sensitivity/specificity for ASRM 3/4 of 96.2%/93.4% and ASRM 0/1/2 of 94.9%/93.8%. Ultrasound has excellent test performance in predicting a dichotomized ASRM stage state, which can have major positive implications on patient triaging to centers of excellence in minimally-invasive gynecology for advanced stage endometriosis. This may have a downstream positive effect on patient outcomes.

Alteration of Myeloid-Derived Suppressor Cells, Chronic Inflammatory Cytokines, and Exosomal miRNA Contribute to the Peritoneal Immune Disorder of Patients With Endometriosis

Immunologic disorder has been reported to promote the progression of endometriosis (EMT). It has been known that myeloidderived suppressor cells (MDSCs) drive the progression of many types of diseases. Few studies have shown the relation between MDSCs and EMT. To test whether MDSCs play a role in the progression of EMT, we defined MDSCs, cytokines, and the exosomal microRNA (miRNA) profile in peritoneal fluid (PF) from EMT patients. Characteristics of MDSCs, regulatory T cells (Tregs) and effector T cells were quantified by flow cytometry. Peritoneal fluid monocyte chemoattractant protein (MCP) 1/3, hepatocyte growth factor (HGF), chemokine (C-X-C motif) ligand (CXCL) 1/2, and 13 other cytokines were performed by enzyme-linked immunosorbent assay kit. Exosomal miRNA sequencing was prepared from PF of 3 women with early-stage EMT, 3 women with advanced stage EMT, and 3 women from control group. Our results showed that accumulations of monocytic MDSCs (Mo-MDSCs) and Tregs were detected in advanced patients with EMT. Patients with EMT displayed a significantly higher production of PF CXCL1, CXCL2, MCP-1, MCP-3, and HGF as compared to those from controls. MicroRNA sequencing showed 13 exosomal miRNAs (miRNA-1908, -130b, -451a, -486-5p, -4488, -432, -342, -425, -505, -6508, -145, -365a, and -365b) which are involved in immune alteration and cell proliferation and were differentially expressed in patients with EMT (fold-change ± 2.0). In conclusion, our study revealed that Mo-MDSCs, inflammatory cytokines, and exosomal miRNA seem to be involved in the progression of EMT; however, the relation between Mo-MDSCs, cytokines, and miRNA needs further research.

Could surgical management improve the IVF outcomes in infertile women with endometrioma?: a review.

Endometriosis is a chronic inflammatory condition that affects fertility and could be toxic to the ovary. Endometrioma per se and surgical interventions for endometrioma significantly reduce the ovarian reserve. Therefore, to prepare for surgical intervention for endometrioma, the high-risk group with decreased ovarian reserve must be considered. There is no evidence to support the use of surgical intervention before in vitro fertilization (IVF) to improve the reproductive outcomes of subsequent IVF in infertile women with advanced-stage endometriosis or endometrioma. As surgical treatment has few benefits, IVF could be recommended immediately for aiding conception in these women. However, the reproductive prognosis of IVF may be worse in the more advanced stages of endometriosis. When dysmenorrhea is severe or when cancer is suspected, surgery prior to IVF may be necessary and justified. When the size of the endometrioma is very large, surgery could be required prior to IVF to facilitate access to follicles during oocyte retrieval or to improve the ovarian response to controlled ovarian stimulation. Prolonged pituitary downregulation in women with surgically diagnosed endometriosis may be helpful to increase the clinical pregnancy rate in subsequent IVF cycles. The purpose of this paper was to review the efficiency and clinical application of the surgical intervention and IVF for infertile women with advanced-stage endometriosis or endometrioma.

Role of interleukin-32 in the pathogenesis of endometriosis: in vitro, human and transgenic mouse data

Does interleukin-32 (IL-32) play a role in the pathogenesis of endometriosis? IL-32 might be involved in the pathogenesis of endometriosis through increased viability, proliferation and invasion of endometrial cells. Endometriosis is characterized as a chronic inflammatory disease and several proinflammatory cytokines are suggested to be involved in its pathogenesis and pathophysiology. IL-32, recognized as a new proinflammatory cytokine and a strong inducer of other proinflammatory cytokines, has been shown to serve as a key modulator in several chronic inflammatory diseases. This study included comparison of IL-32 levels in the peritoneal fluids between women with and without endometriosis, in-vitro experiments using Ishikawa cells and endometrial stromal cells (ESCs), and experiments on IL-32 transgenic mice and wild-type mice with induced endometriosis. IL-32 levels in the peritoneal fluids were measured using enzyme-linked immunosorbent assays. Cell viability, expression of proliferating cell nuclear antigen (PCNA), and cellular invasiveness were analyzed following in-vitro treatment of Ishikawa cells and ESCs with recombinant IL-32 alpha (α) and gamma (γ). Ectopic endometriotic lesions were compared between IL-32 transgenic mice and wild-type mice after autologous endometrial transplantation with immunohistochemistry for Ki-67 antigen and PCNA. The peritoneal fluid concentration of IL-32 was significantly higher in patients with advanced stage endometriosis compared with the controls. In-vitro treatment with IL-32 α and γ caused significant increases in cellular viability, PCNA expression, and invasiveness in Ishikawa cells and ESCs. The IL-32 transgenic mice had a significantly larger size of the ectopic endometrial lesions with higher expression of Ki-67 antigen and PCNA compared with wild-type mice. N/A. It is still unclear whether IL-32 is a main regulator, or one of several downstream proinflammatory cytokines, causing establishment and/or progression of endometriosis. Further investigation on IL-32 signaling pathways may contribute to development a more effective treatment of endometriosis. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C1682). None of the authors has anything to disclose.

Upregulation of Interleukin 35 in Patients With Endometriosis Stimulates Cell Proliferation.

In this study, we investigated the expression of interleukin 35 (IL-35) and its receptors in endometriosis, analyzed the function of IL-35 in primary culture model of endometrial stromal cells (ESCs), and evaluated their clinicapathological significance. Peripheral blood (PB) and peritoneal fluid (PF) were collected from 37 women with endometriosis and 24 control women. The ectopic endometrium was obtained from patients with endometriosis undergoing laparoscopic surgery. The eutopic and normal endometrium were collected by endometrial biopsy. Levels of IL-35 in PB and PF were evaluated by enzyme-linked immunosorbent assay. Women with endometriosis had higher levels of IL-35 compared to controls both in PB and in PF. Levels of n IL-35 were increased in patients with advanced stage endometriosis compared to those with early stages in PF. A significant upregulation of IL-35 was observed in patients with ovarian endometriosis accompanied with pelvic implants (PI) compared to those without PI in PB and PF. The relative messenger RNA and protein expression of EBi3 and p35, the subunits of IL-35, were significantly higher in ectopic endometrium than in eutopic and healthy endometrium as measured by immunohistochemistry and quantitative polymerase chain reaction. The ESCs from endometriosis displayed a remarkable overexpression of IL-35 receptor subunits, IL12Rβ2 and gp130, compared to those from controls . Moreover, recombined human IL-35 protein stimulated the upregulation of IL12Rβ2 and gp130 and facilitated proliferation of ESCs. Our study provides the first evidence that IL-35 was involved in the pathogenesis of endometriosis through suppressing immunoreaction and promoting proliferation of ESCs. IL-35 may potentially serve as a biomarker for endometriosis.