The relationship between uterine corpus cancer and endometriosis was conflicting. We aimed to determine the risk of uterine cancer in patients with endometriosis or pelvic inflammatory disease (PID). In this population-based cohort study, a total of 135,236 females with endometriosis (n = 20,510) or PID (n = 114,726), as well as 135,236 age-matched controls, were included. Cox regression models estimated the risk of uterine cancer in each group. Sub-outcomes of risk for uterine corpus cancer included endometrial cancer and uterine sarcoma were analyzed. An age subgroup analysis was performed to determine the moderator effect of age. A landmark analysis depicted the time varying effect of endometriosis and PID. A propensity score matching analysis was conducted to validate the findings. Patients with endometriosis had significantly higher risk of endometrial cancer (adjusted hazard ratio, aHR = 2.92; 95% CI = 2.12-4.03) and uterine sarcoma (aHR = 5.83; 95% CI = 2.02-16.89), while PID was not associated with the risk of uterine cancer. The increased risk of uterine cancer in patients with endometriosis persisted after propensity score matching (aHR = 2.83, 95%CI = 1.70-4.71). The greatest risk of endometrial cancer occurred in patients who had endometriosis for 37 to 60 months (adjusted relative risk, aRR = 9.15, 95% CI = 4.40-19.02). Females aged 12 to 35 years were at the greatest risk of endometriosis-associated uterine cancer (RR = 6.97, 95% CI = 3.41-14.26). In conclusion, patients with endometriosis were at great risk of uterine cancer, including endometrial cancer and uterine sarcoma, compared with propensity score-matched populations and compared with patients of PID. Younger females with endometriosis and patients who had endometriosis for three to five years were at the greatest risk of endometriosis-associated uterine cancer. 

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The Risk of Endometrial Cancer and Uterine Sarcoma Following Endometriosis or Pelvic Inflammatory Disease

Endometriosis (EM) is a chronic inflammatory disease affecting millions of women worldwide. Chronic pelvic pain is one of the main problems of this condition, leading to quality-of-life impairment. Currently, available treatment options are not able to treat these women accurately. A better understanding of the pain mechanisms would be beneficial to integrate additional therapeutic management strategies, especially specific analgesic options. To understand pain in more detail, nociceptin/orphanin FQ peptide (NOP) receptor expression was analyzed in EM-associated nerve fibers (NFs) for the first time. Laparoscopically excised peritoneal samples from 94 symptomatic women (73 with EM and 21 controls) were immunohistochemically stained for NOP, protein gene product 9.5 (PGP9.5), substance P (SP), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). Peritoneal NFs of EM patients and healthy controls were positive for NOP and often colocalized with SP-, CGRP-, TH-, and VIP-positive nerve fibers, suggesting that NOP is expressed in sensory and autonomic nerve fibers. In addition, NOP expression was increased in EM associate NF. Our findings highlight the potential of NOP agonists, particularly in chronic EM-associated pain syndromes and deserve further study, as the efficacy of NOP-selective agonists in clinical trials.

https://www.mdpi.com/2073-4409/12/10/1395/pdf?version=1684161299

Nociceptin/Orphanin FQ Opioid Peptide-Receptor Expression in the Endometriosis-Associated Nerve Fibers—Possible Treatment Option?

An evaluation of the association between the concentrations of vitamin D-binding protein and lactoferrin in the plasma and peritoneal fluid may facilitate the elucidation of molecular mechanisms in endometriosis. Vitamin D-binding protein and lactoferrin concentrations were measured by ELISA in plasma and peritoneal fluid samples from 95 women with suspected endometriosis as classified by laparoscopy into groups with (n = 59) and without endometriosis (n = 36). There were no differences (p > 0.05) in the plasma and peritoneal fluid concentrations of vitamin D-binding protein and lactoferrin between women with and without endometriosis. In women with endometriosis, there was a significant correlation between plasma and peritoneal fluid vitamin D-binding protein concentrations (r = 0.821; p = 0.000), but there was no correlation between lactoferrin concentrations in those compartments (r = 0.049; p > 0.05). Furthermore, in endometriosis, lactoferrin was found to correlate poorly with vitamin D-binding protein (r= −0.236; p > 0.05) in plasma, while in the peritoneal fluid, the correlation between those proteins was significant (r = 0.399; p = 0.002). The characteristic properties of vitamin D-binding protein and lactoferrin and the associations between their plasma and peritoneal fluid concentrations found in women with endometriosis may provide a novel panel of markers to identify high-risk patients in need of further diagnostic measures.

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Investigation of the Changes in Concentrations of Vitamin D-Binding Protein and Lactoferin in Plasma and Peritoneal Fluid of Patients with Endometriosis

The relationship of genotypes of the RS2414098 polymorphism of the CYP19A1 gene with the risk of endometrial polyps

Purpose Infertility is highly correlated with inflammation. We sought to evaluate the independent relationships between each inflammatory marker in women with infertility. Patients and Methods This cross-sectional study included 1028 infertile patients who were hospitalized at Jining Medical University between January 2016 and December 2022. NLR and PLR were the independent and dependent variables measured at baseline, respectively. Age, body mass index (BMI), and menstrual status were covariates. Based on BMI, the study population was split into two groups: Low-BMI and High-BMI. Results A stratified analysis revealed that the overweight group had significantly higher levels of WBC, platelet count, lymphocyte count, neutrophil count and NLR. Comparing the overweight group to the normal weight group, the levels were noticeably higher in the overweight group. Significantly positive correlations between NLR and PLR were found in both univariate and multiple regression analyses. Conclusion There was a significant positive correlation between NLR and PLR in infertility patients. These results will help in the search for biomarkers of infertility and in the development of infertility prediction models.

https://www.dovepress.com/getfile.php?fileID=88462

Inflammatory Markers in Women with Infertility: A Cross-Sectional Study

Several studies, although with conflicting results, have sought to determine the concentration of soluble CTLA4 antigens in peripheral blood plasma and peritoneal fluid in patients with endometriosis-related infertility. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) through a search of the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library, Health Technology Assessment Database and Web of Science, and Clinical Trials research register. We included observational or prospective human and animal studies with any features related to endometriosis and/or infertility studies involving CTLA4-related pathogenesis published in English. The results of studies in which the size and characteristics of the observed groups were not stated were excluded. From the initial pool of 73 publications identified and screened, we finally included 5 articles to summarize the most recent knowledge about CTLA4-linked autoimmunity in the pathogenesis of endometriosis and related infertility. Evidence from clinical studies shows that CTLA4-based autoimmunity is involved in the maintenance of chronic inflammation in the peritoneal environment, with pre-clinical evidence of anti-CTLA antibodies as a potential novel target therapy for endometriosis. However, CTLA4 gene analyses do not support findings of CTLA4-linked autoimmunity as a primary determinant of the pathogenesis of endometriosis. These findings underlie the role of complex interactions within the family of immune checkpoint molecules involved. Further studies are needed to investigate the clinical relevance of anti-CTLA target therapy, taking into account the potential adverse events and repercussions of novel immunologic therapy modalities. However, with the general scarcity of studies investigating this topic, the clinical importance of CTLA4 autoimmunity still remains unclear.

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CTLA4-Linked Autoimmunity in the Pathogenesis of Endometriosis and Related Infertility: A Systematic Review

The aim of our study was to determine the prevalence of endometrial premalignant and malignant lesions in women undergoing hysteroscopy and to identify anthropologic factors related to the presence of malignancy. Data on 3470 women with submucosal myomas or endometrial polyps suspected on ultrasound were retrospectively analyzed. Hysteroscopy was performed in all these women in order to make a more precise diagnosis. Histologic analysis of endometrial samples obtained during hysteroscopy was used to confirm the diagnosis. Statistical analysis was performed using the SPSS 20.0.0 software. The mean age of study women was 49.1±13.3 years. The number of procedures performed due to the referral diagnosis of endometrial or submucosal myoma significantly increased over the 16-year study period. A significantly higher number of women had a benign histopathologic diagnosis. Histologic analysis revealed malignancy in 67 women. The youngest woman and oldest woman with malignant findings was aged 32 and 75, respectively. A significantly higher number of women with atypical hyperplasia and malignancy were in menopause. A comparable number of women with different histologic findings lived in urban and rural areas. There were a significantly larger proportion of widows among women with the histologic diagnosis of atypical hyperplasia or malignancy. The prevalence rate of malignancy in women having undergone hysteroscopy for polyps and myoma found by ultrasound was 1.93%. Postmenopausal status and older age were associated with an increased risk of malignancies, but premalignant changes and malignancies were also found in young and premenopausal women. Therefore, diagnostic hysteroscopy can be recommended in women of all age groups.

Ivan Brlečić

Papers

CTLA4-Linked Autoimmunity in the Pathogenesis of Endometriosis and Related Infertility: A Systematic Review

Histopathologic findings in women undergoing hysteroscopic resection of endometrial polyps and uterine myomas.