Oxidative Imbalance in Endometriosis-Related Infertility-The Therapeutic Role of Antioxidants.

Endometriosis in half of affected women is closely related to problems with fertility. Endometriosis-associated infertility is caused by a wide range of abnormalities affecting the female reproductive tract, from oocyte quality impairment to disturbances in the eutopic endometrium or mechanical abnormalities resulting from disease progression. Since supportive antioxidant therapies, in addition to surgical treatment or assisted reproductive techniques (ARTs), have overall been proven to be effective tools in endometriosis management, the objective of our review was to analyze the role of antioxidant substances, including vitamins, micronutrients, N-acetylcysteine (NAC), curcumin, melatonin, and resveratrol, in endometriosis-related infertility. Most of these substances have been proven to alleviate the systemic oxidant predominance, which has been expressed through decreased oxidative stress (OS) markers and enhanced antioxidative defense. In addition, we demonstrated that the predominant effect of the aforementioned substances is the inhibition of the development of endometriotic lesions as well as the suppression of pro-inflammatory molecules. Although we can undoubtedly conclude that antioxidants are beneficial in fertility support, further studies explaining the detailed pathways of their action are needed.

The PD-1/PD-L1 Gateway: Peripheral Immune Regulation in the Pathogenesis of Endometriosis.

Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, causing pain and infertility. Despite the rather unclear etiopathogenesis, recent studies suggest the involvement of the immune system in the development and progression of endometriosis. The role of the PD-1/PD-L1 axis in the modulation of the immune response in this disease seems to be particularly interesting. This preliminary study aimed to investigate the expression of PD-1 and PD-L1 on T and B lymphocytes in peripheral blood in patients with endometriosis to assess their potential impact on disease progression. Our study involved peripheral blood samples from 80 patients diagnosed with endometriosis and 20 healthy women as a control group were analyzed. Flow cytometry was used to assess the expression of PD-1 and PD-L1 on T and B lymphocytes, and enzyme-linked immunosorbent assays were used to assess their soluble forms in serum and peritoneal fluid.in our research we observe significantly higher expression of PD-1 and PD-L1 on T and B lymphocytes was found in patients with endometriosis compared to the control group. Higher expression of both tested molecules correlated with the stage of endometriosis. The results of our preliminary studies indicate a potential role of the PD-1/PD-L1 axis in the modulation of the immune response in endometriosis. Modified expression of these proteins may contribute to immune evasion by ectopic tissues, supporting their survival and proliferation. These findings suggest that targeting PD-1/PD-L1 could be explored as a therapeutic option for the treatment of endometriosis, though further research with larger sample sizes is necessary to confirm these results and clarify the role of PD-1/PD-L1 in the pathogenesis of the disease.

Immune Dysregulation in Endometriomas: Implications for Inflammation.

The most common manifestation of endometriosis, a condition characterized by the presence of endometrial-like tissue outside of the uterus, is the endometrioma, a cystic ovarian lesion. It is a commonly occurring condition associated with chronic pelvic pain exacerbated prior to and during menstruation, as well as infertility. The exact pathomechanisms of the endometrioma are still not fully understood. Emerging evidence suggests a pivotal role of immune dysregulation in the pathogenesis of endometriomas, primarily influencing both local and systemic inflammatory processes. Among the factors implicated in the creation of the inflammatory milieu associated with endometriomas, alterations in both serum and local levels of several cytokines stand out, including IL-6, IL-8, and IL-1ß, along with abnormalities in the innate immune system. While numerous signaling pathways have been suggested to play a role in the inflammatory process linked to endometriomas, only NF-κB has been conclusively demonstrated to be involved. Additionally, increased oxidative stress, both resulting from and contributing to endometriomas, has been identified as a primary driver of both systemic and local inflammation associated with the condition. This article reviews the current understanding of immune dysfunctions in the endometrioma and their implications for inflammation.

How Can Selected Dietary Ingredients Influence the Development and Progression of Endometriosis?

Endometriosis is a chronic, hormone-dependent disease characterized by the presence of endometrial tissue in ectopic locations. Since the treatment options for this disease are still limited, and the cure rate is unsatisfactory, the search for ways to treat symptoms and modify the course of the disease is of key importance in improving the quality of life of patients with endometriosis. So far, the literature has shown that nutrition can influence endometriosis through hormonal modification and altering the inflammatory or oxidative response. Since the importance of nutrition in this disease is still a subject of scientific research, we aimed to summarize the current knowledge on the role of dietary modifications in endometriosis. Our review showed that nutrients with anti-inflammatory and antioxidant properties, including most vitamins and several trace elements, may influence the pathogenesis of endometriosis and can be considered as the nutrients preventing the development of endometriosis. However, despite the many discoveries described in this review, further interdisciplinary research on this topic seems to be extremely important, as in the future, it may result in the development of personalized therapies supporting the treatment of endometriosis.

The Efficacy and Safety of Transvaginal Ethanol Sclerotherapy in the Treatment of Endometrial Cysts-A Systematic Review.

Endometriosis, as a chronic disorder that is a source of severe pain ailments and infertility, requires a comprehensive therapeutic approach. Sclerotherapy, consisting of the administration of sclerosing agents into the cyst, is a constantly evolving minimally invasive treatment method for this disease. Hence, the main objective of this systematic review was to evaluate the impact of its most often used variant, transvaginal ethanol sclerotherapy, on endometriosis-related symptoms, endometrial cyst recurrence rate, ovarian reserve, assisted reproductive technology (ART) outcomes, and pregnancy outcomes, as well as to assess potential complications resulting from this treatment. This systematic review was undertaken using PubMed, Scopus, Web of Science, and Cochrane Library databases on 24 November 2023. The risk of bias in included studies was assessed with the use of the Newcastle-Ottawa scale (NOS) and the revised Cochrane risk of bias 2.0 tool for randomized controlled trials. From the 1141 records obtained from all databases, 16 studies have been included in this review. The use of ethanol sclerotherapy was characterized by a low rate of post-procedural complications. The recurrence rate of endometrial cysts after the procedure depended on the ethanol instillation time within the cyst. Although ethanol sclerotherapy had negligible influence on ovarian reserves when compared to laparoscopic cystectomy, the effects of both these methods on pregnancy outcomes were comparable. This review identifies that sclerotherapy is safe, provides significant relief of symptoms, and does not impair the reproductive potential of the patients.

Time Perspective as a Mediator of Depressive Symptoms in Patients with Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a chronic endocrinopathy characterized by oligo- or anovulation, clinical and/or biochemical markers of hyperandrogenism, and polycystic ovaries, and it is associated with an increased prevalence of depression. Research conducted on psychiatric patients has shown correlations between depression and decreased cognitive function. The aim of this study was to examine the possible mediation of the time perspective (TP) in the development of depressive symptoms in patients with PCOS. METHODS: A study was conducted on 83 patients with PCOS and 65 healthy women. Standardized questionnaires were used to assess depressive symptoms (Beck Depression Inventory-BDI-II) and time perspective (Zimbardo Time Perspective Inventory-ZTPI). RESULTS: Our study revealed an indirect influence of depressive symptoms on PCOS through the positive future time perspective. In the logistic regression model, which included depression and a given time perspective as predictors of PCOS, only the future TP (ß = -0.004, p < 0.003, OR = 1.004, 95% CI [1.001, 1.008]) was significantly independently related to the occurrence of PCOS. CONCLUSIONS: Our result is another argument for the role of psychoeducation and appropriate communication with a patient from the risk group in a way that builds hope and allows to regain influence on life situation.

Expression of Gal-9 on Dendritic Cells and Soluble Forms of TIM-3/Gal-9 in Patients Suffering from Endometriosis.

Immune system dysregulation is clinically evident in the pathogenesis of endometriosis (EMS). Changes in the dendritic cells (DCs) activity or phenotype may be involved in the implantation and growth of endometrial tissue outside the uterus in the disease. The TIM-3/Gal-9 axis is implicated in the development of immune tolerance. However, the knowledge about the exact role of this pathway in the EMS is extremely poor. In the present study, we evaluated the expression of Gal-9 on myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the peripheral blood (PB) and peritoneal fluid (PF) of both EMS patients (n = 82) and healthy subjects (n = 10) via flow cytometry. We also investigated the concentrations of soluble Gal-9 and TIM-3 in the plasma and PF of EMS patients and the control group using ELISA. We showed significantly elevated percentages of mDCs-Gal-9+ and pDCs-Gal-9+, and significantly higher concentrations of the soluble form of Gal-9 and TIM-3 in the PF of EMS patients than in circulation. Our results led us to conclude that the accumulation of Gal-9 expressing mDCs and pDCs in the PF and high sTIM-3/Gal-9 production in the peritoneal cavity could represent the hallmark of immune regulation in EMS patients, which may augment the inflammatory process and development/maintenance of local immunosuppression.

Clinical Value of the PD-1/PD-L1/PD-L2 Pathway in Patients Suffering from Endometriosis.

The interaction between dendritic cells (DCs) and T cells mediated by the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1)/programmed cell death ligand 2 (PD-L2) pathway is the most important point in regulating immunological tolerance and autoimmunity. Disturbances in the quantity, maturity, and activity of DCs may be involved in the implantation and growth of endometrial tissue outside the uterus in endometriosis (EMS). However, little is known about the role of the immune checkpoint pathways in EMS. In our study, we examined the expression of PD-L1/PD-L2 on myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the peripheral blood (PB) and peritoneal fluid (PF) of both EMS patients (n = 72) and healthy subjects (n = 20) via flow cytometry. The concentration of soluble PD-L1 and PD-L2 in the plasma and PF of EMS patients and the control group were determined using ELISA. We demonstrated an elevated percentage of mDCs, mDCs and pDCs with the PD-L1or PD-L2 expression, and a higher concentration of the soluble forms of PD-L1 and PD-L2 in the PF than in the plasma of EMS patients. We conclude that the peritoneal cavity environment and the PD-1/PD-L1/PD-L2 axis may play an important role in the modulation of immune response and the development and/or progression of EMS.

P1 promoter IGF-1 polymorphism and IGF-1, IGF-R, LSF, and TSG 101 expression profile in endometriosis.

OBJECTIVES: The presence of the endometrium outside the uterine cavity affects about 10% of women of childbearing age. Studies of the progression of endometriosis to cancer have been supported by numerous evidences of gene expression or gene defect caused by oxidative stress and inflammation. We decided to check the expression of selected factors responsible for the proliferation, as in the stages of neoplasia. MATERIAL AND METHODS: A group of 80 women with ovary localization of endometriosis was qualified for research. The control group was 90 patients with ovarian simplex or follicular cysts. The DNA isolation, immunohistochemical analysis of IGF 1, IGF-R, TSG 101, and LSF expressions with a quantitative scoring of slides and electron microscopy was performed. RESULTS: The IGF-1-immunopositive cells in the reference group were in statistically significantly higher number compared to the cells forming the foci of endometriosis (p = 0.0282). However, the number of IGF-R-immunopositive cells was comparable to the endometriosis (p = 0.1264). In the control group, the number of LSF-immunopositive cells was statistically significantly higher in comparison to endometriosis foci (p = 0.000001), but the number of TSG 101-immunositive cells was comparable to endometriosis foci (p = 0.3834). A weak negative correlation between the number of cells expressing the TSG 101 factor and the IGF-1 receptor was found in the endometriosis group (r = -0.26, p = 0.0196). The analysis of CA single nucleotide polymorphism in the DNA isolated from both groups showed a comparable incidence of MSS and MSI-L genotypes (chi2 p = 0,9160). CONCLUSIONS: How these factors affect the development of endometriosis and whether they could be helpful in the diagnosis requires further research.

Environmental Factors and Endometriosis.

Endometriosis is a common disease, affecting up to 60-80% of women, with pelvic pain or/and infertility. Despite years of studies, its pathogenesis still remains enigmatic. Genetic, hormonal, environmental, and lifestyle-related factors may be involved in its pathogenesis. Thus, the design of the review was to discuss the possible role of environmental factors in the development of endometriosis. The results of individual studies greatly differ, making it very difficult to draw any definite conclusions. There is no reasonable consistency in the role of environmental factors in endometriosis etiopathogenesis.

CD200 and CD200R Expression on Peripheral Blood Lymphocytes and Serum CD200 Concentration as a New Marker of Endometriosis.

The causes of endometriosis (EMS) remain unknown; however, a number of immunological abnormalities contribute to the pathogenesis of the disease. The cluster of differentiation-200 (CD200) and its receptor (CD200R) maintain peripheral self-tolerance by negatively regulating immune responses. In this comparative cross-sectional study, we investigated the expression of CD200 and CD200R on T and B lymphocytes and the serum level of soluble CD200 (sCD200) using flow cytometry and ELISA, respectively. Peripheral blood samples were collected from 54 female patients and 20 healthy, age-matched controls. Results were tested for correlation with disease severity and selected clinical parameters. We demonstrated that the differences in sCD200 levels (p = 0.001), the frequencies of CD200-positive T and B lymphocytes (p < 0.001 and p = 0.004, respectively), and the frequencies of CD200R-positive T and B lymphocytes (p < 0.001 for all comparisons) in the study group correlated positively with disease severity. Receiver operating characteristic (ROC) analysis indicated that aberrant expression of CD200/CD200R might serve as a marker to distinguish between EMS cases. Finally, negative co-stimulatory factors may contribute to the induction and persistence of inflammation associated with EMS. It seems that it is essential to determine whether alteration in the CD200/CD200R pathway can be therapeutically targeted in EMS.

Disrupted iron metabolism in peritoneal fluid may induce oxidative stress in the peritoneal cavity of women with endometriosis.

INTRODUCTION: Data on the possible role of peritoneal fluid free radical-mediated oxidative damage in the pathogenesis of endometriosis still remains inconsistent. The aim of the study was to determine iron metabolism markers and their influence on oxidative stress arameters in the peritoneal fluid of women with endometriosis. MATERIAL AND METHODS: 110 women with endometriosis and 119 patients with benign ovarian cysts were included in the study. All visible peritoneal fluid was aspirated during laparoscopy from the anterior and posterior cul-de-sacs. under direct vision to avoid blood contamination. Haemoglobin, iron, total oxidative status, and total antioxidant status were measured using standard colourimetric kits. RESULTS: Haemoglobin, iron levels, as well as total oxidative status values were significantly higher, whereas total antioxidant status values were significantly lower in the peritoneal fluid of patients with endometriosis, in comparison to the reference groups. No differences were observed in peritoneal fluid concentrations of all parameters measured in relation to the phase of the menstrual cycle. CONCLUSIONS: Peritoneal fluid of women with endometriosis is characterized by disrupted iron metabolism. This is most likely related to an increased number of erythrocytes in the peritoneal cavity of endometriotic women, which leads to a higher concentration of haemoglobin in this environment. Impaired iron homeostasis may have a significant influence on the pathophysiology of peritoneal endometriosis by the direct impact of haemoglobin derivatives and/or formation of the pro-inflammatory and pro-oxidative environment. Peritoneal cavity oxidative stress occurs predominantly in women in advanced stages of the disease.

Neuropilin 1 in uterine leiomyosarcoma. Clinical and pathological analysis.

OBJECTIVES: The role of angiogenesis in leiomyosarcomas still remains unclear. The aim of this study was to evaluate the NRP1 expression in the leiomyosarcoma tissues and to find the relations between its expression and the clinical features. MATERIAL AND METHODS: The study group consisted of 50 patients with diagnosis of the uterine leiomyosarcoma. Clinical and follow up data were collected. Using immunohistochemical methods the expression of NRP1 was detected. RESULTS: The lack of NRP1 expression was found in 14 cases, positive (weak or moderate) expression was noted in 36 cases. The significantly higher expression of NRP1 was observed in more severe clinical stages in comparison to lower stages of the disease. The significantly shorter survival of patients with the positive expression of NRP1 in leiomyosarcoma was observed. CONCLUSIONS: The expression of NRP1 is associated with clinical advancement and worse prognosis in uterine LMS. Neuropilin 1 can be widely used as a postoperative survival predictor for the patients suffering from uterine LMS.

The Increase of Circulating PD-1- and PD-L1-Expressing Lymphocytes in Endometriosis: Correlation with Clinical and Laboratory Parameters.

The cause of endometriosis remains unknown. However, studies investigating the link between this condition and the immune system revealed several immunological abnormalities focused on cell-mediated immunity. As a major immune checkpoint, programmed cell death protein 1 (PD-1) displays an important inhibitory function in the maintenance of peripheral tolerance. The expression of PD-1 and its ligand (PD-L1) may contribute to continuous T cell activation and development of inflammation and injury of the tissue. To our knowledge, this is the first study evaluating frequencies of PD-1-positive T CD3+ cells (CD4+ and CD8+) and B cells (CD19+) in patients with endometriosis. Peripheral blood (PB) samples from 25 female patients and 20 healthy age and sex-matched subjects serving as controls were used in the study. Using flow cytometric analysis, we assessed the differences in the frequencies of PD-1-positive T and B lymphocytes in the study group and healthy individuals. Alteration of the PD-1/PD-L1 axis may contribute to the pathogenesis of endometriosis, as patients with advanced disease are characterized by higher frequencies of PD-1-positive T and B cells. Expression of PD-1 and PD-L1 on T and B cells could represent the hallmark of immune system reaction to chronic antigenic exposition in patients with endometriosis.

New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study.

OBJECTIVE: Endometriosis is a common gynaecological disease, associated with severe pelvic pain and reduced fertility; however, molecular mechanisms remain largely unknown. Genome-wide association studies (GWAS) are able to identify genetic loci, which can play significant role during endometriosis development. AIM: The study aimed at localisation of new genes and chromosomal loci, the nucleotide variants of which determine the level of susceptibility to endometriosis. STUDY DESIGN: Blood samples from 171 patients with endometriosis were used as material for studies. The patients were recruited to the study at the Department of Operative Gynaecology of the Institute of the Polish Mother's Memorial Hospital in Lodz. A control group (n=2934) came from the POPULOUS collection registered at Biobank Lab, Department of Molecular Biophysics, University of Lodz. DNA of the patients with endometriosis was compared with DNA of women free from that disease, the comparison being supported by GWAS. RESULTS: Genome-wide significant correlation was identified between one new, not previously described, single nucleotide polymorphism (SNP), rs10129516, localised on chromosome 14 in intergenic region between PARP1P2 and RHOJ genes (p=1.44×10-10, OR=3.104, 95% CI=2.329-4.136) and endometriosis. We have also identified significant association with endometriosis of 18 SNPs localised on chromosome 6 in position range 31883957 - 32681631 (C2 and HLA-DRA genes region) with the lowest observed p value for rs644045 in C2 gene (p=2.04×10-8, OR=1.955, 95% CI=1.541-2.480). CONCLUSION: Reported GWAS identified the novel loci associated with endometriosis in Polish women, not previously reported. The most interesting observation shown in our study are regions associated with susceptibility to endometriosis of loci located near C2, HLA-DRA and RHOJ genes. RESULTS: of that study did not correspond to previously published data about polymorphism in that regions and further evaluations are necessary in groups with higher numbers of patients to explain whether the above-mentioned genetic variant may be the risk factor for pathogenesis of endometriosis.

Does the patients age at cancer diagnosis affect microvessels density in uterine sarcoma tissues?

OBJECTIVES: The objective of the study was to retrospectively evaluate the density of vessels exhibiting positive glycoprotein CD34 expression in the uterine leiomyosarcoma tissues and their correlation with the age of patients at the time of tumor diagnosis. MATERIAL AND METHODS: The archival paraffin blocks with the cancer tissues collected from 50 patients suffering from uterine leiomyosarcoma were used together with their clinical and demographic data. The immunohistochemical peroxidase-de-pendent methods were used to detect microvessels with positive CD34 expression. The glycoprotein CD34 expression was evaluated as a density of microvessel showing the positive immunohistochemical reaction (MVDCD34). RESULTS: The negative, statistically significant correlation between the age of patients (at the moment diagnosis) and the MVDCD34+ (R = -0.289, p = 0.042) was found. CONCLUSIONS: The study's findings may suggest that the tissues of younger people constitute a permissive environment for pro-angiogenic factors.

[Why ovarian cancer cells escape from immune surveillance?]

Ovarian cancer is a malignancy of high mortality rates. In respect of the number of deaths caused by cancers it occupies the fourth place among women in Poland. Recent studies are focusing on the role of immune system in ovarian cancer pathogenesis. It has been reported that immune response against ovarian cancer cells may be inhibited by a number of immunosuppressive mechanisms active in cancer microenvironment. It causes difficulties in recognizing and destroying cancer cells by immune system which leads to the development of immune tolerance and is associated with a low efficacy of standard therapeutic strategies. In the presented paper we have described selected, new immunosuppressive mechanisms in ovarian cancer patients. They may be a novel, additional and relevant criterion that should be considered whilst developing new therapeutic strategies. Possibly, modulation of immunosuppressive mechanisms could contribute to modifying standard therapies and in consequence improve treatment outcome in ovarian cancer patients.

Myeloid-derived suppressor cells in ovarian cancer: friend or foe?

Although previous decades contributed to major progress in targeted therapy of many malignancies, the treatment of gynaecological cancers remains a challenging task. In the evidence of rising cancer mortality, the search for new methods of treatment is a dire need. Exploring the mechanisms of interaction between tumour cells and host immune response may allow the introduction of new, effective therapies - not as toxic and far more efficient than conventional methods of cancer treatment. Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages. Its incidence and mortality rate is high. Powerful diagnostic tools for this kind of cancer are still under investigation. Multiple mechanisms existing in the ovarian tumour network create a specific immunosuppressive microenvironment, in which accumulation of myeloid-derived suppressor cells (MDSCs) may be a critical component for diagnosis and treatment. This review attempts to verify current knowledge on the role of MDSCs in EOC.

Anti-Müllerian hormone: structure, properties and appliance.

Anti-Müllerian hormone (AMH) is a glycoprotein produced by the granulosa cells of preantral and small antral follicles. AMH concentrations reflect ovarian physiology with high precision, thus serving as a more sensitive marker of the ovarian reserve than the chronological age. This hormone plays a role in the pathogenesis of menstrual disorders and fertility in obesity and polycystic ovary syndrome. The evaluation of AMH may also be useful in the diagnosis or the monitoring therapy of granulosa cells ovarian tumors.

Tumor-Associated Macrophages and Myeloid-Derived Suppressor Cells as Immunosuppressive Mechanism in Ovarian Cancer Patients: Progress and Challenges.

Cancers are complex masses of malignant cells and nonmalignant cells that create the tumor microenvironment (TME). Non-transformed cells of the TME such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been observed in the TME of ovarian cancer (OC) patients. Although these subsets may contribute to each step of carcinogenesis and are commonly associated with poor prognosis, still little is known about creation of the protumor microenvironment in OC. In this review, we focused on the nature and prognostic significance of TAMs and MDSCs in OC patients. Moreover, we discuss the main problems and challenges that must be overcome by researchers and clinicians to enrich our knowledge about the immunosuppressive microenvironment of cancers.