The immune system and endometriosis

The article analyzes the literature data on the immune system and endometriosis. The features of the immune system, as well as the mechanisms of endometriosis development in the case of immune system dysfunction, are considered. Aim. To study the role of the immune system in the pathogenesis of endometriosis. Material and methods. To analyze the literature, we searched for information about this problem up to 10 years deep in PubMed/MEDLINE, PMC, and Web of Sсiеnce. The following terms were used individually or in combination: "genital endometriosis", "immune system", "cytokines", "autoantibodies". The search criteria were key studies related to genital endometriosis and the immune system: meta-analyses, original studies, retrospective and cohort studies. Results and discussion. There is a need to improve understanding of the potential origin of the General immunopathophysiology of endometriosis in order to identify therapeutic target areas that may allow relief or, ultimately, prevention of this disease. Immunological markers in this aspect have certain prospects. Conclusion. Although the role of cytokines in the development of endometriosis has been determined, it is not well understood. In this regard, it is difficult to clearly determine how they affect the pathogenesis of endometriosis. Keywords: endometriosis, immune system, cytokines, autoantibodie.

PENGARUH FLAVONOID EKSTRAK MAHKOTA DEWA (PHALERIA MACROCARPA) TERHADAP PENINGKATAN INDEKS APOPTOSIS PADA PERITONEAL MENCIT MODEL ENDOMETRIOSIS

Background: Endometriosis is one of the main reproductive problems today because the incidence is quite high. The development and progression of endometriosis cells results from an abnormal balance between cell proliferation and apoptosis. Cell apoptosis is triggered by an imbalance between positive signals (cell growth factors) and negative signals (DNA damage) in endometriosis. The anti-cancer effect of Mahkota Dewa has been shown to suppress cancer growth and inhibit cancer cell invasion through inhibition of proliferation and anti-apoptotic activity, Purpose: This study aimed to determine the effect of giving flavonoid extract from Mahkota Dewa fruit on the apoptotic index in endometriosis model mice. Methods: This research is an experimental study conducted at the Laboratory of the Faculty of Veterinary Medicine, Airlangga University, Surabaya. The sample used mice (Mus musculus) endometriosis model. The study was divided into 6 groups: negative control, positive control and treatment with the flavonoid extract of the Mahkota Dewa fruit at a dose of 3.75 mg/day, 7.5 mg/day, 11.25 mg/day and 15 mg/day. Measurement of apoptotic index using Tunel kit immunohistochemistry. Observational data were analyzed by ANOVA dan Tukey. Results: There was significant difference in the mean apoptotic index of the five groups of observational samples, the mean value of the apoptotic index was found between the KP group (7.96 ± 1.02) and the group given flavonoid extract from the Mahkota Dewa fruit group P1 at a dose of 3.75 mg (5.36 ± 0.91), P2 dose 7.5 mg (3.4 ± 0.49), P3 dose 11.25 mg (3.88 ± 0.59), P4 dose 15 mg (3.96 ± 0.75). Conclusion: The administration of flavonoid extract of the Mahkota Dewa fruit had a significant effect on increasing cell apoptotic index in endometriosis model mice.Suggestion Further study is needed to see the effect of flavonoid extract of Mahkota Dewa on rabbit experimental animals. Keywords: endometriosis, flavonoid extract of Mahkota Dewa fruit, apoptotic index ABSTRAK Latar Belakang: Endometriosis menjadi salah satu masalah reproduksi utama saat ini karena angka kejadian cukup tinggi. Perkembangan dan progresi sel endometriosis akibat terjadinya abnormalitas keseimbangan antara proliferasi dan apoptosis sel. Apoptosis sel dipicu karena adanya ketidakseimbangan antara sinyal positif (faktor pertumbuhan sel) dan sinyal negatif (kerusakan DNA) pada kondisi endometriosis. Efek anti kanker mahkota dewa terbukti dapat menekan pertumbuhan kanker dan menghambat terjadinya invasi sel kanker melalui penghambatan aktivitas proliferasi dan anti apoptosis.Tujuan: Penelitian ini bertujuan untuk mengetahui efek pemberian flavonoid ekstrak dari buah mahkota dewa terhadap indeks apoptosis pada mencit model endometriosis.Metode: Penelitian ini merupakan penelitian eksperimental yang dilakukan di Laboratorium Fakultas Kedokteran Hewan Universitas Airlangga Surabaya. Sampel menggunakan mencit (Mus musculus) model endometriosis. Penelitian dibagi menjadi 6 kelompok, yaitu : kontrol negatif, kontrol positif dan perlakuan pemberian ekstrak flavonoid buah mahkota dewa dosis 3,75 mg/hari, 7,5 mg/hari, 11,25 mg/hari dan15 mg/hari. Pengukuran indeks apoptosis menggunakan imunohistokimia Tunel kit. Data hasil pengamatan dianalisis dengan uji ANOVA dan Tukey. Uji statistik dikatakan bermakna bila p<0,05.Proses penghitungan dilakukan dengan bantuan piranti lunak (soft-ware) SPSS for windows 19.0.Hasil: Terdapat perbedaan yang bermakna rerata indeks apoptosis kelima kelompok sampel pengamatan didapatkan nilai rerata indeks apoptosis antara kelompok K- (7.96 ± 1.02) dengan kelompok pemberian ekstrak flavonoid dari buah mahkota dewa kelompok P1 dosis 3,75 mg (5.36 ± 0.91), P2 dosis 7,5 mg (3.4 ± 0.49), P3 dosis 11,25 mg (3.88 ± 0.59), P4 dosis 15 mg (3.96 ± 0.75).Kesimpulan: Pemberian ekstrak flavonoid buah mahkota dewa memberikan pengaruh yang signifikan terhadap peningkatan indeks apoptosis sel pada mencit model endometriosis.Saran Perlu studi lanjut untuk melihat pengaruh flavonoid ekstrak mahkota dewa pada hewan coba kelinci. Kata Kunci: endometriosis, flavonoid ekstrak buah mahkota dewa, indeks apoptosis

Correlation Between Levels of Interleukin-6 in Peritoneal Fluid With Degree of Pain, Adhesion, and Endometriosis Fertility Index Score in Endometriosis

Introduction : Endometriosis is a benign gynecological disorder characterized by the presence of endometrial tissue and stroma outside the uterine cavity. Several theories have been proposed to explain the occurrence of endometriosis, one of which is the theory of inflammation. Endometriosis lesions can produce inflammatory cytokines, resulting in their increased levels in the peritoneal fluid. This process causes disruption in pelvic anatomy, ovarian function, prostaglandin production and growth factor production that causes pain, adhesions and infertility. Interleukin-6 (IL-6) is an important and potential inflammatory cytokine in assisting the diagnosis of endometriosis. These cytokines act as activating macrophages that can stimulate endometrial cell proliferation and modulate the secretion of other cytokines such as IL-10, IL-13 and TNF-α which augments the inflammatory process. High levels of IL-6 in the peritoneum are relatedto advanced endometriosis associated with pain, severe pelvic adhesions and embryotoxic effects leading to infertility. The effect of IL-6, both local and systemic, on the growth of endometriosis lesions and its associated symptoms is great that this cytokine is considered an important marker.Objective : This study aims to determine the relationship between local inflammatory factors (IL-6 in peritoneal fluid) obtained during laparoscopy with the degree of pain, the degree of adhesions and the correlation with the Endometriosis Fertility Index (EFI) score in endometriosis patients.Material and methods : This is a quantitative analytic research with a cross sectional study design which was conducted on 22 patients with endometriosis. Prior to the laparoscopy, historical factor (EFI score) was recorded and an assessment of the pain scale was performed by filling out a questionnaire. Intraoperatively, the peritoneal fluid was obtained. If the peritoneal fluid was found, it was taken directly with a volume of 3-5 cc using 10 cc syringe. If no fluid was found, peritoneal rinsing was performed using 0.9% NaCl fluid, then 3-5 cc fluid was aspirated using a 10 cc syringe. Subsequently, an examination was carried out using the RayBio Human IL-6 ELISA Kit. During the laparoscopy procedure, the degree of adhesion of the pelvic organs was assessed by looking at the shape and how the adhesions can be separated. Surgical factor (EFI score) was assessed intraoperatively to obtain data for the least function score, AFS endometriosis score and AFS total score. Statistical analysis was performed using paired t test and correlation test.Results : The mean age of the respondents was 34.86 ± 6.11 years, 81.8% were nulliparous, 100% were married, 100% experienced both primary and secondary infertility and 81.8% had no prior pregnancy history. In the study, it was found that IL-6 levels of peritoneal fluid were higher in patients with the degree of severe pain (P <0.05) compared to moderate with the results of 32.58 ± 7.31 pg/ml and 25.39 ± 2.70 pg/ml. IL-6 levels were found to be higher in grade three adhesions than grade two (P <0.05) with results of 32.78 ± 6.65 pg/ml and 23.86 ± 2.18 pg/ml. The mean peritoneal fluid IL-6 levels were 30.75 ± 7.01 pg/ml and the mean EFI score was 4.09 ± 2.09. The correlation of IL-6 levels in peritoneal fluid with EFI score showed a value of r = -0.448 which had moderate strength and a negative pattern, indicating that the higher the IL-6 level of peritoneal fluid, the lower the EFI score (P <0.05).Conclusion : There is a relationship between IL-6 levels of peritoneal fluid in endometriosis with the degree of pain and the degree of adhesion, where IL-6 levels were found to be higher in the degree of severe than moderate pain (P <0.05), higher in third degree adhesions than second degree ( P <0.05). There was a correlation between IL-6 levels of peritoneal fluid with EFI score (P <0.05) with a negative pattern of moderate strength analysis results (r = -0.448).Keywords: Endometriosis, Interleukin-6, Degree of Pain, Degree of Adhesion, Endometriosis Fertility Index Score

Endometriosis diagnosis and medical treatment: Present and future

The objective was to review the different diagnostic methods and medical treatments for endometriosis. It was reviewed the Latin-American and international bibliography using the Pub-Med, Google Scholar, Springer, the Cochrane Library, Embase, Scielo, Imbiomed-L, Redalyc, and Latindex websites. The searches included the keywords: endometriosis, endometriotic, endometrial and ectopic endometrium, angiogenesis, angiogenesis and endometriosis, endometriosis, and medical treatment, endometriosis, and new treatment.

Renal endometriosis mimicking a malignancy– a rare case of Reno-Mullerian fusion?

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

COVID-19 Compromises In The Medical Practice And The Consequential Effect On Endometriosis Patients

Background and purpose In response to the ongoing coronavirus disease 2019 (COVID-19) pandemic, self-isolation practices aimed to curb the spread of COVID-19 have severely complicated the medical management of patients suffering from endometriosis and their physical and mental well- being. Endometriosis, the main cause for chronic pelvic pain (CPP), is a highly prevalent disease characterized by the presence of endometrial tissue in locations outside the uterine cavity that affects up to 10% of women in their reproductive age. This study aimed to explore the effects of the global COVID-19 pandemic on patients suffering from endometriosis across multiple countries, and to investigate the different approaches to the medical management of these patients based on their self- reported experiences. Methods A cross-sectional survey, partially based on validated quality of life questionnaires for endometriosis patients, was initially created in English, which was then reviewed by experts. Through the process of assessing face and content validity, the questionnaire was then translated to fifteen different languages following the WHO recommendations for medical translation. After evaluation, the questionnaire was converted into a web form and distributed across different platforms. An analysis of 2964 responses of participants from 59 countries suffering from self-reported endometriosis was then conducted. Results The data shows an association between COVID-19 imposed compromises with the reported worsening of the mental state of the participants, as well as with the aggravation of their symptoms. For the 1174 participants who had their medical appointments cancelled, 43.7% (n=513) reported that their symptoms had been aggravated, and 49.3% (n=579) reported that their mental state had worsened. In comparison, of the 1180 participants who kept their appointments, only 29.4% (n=347) stated that their symptoms had been aggravated, and 27.5% (n=325) stated their mental health had worsened. 610 participants did not have medical appointments scheduled, and these participants follow a similar pattern as the participants who kept their appointments, with 29.0% (n=177) reporting aggravation of symptoms and 28.2% (n=172) reporting that their mental state had worsened. Conclusions These findings suggest that COVID-19 pandemic has had a clinically significant negative effect on the mental and physical well-being of participants suffering from endometriosis based on their self-reported experiences. Thus, they show the importance of further assessment and reevaluation of the current and future management of this condition in medical practices worldwide. Keywords Endometriosis, COVID-19, questionnaire, Quality of life, Mental health, Physical health

Pathogenesis of Implantation Incompetence of Endometrium in Endometriosis-Associated Infertility

Study Objective: To expand the idea of the pathogenesis of implantation incompetence of endometrium in women with endometriosis-associated infertility. Study Design: open perspective comparative study. Materials and Methods. The study enrolled 78 women. The study group included 32 patients with endometriosis genitalis externa (EGE) and infertility; the comparison group included 33 patients with EGE who used their reproductive function not more than 3 years before the study and who were not diagnosed with infertility; the group of morphological control made 13 fertile women without EGE. The subject of the study was endometrium biopsy material obtained on day 5–7 of menstruation, following the peak blood concentration of luteinizing hormone during the expected implantation window. Study Results. When patients with endometriosis-associated infertility were compared to fertile women with EGE, we noted increased expression of GATA2 — 1.6-fold, GATA6 — 1.7-fold, SF-1 — 1.5-fold and reduced HOXA10 expression by 2.9 times (p < 0.05 in all cases) in stroma of infertile women. When patients with endometriosis-associated infertility were compared to fertile women without EGE, we recorded statistically significant (р < 0.05) increase in expression of GATA2 in stroma (2.5-fold) and glands (2.2-fold), GATA6 and SF-1 in stroma (2-fold in both cases), and reduced HOXA10 expression both in stroma (3.6-fold) and glands (2.8-fold). Conclusion. Pathogenesis of implantation incompetence of endometrium in endometriosis-associated infertility is caused by impaired endometrium receptivity because of aberrant expression of transcription factor affecting local hormonal balance. Keywords: endometriosis-associated infertility, implantation incompetence of endometrium

Genital endometriosis: pathogenesis, diagnosis, and association with malignancies

Endometriosis is a hormone-dependent genetic disease that develops in impaired immune homeostasis. However, its pathogenesis remains an enigma. It is known that eutopic endometrium in women with endometriosis is different from that in healthy women. Morphologic examination of eutopic endometrium sample allows diagnosing endometriosis at an early stage. To date, the association between endometriosis and the risk of malignancies is in strong focus. Endometriosis is a benign disorder but shares similarities with malignancies, e.g., apoptosis resistance and stimulation of angiogenesis. Recent findings suggest that endometriosis is a precursor of clear cell and endometrioid ovarian cancer. Further studies are needed to identify novel markers of endometriosis for its timely diagnosis. Timely and adequate therapy reduces the prevalence of ovarian tumors. Further development of molecular studies on endometriosis and ovarian cancer predictors will uncover pathogenic mechanisms and find potential preventive and treatment modalities. KEYWORDS: endometriosis, ovarian cancer, eutopic endometrium, ectopic endometrium, apoptosis, angiogenesis. FOR CITATION: Il’ina I.Yu., Burdin D.V., Narimanova M.R., Ibragimova D.M. Genital endometriosis: pathogenesis, diagnosis, and association with malignancies. Russian Journal of Woman and Child Health. 2021;4(4):339–345 (in Russ.). DOI: 10.32364/2618-8430- 2021-4-4-339-345.

Promising diagnostic tools for endometriosis given the pathogenic role of genetic factors

This paper discusses promising diagnostic modalities for endometriosis considering current ideas about the role of genetic factors in the pathogenesis of this condition. The hypotheses on pathogenesis and modern diagnostic approaches are addressed. The authors uncover the issues of genetic predisposition to endometriosis. The inhibition of tumor suppressor genes (CDKN2B, CDKN2 A, and ARF) and the activation of genes of early (embryonic) development of the female reproductive system (HOXA, HOXB, WNT4) lead to endometrial metaplasia. As a result, endometrial cells gain the ability to proliferate. The role of microRNA in the impaired regulation of the methylation of various genes associated with endometriosis is described. These factors specifically affect the course and clinical manifestations of endometriosis. Certain key proteins involved in the pathogenesis of endometriosis and whose synthesis is controlled by microRNA may be regarded as the diagnostic markers of endometriosis. Their in-depth study will identify novel therapeutic targets and promote the development of new non-hormonal treatment approaches to endometriosis. KEYWORDS: endometriosis, proliferation, endometrium, genes, polymorphism, diagnostic, epigenetics, microRNA. FOR CITATION: Ikhtiyarova G.A., Aslonova M.Zh., Kurbanova Z.Sh., Kalimatova D.M. Promising diagnostic tools for endometriosis given the pathogenic role of genetic factors. Russian Journal of Woman and Child Health. 2021;4(1):12–16. DOI: 10.32364/2618-8430- 2021-4-1-12-16.

Impaired Expression of Estrogen and Progesteron Receptors During the Implantation Window in Eutopic Endometrium of Infertile Women Associated with Endometriosis Genitalis Externa

Study Objective: To study impaired expression of estrogen (ER) and progesteron (PR) receptor isoforms during the implantation window in eutopic endometrium of infertile women associated with endometriosis genitalis externa (EGE). Study Design: open perspective comparative study. Materials and Methods. The study included 32 patients with endometriosis-associated infertility and implantation failures within the scope of assisted reproductive technology programme (study group), and 33 fertile women with EGE rAFS (stages I to IV) (comparison group). We performed morphological and immunohistochemical examination of endometrium biopsy samples (pipelle biopsy) during an expected implantation window. Study Results. Eutopic endometrium of women with EGE and infertility during the implantation window demonstrated statistically higher (р < 0.05) expression of ERα (19-fold), ERβ (2.3-fold) in stroma and PR-B in glands (1.7-folds) as compared to fertile women win EGE with lower PR-A expression in stroma (2.5-fold). Conclusion. The morphofunctional condition of endometrium and its receptive properties during the implantation window in women with endometriosis-associated infertility reflect the nature of ER (α and β) and PR (А and В) isoforms expression, the abnormalities underlying the endometrium receptivity disorders, with clinical manifestations being absent pregnancy. Keywords: endometriosis-associated infertility; implantation window; endometrium receptivity