Chronic endometritis - is it time to clarify diagnostic criteria?

Chronic endometritis is a persistent, low-intensity inflammation of endometrial mucosa, characterized by the infiltration of plasma cells into the endometrial stroma This immunological alteration is thought to be a consequence of a bacterial infection. For a long time, chronic endometritis was poorly investigated and rarely considered in clinical practice because it is either asymptomatic or presents with no specific symptoms. Its association with adverse effects on fertility and retrospectively reported effectiveness of antibiotic treatment were the main reasons for a growing interest in this endometrial pathology. Chronic endometritis is now a hot topic in recurrent pregnancy loss and recurrent implantation failure research. Nevertheless, there are still no recommendations to include chronic endometritis investigation in a clinical evaluation of infertile patients. The uncertain role of this condition is an effect of significant differences in study results presented by different research groups. One important reason for these inconsistent findings is a lack of standardised chronic endometritis diagnostic methods. We present a review of the literature, focusing on the currently available chronic endometritis diagnostic techniques. The review is subdivided into three parts concerning the diagnostic accuracy of three main diagnostic modalities. Histopathological examination of endometrial tissue, hysteroscopic evaluation of uterine cavity and identification of the bacterial factor. In conclusion, it is of great importance to establish a consensus on the diagnostic criteria for chronic endometritis. This is the only way to enhance international cooperation and create well-design multicenter studies to evidence the role of this endometrial pathology in infertility.

Endometriosis is associated with an increased whole-blood thrombogenicity detected by a novel automated microchip flow-chamber system (T-TAS®).

OBJECTIVES: Potential thrombotic and antifibrinolytic influence of endometriosis on haemostasis has been recently reported in the literature, as well as increased cardiovascular morbidity in women suffering from the disease. We performed a pilot study to assess the influence of endometriosis on the thrombus formation process under in vitro flow conditions. MATERIAL AND METHODS: This study compared women with confirmed endometriosis (n = 23) surgically and control healthy subjects (n = 10). In both groups, the same exclusion criteria were used: a prior episode of thrombosis diagnosed as acquired or inherited thrombophilia, neoplasm, and an uncertain family history of thrombosis. We evaluated the whole blood thrombogenicity using T-TAS® at a shear rate of 240 s-1 (Total-Thrombus Analysis System, Zacros, Japan). RESULTS: The blood clot formation initiation time (T10) and occlusion time (OT) were significantly shortened in the endometriosis group (p < 0.05). The area under the curve (AUC30) of blood clot time formation values (BCTF) was substantially higher in the patients suffering from a disease (p = 0.03). An increase in AUC (TTAS) values by 100 increases the risk of developing endometriosis by 1.56-fold [adjusted OR = 1.56 (p = 0.01); (95% CI: 1.10-2.18)]. Inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and the leucocyte, neutrophil, basophil, and neutrophil concentrations) were also substantially higher in the endometriosis group (p < 0.05). CONCLUSIONS: The alteration of the T-TAS® and NLR values supports the thesis of a shift of the equilibrium towards thrombosis in women who have endometriosis. This phenomenon links to a state of chronic inflammation. It is detectable using a novel system for the quantitative assessment of the platelet thrombus formation process under flow conditions in vitro.

Epigenetic Factors in Eutopic Endometrium in Women with Endometriosis and Infertility.

Eutopic endometrium in patients with endometriosis is characterized by aberrant expression of essential genes during the implantation window. It predisposes to disturbance of endometrial receptivity. The pathomechanism of implantation failures in women with endometriosis remains unclear. This paper aims to summarize the knowledge on epigenetic mechanisms in eutopic endometrium in the group of patients with both endometriosis and infertility. The impaired DNA methylation patterns of gene promoter regions in eutopic tissue was established. The global profile of histone acetylation and methylation and the analysis of selected histone modifications showed significant differences in the endometrium of women with endometriosis. Aberrant expression of the proposed candidate genes may promote an unfavorable embryonic implantation environment of the endometrium due to an immunological dysfunction, inflammatory reaction, and apoptotic response in women with endometriosis. The role of the newly discovered proteins regulating gene expression, i.e., TET proteins, in endometrial pathology is not yet completely known. The cells of the eutopic endometrium in women with endometriosis contain a stable, impaired methylation pattern and a histone code. Medication targeting critical genes responsible for the aberrant gene expression pattern in eutopic endometrium may help treat infertility in women with endometriosis.

Assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility.

Endometriosis is the cause of infertility. The eutopic endometrium of women with endometriosis showed an aberrant expression pattern of multitude genes. The role of TET1 protein in the pathogenesis of endometriosis and related infertility is not sufficiently known. Further, knowledge on TET1 transcriptional control still remains incomplete. The aim of the study was assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility. The study included 44 infertile patients with endometriosis (IWE) and 77 infertile (IW) and fertile (FW) patients without endometriosis. The research material was eutopic endometrium. The TET1 mRNA level was analyzed by qPCR. Western blot was used to evaluate the level of TET1 protein. The level of DNA methylation and H3K27me3 level of TET1 gene's promoter region were assessed using HRM and ChIP qPCR, respectively. The level of TET1 expression (TET1 mRNA; TET1 protein level) was lower in IWE during the implantation window (p < 0.001; p = 0.0329). The level of TET1 DNA methylation was higher in the secretory endometrium in mild and advanced IWE (p < 0.004; p < 0.008). H3K27me3 level did not differ between the study groups. The diminished expression of TET1 gene during the secretory phase, may account for the aberrant process of embryonic implantation in infertile endometriosis patients. DNA hypermethylation of TET1 gene is a potential relevant regulator of its expression. H3K27me3 occupancy does not affect the expression of TET1 gene in our study group.

Inflammatory rheumatic diseases and pregnancy.

Pregnancy in a patient diagnosed with systemic connective tissue disorder is a challenge that requires a close co-operation between a rheumatologist and gynaecologist. Good control over the activity of the underlying condition and the choice of appropriate time for planning a pregnancy have direct effect on the pregnancy results in these patients. Applying gynaecological supervision adequate to the increased risk of complications is also very important. The aim of this study is to present the current knowledge on the care over pregnant patients with systemic connective tissue diseases and to draw attention to the importance of pregnancy planning in this group of patients.

Alpha-1 Antitrypsin Z Variant (AAT PI*Z) as a Risk Factor for Intrahepatic Cholestasis of Pregnancy.

Background: Intrahepatic cholestasis of pregnancy (ICP; prevalence 0.2-15.6%) is the most common pregnancy-related liver disorder. It may have serious consequences for a pregnancy, including increased risk of preterm delivery, meconium staining of amniotic fluid, fetal bradycardia, distress, and fetal demise. In cases of high bile acids (>100µmol/L), patients have 10-fold increase in the risk of stillbirth. Biophysical methods of fetal monitoring, such as cardiotocography, ultrasonography, or Doppler have been proven unreliable for risk prediction in the course of intrahepatic cholestasis. Therefore, we believe extensive research for more specific, especially early, markers should be carried out. By analogy with cholestasis in children with inherited alpha-1 antitrypsin deficiency (AATD), we hypothesized the SERPINA1 Z pathogenic variant might be related to a higher risk of cholestasis in pregnancy. This study aimed to investigate the most common AATD variants (Z and S SERPINA1 alleles) in a group of cholestatic pregnant women. Results: The Z carrier frequency was calculated to be 6.8%, which is much higher compared to the general population [2.3%; the Chi-squared test with Yates correction is 6.8774 (p=0.008)]. Conclusion: Increased prevalence of SERPINA1 PI*Z variant in a group of women with intrahepatic cholestasis may suggest a possible genetic origin of a higher risk of intrahepatic cholestasis in pregnancy.

Poor glycaemic control contributes to a shift towards prothrombotic and antifibrinolytic state in pregnant women with type 1 diabetes mellitus.

OJECTIVES: Thrombotic and antifibrinolytic influence of Diabetes mellitus type 1 (T1DM) on haemostasis have been well demonstrated. There has been no research assessing the influence of poor glycemic control on thrombus formation under flow conditions in vitro or in pregnant type 1 diabetic women to date. PATIENTS/METHODS: This study compared singleton pregnant T1DM women (n = 21) and control pregnant subjects without any metabolic disease (n = 15). The T1DM group was divided into two subgroups of sufficient (SGC-DM; HbA1c ≤6,5%,n = 15) and poor glycaemic control (PGC-DM; HbA1c >6,5%,n = 6). Evaluation of the whole blood thrombogenicity we assessed using T-TAS® at a shear rate of 240 s-1 (Total-Thrombus Analysis System, Zacros, Japan). RESULTS: Blood clot formation initiation time (T10) was significantly shortened in PGC-DM subgroup when compared to SGC-DM subgroup (p = 0,03). The area under the curve (AUC30) of blood clot time formation and the MPV (mean platelet volume) values were substantially higher in the PGC-DM subgroup in comparison to the SGC-DM group (p = 0,03). Negative correlations were noted between HbA1c and T10 values (p = 0,02) and between T10 and MPV values in the T1DM group (p = 0,04). CONCLUSIONS: Poor glycaemic control in T1DM subjects triggers a shift towards a prothrombotic and antifibrinolytic state. This phenomenon can be detected using the novel system for quantitative assessment of the platelet thrombus formation process under flow conditions in vitro. The alteration of T-TAS values in PGC-DM subgroup proves that a poor glycemic control-related shift of the equilibrium toward thrombogenesis occurs in this group of patients. Our findings need a further elucidation in research on more massive data sets to be confirmed.

Evaluation of predictive value of biochemical markers for adverse obstetrics outcomes in pregnancies complicated by cholestasis.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is significantly more often associated with an abnormal perinatal outcome compared to a group of healthy pregnant women. The aim of the study was to analyse the correlation between the adverse perinatal outcome and the biochemical parameters in pregnancy complicated by cholestasis, and to assess their predictive value for neonatal complications. MATERIAL AND METHODS: Eighty-six patients with ICP were divided into 3 groups according to their fasting serum bile acid level [group I n = 60, 10-39.90 µmol/L; group II n = 20, 40-99.90 µmol /L; group III n = 6, TBA (total bile acids) ≥ 100.00 µmol/L]. Linear regression models were created to determine the relation of serum TBA, ALT, and AST concentration with total adverse perinatal outcome, defined as an occurrence of at least one perinatal outcome: stillbirth, preterm birth, spontaneous and iatrogenic preterm birth, presence of meconium in amniotic fluid, Apgar score (< 7 in 5th min), pH from umbilical artery (< 7.1), necessity for NICU admission, the presence of breathing disorders, and the need to perform phototherapy. RESULTS: TBA ≥ 40.00 µmol/L is connected to an elevated risk of the occurrence of total adverse perinatal outcome (OR = 4.17, p = 0.0037, AUC = 0.62, p = 0.046). TBA ≥ 40.00 µmol/L is a predictor of preterm birth (OR 2.3, p = 0.0117), iatrogenic preterm birth (OR 2.5, p = 0.006), admission to NICU (OR 2.38, p = 0.0094), intubation or assisted ventilation (OR 2.16, p = 0.0301), and phototherapy (OR 2.0, p = 0.0438). The threshold value of TBA for the need for phototherapy was 52.7 µmol/L (AUC = 0.67, p = 0.0089) and for preterm birth, 32.1 µmol/L (AUC = 0.62, p = 0.0251). CONCLUSIONS: Pregnant women with ICP and TBA serum level over 40.00 µmol/L have a worse prognosis regarding obstetric outcomes. The concentration of bile acids is a predictor of the occurrence of adverse perinatal outcomes, although the concentration of ALT and AST failed to show such a connection.