Purpose
Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE impairs proper ...decidualization and, subsequently, implantation. Although this correlation has been clearly clarified, a pathophysiological explanation assembling all the studies performed has not been elucidated yet. For this reason, we have structured a systematic review considering all the original articles that evaluated a pathological element involved in CE and implantation impairment.
Methods
The authors searched electronic databases and, after screening, collected 15 original articles. These were fully scanned and used to create a summary pathway.
Results
CE is primarily caused by infections, which lead to a specific cytokine and leukocyte pattern in order to prepare the uterus to fight the noxa. In particular, the immunosuppression requested for a proper semi-allogenic embryo transfer implantation is converted into an immunoreaction, which hampers correct embryo implantation. Moreover, endometrial vascularization is affected and both irregular vessel density and luminal thickening and thrombosis reduce what we have first identified as endometrial flow reserve. Finally, incorrect uterine wave propagation could affect embryo contact with decidua.
Conclusion
This is the first summary of evidence on CE pathophysiology and its relationship with infertility. Understanding the CE pathophysiology could improve our knowledge in embryo transfer success.
Chronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens such as Enterobacteriaceae, Enterococcus, Streptococcus, Staphylococcus, Mycoplasma, and ...Ureaplasma. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily culturable needing a turnaround time of up to 1 week.
We sought to develop a molecular diagnostic tool for chronic endometritis based on real-time polymerase chain reaction equivalent to using the 3 classic methods together, overcoming the bias of using any of them alone.
Endometrial samples from patients assessed for chronic endometritis (n = 113) using at least 1 or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture, were blindly evaluated by real-time polymerase chain reaction for the presence of 9 chronic endometritis pathogens: Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis vs the classic diagnostic techniques were compared in the 65 patients assessed by all 3 recognized classic methods.
The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.15%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double positive and 1 double negative), with an accuracy of 58.46%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.92%. When cases of potential contamination and/or noncultivable bacteria were considered, the accuracy increased to 66.15%. Of these 65 patients, only 27 patients had consistent histological + hysteroscopic diagnosis, revealing 58.64% of nonconcordant results. Only 13 of 65 patients (20%) had consistent histology + hysteroscopy + microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.92%. Interestingly, the molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of nonculturable microorganisms. These results were confirmed by the microbiome assessed by next-generation sequencing. In the endometrial samples with concordant histology + hysteroscopy + microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, and 0% false-positive and 25% false-negative rates.
The molecular microbiology method describe herein is a fast and inexpensive diagnostic tool that allows for the identification of culturable and nonculturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all 3 classic diagnostic methods together with a degree of concordance of 76.92% providing an opportunity to improve the clinical management of infertile patients with a risk of experiencing this ghost endometrial pathology.
The authors review aberrations of uterine anatomy and physiology affecting pregnancy outcomes with IVF. In the case of endometriosis and hydrosalpinx, pathologies outside of the uterus alter the ...uterine endometrium. In the case of endometriosis, Dominique de Ziegler outlines the numerous changes in gene expression and the central role of inflammation in causing progesterone resistance. With endometriosis, the absence of ovarian function inherent in deferred transfer, with or without a more lengthy suppression of ovarian function, appears to be sufficient to restore normal function of eutopic endometrium. Because laparoscopy is no longer routine in the evaluation of infertility, unrecognized endometriosis then becomes irrelevant in the context of assisted reproductive technology. With hydrosalpinx and submucus myomas, the implantation factor HOXA-10 is suppressed in the endometrium and, with myomas, even in areas of the uterus not directly affected. Daniela Galliano reviews various uterine pathologies, the most enigmatic being adenomyosis, where the endometrium also manifests many of the changes seen in endometriosis and deferred transfer with extended suppression appears to provide the best outcomes. Ettore Cicinelli's group has extensively studied the diagnosis and treatment of endometritis, and although more definitive diagnosis and care of this covert disorder may await techniques such as sequencing of the endometrial microbiome, it undoubtedly is an important factor in implantation failure, deserving our attention and treatment.
The need for anesthesia or analgesia for performing hysteroscopy is still matter of debate. Many factors explain the lack of agreement about anesthesia in hysteroscopy depending on the ...instrumentation, technique employed, need of performing surgical procedure, operator skill and patients' characteristics. Diagnostic minihysteroscopy (3.5 mm or less in size) is less painful and easier to perform than hysteroscopy performed with instruments sized around 5 mm. Thanks to miniaturized instruments, office hysteroscopy allows a growing number of women to be treated in an office setting avoiding the operating room. The main limitation to its widespread use is pain and low patient tolerance. Intrauterine surgical procedures involving only the endometrial mucosa (biopsies, adhesiolisis, cervical and endometrial polyectomies) are not painful. For endometrial polypectomy size of polyps (<2.2m) and duration of the procedure (more than 15 min) are limiting factors. Most literature suggests that office hysteroscopy in experienced hands is a well-tolerated technique and requires the use of analgesics only in selected patients like women with previous caesarean section, history of chronic pelvic pain, anxiety and in menopause.
To evaluate the association between endometriosis end chronic endometritis (CE) diagnosed by hysteroscopy, conventional histology, and immunohistochemistry.
Case-control study.
University hospital.
...Women with and without endometriosis who have undergone hysterectomy.
Retrospective evaluation of 78 women who have undergone hysterectomy and were affected by endometriosis and 78 women without endometriosis.
CE diagnosed based on conventional histology and immunohistochemistry with anti-syndecan-1 antibodies to identify CD138 cells.
The prevalence of CE was statistically significantly higher in the women with endometriosis as compared with the women who did not have endometriosis (33 of 78, 42.3% vs. 12 of 78, 15.4% according to hysteroscopy; and 30 of 78, 38.5% vs. 11 of 78, 14.1% according to histology). The women were divided into two groups, 115 patients without CE and 41 patients with CE. With univariate analysis, parity was associated with a lower risk for CE, and endometriosis was associated with a statistically significantly elevated risk of CE. Using multivariate analysis, parity continued to be associated with a lower incidence of CE, whereas endometriosis was associated with a 2.7 fold higher risk.
The diagnosis of CE is more frequent in women with endometriosis. Although no etiologic relationships between CE and endometriosis can be established, this study suggests that CE should be considered and if necessary ruled out in women with endometriosis, particularly if they have abnormal uterine bleeding. Identification and appropriate treatment of CE may avoid unnecessary surgery.
The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women-epithelial ovarian cancer, endometrial cancer ...and cervical cancer. Their
acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer
is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies.
The creation of new blood vessels from existing ones, which is a mechanism called "angiogenesis", is essential in cancer to supply cancerous growth. Moreover, the development and the progression of ...the tumor and its metastases are the result of an efficient vascular response. Cancer cells release and activate different angiogenic growth factors and their receptors in the tumor microenvironment to promote the angiogenic process. The most important pro-angiogenic factor is the "Vascular Endothelial Growth Factor" (VEGF) because of its mitogen activity on vascular endothelium. Bevacizumab is a monoclonal antibody that obstructs the binding of circulating vascular endothelial growth factor to its receptors and has been approved for the treatment of primary and recurrent ovarian cancer but also for many other solid tumors.
Background Although widely adopted, the use of a uterine manipulator during laparoscopic treatment of endometrial cancer represents a debated issue, and some authors hypothesize that it potentially ...may cause an increased risk of relapse, particularly at specific sites. Objective Our aim was to evaluate the risk and site of disease recurrence, overall survival, and disease-specific survival in women who had laparoscopic surgery with and without the use of a uterine manipulator. Study Design Data were reviewed from consecutive patients who had laparoscopic surgery for endometrial cancer staging in 7 Italian centers. Subjects were stratified according to whether a uterine manipulator was used during surgery; if so, the type of manipulator was identified. Multivariable analysis to correct for possible confounders and propensity score that matched the minimize selection bias were utilized. The primary outcome was the risk of disease recurrence. Secondary outcomes were disease-specific and overall survival and the site of recurrence, according to the use or no use of the uterine manipulator and to the different types of manipulators used. Results We included 951 patients: 579 patients in the manipulator group and 372 patients in the no manipulator group. After a median follow-up period of 46 months (range,12–163 months), the rate of recurrence was 13.5% and 11.6% in the manipulator and no manipulator groups, respectively ( P =.37). Positive lymph nodes and myometrial invasion of >50% were associated independently with the risk of recurrence after adjustment for possible confounders. The use of a uterine manipulator did not affect the risk of recurrence, both at univariate (odds ratio, 1.18; 95% confidence interval, 0.80–1.77) and multivariable analysis (odds ratio, 1.00; 95% confidence interval, 0.60–1.70). Disease-free, disease-specific, and overall survivals were similar between groups. Propensity-matched analysis confirmed these findings. The site of recurrence was comparable between groups. In addition, the type of uterine manipulator and the presence or not of a balloon at the tip of the device were not associated significantly with the risk of recurrence. Conclusion The use of a uterine manipulator during laparoscopic surgery does not affect the risk of recurrence and has no impact on disease-specific or overall survival and on the site of recurrence in women affected by endometrial cancer.
To assess the relationship between chronic endometritis (CE) and proinflammatory cytokine levels in menstrual effluents and to develop a simple noninvasive test for screening CE.
Case-control study.
...Academic center.
Sixty-four women referred to our center for infertility.
Office hysteroscopy; endometrial biopsy; collection of menstrual blood at subsequent cycle.
Interleukin (IL) 6, IL-1β, and tumor necrosis factor (TNF) α concentrations in menstrual effluents.
Thirty-six out of 64 infertile women had histologically proven CE. The remaining 28 women were included as controls. IL-6, IL-1β, and TNF-α levels were markedly higher in menstrual effluents of women with CE compared with control subjects. Receiver operating characteristic curve analysis revealed a good CE screening capacity for all of the cytokines. The combined evaluation of either IL-6/TNF-α or IL-6/IL-1β increased the diagnostic capacity of the test, which reached a 100% sensitivity and a negative predictive value of 100 when at least one cytokine was found to exceed its cutoff value; it also reached a 100% specificity and a positive predictive value of 100 in cases of positivity of both cytokines. Logistic regression analysis confirmed the IL-6/TNF-α-based model as a significant predictor of CE.
Proinflammatory cytokine levels are increased in menstrual effluents of women with CE. A test dosing IL-6 and TNF-α seems to have a high screening capacity for CE.
Purpose
The current gold standard for chronic endometritis (CE) diagnosis is immunohistochemistry (IHC) for CD-138. However, IHC for CD-138 is not exempt from diagnostic limitations. The aim of our ...study was to evaluate the reliability and accuracy of MUM-1 IHC, as compared with CD-138.
Methods
This is a multi-centre, retrospective, observational study, which included three tertiary hysteroscopic centres in university teaching hospitals. One hundred ninety-three consecutive women of reproductive age were referred to our hysteroscopy services due to infertility, recurrent miscarriage, abnormal uterine bleeding, endometrial polyps or myomas. All women underwent hysteroscopy plus endometrial biopsy. Endometrial samples were analysed through histology, CD138 and MUM-1 IHC. The primary outcome was to evaluate the diagnostic accuracy of MUM-1 IHC for CE, as compared with CD-138 IHC.
Results
Sensitivity and specificity of CD-138 and MUM-1 IHC were respectively 89.13%, 79.59% versus 93.48% and 85.03%. The overall diagnostic accuracy of MUM-1 and CD-138 IHC were similar (AUC = 0.893 vs AUC = 0.844). The intercorrelation coefficient for single measurements was high between the two techniques (ICC = 0.831, 0.761–0.881 95%CI). However, among CE positive women, MUM-1 allowed the identification of higher number of plasma cells/hpf than CD-138 (6.50 SD 4.80 vs 5.05 SD 3.37;
p
= 0.017). Additionally, MUM-1 showed a higher inter-observer agreement as compared to CD-138.
Conclusion
IHC for MUM-1 and CD-138 showed a similar accuracy for detecting endometrial stromal plasma cells. Notably, MUM-1 showed higher reliability in the paired comparison of the individual samples than CD-138. Thus, MUM-1 may represent a novel, promising add-on technique for the diagnosis of CE.
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