RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. AIMS OF THE STUDY: The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. MATERIALS AND METHODS: The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. RESULTS: WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. CONCLUSION: WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.
Assuntos
Diferenciação Celular , Medicamentos de Ervas Chinesas , Endometriose , Endométrio , Fibrose , Células-Tronco Mesenquimais , Camundongos Nus , Comunicação Parácrina , Endometriose/tratamento farmacológico , Endometriose/patologia , Endometriose/metabolismo , Feminino , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Humanos , Diferenciação Celular/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Camundongos , Células Cultivadas , Adulto , Modelos Animais de DoençasRESUMO
BACKGROUND: Endometrial Tuberculosis is one of the most common gynecological problems known to have serious implications for the quality of life like infertility. The commonly practiced histopathology solely relies on the suggestive feature of Tuberculosis (TB) with low specificity. Regarding the alternative bacteriological and molecular detection tools, little evidence was generated on their utility in the diagnosis of endometrial tuberculosis in Ethiopia. Therefore, we aim to investigate the detection rate of molecular and bacteriological detection methods on formalin-fixed paraffin-embedded biopsy samples for the diagnosis of endometrial and lymph node TB. METHODS: A retrospective cross-sectional study was conducted on 90 formalin fixed paraffin embedded biopsy samples from patients with gynecologic and lymph problems collected between 2018 and 2022 at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. SPSS version 26 was used for statistical analysis. The diagnostic performance was calculated using the histopathology method as the reference standard. Cohen's Kappa value was used to measure the level of agreement. A test with a P-value of < 0.05 was considered statistically significant. RESULTS: A total of 90 samples were analyzed in the current study. Auramine O, GeneXpert MTB/RIF assay, and Real-Time PCR tests have shown a detection rate of 32/90 (36%), 43/90 (47.8%), and 54/90 (60%) respectively (P ≤ 0.01). The sensitivity and specificity of AO were 38.1% and 95% respectively. RT PCR showed superior sensitivity followed by GeneXpert MTB/RIF assay, 70% and 58.6%. AO and molecular methods have shown a similarly low level of agreement with histopathology (Kappa value = 0.2). CONCLUSIONS: In a resource-limited setting, the selection of diagnostic tools needs careful attention. Putting the patients on anti-TB treatments based solely on histopathological findings may lead to undesired and adverse complications. Therefore, applying molecular and bacteriological detection methods along with histopathology, could help minimize inappropriate antimicrobial use.
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Endométrio , Mycobacterium tuberculosis , Inclusão em Parafina , Sensibilidade e Especificidade , Tuberculose dos Linfonodos , Humanos , Feminino , Estudos Transversais , Estudos Retrospectivos , Adulto , Endométrio/microbiologia , Endométrio/patologia , Biópsia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose dos Linfonodos/diagnóstico , Tuberculose dos Linfonodos/microbiologia , Tuberculose dos Linfonodos/patologia , Adulto Jovem , Etiópia , Linfonodos/microbiologia , Linfonodos/patologia , Formaldeído , Técnicas de Diagnóstico Molecular/métodos , Tuberculose dos Genitais Femininos/diagnóstico , Tuberculose dos Genitais Femininos/patologia , Tuberculose dos Genitais Femininos/microbiologia , AdolescenteRESUMO
PURPOSE: To investigate the correlation between hysteroscopic findings of chronic endometritis and CD138 immunohistochemistry positive in endometritis and to analyze the pregnancy outcomes and associated risk factors following embryo transfer in women diagnosed with chronic endometritis via hysteroscopy. METHODS: A retrospective observational study carried out at the Reproductive Medicine Center of Tangdu Hospital of Air Force Medical University, from January 2021 to December 2021, was performed by obtaining data from 194 medical records of women who underwent hysteroscopies for infertility and were diagnosed with chronic endometritis based on Delphi criteria. Spearman correlation analysis was used to evaluate the correlation between hysteroscopic findings and endometrial CD138 immunohistochemistry. The study also observed the differences in relevant indexes between the CD138-positive and CD138-negative groups after embryo transfer and analyzed factors influencing implantation failure using logistic regression analysis. RESULTS: The correlation analysis between hysteroscopic findings and CD138 immunohistochemistry showed that micropolyps were correlated with CD138 immunohistochemistry positivity. The correlation coefficient was 0.32 (P < 0.01). After embryo transfer, the clinical pregnancy rate of the CD138-positive group was lower compared to that of the CD138-negative group [64.79% (46/71) vs. 81.30% (100/123), P < 0.05]. The results of the multivariate logistic regression analysis revealed that age (P = 0.43) and CD138 immunohistochemistry positivity (P = 0.008) were the independent risk factors for predicting whether or not embryo implantation was successful. CONCLUSION: Hysteroscopic findings do not correlate strongly with endometrial CD138 immunohistochemistry, and chronic endometritis cannot be diagnosed by hysteroscopy alone. CD138 immunohistochemistry positivity is an independent factor contributing to the decrease in clinical pregnancy rate following embryo transfer.
Assuntos
Transferência Embrionária , Endometrite , Histeroscopia , Imuno-Histoquímica , Resultado da Gravidez , Taxa de Gravidez , Sindecana-1 , Humanos , Feminino , Gravidez , Sindecana-1/metabolismo , Endometrite/patologia , Endometrite/metabolismo , Histeroscopia/métodos , Adulto , Imuno-Histoquímica/métodos , Estudos Retrospectivos , Implantação do Embrião , Endométrio/patologia , Endométrio/metabolismo , Fertilização in vitro , Doença CrônicaRESUMO
OBJECTIVES: To transform the standardized descriptions of the ultrasound characteristics of endometrial and intrauterine lesions devised by the International Endometrial Tumor Analysis (IETA) group into a practical scoring method and to investigate whether application of this method enhances the diagnostic accuracy of ultrasound radiologists with different levels of experience in detecting malignancy compared with subjective assessment. METHODS: This was a retrospective study of 855 patients with endometrial and/or intrauterine lesions, who were divided into a training (n = 600) and a validation (n = 255) set. Ultrasound radiologists with varying levels of experience (expert, intermediate and junior) evaluated all lesions by subjective assessment and according to IETA rules. Using IETA rules, the experts identified signs of malignancy in the training set, assigned scores for each indicator and validated the scoring method in the validation set. The intermediate-level and junior ultrasound radiologists reassessed the malignancy of the lesions using the IETA scoring method and compared their classifications with those made previously by subjective assessment. Postsurgical pathological evaluation was used as the reference standard. RESULTS: Using subjective assessment, the experts demonstrated the highest level of diagnostic accuracy, with a sensitivity of 85.0%, specificity of 94.3% and an area under the receiver-operating-characteristics curve (AUC) of 0.897. Applying the IETA scoring method (comprising eight ultrasound characteristics that contributed to the total score) with a threshold of > 25 points for the diagnosis of malignancy achieved a sensitivity of 84.7%, specificity of 94.7% and AUC of 0.9533 in the training set, with similar performance in the validation set, when performed by experts. Using the IETA scoring method, both junior and intermediate ultrasound radiologists showed improvement in sensitivity (from 55.5% to 74.8% and from 70.2% to 77.1%, respectively), specificity (from 88.4% to 91.5% and from 87.4% to 92.2%, respectively) and AUC (from 0.704 to 0.827 and from 0.793 to 0.841, respectively) for diagnosing malignant lesions. CONCLUSIONS: The IETA scoring method exhibits high diagnostic efficacy for malignant endometrial and intrauterine lesions. This method compensates for the lack of experience among junior and intermediate-level ultrasound radiologists, enhancing their diagnostic skill to a level nearing that of experienced senior ultrasound radiologists. Further research is essential to validate the practicality of implementing this method and to confirm its clinical value. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
Neoplasias do Endométrio , Sensibilidade e Especificidade , Ultrassonografia , Humanos , Feminino , Estudos Retrospectivos , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Ultrassonografia/métodos , Pessoa de Meia-Idade , Adulto , Radiologistas , Competência Clínica , Endométrio/diagnóstico por imagem , Endométrio/patologia , Idoso , Neoplasias Uterinas/diagnóstico por imagem , Curva ROC , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: This prospective observational study aims to demonstrate the clinical efficacy of dienogest in treating endometriomas with a maximum diameter of ≥4 cm. METHODS: Patients (n = 81) with endometriomas (diameter of ≥4 cm) were enrolled and administered orally with dienogest (2 mg daily) and followed up for a year [Ethical approval code: 2020 Research 343]. Further, the efficacy was determined by recording the largest diameter and volume of the endometriomas, uterine volume, endometrial thickness, and the largest diameter of uterine fibroids in the patients during 0, 6, and 12 months. The pain symptoms were assessed using the Numerical Rating Scale (NRS), and the side effects of medication were monitored. With the consent, some patients underwent routine blood tests, and serum hormone, as well as Anti-Müllerian Hormone (AMH) levels were measured. RESULTS: The dienogest treatment resulted in a significant reduction of the maximum diameter of these cysts from 50.5 mm to 41 mm in 6 months and 34 mm in 12 months. In addition, the volume of the cysts significantly decreased from 37.8 ml from baseline to 18.5 ml in 6 months and 11.8 ml in 12 months. Among 26 subjects with ultrasonic signs of endometrial polyps, 92.3% of cases displayed no polyps after 12 months. No significant changes were observed in the size of uterine fibroids and AMH levels. The NRS score showed a decrease from an average of 6.6-1.2 in 12 months. CONCLUSION: Dienogest could effectively reduce the diameter and volume of endometriomas with a maximum diameter of ≥4 cm, improving anemia, as well as pain symptoms and preserving ovarian function.
Assuntos
Endometriose , Nandrolona , Humanos , Nandrolona/análogos & derivados , Nandrolona/uso terapêutico , Nandrolona/administração & dosagem , Nandrolona/farmacologia , Feminino , Endometriose/tratamento farmacológico , Endometriose/patologia , Adulto , Estudos Prospectivos , Resultado do Tratamento , Pessoa de Meia-Idade , Leiomioma/tratamento farmacológico , Leiomioma/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Endométrio/diagnóstico por imagemRESUMO
Intrauterine adhesion (IUA), also referred to as Asherman's syndrome, is characterized by fibrosis, inflammation, and can cause amenorrhea and infertility due to abnormal endometrial healing. Histological and Molecular methods were used to evaluate the efficacy of EPO, which is traditionally known for its anti-inflammatory and fibrinolytic properties, in preventing the formation of IUA. Oral administration of EPO reduced the formation of adhesion bands and promoted endometrial regeneration. EPO administration decreased extracellular matrix accumulation, evidenced by the down-regulation of tissue COL1A1 and COL3A1 expression. The anti-inflammatory effect of EPO was confirmed by a reduction in oxidants and down-regulation of pro-inflammatory cytokines including TNF-α, IL-6, IFN-γ, and IL-1ß. Furthermore, EPO improved embryonic development parameters, including size and weight of embryo, as well as increased embryo count and live embryo percentage in the rat IUA model. EPO also positively enhanced implantation markers, particularly enlargement and mass gain in the placenta of the treated group, consequently improving pregnancy outcomes such as the number of babies, percent of live babies, baby weight and gestation time. Histopathological investigation provides evidence that oral administration of EPO showed no toxicity on the main three organs including liver, kidney and heart. These results showed that EPO can be considered as a safe and natural product with potent anti-inflammatory and fibrinolytic properties without any observed side effects for the treatment of IUA.
Assuntos
Modelos Animais de Doenças , Fibrose , Inflamação , Resultado da Gravidez , Animais , Feminino , Gravidez , Ratos , Aderências Teciduais/tratamento farmacológico , Aderências Teciduais/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Extratos Vegetais/farmacologia , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Útero/efeitos dos fármacos , Útero/patologia , Útero/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/patologia , Endométrio/metabolismoRESUMO
BACKGROUND: Although clinical guidelines exist for diagnosing abnormal uterine bleeding, there is a significant lack of agreement on the best management strategies for women presenting with symptom, particularly in diagnosing endometrial cancer. This study aimed to develop a preoperative risk model that utilizes demographic factors and transvaginal ultrasonography of the endometrium to assess and predict the risk of malignancy in females with endometrial cancer. METHODS: In this retrospective study, a logistic regression model was developed to predict endometrial carcinoma using data from 356 postmenopausal women with endometrial lesions and an endometrial thickness (ET) of 5 mm or more. These patients had undergone transvaginal ultrasonography prior to surgery, with findings including 247 benign and 109 malignant cases. The model's predictive performance was evaluated using receiver operating characteristic (ROC) curve analysis and compared with post-surgical pathological diagnoses. RESULTS: Our model incorporates several predictors for endometrial carcinoma, including age, history of hypertension, history of diabetes, body mass index (BMI), duration of vaginal bleeding, endometrial thickness, completeness of the endometrial line, and endometrial vascularization. It demonstrated a strong prediction with an area under the curve (AUC) of 0.905 (95% CI, 0.865-0.945). At the optimal risk threshold of 0.33, the model achieved a sensitivity of 82.18% and a specificity of 92.80%. CONCLUSIONS: The established model, which integrates ultrasound evaluations with demographic data, provides a specific and sensitive method for assessing and predicting endometrial carcinoma.
Assuntos
Neoplasias do Endométrio , Endométrio , Pós-Menopausa , Ultrassonografia , Humanos , Feminino , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Ultrassonografia/métodos , Endométrio/diagnóstico por imagem , Endométrio/patologia , Hemorragia Uterina/etiologia , Curva ROC , Modelos Logísticos , Valor Preditivo dos Testes , Fatores de Risco , Índice de Massa Corporal , Medição de Risco/métodosRESUMO
The endocannabinoid system (ECS) plays a crucial role in reproductive health, but its function in postpartum dairy cows remains poorly understood. This study investigated the expression patterns of ECS-related genes in the endometrium of postpartum dairy cows and their associations with endometrial health and the presence of fatty liver. Endometrial biopsies were collected from 22 Holstein Friesian cows at 4 and 7 weeks postpartum. Gene expression was analyzed using RT-qPCR, focusing on key ECS components including CNR2, MGLL, FAAH1, NAAA, NAPEPLD, PADI4 and PTGDS. The results reveal dynamic changes in ECS gene expression associated with endometritis and fatty liver. MGLL expression was significantly upregulated in cows with endometritis at 7 weeks postpartum, while NAAA expression was consistently downregulated in cows with fatty liver. CNR2 showed a time-dependent pattern in endometritis, and PTGDS expression was elevated in clinical endometritis at 4 weeks postpartum. The presence of fatty liver was associated with altered expression patterns of several ECS genes, suggesting a link between metabolic stress and endometrial ECS function. These findings indicate a potential role for the ECS in postpartum uterine health and recovery, offering new insights into the molecular mechanisms underlying reproductive disorders in dairy cows and paving the way for novel therapeutic approaches.
Assuntos
Doenças dos Bovinos , Endocanabinoides , Endométrio , Fígado Gorduroso , Período Pós-Parto , Animais , Feminino , Bovinos , Endométrio/metabolismo , Endométrio/patologia , Endocanabinoides/metabolismo , Endocanabinoides/genética , Fígado Gorduroso/genética , Fígado Gorduroso/veterinária , Fígado Gorduroso/metabolismo , Período Pós-Parto/genética , Período Pós-Parto/metabolismo , Doenças dos Bovinos/genética , Doenças dos Bovinos/metabolismo , Endometrite/veterinária , Endometrite/genética , Endometrite/metabolismo , Regulação da Expressão GênicaRESUMO
BACKGROUND: Endometriosis is well known as a chronic inflammatory disease. The development of endometriosis is heavily influenced by the estrogen receptor ß (ERß), while NOD-like receptors (NLRs) family CARD domain-containing 5 (NLRC5) exhibits anti-inflammatory properties during endometriosis. However, whether NLRC5-mediated anti-inflammation is involved in the ERß-mediated endometriosis is still uncertain. This study aimed to assess that relation. METHODS: Nine cases of eutopic endometrial tissue and ten cases of ectopic endometrial tissue were collected from patients with endometriosis, and endometrial samples from ten healthy fertile women were analyzed, and the expression levels of ERß were quantified using immunohistochemistry (IHC). Subsequently, we constructed mouse model of endometriosis by intraperitoneal injection. We detected the expression of ERß, NLRC5, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 and measured the volume of ectopic lesions in mice with endometriosis. In vitro, human endometrial stromal cells (hESCs) were transfected respectively with ERß-overexpressing and NLRC5-overexpressing plasmids. We then assessed the expression of ERß and NLRC5 using quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, we measured the concentrations of TNF-α, IL-6, and IL-10 in the cell culture supernatant through enzyme-linked immunosorbent assay (ELISA). Additionally, we evaluated the migration and invasion ability of hESCs using transwell and wound healing assays. RESULTS: Inhibition of NLRC5 expression promotes the development of ectopic lesions in mice with endometriosis, upregulates the expression of pro-inflammatory factors TNF-α and IL-6, and downregulates the expression of anti-inflammatory factor IL-10. The high expression of NLRC5 in endometriosis depended on the ERß overexpression. And ERß promoted the migration of hESCs partially depend on inflammatory microenvironment. Lastly, NLRC5 overexpression inhibited ERß-mediated development and inflammatory response of endometriosis. CONCLUSIONS: Our results suggest that the innate immune molecule NLRC5-mediated anti-inflammation participates in ERß-mediated endometriosis development, and partly clarifies the pathological mechanism of endometriosis, expanding our knowledge of the specific molecules related to the inflammatory response involved in endometriosis and potentially providing a new therapeutic target for endometriosis.
Assuntos
Endometriose , Receptor beta de Estrogênio , Peptídeos e Proteínas de Sinalização Intracelular , Adulto , Animais , Feminino , Humanos , Camundongos , Modelos Animais de Doenças , Endometriose/metabolismo , Endometriose/patologia , Endometriose/genética , Endométrio/metabolismo , Endométrio/patologia , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Imuno-Histoquímica , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.
Assuntos
Endometriose , Macrófagos , Análise de Célula Única , Feminino , Análise de Célula Única/métodos , Animais , Humanos , Endometriose/metabolismo , Endometriose/patologia , Endometriose/genética , Camundongos , Macrófagos/metabolismo , Fenótipo , Endométrio/metabolismo , Endométrio/patologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/metabolismo , TranscriptomaRESUMO
Zearalenone (ZEA) is a mycotoxin produced by Fusarium fungi that has been shown to have adverse effects on human and animal health, particularly on the fertility of females. As a saponin derived from the medicinal plant Centella asiatica, asiaticoside (AS) has multiple bioactivities. This study aimed to investigate the protective effects of AS on ZEA-induced uterine injury and the underlying mechanism. In the present study, we demonstrated that AS could rescue ZEA-induced uterine histopathological damage and modulate the secretion of sex hormones, including progesterone (P4), luteinizing hormone (LH), and estradiol (E2), in ZEA-treated mice. Moreover, AS alleviated ZEA-induced damage to endometrial barrier function by upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-3). Further mechanistic investigations indicated that ZEA reduces the antioxidant capacity of uterine tissues, whereas AS improves the antioxidant capacity through activating the Nrf2 signaling pathway. Most notably, the protective effect of AS was blocked in Nrf2 gene knockout (Nrf2-/-) mice. Moreover, the p38/ERK MAPK pathway has been implicated in regulating ZEA toxicity and the beneficial effect of AS. Additionally, an Nrf2 inhibitor (ML385) weaken the suppressive effect of AS on the oxidative stress and MAPK pathway. AS also inhibits ZEA-induced apoptosis in uterine tissues via the PI3K/Akt signaling pathway. However, when the PI3K small molecule inhibitor LY294002 was co-administered, the ability of AS to suppress the expression of apoptosis-related proteins and inhibit ZEA-induced apoptosis decreased. Collectively, these findings reveal the involvement of multiple pathways and targets in the protective effect of AS against ZEA-induced uterine injury, providing a new perspective for the application of AS and the development of a ZEA antidote.
Assuntos
Apoptose , Endométrio , Estresse Oxidativo , Triterpenos , Útero , Zearalenona , Animais , Feminino , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/farmacologia , Zearalenona/toxicidade , Apoptose/efeitos dos fármacos , Camundongos , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , Transdução de Sinais/efeitos dos fármacos , Doenças Uterinas/patologia , Doenças Uterinas/metabolismo , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/prevenção & controle , Doenças Uterinas/genéticaRESUMO
Chronic endometritis (CE) is a frequent pathological condition that is defined as localized inflammation in the endometrium. Some adverse fertility consequences such as recurrent miscarriage and failure of implantation are associated with chronic endometritis. On the one hand, inflammation plays an important role in the pathogenesis of endometritis, and on the other hand, the role of viral infections in inducing inflammation can make this review strongly attractive and practical. We set out to provide an overview of viral infections as a potential etiology of CE pathophysiology through the alteration of an endometrial microenvironment and its association with infertility. To the best of our knowledge, this is the first review to demonstrate the role of viral infection in chronic endometritis, and whether or not infection ultimately plays a role..
Assuntos
Endometrite , Endométrio , Viroses , Humanos , Feminino , Endometrite/virologia , Endometrite/imunologia , Viroses/imunologia , Viroses/complicações , Endométrio/patologia , Endométrio/virologia , Endométrio/imunologia , Doença Crônica , Animais , Infertilidade Feminina/virologia , Infertilidade Feminina/imunologia , Infertilidade Feminina/etiologiaRESUMO
This study aimed to evaluate the localised effects of intrauterine ozone therapy on endometrial recovery in mares with endometritis. Our investigation assessed changes in gene expression profiles of anti-inflammatory (IL-1RA and IL-10), proinflammatory (IL-R1B3i and TNFα) and pleiotropic (IL-6) cytokines, along with detailed histological measurements of epithelial and endometrial thickness and the glandular area ratio. Twenty mares were assigned to a 2 × 2 factorial design based on endometritis diagnosis and treatment (control or 42 µg/mL ozone insufflation), resulting in four groups: NC (negative for endometritis/control), NO (negative/ozone), PC (positive/control) and PO (positive/ozone). Oestrus was induced with 2 mg of oestradiol benzoate on Days -1, 1 and 3, plus 1 mg on Day 5. Day 0 marked the initial uterine treatment, followed by insufflations on Days 1 and 2 with O3 (ozone) or O2 (control). Uterine biopsies were taken before treatment on Day 0 and Day 6 for histological analysis and gene expression assessment. Data were analysed using a statistical model that included endometritis status, treatment type, biopsy times (D0 and D6) and their interactions, analysed with Proc Glimmix. Regardless of treatment or endometritis status, significant biopsy effects (p < 0.01) indicated increased epithelial height and endometrial thickness in Day 6 samples. Analysis of IL-1 and TNFα revealed a significant interaction (p < 0.05) among endometritis, treatment and biopsy, with higher IL-1B3i expression on Day 6 in the PC group. The treatment effect (p < 0.04) showed a higher frequency (p < 0.01) of animals with positive modulation in the PC group (66.7%) versus the PO group (0.0%). An interaction effect (p = 0.08) between endometritis and treatment resulted from higher IL-1RA expression on Day 6 in the PC group compared to the PO group. Biopsy effect was significant for IL-10 (p < 0.01), indicating higher values in the second sample associated with tissue repair. In the short-term evaluation, ozone therapy did not influence endometrial morphology and may modulate cytokine expression, specifically the reduction in IL-1 and TNFα levels. Therefore, this therapy appears to be a safe and potentially effective treatment for modulating the inflammatory response in mares with endometritis.
Assuntos
Citocinas , Endometrite , Doenças dos Cavalos , Ozônio , Útero , Animais , Feminino , Ozônio/farmacologia , Endometrite/veterinária , Endometrite/tratamento farmacológico , Cavalos , Doenças dos Cavalos/tratamento farmacológico , Útero/patologia , Citocinas/genética , Citocinas/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Estradiol/farmacologia , Estradiol/análogos & derivados , TranscriptomaRESUMO
PROBLEM: Endometrial immune cells are essential for maintaining homeostasis and the endometrial receptivity to embryo implantation. Understanding regional variations in endometrial immune cell populations is crucial for comprehending normal endometrial function and the pathophysiology of endometrial disorders. Despite previous studies focusing on the overall immune cell composition and function in the endometrium, regional variations in premenopausal women remain unclear. METHOD OF STUDY: Endometrial biopsies were obtained from four regions (anterior, posterior, left lateral, and right lateral) of premenopausal women undergoing hysteroscopy with no abnormalities. A 15-color human endometrial immune cell-focused flow cytometry panel was used for analysis. High-dimensional flow cytometry combined with a clustering algorithm was employed to unravel the complexity of endometrial immune cells. Additionally, multiplex immunofluorescent was performed for further validation. RESULTS: Our findings revealed no significant variation in the distribution and abundance of immune cells across different regions under normal conditions during the proliferative phase. Each region harbored similar immune cell subtypes, indicating a consistent immune microenvironment. However, when comparing normal regions to areas with focal hemorrhage, significant differences were observed. An increase in CD8+ T cells highlights the impact of localized abnormalities on the immune microenvironment. CONCLUSIONS: Our study demonstrates that the endometrial immune cell landscape is consistent across different anatomical regions during the proliferative phase in premenopausal women. This finding has important implications for understanding normal endometrial function and the pathophysiology of endometrial disorders.
Assuntos
Microambiente Celular , Endométrio , Humanos , Feminino , Endométrio/imunologia , Endométrio/patologia , Adulto , Microambiente Celular/imunologia , Citometria de Fluxo , Pré-Menopausa/imunologia , Linfócitos T CD8-Positivos/imunologia , BiópsiaRESUMO
OBJECTIVE: Endometrial polyp (EP) is a type of pathology that is quite common in clinical practice. Although its exact etiology is not fully known, there is evidence to support that it is sensitive to hormonal stimuli. We aimed to investigate the relationship between kisspeptin (KP) and EP by comparing the genetic (tissue-blood) and immunohistochemical (IHC) expression of KP in EP lesions in patients with normal endometrial findings. MATERIALS AND METHODS: A prospective case-control study of 50 patients with EP (N = 25) and normal endometrial findings (N = 25) on biopsy and/or excision material was performed. Blood and biopsy samples obtained from all patients were stored at -80 °C. KP gene expression levels were determined from paraffin blocks, and peripheral venous blood samples obtained from biopsy specimens and IHC-H-score analysis were performed from paraffin blocks. EP and matched controls were compared for KP. RESULTS: After IHC, the KP H-score of the control group was higher than the EP group, and this difference was statistically significant; H-score: control: 5 (++; 1-15); polyp: 1 (+; 0-12) (P < 0.05). Although KP expression in both tissue and blood was higher in the control group than in the EP group, this difference was not statistically significant (P > 0.05). No significant correlation was found between IHC H-score and KP expression levels in tissue and blood. According to the ROC analysis, the tissue and blood KP expression cut-off value and area under the curve (AUC) predicting the likelihood of developing EP were not significant (tissue KP: 1.04, AUC: 0.570, P = 0.388, sensitivity 56%, specificity 60%, Blood KP: 1.06, AUC: 0.569, P = 0.401, sensitivity 80%, specificity 40%). CONCLUSIONS: Decreased KP expression level in EP lesions may predict the diagnosis of EP, and in the future, KP may have therapeutic potential for benign gynecological pathologies such as polyps.
Assuntos
Imuno-Histoquímica , Kisspeptinas , Pólipos , Humanos , Feminino , Pólipos/genética , Pólipos/metabolismo , Pólipos/patologia , Kisspeptinas/genética , Kisspeptinas/metabolismo , Estudos de Casos e Controles , Doenças Uterinas/genética , Doenças Uterinas/metabolismo , Doenças Uterinas/patologia , Doenças Uterinas/sangue , Estudos Prospectivos , Adulto , Endométrio/metabolismo , Endométrio/patologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin's effects on endometrial stromal cells. METHODS: Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin. RESULTS: Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype. CONCLUSIONS: These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis.
Assuntos
Senescência Celular , Endometriose , Proteínas Proto-Oncogênicas c-akt , Quercetina , Células Estromais , Proteína Supressora de Tumor p53 , Quercetina/farmacologia , Feminino , Humanos , Endometriose/metabolismo , Endometriose/patologia , Endometriose/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Senescência Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células CultivadasRESUMO
In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3 and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including ß-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure.
Assuntos
Apoptose , Endometriose , Transdução de Sinais , Animais , Feminino , Humanos , Camundongos , Apoptose/genética , Adesão Celular/genética , Proliferação de Células , Endometriose/metabolismo , Endometriose/patologia , Endometriose/genética , Endométrio/metabolismo , Endométrio/patologia , Interferons/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Células Estromais/metabolismoRESUMO
PURPOSE: The treatment of early miscarriage with medication is effective and low in side effects. Nevertheless, no uniform dosage regimen has yet been established, nor has it been possible to determine whether previous pregnancies and births with their respective modes of delivery play a role in the effectiveness of Misoprostol. This study aimed to find predictive parameters for successful treatment with Misoprostol in early miscarriage. METHODS: In a retrospective study at the Otto von Guericke University Women's Hospital, records of patients with early miscarriage and medical treatment using Misoprostol from 2018 to 2021 were reviewed for this purpose. The need for a curettage subsequent to treatment was scored as a parameter of failure. The data were analyzed using Statistical Package for the Social Science Version 28.0. The significance level was set to 0.050. RESULTS: We found that successful therapy with misoprostol was seen in 86% (n = 114). 14% (n = 20) of the patients had curettage after taking Misoprostol as advised. Out of 134 women, 16% (n = 21) reported mild side effects, with nausea as the leading one (9.2% (n = 12)). Significance was found comparing the measurement of double endometrial stripe thickness after the second cycle of Misoprostol in women with and without curettage after medical treatment (exact value two-sided 0.035 at p < 0.05). A cutoff value at 8.8 mm was calculated using ROC Analysis. CONCLUSIONS: Our results indicate that the treatment of early miscarriage in the first trimester with Misoprostol is effective and has few side effects. The measurement of the endometrial stripe thickness after the second cycle of Misoprostol via transvaginal ultrasound could present a predictive marker during therapy.
Assuntos
Abortivos não Esteroides , Aborto Espontâneo , Misoprostol , Humanos , Misoprostol/administração & dosagem , Misoprostol/uso terapêutico , Feminino , Estudos Retrospectivos , Abortivos não Esteroides/uso terapêutico , Abortivos não Esteroides/administração & dosagem , Adulto , Gravidez , Resultado do Tratamento , Primeiro Trimestre da Gravidez , Endométrio/efeitos dos fármacos , Endométrio/patologia , Endométrio/diagnóstico por imagem , Adulto JovemRESUMO
PURPOSE: This study was presented to investigate the clinical-pathological characteristics of gestational trophoblastic neoplasia (GTN) following non-molar pregnancy and differentiated with ectopic pregnancy (EP). METHODS: The clinical data of 83 patients who were admitted for suspected GTN after non-molar pregnancy at the Women's Hospital School of Medicine Zhejiang University from January 2015 to September 2022 were selected for analysis. RESULTS: In total, 41 cases were confirmed non-molar GTN, including 31 choriocarcinoma, 9 PSTT (placental site trophoblastic tumor), and 1 ETT (epithelioid trophoblastic tumor), while 42 cases were confirmed EP. Compared with ectopic pregnancy, non-molar GTN patients had lower levels of serum progesterone compared with EP (3.81 nmol/L vs 17.70 nmol/L, P = 0.001). Based on the ultrasound, the thickness of the endometrium was thinner in patients with non-molar GTN compared with EP (0.565 cm vs 0.70 cm, P = 0.018). By histopathologic examination, the endothelium of non-molar GTN showed less decidual-like changes compared with EP (64.3% vs 14.6%, P = 0.001). CONCLUSION: A combination of serum progesterone levels, endometrium thickness, and histopathologic features of the endometrium can help to differentiate non-molar GTN and EP. Surgeries including hysteroscopy with curettage and/or laparoscopy are needed.
Assuntos
Doença Trofoblástica Gestacional , Gravidez Ectópica , Progesterona , Humanos , Feminino , Gravidez , Adulto , Diagnóstico Diferencial , Doença Trofoblástica Gestacional/sangue , Doença Trofoblástica Gestacional/patologia , Doença Trofoblástica Gestacional/diagnóstico , Gravidez Ectópica/sangue , Gravidez Ectópica/diagnóstico , Gravidez Ectópica/patologia , Progesterona/sangue , Neoplasias Uterinas/patologia , Neoplasias Uterinas/sangue , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/cirurgia , Estudos Retrospectivos , Endométrio/patologia , Tumor Trofoblástico de Localização Placentária/patologia , Tumor Trofoblástico de Localização Placentária/sangue , Tumor Trofoblástico de Localização Placentária/diagnóstico , Tumor Trofoblástico de Localização Placentária/cirurgia , Ultrassonografia , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: COVID-19 vaccination has been related to menstrual irregularities; however, the effect on postmenopausal women is unknown. The aim of this study was to analyze the prevalence of postmenopausal bleeding (PMB) after COVID-19 vaccination. METHODS: A retrospective study was conducted in the Department of Gynecology in Hospital del Mar. Consecutive postmenopausal women with data available and endometrial biopsy were included between February 2021 and January 2022. Patients were stratified between COVID-19 vaccinated and unvaccinated groups. PMB after 30 days from last vaccine dose was considered unrelated to vaccine. Endometrial pathology diagnoses were stratified into benign or malignant. Univariable and multivariable of regression analysis on variables potentially associated with PMB was performed. RESULTS: A total of 381 patients were included, 91 in the vaccinated group and 290 in the unvaccinated group. Prevalence of PMB in the vaccinated group was 75.8% compared to 59.0% in the unvaccinated group (p < 0.005). No increase in endometrial malignant pathology was observed among the vaccinated group (p = 0.189). Multivariable analysis that correlates factors associated with PMB suggests COVID-19 vaccine and malignant endometrial biopsy as independent risk variables. CONCLUSIONS: A higher prevalence of PMB was associated with COVID-19 vaccine. Endometrial histological results showed no association with COVID-19 vaccination, but endometrial biopsy should be performed for PMB.