Search Results (105)

Understanding the molecular basis of endometrial receptivity is crucial for improving implantation outcomes in assisted reproduction, especially for patients with recurrent implantation failure (RIF). This study investigates the timing relationship between microRNA (miRNA) and messenger RNA (mRNA) profiles in the endometrium using simultaneously the endometrial receptivity array (ERA) and the microRNA receptivity assay (MIRA) in 100 RIF patients undergoing euploid blastocyst transfer. The concordance rate between ERA and MIRA was 72% (Kappa = 0.50), suggesting partial overlap in profiling. Patients were stratified by the timing sequence of miRNA relative to mRNA into Fast, Equal, and Slow groups. Those with delayed miRNA expression (Slow group) had significantly lower pregnancy rates (54.5%) than those with synchronous or leading miRNA expression (81.9% and 94.1%, respectively; p = 0.031). Moreover, the Slow group exhibited higher prior implantation failure counts and altered expression in 15 miRNAs, many involved in aging-related pathways. These findings highlight that asynchronous miRNA–mRNA profiles may reflect impaired receptivity and suggest that miRNA-based staging adds valuable diagnostic insight beyond mRNA profiling alone. Dual assessment of mRNA and miRNA profiles may offer additional diagnostic insight into endometrial receptivity but requires further validation before clinical application. Full article

Tissue remodeling of human endometrium occurs during the menstrual cycle to prepare for embryo adhesion and invasion. The ovarian steroid hormones 17β-estradiol and progesterone control the menstrual cycle to achieve the receptive state during the “window of implantation” (WOI). Here, we focus on the human endometrial epithelium and its changes in polarity, adhesion, cytoskeletal organization and the underlying extracellular matrix enabling embryo implantation. The adhesion and invasion of the trophoblast via the apical plasma membrane of epithelial cells is a unique cell biological process, which is coupled to partial epithelial–mesenchymal transition (EMT). Given the fundamental species differences during implantation, we restrict the review mainly to the human situation and focus on cell culture systems to study the interaction between human trophoblast and endometrial cells. We summarize current knowledge based on the relatively scarce in vivo data and the steadily growing in vitro observations using various cell culture systems. Full article

Background: Recurrent implantation failure (RIF) poses a major challenge in assisted reproductive technologies, with thin endometrium (≤7 mm) being a frequently observed yet poorly understood condition. Emerging evidence implicates nuclear factor-kappa B (NF-κB), a key transcription factor in inflammatory signaling, in impaired endometrial receptivity. However, its clinical relevance and prognostic value for live birth outcomes still need to be fully elucidated. Objective: We aim to evaluate the expression levels of endometrial NF-κB in patients with RIF and thin endometrium and to determine its potential as a predictive biomarker for live birth outcomes following IVF treatment. Methods: In this prospective case–control study, 158 women were categorized into three groups: Group 1 (RIF with thin endometrium, ≤7 mm, n = 52), Group 2 (RIF with normal endometrium, >7 mm, n = 38), and fertile controls (n = 68). NF-κB levels were assessed using ELISA and immunohistochemical histoscore. Pregnancy outcomes were compared across groups. ROC analysis and multivariable logistic regression were performed to assess the predictive value of NF-κB. Results: NF-κB expression was significantly elevated in Group 1 compared to Group 2 and controls (p = 0.0017). ROC analysis identified a cut-off value of 7.8 ng/mg for live birth prediction (AUC = 0.72, sensitivity 74%, specificity 75%). Multivariable analysis confirmed NF-κB is an independent predictor of live birth (p = 0.045). Histological findings revealed increased NF-κB staining in luminal and glandular epithelial cells in the thin endometrium group. Conclusions: Increased endometrial NF-κB expression is associated with thin endometrium and reduced live birth rates in RIF patients. NF-κB may serve not only as a biomarker of pathological inflammation but also as a prognostic tool for treatment stratification in IVF. Based on findings in the literature, the therapeutic targeting of NF-κB may represent a promising strategy to improve implantation outcomes. Full article

Chronic endometritis (CE) is a persistent, often asymptomatic inflammatory condition of the endometrium, increasingly recognized as a potential contributor to infertility and recurrent implantation failure. Despite its clinical significance, CE remains underdiagnosed due to a lack of standardized diagnostic criteria and its subtle clinical presentation. Objective: This review aims to synthesize the current evidence on the pathophysiology, diagnosis, and treatment of CE, highlighting its impact on reproductive outcomes and the effectiveness of therapeutic interventions. A comprehensive literature review was conducted, analyzing 85 peer-reviewed studies published in the last decade, of which 65 were deemed relevant and retained for further analysis. These studies were selected based on their relevance to the pathophysiology, diagnostic methodologies, and treatment outcomes for CE, focusing on their implications for fertility and assisted reproductive technologies (ARTs). The findings suggest that CE is associated with impaired endometrial receptivity, increased inflammatory markers, and reduced implantation and pregnancy rates with ARTs. Histopathological assessment using CD138 immunostaining remains the gold standard for diagnosis, while hysteroscopy and molecular microbiological techniques provide complementary diagnostic value. Antibiotic treatment has been shown to significantly improve implantation rates and pregnancy outcomes, particularly in women with recurrent implantation failure. Emerging therapies, including probiotics and regenerative medicine approaches, are being explored as potential adjuncts to the conventional treatment. Early and accurate diagnosis of CE is essential for optimizing reproductive outcomes. Standardized diagnostic protocols and individualized treatment strategies are crucial for improving implantation success and pregnancy rates in affected women. Future research should focus on refining the diagnostic methods and exploring novel therapeutic options to enhance endometrial health and fertility outcomes. Full article

Endometrial organoids (EOs) have emerged as a powerful three-dimensional (3D) model for studying the human endometrium, offering new insights into infertility and reproductive disorders. These self-organizing miniature structures closely mimic the cellular composition, hormonal responsiveness, and functional characteristics of the endometrium, making them valuable preclinical tools for investigating implantation failure, endometrial receptivity, and disease pathophysiology. This review explores the role of EOs in reproductive medicine, with a focus on their applications in infertility research, environmental toxicology, and regenerative therapies. Traditional 2D cell cultures fail to capture the complexity of these physiological and pathological interactions, whereas organoids provide a physiologically relevant system for studying implantation mechanisms. Additionally, co-culture models incorporating stromal and immune cells have further enhanced our understanding of the maternal–fetal interface. Beyond modeling infertility, EOs hold significant promise for therapeutic applications. Advances in organoid transplantation have demonstrated potential for treating endometrial dysfunction-related infertility, including conditions such as Asherman’s syndrome and thin endometrium. Moreover, these models serve as a platform for drug screening and biomarker discovery, paving the way for personalized reproductive medicine. Despite their transformative potential, limitations remain, including the need for improved extracellular matrices, vascularization, and immune system integration. This review emphasizes the significant contributions of EOs to the field of infertility treatment and reproductive biology by examining recent advancements and emerging research. The continued refinement of these models would offer a paradigm for improving assisted reproductive technologies (ARTs) and regenerative medicine outcomes, offering new hope for individuals facing infertility challenges. Full article

Cellular senescence has emerged as a key mediator in organ-specific fibrosis. Here, we have established the role of endometrial stromal senescence in the progression of endometrial fibrosis, termed intrauterine adhesions (IUA). IUA have significant negative effects on women’s reproductive health and are associated with infertility. We have generated original gene signatures to identify endometrial stromal senescence in single-cell and bulk RNA-sequencing data. By applying generated gene signatures, we revealed an increased level of stromal senescence during the proliferative phase in the endometrium of patients with IUA. Further comparative analysis of cell–cell communications demonstrated that senescent stromal cells in the IUA endometrium create an immunosuppressive and profibrotic microenvironment through an elevated expression of LGALS9. Endometrial stromal senescence persists during the window of implantation and correlates with impaired embryo receptivity of the IUA endometrium. Therefore, stromal senescence can be regarded as a primary cause of an unresponsive endometrium with decreased receptivity and thickness in IUA patients. A LGALS9 immunotherapy protocol, specifically designed to neutralize LGALS9 immunosuppressive activity of senescent cells, may offer a promising opportunity to restore effective immune clearance of these cells within the IUA stroma. Consequently, an LGALS9-based strategy could emerge as a novel therapeutic avenue in the treatment of IUA. Full article

Platelet-rich plasma (PRP) is a concentrated product of autologous plasma platelets. It promotes the repair of tissues with low healing potential by providing supraphysiological amounts of essential growth factors and has recently become more popular in endometrial repair, achieving exciting clinical results. PRP treatment has proven to improve fertility outcomes in patients with a poor endometrial environment. However, the mechanism is not yet clear. Previous preclinical models also showed that PRP treatment decreased the expression of inflammatory markers and fibrosis, increased the endometrial proliferation rate and gene expression, and enhanced the pregnancy rate. The modulation of the endometrial immune environment and endometrial microbial community by PRP treatment appeared to be the key mechanism by which it improved endometrial receptivity. This review summarized the potential of adult PRP based on its composition and applications and the biological mechanisms and biological modifications in the endometrium after PRP instillation in preclinical models. Full article

It is a great challenge to obtain an ideal hydrogel for the clinical treatment of intrauterine adhesion (IUA) disease. Here, a novel injectable chitosan–lignin/poloxamer hydrogel loaded with platelet-rich plasma (CL-PF127@PRP) was prepared by self-assembly at room temperature. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), rheological analysis, and injectable writing were used to characterize the structure of the hydrogel. The results confirmed that the amino group of chitosan and the sulfonic group of sodium lignosulfonate were ionic-crosslinked by electrostatic attraction, which stabilized the three-dimensional structure of the PF127 hydrogel loaded with PRP, and PRP made the porous structure gradually become tight. Moreover, the CL-PF127@PRP hydrogel displayed good injectability and a solid state. The soaking experiment showed that the CL-PF127@PRP hydrogel had suitable degradation at pH = 7 and a good PRP release rate (PRP release 70% at 96 h). Cell experiments in vitro demonstrated that the CL-PF127@PRP hydrogel possessed good biocompatibility, an anti-inflammatory function, and pro-angiogenic activity. Furthermore, an animal experiment of skin wound and IUA confirmed that the skin wound closure rate of the CL-PF127@PRP hydrogel was over 50% on the seventh day. PRP improved the thickness of the endometrium and uterus receptivity, suggesting that the CL-PF127@PRP hydrogel offers great promise for the clinical treatment of IUA. Full article

Objective: This study investigated the effects of a supraphysiological dose of testosterone on uterine morphology and the regulation of the leukaemia inhibitory factor (LIF) signalling pathway during endometrial receptivity. Methods: In this study, 30 adult female Sprague–Dawley rats were divided into treatment and control groups. The treatment groups received subcutaneous injections of 1 mg/kg/day of testosterone from gestational day 1 to day 3, either testosterone alone or in combination with inhibitors (anastrozole, finasteride, or both). A control group of six untreated rats was maintained for comparison. Rats were euthanised on the evening of gestational day 4 to examine uterine morphological changes, gene expression and the distribution of proteins associated with the LIF signalling pathway (LIF, LIFR, JAK1 and STAT3) and MUC1 by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), respectively. Results: The results of this study showed that the thickness of the endometrium and myometrium, as well as the number of glands, markedly decreased in all testosterone-treated rats. In addition, the mRNA levels of LIF, LIFR, JAK1 and STAT3 were significantly downregulated in response to supraphysiological testosterone treatment, while the mRNA of MUC1 was significantly upregulated. The IHC results were consistent with the mRNA data and confirmed the changes in protein distribution in all treatment groups. Conclusions: A supraphysiological dose of testosterone may impair endometrial receptivity through dysregulation of the LIF signalling pathway, potentially affecting fertility. Full article

Background and Objectives: Autologous platelet-rich plasma (PRP) transfusions are a relatively new treatment method used in different fields of medicine, including the field of reproductive medicine. One of the applications of these concentrated platelet infusions is the treatment of endometrial receptivity, which is a key factor for embryo implantation. There are implications that PRP infusions can lead to increased endometrial thickness, endometrial receptivity, and significantly elevated clinical pregnancy rates. Our objective is to briefly understand what PRP is and to, through a narrative review, summarize the findings from studies focused on evaluating the benefits of PRP infusions to treat thin endometrium with the goal of achieving better endometrial receptivity. Materials and Methods: Reference data was searched using Medline, PubMed, and EMBASE to identify reports from 2015 to 2024. The combination of search words used was “PRP” and “platelet-rich plasma” with “thin endometrium”, “endometrial receptivity”, “endometrial thickness”, and “endometrial implantation”. Obtained articles were screened, and suited studies (randomized controlled trials, case reports, case series, pilot studies, and reviews) were included in the present review. Reports not available in the English language were eliminated from the current review. Results: The results from most of the reviewed studies showed a positive effect of autologous PRP infusions on increasing endometrial thickness, enhancing endometrial receptivity, and elevating clinical pregnancy rates. The majority of the evaluated findings revealed endometrial thickness > 7 mm (increased endometrial thickness was observed in each evaluated study) following the PRP treatment. More than 50% of the evaluated studies resulted in enhanced endometrial thickness, increased endometrial receptivity, and an elevated pregnancy rate after the PRP application. Conclusions: Autologous PRP infusions for treating endometrium are a relatively new method that has shown promising results. Its major strengths are availability and proper application, which eliminates possible immunological reactions or disease transmission. The main drawbacks are not enough data on safety (i.e., its effect on endometriosis) and the lack of uniformity in the PRP preparation, which would provide optimal standardized quality and quantity of the PRP product and, thus, optimal treatment results. Full article

Objectives: The downregulation of anti-adhesive regulatory proteins and upregulation of adhesive genes are critical for the receptive endometrium. This study was designed to determine whether switching between the anti-adhesive podocalyxin (PDX) and adhesive HOXA10 receptivity modulator occurs in the endometrium of women with recurrent implantation failure (RIF). Methods: Twenty-four patients with RIF who could not conceive for three or more cycles despite good-quality embryo transfer constituted the study group. Twenty-four patients with unexplained infertility (UEI) matched for age, BMI, and infertility duration were included in the control group. Twenty women scheduled to undergo intrauterine device (IUD) placement for birth control were included in the comparative group. Endometrial tissue was collected from patients with RIF and UEI during egg retrieval after ovarian stimulation using the GnRH antagonist protocol. In the fertile group, endometrial tissues were collected during IUD insertion. HOXA10 mRNA expression was analyzed by qRT-PCR and PDX protein expression was analyzed by ELISA. The relative expression of endometrial HOXA10 mRNA was calculated using the 2^−ΔΔCt equation. Results: The relative expression of HOXA10 mRNA in the RIF group was significantly lower than that in the UEI group (p < 0.001). HOXA10 mRNA expression in the fertile group was significantly higher than that in the RIF group and was similar to that in the UEI group. PDX expression in the RIF group was significantly higher than that in the UEI group (p < 0.001). PDX expression in the fertile group was significantly lower than in the RIF and UEI groups. A negative correlation was detected between the anti-adhesive PDX protein and adhesive HOXA10 (r = −0.797, p < 0.001). Although there was a positive correlation between endometrial thickness recorded on the day of hCG administration and HOXA10 (r = 0.590, p < 0.01), endometrial thickness was negatively correlated with PDX (r = −0.529, p < 0.01). Conclusions: The failed physiological downregulation of the anti-adhesive PDX protein in patients with RIF prevented the upregulation of adhesive HOXA10 mRNA. Full article

Uterine infections reduce ruminant reproductive efficiency. Reproductive dysfunction caused by infusion of Gram-negative bacteria is characterized by the failure of embryo implantation and reduced conception rates. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, is highly abortogenic. In this study, the effects of LPS infusion on the endometrial receptivity of sheep were studied during three critical periods of embryo implantation. The results showed that LPS infusion on d12, d16, and d20 of pregnancy in vivo interfered with the expression of prostaglandins (PGs) and affected the expression of adhesion-related factors (ITGB1/3/5, SPP1), key implantation genes (HOXA10, HOXA11 and LIF), and progestational elongation genes (ISG15, RSAD2 and CXCL10) during embryo implantation. In addition, after LPS infusion on d12, d16, and d20, the phosphorylation level of STAT1 significantly decreased and the protein expression level of IRF9 significantly increased on d12, suggesting that LPS infusion in sheep impairs endometrial receptivity through the JAK2/STAT1 pathway. Sheep endometrial epithelial cells were treated with 17 β-estrogen, progesterone, and/or interferon-tau in vitro to mimic the receptivity of the endometrium during early pregnancy for validation. LPS and the p-STAT1 inhibitor fludarabine were both added to the model, which resulted in reduced p-STAT1 protein expression, significant inhibition of PGE2/PGF2α, and significant suppression of the expression of key embryo implantation genes. Collectively, these results indicate that LPS infusion in sheep on d12, d16, and d20 impairs endometrial receptivity through the JAK2/STAT1 pathway, which is responsible for LPS-associated pregnancy failure. Full article

Background/Objectives: Embryo implantation is a highly complex process that requires the precise regulation of numerous molecules to be orchestrated successfully. Micro RNAs (miRNAs) are small non-coding RNAs that regulate gene expression and play a crucial role in the regulation of embryo implantation. This article aims to summarize the key findings of the literature regarding the role of miRNAs in human embryo implantation, emphasizing their involvement in critical stages such as decidualization, endometrial receptivity and trophoblast adhesion. Methods: This review includes primary research articles from the past decade. The studies utilize a range of experimental methodologies, including gene expression analysis and in vitro studies. Results: MicroRNAs, like miR-320a, miR-149, and miR30d secreted by preimplantation embryos and blastocysts significantly influence endometrial receptivity by promoting essential cellular processes, such as cell migration and trophoblast cell attachment, while others—miR17-5p, miR-193-3p, miR-372, and miR-542-3p—secreted from the endometrium regulate the decidualization phase. During the apposition and adhesion phases, miRNAs play a complex role by promoting, for example, miR-23b-3p, and inhibiting—as do miR-29c and miR-519d-3p—important biological pathways of these stages. During invasion, miR-26a-5p and miR-125-5p modulate important genes. Conclusions: This review underscores the critical impact of miRNAs in the regulation of embryo implantation and early pregnancy. The ability of miRNAs to modulate gene expression at various stages of reproduction presents promising therapeutic avenues for improving assisted reproductive technologies outcomes and addressing infertility. Further research into miRNA-based diagnostic tools and therapeutic strategies is essential to enhance our understanding of their role in reproductive health and to exploit their potential for clinical applications. Full article

Heat stress (HS) is a significant factor that adversely affects the health, welfare, and productivity of domestic animals, particularly impacting embryo implantation rates. However, the effects of HS on endometrial function during the peri-implantation period in Hainan black goats remain unclear. This study explores the influence of HS on the endometrium of these goats. We collected uterine tissue samples from both control and heat-stressed goats and performed in vitro experiments using a 2 × 2 factorial design. This design included two temperature conditions (37 °C as the control and 42 °C to simulate heat stress) and two pharmacological treatments: chloroquine (CQ), an autophagy inhibitor, and rapamycin (RAPA), an autophagy activator. Our results showed that heat stress initially suppresses autophagy activity, which is subsequently enhanced with prolonged exposure. The pharmacologic modulation of autophagy, through activation or inhibition, resulted in corresponding upregulation or downregulation of the endometrial epithelial cells’ (EECs) receptivity markers. The overexpression of ATG7 partially reversed the HS-induced downregulation of these markers. Additionally, TJP1, a tight-junction marker, was degraded under the pharmacologic and genetic activation of autophagy in HS conditions but accumulated more in the EECs pre-treated with CQ. These findings suggest that autophagy plays a protective role in maintaining endometrial function under HS conditions in Hainan black goats. This study offers valuable insights into the role of autophagy in endometrial receptivity and proposes a potential strategy to mitigate the adverse effects of HS on goat reproduction. Full article

Reproductive disorders are common events in modern reproductive medicine, occurring both in spontaneous and assisted pregnancies. Studies on the molecular mechanisms of implantation disorders in thin endometria, including the study of gene transcriptional activities, have shed light on the identification of the potential biological markers of endometrial receptivity. Background/Objectives: The goal of this study was to reveal the significantly dysregulated selected gene expressions between RIF and RPL patients with thin endometria. Methods: Endometrial samples were collected from RIF patients (n = 20) and RPL patients (n = 19) during the implantation window days (LH + 7—LH + 10) of their natural menstrual cycles. Ten genes were chosen as the target genes regarding their possible relations with the implantation process. The total RNA was purified and reverse-transcribed, and gene expressions were quantified by RT-PCR. Results: The expressions of the IL-15, INFG, and HPRT1 genes were significantly decreased in the RIF patients with thin endometria compared to the RPL patients (log₂ fold change = 0.92, p = 0.023 for IL-15; log₂ fold change = 1.24, p = 0.046 for INFG; and log₂ fold change = 0.579, p = 0.046 for HPRT1). There were no significant differences in the expressions of the CXCL8, CXCL1, MMP10, C4BPA, TNC, VEGFB, and HAND2 genes between the groups. Conclusions: Decreased expressions of the IL-15, INFG, and HPRT1 genes were found in patients with RIF with thin endometria compared to the endometria of women with RPL. This has practical significance for clinicians for the differentiated prescription of immunomodulatory therapy in patients undergoing ART programs. Full article