A Comprehensive Review of the Endometrial Receptivity Array in Embryo Transfer: Advancements, Applications, and Clinical Outcomes.

Embryo transfer is a pivotal procedure in assisted reproductive technologies (ART). Yet, the success of this process hinges on multiple factors, with endometrial receptivity playing a critical role in determining the likelihood of successful implantation. The endometrial receptivity array (ERA) is an advanced diagnostic tool designed to personalize embryo transfer timing by assessing the endometrium's receptivity. This review comprehensively examines the ERA, exploring its biological foundation, technological development, and clinical applications. The ERA's ability to analyze the expression of genes associated with endometrial receptivity offers a tailored approach to identifying the optimal window of implantation (WOI), particularly benefiting patients with recurrent implantation failure (RIF) or repeated unsuccessful in vitro fertilization (IVF) cycles. Clinical outcomes from ERA-guided embryo transfers indicate improvements in implantation rates and overall pregnancy success, although challenges such as result variability and cost-effectiveness persist. This review also discusses the latest advancements in ERA technology, including integrating genomic and transcriptomic analyses, non-invasive techniques, and using artificial intelligence (AI). Controversies regarding the widespread application of ERA and its necessity in all IVF cases are critically examined. By summarizing the current state of ERA in embryo transfer, this review aims to inform clinicians, researchers, and patients about its potential to enhance ART outcomes and to highlight areas for future research and innovation.

A Comprehensive Review of the Endometrial Receptivity Array in Euploid Embryo Transfer Cycles.

The Endometrial Receptivity Array (ERA) is a revolutionary molecular diagnostic tool that determines the optimal timing for embryo transfer by analyzing the gene expression profile of endometrial tissue. This comprehensive review examines the significance and application of ERA in euploid embryo transfer cycles, where the implantation of embryos with the correct number of chromosomes is critical for achieving successful pregnancy outcomes. This review underscores its role in enhancing implantation rates and reducing pregnancy loss by assessing the evolution, methodology, clinical applications, efficacy, and challenges associated with ERA. Key findings highlight ERA's superior accuracy in identifying the window of implantation compared to traditional methods, resulting in improved clinical outcomes in assisted reproductive technology (ART) cycles. Despite its benefits, the review acknowledges challenges such as cost, accessibility, and the need for standardization. Recommendations for clinical practice emphasize the integration of ERA into routine ART protocols, comprehensive patient counseling, and the importance of multidisciplinary collaboration. The review outlines promising prospects, including technological advancements to make ERA more cost-effective, the development of refined gene expression profiles, and the potential integration with other emerging ART technologies. Further research directions include long-term studies on the outcomes of ERA-guided pregnancies and exploring its application in cases of recurrent implantation failure and unexplained infertility. Overall, ERA represents a significant advancement in reproductive medicine, offering a personalized approach to embryo transfer timing that can significantly improve the success rates of euploid embryo transfers.

Exploring Natural Killer Cell Testing in Embryo Implantation and Reproductive Failure: An Overview of Techniques and Controversies.

The blastocyst nidation is the most crucial stage to a successful pregnancy, as the white cells work to promote a favorable endometrial microenvironment for this process. Intriguingly, this implantation window lasts, on average, 6 days in most regular women, and its quality is affected by many pathological conditions. Since the grounds of reproductive failure in healthy couples are still uncharted, studies have widely suggested a potential hostile role of the immune system in the equilibrium of the maternal-fetal interface. In recent years, natural killer cells have been the highlight as they represent the greatest lymphocyte in the uterus and have immune surveillance through cytotoxicity during the implantation window. This review explored the main techniques used for natural killer (NK) cell testing in the implantation window over the last 13 years on the PubMed® database. Of 2167 published articles potentially relevant for the review, only thirty-three were about cell evaluation in healthy women, met the inclusion criteria, and had their methodology critically analyzed. Here, we bring a summary from the study group and sample collection to evidence comments about their findings and correlations. Meanwhile, we also summarize the current relationship between NK cells and endometrial receptivity with reproductive failure to help enhance the possibilities for future research. In conclusion, our overview points out that restricted and unstandardized methods support the controversy between the NK population and unsuccessful embryo implantation, which is an obstacle to studying why healthy eggs do not thrive and finding a solution for one of the most controversial topics in human reproduction.

The predictive value of uterine artery Doppler in the success rate of pregnancy from the first frozen embryo transfer during the implantation window.

BACKGROUND: Worldwide, frozen embryo transfer (FET) has become a new strategy for the treatment of infertility. The success of FET is closely related to endometrial receptivity. Does uterine artery Doppler during the implantation window predict pregnancy outcome from the first FET? METHODS: A total of 115 retrospectively collected cycles were included in the study, with 64 cycles of clinical pregnancy and 51 cycles of nonclinical pregnancy; There were 99 nonabsent end-diastolic flow (NAEDF) cycles and 16 absent end-diastolic flow (AEDF) cycles. The differences in uterine artery Doppler findings between different pregnancy outcomes were investigated. The clinical pregnancy rate and spontaneous abortion rate in the NAEDF and AEDF groups were compared. The predictive value of uterine artery Doppler during the implantation window in the success rate of pregnancy from the first FET was also investigated. RESULTS: Between the clinical pregnancy group and the nonclinical pregnancy group, there were no significant differences in the mean resistance index (mRI) (Z = -1.065, p = 0.287), mean pulsatility index (mPI) (Z = -0.340, p = 0.734), and mean peak systolic/end-diastolic velocity(mS/D) (Z = -0.953, p = 0.341); there were significant differences in the mean peak systolic velocity (mPSV) (Z = -1.982, p = 0.048) and mean end-diastolic velocity (mEDV) (Z = -2.767, p = 0.006). Between the NAEDF and AEDF groups, there was no significant difference in the clinical pregnancy rate (χ2 = 0.003, p = 0.959), and there was a significant difference in the spontaneous abortion rate (χ2 = 3.465, p = 0.019). Compared with uterine artery Doppler alone, its combination with artificial abortion history, waist-to-hip ratio, LH (Luteinizing hormone) of P (Progesterone) administration day, mPSV and mEDV had a higher predictive value regarding clinical pregnancy from the first FET [ROC-AUC 0.782, 95% CI (0.680-0.883) vs. 0.692, 95% CI (0.587-0.797)]. CONCLUSIONS: Uterine artery Doppler, particularly mPSV and mEDV during the implantation window, was useful for predicting clinical pregnancy, and AEDF was related to spontaneous abortion in the first trimester. Uterine artery Doppler combined with artificial abortion history, waist-to-hip ratio, LH of P administration day, mPSV and mEDV have a higher predictive value than uterine artery Doppler alone regarding the pregnancy from the first FET.

Changes in the immunophenotype of endometrium during implantation window receptivity formation in healthy fertile women.

INTRODUCTION: Endometrial receptivity is largely determined by the immunophenotype of endometrium, especially uterine NK-cells (uNK). Immune component is directly involved in the formation of favourable microenvironment for the blastocyst implantation and placenta formation, but the way it changes during the maturation of endometrial tissue in healthy fertile women is still underexplored. METHODS: The endometrium was collected from 47 healthy oocyte donors after controlled ovarian stimulation: 23 women on the day of oocytes retrieval (OR) and 24 women on the term of implantation window (IW). The OR group was analysed, published previously and used as a comparison group to show the dynamic of changes. Isolated endometrial lymphocytes and peripheral blood samples were stained with monoclonal antibodies and analysed according to the three-color flow cytometry protocol. RESULTS: The proportion of NK-cells (CD3-CD56+) in endometrium grew significantly in the implantation window compared to the oocytes retrieval day. NK-cells acquired a more differentiated phenotype from the day of OR until IW: the expression of CD8 and CD158a significantly increased, while the expression of HLA-DR significantly decreased. Significant correlations between peripheral blood and endometrial NK-cells were found in CD8 expression during OR and IW, CD335(p46)neg and CD335(p46)++ subsets during IW term. DISCUSSION: Immunophenotype of receptive endometrium forms due to the accumulation of uNK-cells, which actively proliferate, become mature, differentiative, and ready to meet the embryo. Endometrial immunophenotype is peculiar and specific but not autonomic and isolated. Differentiation (CD8 on NK-cells), and activity (p46 on NK-cells) of peripheral blood lymphocytes is reflected in endometrial lymphocytes profile, and therefore the research of peripheral blood immunophenotype is relevant.

Effect of acupuncture on the opening time of implantation window and endometrial receptivity in controlled ovarian hyperstimulation rats during peri-implantation period.

Purpose: To investigate the effect of acupuncture for improving the pregnancy rate of COH rats from the viewpoint of regulating the opening time of the implantation window and endometrial receptivity. Methods: Experimental rats were randomly divided into normal group (N), model group (M) and acupuncture group(A), and samples were collected on Day 4, 5 and 6 after mating. COH rats were treated with acupuncture at SP6, LR3, and ST36 once a day for 7 times. The pinopodes were observed under a scanning electron microscope. Serum estrogen and progesterone levels were measured via ELISA. The protein and mRNA levels of estrogen receptor (ER), progesterone receptor (PR), leukemia inhibitory factor (LIF), integrin ß3, vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF-2) in the endometrium were evaluated via West-blot, immunohistochemistry, and PCR. Results: Compared with group N, the pregnancy rate of group M was significantly decreased (P<0.05), and the abnormal serum hormone levels and implantation window advancement were observed. Compared with group M, the pregnancy rate of group A was significantly increased (P<0.05), the supraphysiological serum progesterone levels were restored to normalcy (P<0.05), and the advanced implantation window was restored to a certain extent. Further, the abnormal ER, PR, LIF, integrin ß3, VEGF, and FGF-2 expression levels of the endometrium got recovered to varying degrees. Conclusion: Acupuncture may restore the estrogen and progesterone balance in COH rats and the forward shift of the implantation window to a certain extent, improving the endometrial receptivity and finally improving the pregnancy rate of COH rats.

Endometrial Heparin-Binding Epidermal Growth Factor Gene Expression and Hormone Level Changes in Implantation Window of Obese Women with Polycystic Ovarian Syndrome.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder amongst reproductive-age women, and 61% to 76% of women with PCOS are obese. Obese women with PCOS are usually burdened with infertility problems due to implantation failure. Thus, progesterone treatment is usually used to improve implantation rates. Although Hb-EGF expression is actively involved in endometrial receptivity and implantation, the data on heparin-binding epidermal growth factor (Hb-EGF) expression following progesterone therapy in obese women with PCOS are still lacking. OBJECTIVE: To investigate the changes in serum follicle-stimulating hormone (FSH), luteinising hormone (LH), dehydroepiandrosterone sulphate (DHEA), progesterone and oestradiol levels and Hb-EGF expression in obese women with PCOS during the implantation window following progesterone therapy. METHOD: A total of 40 participants aged 18-40 years old were recruited following the provision of written consent. The participants were divided into the obese PCOS, normal-weight PCOS, obese fertile and normal-weight fertile groups. First blood collection was done before ovulation. Then, daily oral micronised progesterone (Utrogestan 200 mg) was given to the PCOS group for 10 days. The treatment was followed by a second blood collection and endometrial tissue sampling by using a Pipelle de Cornier catheter. In the fertile group, ovulation was confirmed by using ultrasound, and a second blood sample was collected on days 7 to 9 postovulation. The serum levels of FSH, LH, DHEA, progesterone and oestradiol were measured in all participants. Wilcoxon signed-rank test was used to compare FSH, LH, DHEA, progesterone and oestradiol levels during pre- and postovulation. Mann-Whitney test was performed to compare FSH, LH, DHEA, progesterone and oestradiol levels between two groups: (1) the PCOS group and the fertile group, (2) the obese PCOS group and the non-obese PCOS group and (3) the obese group and the non-obese fertile group. RESULT: Serum FSH levels were lower in obese women in their follicular phase than in women with normal weight regardless of their PCOS status, whereas serum LH/FSH ratios and DHEA levels were higher in women with PCOS than in women without PCOS. However, endometrial Hb-EGF expression was lower in the obese PCOS group than in the normal-weight PCOS group. CONCLUSIONS: Different patterns of hormonal levels and Hb-EGF expression levels were seen between the studied groups. However, further in vitro and in vivo studies are needed to investigate the mechanism underlying the changes in FSH, LH/FSH ratio, DHEA and Hb-EGF expression in PCOS after progesterone treatment.

Endometrial microstimulation effects on endometrial receptivity assessed by transvaginal color Doppler sonography.

OBJECTIVE: This study investigated the effect of endometrial microstimulation (EM) on endometrial receptivity using transvaginal color Doppler sonography (TVCDS). METHOD: Women of childbearing age who were preparing to conceive (n = 90) were randomly divided into the EM group (n = 30), who were examined by EM on days 3-5 of the menstrual cycle, and the control group (n = 60). TVCDS was conducted during the implantation window phase, and endometrial thickness, endometrial pattern, endometrial movement, blood flow type, and uterine and spiral arterial hemodynamic parameter measurements were made. The groups were compared to identify differences. RESULTS: Endometrial thickness (0.97 ± 0.18 cm and 0.95 ± 0.17 cm), endometrial movement (type 1: 46.7% and 51.7%; type 2: 30.0% and 28.3%; type 3: 6.7% and 5.0%; type 5: 16.7% and 15.0%), and hemodynamic parameters of the uterine (pulsatility index [PI]: 2.46 ± 0.50 and 2.41 ± 0.48; resistance index [RI]: 0.85 ± 0.05 and 0.84 ± 0.05) and spiral (PI: 1.11 ± 0.32 and 1.19 ± 0.33; RI: 0.48 ± 0.11 and 0.51 ± 0.08) arteries did not differ significantly between groups (P > 0.05). However, the endometrial pattern (a trilaminar pattern: 80.0% and 58.3%; P = 0.041) and blood flow type (type I: 16.7% and 43.3%; type II: 63.3% and 40.0%; type III 20.0% and 16.7%; P = 0.038) differed significantly between groups. CONCLUSION: Endometrial microstimulation did not alter endometrial pathological staging, endometrial thickness, or movement, nor did it affect uterine and spiral arterial blood flow parameters. However, it may be able to abrade abnormal endometrial tissue, optimizing the endometrial pattern. Endometrial microstimulation may support local spiral artery regeneration and increase endometrial blood supply in new cycles.

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature.

Despite the advances in the field of reproductive medicine, implantation failure represents a challenging condition affecting 10-30% of patients subjected to in vitro fertilization (IVF). Research has focused on the identification of molecules playing crucial roles in endometrial receptivity, with the aim of designing predictive tools for efficient detection of the implantation window. To that end, novel molecular genomic and transcriptomic approaches have been introduced as promising tools to enable personalized approaches with the aim of optimizing embryo transfer dating. However, the clinical value of these approaches remains unclear. The aim of this study is to provide a systematic review and critical analysis of the existing evidence regarding the employment of commercially available novel approaches to evaluate endometrial receptivity. An Embase and PubMed/Medline search was performed on 1 February 2022. From the 475 articles yielded, only 27 were included and analyzed. The considerable heterogeneity of the included articles indicates the uniqueness of the implantation window, showcasing that the optimal time for embryo transfer varies significantly between women. Moreover, this study provides information regarding the technical aspects of these advanced molecular tools, as well as an analysis of novel possible biomarkers for endometrial receptivity, providing a basis for future research in the field.

A Systematic Review and Integrated Bioinformatic Analysis of Candidate Genes and Pathways in the Endometrium of Patients With Polycystic Ovary Syndrome During the Implantation Window.

Polycystic ovary syndrome (PCOS) is a common disorder with wide-ranging clinical heterogeneity that causes infertility. However, the comprehensive molecular mechanisms of PCOS in causing infertility is remaining unclear. Hence, a comprehensive literature search was conducted using PubMed, Scopus, EBSCOhost, and Science Direct. Medical Subject Heading (MeSH) terms like PCOS, gene expression, implantation window and endometrium were used as the keywords. From 138 studies retrieved, original articles with RNA profiling on human endometrial tissues in PCOS women during the implantation window were included. Study design, sample size, sample type, method, and differentially expressed genes (DEGs) were identified from all publications. The DEGs were analyzed using the software packages DAVID, STRING, and Cytoscape. Three studies that met inclusion criteria were included, and 368 DEGs were identified. Twelve significant clusters from the protein-protein interaction network (PPI) complex were found, and cluster 1 showed very high intermolecular interactions. Five candidate genes (AURKA, CDC25C, KIF23, KIF2C, and NDC80) were identified from the systematic review and integrated bioinformatics analysis. It is concluded that cell cycle is the fundamental biological processes that were dysregulated in the endometrium of PCOS women, affecting decidualization progression in the endometrium during the implantation window.