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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. [ABSTRACT FROM AUTHOR]

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Endometrial immunophenotype forms the receptivity and conditions for the implantation. • Endometrium matures with changes in the number and phenotype of uNK-cells. • On implantation window term, NK-cells actively proliferate and become differentiative. • Endometrial immunophenotype is specific but not autonomic and isolated. [ABSTRACT FROM AUTHOR]

Introduction. Due to the rapidly current reproductive technologies developing in recent years, much attention has been paid to patients who suffered from infertility (up to 55 %) mainly caused by chronic endometritis (CE). Due to the lack of prominent and specific clinical manifestations, laborious microscopic examination necessary for diagnostics, CE often receives no proper clinical attention. However, the undeniable relationship between CE and conditions associated with infertility such as repeated unsuccessful implantations and habitual miscarriage, dictates a need to expand knowledge about etiology and pathogenesis of this pathology in order to develop both highly informative diagnostic methods and create effective therapeutic regimens. Aim: to analyze the literature data on CE pathogenetic mechanisms. Materials and Methods. The available publications were searched in the databases Web of Science, eLIBRARY, Scopus, PubMed/MEDLINE released within the 1995–2022 period aimed at assessing CE pathogenetic and morphological features using query "chronic endometritis", "plasmocellular endometritis", "endometrial receptivity", "primary infertility", "secondary infertility", "implantation window". To avoid omission of suitable articles, a methodological filter was not applied. There were included full-text sources and literary reviews on the subject under study. Articles directly unrelated to CE topic were excluded from the review. In order to avoid inclusion of duplicate publications in the literature review if two studies by the same authors were found, the study period of each author was examined, and if the dates of publication coincided, most recent publication were used. Results. New morphological, immunohistochemical, genetic and immunological aspects of СЕ were summarized. The presence of plasma cells is the "gold standard" for CE morphological diagnostics, but their similarity to fibroblasts complicates histological examination and requires using expanded range of diagnostic markers. Thus, in CE patients, were identified a reduced expression of NK cells, with increased level of CD3+, CD+8, CD20+, CD138+ cells as well as pro-inflammatory factors, such as tumor necrosis factor-α – by 3-fold, interleukin-6 – by 2.7-fold, interleukin-8 – by 1.2-fold, interferon-γ – by 1.4-fold compared to healthy women. Special attention is paid to the features of hormone receptor network in chronic endometrial inflammation regarding reproductive losses in infertile women, while a favorable marker for successful pregnancy turned out to be the ratio of progesterone and estrogen receptors ranging from 2 to 3. Conclusion. Thus, CE rate in the pattern of the causes of infertility and unfavorable reproductive outcomes can up to reach 50 %, however, due to the difficulties of morphological diagnostics, verification of this diagnosis is complicated. The wide range of pathogenetic features of developing chronic inflammation in the endometrium highlighted here may be promising not only for identification of diagnostic markers, but also forimproving endometrialregenerative ability,whichwill increase odds for successfully executed reproductive function in infertile women.

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 andmRNA levels of estrogen receptor (ER), progesterone receptor (PR), leukemia inhibitory factor (LIF), integrin b3, vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF-2) in the endometrium were evaluated via Westblot, 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 β3, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: To explore the predictive value of endometrial receptivity and pregnancy outcomes using pipelle biopsy examination during the luteal phase of the menstruation cycle in infertile women. We also compare the importance of this factor with other potential causes of infertility. Methods: This retrospective study included 279 women with repeated implantation failures. All patients were examined and treated at the Intersono in vitro fertilization (IVF) center. To determine the cause of the implantation failure, an implantation window (IW) was defined for all patients included in this retrospective cohort. Examinations were performed by three-fold aspiration biopsies of the endometrium during the luteal phase of the cycle as this period is when the endometrium is most receptive for implantation. Analysis of the tissue was done by scanning electron microscopy of endometrial tissues and, based on results obtained, an endometrial preparation protocol was individualized for the next attempt. Statistical analyses were performed using Microsoft Excel (Office 365) and RStudio software v. 1.4.1106. Results: According to the results obtained, 206 women included in this study displayed a unique IW (74%), and 73 women had a standard IW period (26%). Patient characteristics, screening indicators, previous IVF treatment details, IVF cycle characteristics, as well as number, quality, and stage of embryos transferred were comparable between the two groups. Clinical pregnancy rates of 59.2% (95% confidence interval (CI) 52.5–65.8) versus 57.5% (95% CI 46.1–68.6) (p = 0.80), and live birth rates of 50.7% (95% CI 43.9–57.6) versus 47.9% (95% CI 36.6–59.4) (p = 0.49) in the unique and standard IW groups, respectively, did not show significant differences. Conclusions: Unique IW is one of the underlying causes of implantation failures. The personalization of an endometrial preparation protocol is a method to improve IVF outcomes.

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. [ABSTRACT FROM AUTHOR]

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.

This is a retrospective study to evaluate if the miRNome profile of endometrium samples collected during the implantation window predicts Assisted Reproduction Technology (ART) outcomes. We first investigated the endometrial miRNome profile according to the receptivity status in 20 patients with repeated implantation failures (RIF) (discovery cohort). After customized embryo transfer, the miRNome profiles of receptive patients with a positive or negative β-hCG, and with early miscarriage or live birth were analysed. Some differentially expressed miRNAs were selected for validation by RT-qPCR in endometrial samples from 103 RIF patients (validation cohort). Analysis of the different miRNome profiles identified endometrial receptivity, implantation failure, and early miscarriage-associated miRNA signatures that included 11, 261, and 76 miRNAs, respectively. However, only four miRNAs associated with the endometrial receptivity status (miR-455-3p and miR-4423-3p) and implantation failure (miR-152-3p and miR-155-5p) were significantly validated in endometrial samples. The miRNome profile of endometrial tissues during the implantation window can predict the pregnancy outcome. These data are crucial for opening new perspectives to predict implantation failure and consequently, to increase ART success. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate optimal warming time, the early warming or the routine warming time, for transferring vitrified-warmed and cultured overnight cleavage stage of the slow-growing embryos on day 3 in frozen embryo transfer (FET) cycle. Methods: This was a retrospective cohort study from January 2017 to July 2018. A total of 705 FET patients aged < 40 years were included and 1486 embryos were formed, of which 1366 embryos were eventually transferred. Results: For slow-growing embryos, the clinical pregnancy rate of early warming group [152/468 (32.5%)] was significantly higher than that of routine warming group (55/235 (23.4%)) [OR 1.39 (CI 1.06–1.81), p = 0.01], while there was no statistically significant difference in pregnancy loss in early warming group [39/170 (22.9%)] versus in routine warming group [16/62 (25.8%)] [OR 0.89 (CI 0.53–1.47), p = 0.65]. Conclusion: For slow-growing embryos, higher pregnancy outcomes were shown in early warming strategy as compared to the routine warming, which suggested that the improvement of endometrium–embryo synchronism may correct the time difference brought by the slow-growing embryos. [ABSTRACT FROM AUTHOR]

Abstract Background Little research is available on follicular development and endometrial receptivity in older women. This study aimed to assess follicular development and endometrial receptivity, and to evaluate ultrasonic parameters in predicting endometrial receptivity during the implantation window in older women. Methods For this prospective case-control study, 224 older women and 215 young women were recruited. The follicular development and endometrial thickness were monitored by transvaginal ultrasound. During the implantation window, the pulsatility index (PI) and resistance index (RI) of the uterine arteries and subendometrial region, endometrial volume, vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated between the two groups. The ultrasonic parameters were used to assess endometrial receptivity in older women. Results The serum anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC) were significantly lower in older women than in young women. The average diameter of the dominant follicle on days 14, 16, and 18 of the menstrual cycle were significantly smaller, and the subendometrial region RI on days 12, 14, 16, and 18 of the menstrual cycle were significantly higher in older women than in young women. The normal ovulation rate was significantly lower in older women than in young women. The subendometrial region RI was significantly higher, and the endometrial VI, FI, and VFI were significantly lower in older women compared with young women. The biochemical pregnancy rate, clinical pregnancy rate and ongoing pregnancy rate of older women were significantly lower than in young women. The best ultrasonic parameter for predicting endometrial receptivity during the implantation window in older women was VI (AUC =0.889, sensitivity 92.6% and specificity 85.4%). Conclusions Older women present decreased serum AMH concentrations and AFC, defined as indicators of ovarian reserve function. Older women are characterized by decreased follicular development and endometrial receptivity, which may lead to fecundity disorders.

Relevance. The success of the in vitro fertilisation (IVF) program, among other factors, depends on the readiness of the endometrium to accept the embryo. It is believed that this is possible during the so-called implantation window, the timing of which can be shifted under the influence of various factors. Evaluation of endometrial receptivity and the implantation window based on analysis of endometrial gene expression before embryo transfer is a promising approach for predicting the likelihood of pregnancy in IVF programs. Aim. To construct a classifier based on the expression of endometrial genes for predicting the outcome of an IVF program in patients with tubal-peritoneal infertility factor and repeated failed IVF attempts in history. Materials and methods. Before the IVF program, a genome-wide transcriptome profiling of endometrial samples of 15 women with tubal-perioneal infertility factor and repeated unsuccessful IVF attempts in history was carried out using Affymetrix arrays. Potential genes capable of classifying IVF program outcomes were selected, after which the expression of these genes was analyzed by qPCR-RT in the endometrium of 47 women to construct IVF outcome classifiers based on the expression of pairs or triples of genes. Results. A classifier based on the expression of the triple of genes MSX1 (HOX7), HOXA11, and TP53I3 made it possible to determine the onset of pregnancy in an IVF program with a sensitivity of 73% and a specificity of 71% with an area under the ROC-curve (AUC) of 0.738 (95% confidence interval 0.5770.898). Earlier, a relationship was found between the expression of these genes and receptivity of the endometrium, which suggests that these genes play a role in the onset of the implantation window. Conclusions. The use of a classifier based on the genes MSX1 (HOX7), HOXA11, and TP53I3 can determine the readiness of the endometrium to accept an embryo and create an individual prognosis of the outcome of an IVF program in women with tubal-peritoneal infertility factor and repeated failed IVF attempts in history.

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., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dahiphale et al.)

To date, there are several approaches to the treatment of endometrial hyperplasia, but it is quite unclear which approach provides a higher clinical response with a lower recurrence rate, in addition to preservation and restoration of fertility in infertile women with complex non-atypical endometrial hyperplasia (NEH) and excess body weight. The purpose of the study was to evaluate the effectiveness of the restoration of reproductive function in patients with infertility, complex NEH and with excess body weight according to the proposed method. Material and methods. 74 women of reproductive age with complex NEH, infertility and excess body weight were under observation, of which 34 patients of the main group after hysteroscopic resection of the lesion at the first stage of treatment, at the second stage of treatment received gonadotropin-releasing hormone agonists (aGnRH) and adjuvant therapy with drugs indole-3-carbinol, metformin, fenofibrate for three months, and then at the third stage of treatment dydrogesterone, metformin, a vitamin-mineral complex that included myo-inositol, banaba leaves, extract of 1% corosolic acid, vitamin D3, methylfolate-quatrafolic, chromium for 6 months. 40 patients of the control group after hysteroscopic resection of the lesion at the first stage of treatment were prescribed aGnRH for 3 months in the second stage of treatment, then methylfolate-mvatrafolic for 6 months. Anthropometric data, echometric and morphofunctional characteristics of the endometrium during the expected window of implantation, hormonal profile and levels of peripheral blood lipokines in the dynamics of treatment were studied. Reproductive results were evaluated within a year after the end of treatment. The results. Treatment of complex NEH in the main group led, compared to the control group, to a decrease in body mass index, improvement in echometric and morphofunctional characteristics of the endometrium, its receptivity during the expected window of implantation, hormonal profile and lipokines level in peripheral blood, a decrease in insulin resistance, and an increase in the frequency of pregnancy. Conclusion. The proposed scheme for the treatment of complex NEH in infertile women with excess body weight allowed to improve their reproductive results, is effective and can be recommended for implementation in wide clinical practice.

Problem: Decidualized cells display an active role during embryo implantation sensing blastocyst quality, allowing the implantation of normal developed blastocysts and preventing the invasion of impaired developed ones. Here, we characterized the immune microenvironment generated by decidualized cells in response to soluble factors secreted by blastocysts that shape the receptive milieu. Method of Study: We used an in vitro model of decidualization based on the Human Endometrial Stromal Cells line (HESC) differentiated with medroxiprogesterone and dibutyryl‐cAMP, then treated with human blastocysts‐conditioned media (BCM) classified according to their quality. Results: Decidualized cells treated with BCM from impaired developed blastocysts increased IL‐1β production. Next, we evaluated the ability of decidualized cells to modulate other mediators associated with menstruation as chemokines. Decidualized cells responded to stimulation with BCM from impaired developed blastocysts increasing CXCL12 expression and CXCL8 secretion. The modulation of these markers was associated with the recruitment and activation of neutrophils, while regulatory T cells recruitment was restrained. These changes were not observed in the presence of BCM from normal developed blastocysts. Conclusion: Soluble factors released by impaired developed blastocysts induce an exacerbated inflammatory response associated with neutrophils recruitment and activation, providing new clues to understand the molecular basis of the embryo‐endometrial dialogue. [ABSTRACT FROM AUTHOR]

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.

Background: Pregnant women with subclinical hypothyroidism are associated with an increased risk of spontaneous abortion. This study aims to investigate the mechanisms underlying the effects of maternal subclinical hypothyroidism du ring early pregnancy on abortion in the uterus, focusing upon the LIF/STAT3 signaling pathway. Methods: One hundred five Wistar rats were randomly divided into three groups (35 rats in each group): control (CON) group, subclinical hypothyroidism (SCH) group and overt hypothyroidism (OH) group. We examined the weight of rat uteri, rat placenta and embryos. We also determined the number of implantation site s and the embryo absorption rates. The protein and mRNA expressions of TSHR, TR- α, TR-β, LIFR, gp130, JAK1, p-STAT3 and STAT3 were measured by immunohistochemical staining, real-time PCR and Western blotting. Results: The weights of rat uteri, rat placenta and embryos were significantly reduced in the SCH and OH groups. The number of implantation sites was significantly decreased in the SCH and OH groups, while embryo absorption rates were significantly increased. The mRNA and protein expressions of TSHR were upregulated in the SC H and OH groups, while TR-α and TR-β showed no difference when compared between the three groups. The expression levels of LIFR, gp130, JAK1 and p-STAT3 were significantly higher in the SCH and OH groups. Conclusions: Clinical and subclinical hypothyroidism during early pregnancy might cause adverse pregnancy outcomes. Implantation failure in rats with subclinical hypothyroidism was associated with abnormal LIF/STAT3 signaling.

Background: Despite significant improvements in the efficiency of assisted reproductive technologies (ART) for the past 10 years, proportion of unsuccessful cycles still remains significant and can reach up to 40%. Impairment of embryonic implantation is considered as one of the possible causes for low ART efficiency. Implantation failure may be a consequence of a shift in the “window of implantation”, i.e. the period of a cycle when endometrium is most receptive and ready for embryo implantation. Several methods have been developed to evaluate endometrial receptivity, but their accuracy and efficiency are quite different.Aim: Review and efficiency evaluation of the methods used for endometrial receptivity assessment and the window of implantation determination.Methods: We performed a comprehensive literature search (September 2018) with the key words “endometrial receptivity”, “endometrial receptivity evaluation”, “implantation window”, “window of implantation”, “pinopodes” from PubMed and E-library (Russian) databases. One hundred and thirty four (134) publications were selected for the analysis, including 101 original papers and 33 literature reviews.Results: The methods of conventional histology, scanning electronic microscopy, immunohistochemistry, as well as techniques based on the measurement of prostaglandin levels in endometrial fluid and mRNA profiling in an endometrium biopsy sample to assess endometrial receptivity are reviewed. The issue of a search for an ideal endometrial receptivity marker is discussed.Conclusion: At present, the most efficient and accurate methods to diagnose the window of implantation are those based on the mRNA profile assessment of an endometrial tissue sample. Аnalysis of mRNAs allows not only the accurate diagnosis of endometrial receptivity at the time of biopsy to be determined, but also the window of implantation shift to earlier or later periods to be reliably predicted.

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., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sharma et al.)

Objective. To carry out an analysis of the data available in scientific literature on modern methods of influence at endometrial receptivity in patients with recurrent implantation failure. Materials and methods. The review includes the data of foreign and Russia papers published on PubMed during the last 7-10 years. Results. There are studies described the role of endometrial scratching, infusion granulocyte colony stimulating factor, autologous peripheral blood mononuclear cells, autologous platelet-rich plasma, the endometrial receptivity array in treatment for patients with repeated implantation failure. Conclusion. Several adjuvant therapies and diagnostic tests have been used along with IVF to increase the pregnancy rates for women with repeated implantation failure. Perhaps a new test-system to find personal predictors of endometrial receptivity can tern up a positive effect at patients with RIF.

The good endometrial receptivity is a key factor for embryo implantation. The gene expression profile of endometrial tissue cells in the receptive period is closely related to the endometrial receptivity. High-throughput transcriptome sequencing technology can obtain gene expression profiles of the endometrium at different periods of menstruation, as well as microRNA (miRNA) and long non-coding RNA (lncRNA) sequences that regulate gene expression. Combined with bioinformatics analysis, these profiles are very helpful for us to understand the expression of specific genes in the endometrium during the receptivity period, and provide technical support for the mechanism study. This high-throughput method may be used for the diagnosis and treatment of patients with infertility and repeated implantation failure. This review summarized the research progress of high-throughput transcriptome sequencing in the evaluation of endometrial receptivity and embryo implantation. [ABSTRACT FROM AUTHOR]

The aim of this prospective study was to evaluate outcome benefits expected in repeated implantation failure (RIF) patients (n = 217) after customized embryo transfer based upon identification of the receptivity window by transcriptomic approach using the Win-Test. In this test, the expression of 11 endometrial genes known to be predictive of endometrial receptivity is assessed by RT-PCR in biopsies collected during the implantation window (6–9 days after the spontaneous luteinizing hormone surge during natural cycles, 5–9 days after progesterone administration during hormone replacement therapy cycles). Then, patients underwent either customized embryo transfer (cET, n = 157 patients) according to the Win-Test results or embryo transfer according to the classical procedure (control group, n = 60). Pregnancy and live birth rates were compared in the two groups. The Win-Test showed that in 78.5% of women, the receptivity window lasted less than 48 h, although it could be shorter (< 24 h, 9.5%) or longer (> 48 h, 12%). This highlighted that only in 20% of patients with RIF the endometrium would have been receptive if the classical embryo transfer protocol was followed. In the other 80% of patients, the receptivity window was delayed by 1–3 days relative to the classical timing. This suggests that implantation failure could be linked to inadequate timing of embryo transfer. In agreement, both implantation (22.7% vs. 7.2%) and live birth rates per patient (31.8% vs. 8.3%) were significantly higher in the cET group than in the control group. cET on the basis of the Win-Test results could be proposed to improve pregnancy and live birth rates. ClinicalTrials.gov ID: NCT04192396; December 5, 2019, retrospectively registered. [ABSTRACT FROM AUTHOR]

Problem: Approximately one‐third of infertility cases are related to the female partner, and implantation failure is the primary reason for female infertility. The current research was established to assess the impact of calcitonin on endometrial receptivity. Methods of study: 64 female BALB/c mice were assigned to 2 groups as follows: mice with regular ovarian cycle and mice with stimulated ovarian cycle. The two groups were further divided into four subgroups as follows: control (Ctrl), calcitonin (CT), pp242, and CT + pp242 groups. Calcitonin and pp242 were injected on days 3, 4, and 5 of pregnancy. On day 5 of gestation, all of the animals were sacrificed, and their uterine was removed for the morphological analysis, as well as the expression assessment genes and proteins. Results: The results demonstrated that ovarian stimulation increased the rate of phosphorylation of ERK1/2 and mTOR proteins, and resulted in the upregulation of miR‐223‐3p. The administration of calcitonin also elevated the expression levels of LIF and HAND2 gene in both regular ovarian and ovarian‐stimulated cycles. In ovarian‐stimulated groups, the administration of calcitonin led to a decrease in the expression of miR‐223‐3p. Calcitonin administration also markedly increased the phosphorylation of 4EBP1 and ERK1/2 in the regular ovarian cycle. Conclusion: It seems that calcitonin is capable of enhancing the endometrial receptivity of the uterine, thereby the overexpression of HAND2 and LIF and downregulation of miR‐223‐3p through the ERK1/2‐mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

This study aimed to assess the endometrial receptivity during implantation window in women with unexplained infertility. A prospective study recruited 168 women with unexplained infertility and 169 fertile women. Ultrasonic parameters and biomarkers in the uterine fluid were detected. The endometrial vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly higher in fertile women as compared with unexplained infertile women, and the integrin αvβ3, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and leukemia inhibitory factor (LIF) levels in uterine fluid were significantly higher in fertile women. The biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate in fertile women were 20.12%, 18.34%, and 17.75%, respectively, which were significantly higher compared with unexplained infertile women (7.14%, 5.36%, and 4.17%, respectively). Endometrial thickness (ET), endometrial volume (EV), VI, FI, and VFI measured by ultrasound, and the integrin αvβ3, VEGF, TNF-α, and LIF levels in uterine fluid were all significantly higher in pregnant women as compared with nonpregnant women. The best parameters of ultrasonic indicators for predicting endometrial receptivity in women with unexplained infertility were FI(AUC = 0.894, sensitivity 93.8%, and specificity 83.1%). Integrin αvβ3 had the best predictive value for endometrial receptivity among biomarkers in the uterine fluid (AUC = 0.921, sensitivity 96.7%, and specificity 89.5%). Women with unexplained infertility present declined endometrial receptivity. Endometrial ultrasonic parameters detected by three-dimensional power Doppler and biomarkers in the uterine fluid may be effective indicators to predict endometrial receptivity. [ABSTRACT FROM AUTHOR]

Background: Little research is available on follicular development and endometrial receptivity in older women. This study aimed to assess follicular development and endometrial receptivity, and to evaluate ultrasonic parameters in predicting endometrial receptivity during the implantation window in older women.Methods: For this prospective case-control study, 224 older women and 215 young women were recruited. The follicular development and endometrial thickness were monitored by transvaginal ultrasound. During the implantation window, the pulsatility index (PI) and resistance index (RI) of the uterine arteries and subendometrial region, endometrial volume, vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated between the two groups. The ultrasonic parameters were used to assess endometrial receptivity in older women.Results: The serum anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC) were significantly lower in older women than in young women. The average diameter of the dominant follicle on days 14, 16, and 18 of the menstrual cycle were significantly smaller, and the subendometrial region RI on days 12, 14, 16, and 18 of the menstrual cycle were significantly higher in older women than in young women. The normal ovulation rate was significantly lower in older women than in young women. The subendometrial region RI was significantly higher, and the endometrial VI, FI, and VFI were significantly lower in older women compared with young women. The biochemical pregnancy rate, clinical pregnancy rate and ongoing pregnancy rate of older women were significantly lower than in young women. The best ultrasonic parameter for predicting endometrial receptivity during the implantation window in older women was VI (AUC =0.889, sensitivity 92.6% and specificity 85.4%).Conclusions: Older women present decreased serum AMH concentrations and AFC, defined as indicators of ovarian reserve function. Older women are characterized by decreased follicular development and endometrial receptivity, which may lead to fecundity disorders. [ABSTRACT FROM AUTHOR]

The aim of study. To reveal the peculiarities of mRNA expression of the inflammatory component genes of the immune response in the expected window of the implantation in women with RPL in ART programs. Material and methods. 240 patients with RPL in ART programs and 100 conditionally healthy fertile women in the control group with the presence in history of at least one childbirth in time and the absence of episodes of miscarriage were examined. The average age of the examined women of the main group was 29.80 ± 0.30 years, the control group – 30.09 ± 0.32 (p >0.05). The average number of cases of involuntary termination of pregnancy after conduction of ART in main group was 3.24 ± 0.11, the average term of termination of pregnancy was 8.15 ± 0.65 weeks. All women had a paipel-biopsy of the endometrium during the expected implantation window. Samples were frozen at t = -70 °C. until the study. Reverse transcription -polymerase chain reaction was used to study mRNA expression of IL-1β, IL-2, IL-10, Foxp3, TLR9, IL-2Rα cytokine genes in endometrial biopsy obtained on the day of the implantation window. Results. It was found that the relative level of mRNA expression of IL-1β, IL-2, Foxp3, TLR9, IL-2Rα genes did not differ significantly in patients with RPL in the cycles of VRT and control group. A statistically significant decrease in mRNA expression of the IL-10 gene was noted. Conclusion. RPL in the treatment of infertile women in ART programs is associated with changes in the transcription profile of the endometrium during the intended implantation window and with a decrease in the expression level of the IL-10 gene mRNA.

Study Question: Compared to healthy women, is the profile of transcripts altered in the eutopic endometrium of infertile women with endometriosis during the implantation window (IW)?Summary Answer: The eutopic endometrium of infertile women with endometriosis seems to be transcriptionally similar to the endometrium of infertile and fertile controls (FC) during the IW.What Is Known Already: Endometriosis is a disease related to infertility; nevertheless, little is known regarding the ethiopathogenic mechanisms underlying this association. Some studies evaluating the eutopic endometrium of endometriosis patients suggest there is an endometrial factor involved in the disease-related infertility. However, no study to date has evaluated the endometrial transcriptome (mRNA and miRNA) by next generation sequencing (NGS), comparing patients with endometriosis as the exclusive infertility factor (END) to infertile controls (IC; male and/or tubal factor) and FC.Study Design, Size, Duration: From November 2011 to November 2015 we performed a case-control study, where 17 endometrial samples (six END, six IC, five FC) were collected during the IW.Participants/materials, Setting, Methods: All endometrial samples had the RNA extracted. Two libraries were prepared for each one (mRNA and miRNA), which were sequenced, respectively, at HISEQ 2500 (RNA-Seq) and MiSeq System (miRNA-Seq), Illumina. The normalization and differential expression were conducted in statistical R environment using DESeq2 package. qPCR was used for data validation, which were analyzed by Kruskal-Wallis test and Dunn posttest (P < 0.05).Main Results and the Role Of Chance: RNA-Seq revealed no differentially expressed genes (DEG) among END, IC and FC groups. miRNA-Seq revealed three differentially expressed miRNAs (has-27a-5p, has-miR-150-5p, has-miR-504-5p) in END group compared to FC group. However, none of the miRNAs identified in the sequencing was validated by qPCR.Limitations, Reasons For Caution: The main limitation of this study was the small sample size evaluated as a result of the restrictive eligibility criteria adopted, limiting the generalization of the results obtained here. On the other hand, strict eligibility criteria, which eliminated factors potentially related to impaired endometrial receptivity, were required to increase the study's internal validity.Wider Implications Of the Findings: This study brings new perspectives on the mechanisms involved in endometriosis-related infertility. The present findings suggest the eutopic endometrium of infertile women with endometriosis, without considering the disease's stage, is transcriptionally similar to controls during the IW, possibly not affecting receptivity. Further studies are needed to evaluate endometrial alterations related to endometriosis' stages.Study Funding/competing Interest(s): This study received financial support from the Sao Paulo Research Foundation (FAPESP-Fundação de Amparo à Pesquisa do Estado de São Paulo; fellowship 2011/17614-6, MGB) and from the National Council for Scientific and Technological Development (CNPq-Conselho Nacional de Desenvolvimento Científico e Tecnológico; INCT-National Institutes of Hormones and Woman's Health, grant 471 943/2012-6, 309 397/2016-2, PAN; fellowship 140 137/2015-7, MGB). The authors have no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Calcitonin (CT) is one of the factors affecting the embryo implantation, but its effects on the implantation window have not been fully investigated. The current study investigated the effects of CT on the endometrium receptivity by morphological study and evaluation of leukemia inhibitory factor (LIF), mucin 1 (Muc‐1), and microRNA (miRNA) Let‐7a in the ovarian stimulation and the normal ovarian cycle. Then the mechanism of the CT effects through the mammalian target of rapamycin (mTOR) signaling pathway was studied by using PP242. A total of 64 BALB/c mice were divided into the normal ovarian cycle and ovarian stimulation groups. Each group consisted of four subgroups: control, calcitonin, PP242, and calcitonin+PP242. CT and PP242 were injected on the fourth of pregnancy into the mice and 24 hr later all the mice were killed. The uterine tissue samples were used for morphological analysis, and endometrial cells were mechanically isolated for evaluation of gene and protein expression. The results showed that ovarian stimulation induced mTOR phosphorylation as well as increased expression of the Let‐7a miRNA. In addition, CT injection increased the expression of LIF and miRNA Let‐7a in ovarian stimulation similar to that in normal ovarian cycles. However, injection of PP242 reduced expression of miRNA Let‐7a and increased Muc‐1 expression in ovarian stimulation group. In conclusion, the administration of CT improved endometrial receptivity in mice. This phenomenon occurred by upregulation of LIF, miRNA Let‐7a and downregulation of Muc‐1 via mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the molecular mechanisms governing aquaporin-1 (AQP1)-mediated, mifepristone-induced angiogenesis and improve the understanding of low-dose mifepristone serving as an anti-implantation contraceptive drug.Methods: Human umbilical vein endothelial cells (HUVECs) were used to explore the effects of different concentrations of mifepristone (0, 65, and 200 nmol/L) on the activity of angiogenesis. Forty-five pregnant mice during the "window of implantation" were treated with different concentrations of mifepristone. HUVECs' proliferation was examined using a methyl thiazolyl tetrazolium (MTT) assay. The microvessel density (MVD) and the expression of AQP1 in endometrium were determined with immunohistochemical methods.Results: The MVD and the expression of AQP1 were significantly higher than controls. Mifepristone at 200 nmol/L significantly affected HUVECs' proliferation during culture over 12 h, and pretreatment with AQP1-specific siRNA significantly inhibited the mifepristone-enhanced cell proliferation.Conclusions: Low-dose mifepristone increased angiogenesis in a manner involving AQP1. This affords a new insight into the molecular mechanism underpinning the angiogenic effects of low-dose mifepristone. [ABSTRACT FROM AUTHOR]

Ultrastructural changes on the apical surface of the luminal epithelium of the uterus are known as pinopodes. Their morphology in species and in special species is associated with different results about size, duration, and percentage of surface area covered by pinopodes. The content of pinopodes is different in rodents and humans. In mice and rats pinopodes have many vacuoles and no organelle that extends to the actin stalk above the microvilli. Human pinopodes do not have a large vacuole and contain the golgi complex, a rough endoplasmic reticulum, secretory vesicles, and mitochondria that extend from the entire cell surface. It has been suggested that pinopodes are good markers of endometrial receptivity and implantation window. There are several molecular markers related to the presence of pinopodes, including integrins, leukemia inhibiting factor (LIF), l‐selectin, HOXA10, glutaredoxin, glycodelinA, heparin‐binding epidermal growth factor, mucins, and microRNAs (miRNAs). Multiple lines of evidence have indicated that miRNAs could affect the expression of LIF and pinopodes in the endometrium and these molecules play key roles in implantation window processes. Here, we have summarized the morphology and function of pinopodes. Moreover, we have highlighted several molecules in relation to pinopodes that could be used as biomarkers. Here, we summarized morphology and function of pinopodes. Moreover, we highlighted several molecules related with pinopodes which could be used as biomarkers. [ABSTRACT FROM AUTHOR]

Non-atypical endometrial hyperplasia (EH) most often occurs against a background of relative or absolute hyperestrogenism, responds to abnormal hormonal effects. In the reproductive age, the presence of EH can be a factor in the development of fertility disorders. The aim of the study was to learn the expression of pinopodes in ovulatory infertile women with non-atypical EH on the day of the implantation window. Under observation there were 196 women of reproductive age, of which 166 had been treated for infertility, and 30 conditionally gynecologically and somatically healthy, fertile women of the control group. A special examination of women included the determination in the endometrium by scanning electron microscopy of pinopodes’ expression. It was found that in women with non-atypical hyperplasia of the endometrium, areas without pinopodia were recorded in 47.59% of cases, pinopodes of small size - in 79.52% and abundant, small, thick microvilli - in 37.95%; the decrease in the incidence of developed pineapods in comparison with healthy prolific women was 2.72 times, that of pinopodes of large size was 3.39 and the small number of microvilli was 3.64, an increase in the occurrence of pinopodes of medium size 3.65, microvilli in moderate amounts - at 3.74. The authors conclude that the characteristic feature of endometrial pinopodes in EH is the presence of mosaicism of their shape (60.24%), size (64.46%) and the presence of numerous areas of absence of pinopodes (47.59%), which plays a significant role in disorders fertility.

Despite the significant advances in the last decades, low implantation rate per transferred embryo still remains a major concern in assisted reproductive techniques, highlighting a need to better characterize endometrial receptivity also by mean of specific biomarkers. Based on physiology and on the intimate contact with endometrium as the tissue of interest, in this study we developed and validated an optimized protocol that uses extracellular vesicles (EVs) recovered from uterine flushings and from a cervical brush, the latter never used until now as an EVs source, as surrogates for endometrial biopsies. This method combines the safety of sampling with the ability to study the expression profile across the uterine cycle. We have compared the yield and composition of EVs recovered from different biofluids samples and fractions thereof, opting for chemical precipitation as the EV isolation procedure, assuring the highest yield without introducing any bias in specific EV recovery. Moreover, collected EVs, in particular exosome-like vesicles, express putative endometrial markers, such as glycodelin A and receptors for estrogen and progesterone, thus confirming their endometrial origin. We also identified uterine flushing EVs, in particular those recovered from its mucous fraction, as the richest source of endometrial transcripts, likely correlated to cellular (epithelial) origin of these vesicles. Finally, our pilot quantitative assessment of three endometrial gene profiles, in samples collected at different time points along the luteal phase, revealed the fluctuations apparently recapitulating gene expression variability prior reported during the menstrual cycle. Unlike tissue biopsy that is subjected to inter- and intra-sample differences, our data suggest that EVs from liquid biopsies (from uterine flushings and a cervical brush) obtained through less-invasive procedures, can be substrate to detect and track the tissue representative expression profiles, better depicting the total endometrium complexity.

Objective: To analyze the influence of the start point of luteal support on clinical pregnancy rate, implantation rate, and live birth rate of in vitro fertilization and embryo transfer (IVF-ET) cycles.Design: Single-center prospective randomized controlled trial.Setting: University-affiliated IVF unit.Patient(s): Women ≤35 years of age with day 3 FSH levels <15 mIU/mL, who were undergoing their first IVF-ET cycles and received ovarian stimulation with the use of a GnRH agonist long protocol.Intervention(s): The patients were randomized on the day of hCG trigger to receive luteal phase support either 1 day after oocyte retrieval (group A) or on the day of oocyte retrieval (group B).Main Outcome Measure(s): Clinical pregnancy rate, implantation rate, miscarriage rate in the first trimester of pregnancy, and live birth rate per embryo transfer cycle.Result(s): Two hundred thirty-three patients were enrolled in this study: 117 were assigned to group A and 116 to group B. The clinical pregnancy rate (group A vs. group B: 55.3% vs. 51.5%), implantation rate (38.4% vs. 38.0%), and miscarriage rate (7.7% vs. 7.5%) were similar between the two groups. The live birth rate also did not significantly differ between the two groups (45.7% vs. 46.6%).Conclusion(s): Our study indicated that the initiation of progesterone supplementation 1 day after oocyte retrieval did not decrease the clinical pregnancy rate, implantation rate, or live birth rate in women undergoing IVF-ET cycles with the use of the GnRH agonist long protocol.Clinical Trial Registration Number: ChiCTR-IPR-14005293. [ABSTRACT FROM AUTHOR]

Aim This study aimed to assess the efficacy of the endometrial receptivity array ( ERA) as a diagnostic tool and the impact of personalized embryo transfer ( pET) for the treatment of patients with recurrent implantation failure ( RIF) in Japan. Methods Fifty patients with a history of RIF with frozen-thawed blastocyst transfers were recruited from July, 2015 to April, 2016. Endometrial sampling for the ERA and histological dating and a pET according to the ERA were performed. The receptive (R) or non-receptive ( NR) status of the endometrium as a result of the first ERA, endometrial dating, and pregnancy rates after the pET were analyzed. Results Of the patients with RIF, 12 (24%) were NR. Among them, eight (66.7%) were prereceptive. A clinical follow-up was possible in 44 patients who underwent the pET. The pregnancy rates were 58.8% per patient and 35.3% per first pET in the R patients and 50.0% per patient and 50.0% per first pET in the NR patients. Discrepancies between the ERA results and histological dating were seen more in the NR patients than in the R patients. Conclusions For patients with unexplained RIF, there is a significance in searching for their personal window of implantation ( WOI) using the ERA, considering the percentage of those who were NR and the pregnancy rates that resulted from the pET. By transferring euploid embryos in a personal WOI, much better pregnancy rates are expected. [ABSTRACT FROM AUTHOR]

Background: Implantation failure ofin vitrofertilization (IVF) cycles is recognized as one of key problems in contemporary reproductive medicine. Implantation itself is a multifactorial process and one can hardly expect to find a single criterion for the endometrium receptivity. Endometrium biopsy still remains the most applicable technique to diagnose abnormalities causing decrease or complete loss of endometrial receptivity. Materials and methods: We have studied 95 endometrial biopsy samples from 45 patient with I/II stage endometriosis and 40 controls from October 2014 to December 2015. Immunohistochemical analysis of key biological molecules participating in implant window formation (LIF, ER, PR, integrin, TGF-β1 and VEGF) was done to assess their predicting value for endometrial receptivity troubles. Results: The discriminant analysis demonstrated that highest information capacity was characteristic for LIF expression percent area, integrin αVβ3 both percent area and optic density in endometrial stroma and glands and finally TGFβ1 and VEGF-А percent area expression in endometrial stroma. The model test done on a checking group showed 89.1% correct discrimination. Cross-checking in a teaching group showed a bit lower but still high correct answer percentage (88.8%). A decision-making classification tree was worked out. Conclusion: The produced model is sufficient for predicting IVF treatment failure and allows producing reasonable treatment tactics as well as encourages IVF treatment effectiveness improvement in patients with endometriosis. [ABSTRACT FROM PUBLISHER]