The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure.
TL;DR: There is an increased percentage of WOI displacement in RIF patients compared with comparison group patients, leading to the concept of pET as a therapeutic strategy.
About: This article is published in Fertility and Sterility.The article was published on 2013-09-01. It has received 351 citations till now.
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TL;DR: The endocrine, paracrine, and autocrine cues that tightly govern this differentiation process are reviewed and how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure is discussed.
Abstract: Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.
679 citations
TL;DR: The results demonstrate the existence of an endometrial microbiota that is highly stable during the acquisition of endometrian receptivity, however, pathological modification of its profile is associated with poor reproductive outcomes for in vitro fertilization patients.
448 citations
TL;DR: A new initial step in approach to patients with RIF is suggested, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body.
Abstract: Recurrent implantation failure (RIF) refers to cases in which women have had three failed in vitro fertilization (IVF) attempts with good quality embryos. The definition should also take advanced maternal age and embryo stage into consideration. The failure of embryo implantation can be a consequence of uterine, male, or embryo factors, or the specific type of IVF protocol. These cases should be investigated to determine the most likely etiologies of the condition, as this is a complex problem with several variables. There are multiple risk factors for recurrent implantation failure including advanced maternal age, smoking status of both parents, elevated body mass index, and stress levels. Immunological factors such as cytokine levels and presence of specific autoantibodies should be examined, as well as any infectious organisms in the uterus leading to chronic endometritis. Uterine pathologies such as polyps and myomas as well as congenital anatomical anomalies should be ruled out. Sperm analysis, pre-implantation genetic screening and endometrial receptivity should be considered and evaluated, and IVF protocols should be tailored to specific patients or patient populations. Treatment approaches should be directed toward individual patient cases. In addition, we suggest considering a new initial step in approach to patients with RIF, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body.
287 citations
TL;DR: The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby.
Abstract: Background Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. Methods This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. Results Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometrium to hCG, resulting from controlled ovarian stimulation. The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. Conclusions This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.
253 citations
Cites background from "The endometrial receptivity array f..."
...In view of this and the potential for cycle-to-cycle variability of endometrial receptivity (Ruiz-Alonso et al., 2013), the ideal test would be relatively non-invasive and performed within the embryo transfer cycle itself....
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TL;DR: The post-test probabilities from the analyses may be used in clinical practice to manage couples' expectations during fertility treatments (IUI and IVF), and it is proposed that various levels of endometrial receptivity exist within the window of implantation.
Abstract: Background Early reproductive failure is the most common complication of pregnancy with only 30% of conceptions reaching live birth. Establishing a successful pregnancy depends upon implantation, a complex process involving interactions between the endometrium and the blastocyst. It is estimated that embryos account for one-third of implantation failures, while suboptimal endometrial receptivity and altered embryo-endometrial dialogue are responsible for the remaining two-thirds. Endometrial receptivity has been the focus of extensive research for over 80 years, leading to an indepth understanding of the processes associated with embryo-endometrial cross-talk and implantation. However, little progress has been achieved to translate this understanding into clinically meaningful prognostic tests and treatments for suboptimal endometrial receptivity. Objective and rationale The objective of this systematic review was to examine the evidence from observational studies supporting the use of endometrial receptivity markers as prognostic factors for pregnancy outcome in women wishing to conceive, in order to aid clinicians in choosing the most useful marker in clinical practice and for informing further research. Search methods The review protocol was registered with PROSPERO (CRD42017077891). MEDLINE and Embase were searched for observational studies published from inception until 26 February 2018. We included studies that measured potential markers of endometrial receptivity prior to pregnancy attempts and reported the subsequent pregnancy outcomes. We performed association and accuracy analyses using clinical pregnancy as an outcome to reflect the presence of receptive endometrium. The Newcastle-Ottawa scale for observational studies was employed to assess the quality of the included studies. Outcomes We included 163 studies (88 834 women) of moderate overall quality in the narrative synthesis, out of which 96 were included in the meta-analyses. Studies reported on various endometrial receptivity markers evaluated by ultrasound, endometrial biopsy, endometrial fluid aspirate and hysteroscopy in the context of natural conception, IUI and IVF. Associations were identified between clinical pregnancy and various endometrial receptivity markers (endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity and various molecules); however, their poor ability to predict clinical pregnancy prevents them from being used in clinical practice. Results from several modern molecular tests are promising and further data are awaited. Wider implications The post-test probabilities from our analyses may be used in clinical practice to manage couples' expectations during fertility treatments (IUI and IVF). Conventionally, endometrial receptivity is seen as a dichotomous outcome (present or absent), but we propose that various levels of endometrial receptivity exist within the window of implantation. For instance, different transcriptomic signatures could represent varying levels of endometrial receptivity, which can be linked to different pregnancy outcomes. Many studies reported the means of a particular biomarker in those who achieved a pregnancy compared with those who did not. However, extreme values of a biomarker (as opposite to the means) may have significant prognostic and diagnostic implications that are not captured in the means. Therefore, we suggest reporting the outcomes by categories of biomarker levels rather than reporting means of biomarker levels within clinical outcome groups.
228 citations
Cites background from "The endometrial receptivity array f..."
...One study (Ruiz-Alonso et al., 2013) assessed the endometrial receptivity in 85 women scheduled to undergo frozen–thawed embryo transfer in natural or hormonally prepared cycles....
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References
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TL;DR: Endometrial samples obtained by two different sampling techniques from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods.
Abstract: Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping (54,600 genes and expressed sequence tags) of this tissue sampled across the cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. Unsupervised principal component analysis of all samples revealed that samples self-cluster into four groups consistent with histological phenotypes of proliferative (PE), early-secretory (ESE), mid-secretory (MSE), and late-secretory (LSE) endometrium. Independent hierarchical clustering analysis revealed equivalent results, with two major dendrogram branches corresponding to PE/ESE and MSE/LSE and sub-branching into the four respective phases with heterogeneity among samples within each sub-branch. K-means clustering of genes revealed four major patterns of gene expression (high in PE, high in ESE, high in MSE, and high in LSE), and gene ontology analysis of these clusters demonstrated cycle-phase-specific biological processes and molecular functions. Six samples with ambiguous histology were identically assignable to a cycle phase by both principal component analysis and hierarchical clustering. Additionally, pairwise comparisons of relative gene expression across the cycle revealed genes/families that clearly distinguish the transitions of PE-->ESE, ESE-->MSE, and MSE-->LSE, including receptomes and signaling pathways. Select genes were validated by quantitative RT-PCR. Overall, the results demonstrate that endometrial samples obtained by two different sampling techniques (biopsy and curetting hysterectomy specimens) from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods. Also, the results enable global identification of biological processes and molecular mechanisms that occur dynamically in the endometrium in the changing steroid hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore the potential of gene expression profiling for developing molecular diagnostics of endometrial normalcy and abnormalities and identifying molecular targets for therapeutic purposes in endometrial disorders.
545 citations
"The endometrial receptivity array f..." refers background in this paper
...In the search for objective diagnostic criteria,pioneering work has demonstrated the feasibility of the molecular classification of human endometrial receptivity (12) and endometrial cycle stages (13, 14) with the use of transcriptomic profiling....
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TL;DR: A genomic tool composed of a customized microarray and a bioinformatic predictor for endometrial dating and to detect pathologies ofendometrial origin can be used clinically in reproductive medicine and gynecology and the transcriptomic signature is a potential endometrian receptivity biomarkers cluster.
464 citations
"The endometrial receptivity array f..." refers background or methods in this paper
...Acknowledging the need for an objective endometrial diagnostic test that can guide and improve our clinical practice, and based on a decade of research in the transcriptomics of endometrial receptivity (16), our group developed the ERA test (17)....
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...The endometrial receptivity array (ERA) consists of a customized array containing 238 genes expressed at the different stages of the endometrial cycle and is coupled to a computational predictor that is able to identify the receptivity status of an endometrial sample and diagnose the personalized WOI (pWOI) of a given patient regardless of the sample's histologic appearance (17)....
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...To analyze and visualize the gene expression profile of NR samples, a principal component analysis (PCA) with the use of Babelomics (24) was performed against the sample training sets (proliferative, prereceptive, receptive, and postreceptive samples) used in the development of the ERA prediction profile (17)....
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...Fragmented cRNA samples were hybridized onto the customised ERA array (17), by incubation at 65 C for 17 hours with constant rotation....
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...(B) Principal component , and Pþ6, the ERA gene expression training sets (proliferative, ent of the ERA prediction tool (17)....
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TL;DR: It is suggested that IVF treatment that is preceded by endometrial biopsy doubles the chance for a take-home baby.
422 citations
"The endometrial receptivity array f..." refers background in this paper
...Although controversial, it has been suggested that the local injury induced by an endometrial biopsy might improve embryo implantation in the next ART cycle (25, 26)....
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TL;DR: The suggested methods for evaluation and treatment of RIF are discussed: repeated hysteroscopy, myomectomy, endometrial stimulation, immunotherapy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation protocols and salpingectomy for hydrosalpinges.
Abstract: Pregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, some couples fail repeatedly. The causes for repeated implantation failure (RIF) may be because of reduced endometrial receptivity, embryonic defects or multifactorial causes. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules and immunological factors, may decrease endometrial receptivity, whereas genetic abnormalities of the male or female, sperm defects, embryonic aneuploidy or zona hardening are among the embryonic reasons for failure of implantation. Endometriosis and hydrosalpinges may adversely influence both. In this mini review, we discuss the suggested methods for evaluation and treatment of RIF: repeated hysteroscopy, myomectomy, endometrial stimulation, immunotherapy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation protocols and salpingectomy for hydrosalpinges.
397 citations
"The endometrial receptivity array f..." refers background in this paper
...818 healthy women and one that has remained poorly characterized (1, 2)....
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TL;DR: Gene expression profiles of pre-receptive versus receptive endometria obtained from the same fertile woman in the same menstrual cycle are compared to gain a global molecular understanding of human endometrial receptivity.
Abstract: In humans, embryonic implantation and reproduction depends on the interaction of the embryo with the receptive endometrium. To gain a global molecular understanding of human endometrial receptivity, we compared gene expression profiles of pre-receptive (day LH+2) versus receptive (LH+7) endometria obtained from the same fertile woman (n = 5) in the same menstrual cycle in five independent experiments. Biopsies were analysed using the Affymetrix HG-U95A array, a DNA chip containing ~12 000 genes. Using the pre-defined criteria of a fold change >3 in at least four out of five women, we identified 211 regulated genes. Of these, 153 were up-regulated at LH+7 versus LH+2, whereas 58 were down-regulated. Amongst these 211 regulated genes, we identified genes that were known to play a role in the development of a receptive endometrium, and genes for which a role in endometrial receptivity, or even endometrial expression, has not been previously described. Validation of array data was accomplished by mRNA quantification by real time quantitative fluorescent PCR (Q-PCR) of three up-regulated [glutathione peroxidase 3 (GPx-3), claudin 4 (claudin-4) and solute carrier family 1 member 1 (SLC1A1)] genes in independent LH+2 versus LH+7 endometrial samples from fertile women (n = 3) and the three up-regulated genes throughout the menstrual cycle (n = 15). Human claudin-4 peaks specifically during the implantation window, whereas GPx-3 and SLC1A1 showed highest expression in the late secretory phase. In-situ hybridization (ISH) experiments showed that GPx-3 and SLC1A1 expression was restricted to glandular and luminal epithelial cells during the mid- and late luteal phase. The present work adds new and important data in this field, and highlights the complexity of studying endometrial receptivity even using global gene-expression analysis.
393 citations
"The endometrial receptivity array f..." refers background in this paper
...In the search for objective diagnostic criteria,pioneering work has demonstrated the feasibility of the molecular classification of human endometrial receptivity (12) and endometrial cycle stages (13, 14) with the use of transcriptomic profiling....
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