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David Blesa 1 , 2 , a david. Simon a These authors contributed equally to this work The endometrium and endometrial receptivity The endometrium is the tissue that lines the inside of the endometrial cavity. Morphologically it is divided into the functional and the basal layers. The functional layer presents different cellular compartments: The epithelium is composed of epithelial cells on the surface or coating epithelial glands; the stroma consists in an extracellular matrix ECM and fibroblasts that differentiate during the decidualization process. In the stroma, blood vessels spiral arteries are also present, along with immune resident cells such as macrophages and NK cells [ ]. The functional layer is responsible for proliferation, secretion and tissue degeneration, while the regenerative capacity of this organ lies in the basal layer [ ]. The gene expression of the different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules from neighboring cells. Due to this regulation, the endometrium goes through cyclic modifications which compose the endometrial cycle. An endometrial cycle can be divided simply into the proliferative phase, corresponding to the follicular phase in the ovary, the secretory phase, corresponding to the luteal phase in the ovary, and the menstrual phase.


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Jun 15,  · More specifically, the invention consists of developing a specific expression microarray of endometrial receptivity (Endometrial Receptivity Array or ERA) which allows evaluating the receptive state of a human endometrium, as well as assessing said state for diagnostic and therapeutic purposes.

All patients underwent three endometrial biopsies in consecutive spontaneous cycles, regardless of the previous histological findings. All endometrial samples were obtained on postovulatory d 7 as determined by ultrasonography. Agreement between the repeated observations first vs. Overall, these results demonstrate that all endometrial variables investigated had poor reproducibility and high variability cycle to cycle.

Traditionally, this has been accomplished by histological dating of the endometrial biopsy specimen obtained in the late secretory phase 1 , 2. It has been accepted that the endometrial biopsy, properly obtained and properly diagnosed, can serve as a bioassay. If the biopsy is obtained as close to the expected menses as possible, almost the entire steroidogenic function of the corpus luteum is reflected in the endometrial histological pattern.

Also, it was considered that the biopsy reflects the response of the target organ to the hormone 1. The basis for the use of the endometrial biopsy as a bioassay of the steroidogenic function of the corpus luteum has been the traditional morphological endometrial dating according to the criteria of Noyes et al. A biopsy specimen was considered abnormal when there was a lack of expected endometrial development, which represented a lag of 2 or more days between endometrial date and calendar dating from the subsequent menstrual period 1 , 2.

If the biopsy was out of phase, a second biopsy should be done during a subsequent cycle, and the original finding should be confirmed. Unless this finding was consistent and repetitive, it could not be considered as a factor responsible for infertility 1.

Endometrial receptivity by sunitafeme

Original studies on endometrial transcriptomics in assisted reproductive medicine Most of these studies investigate the transcriptomic signature in the whole endometrial tissue without separating the different compartments. However, in some studies, laser capture micro-dissection has facilitated specific compartment gene expression profiles Yanaihara et al. Even the specific profiles for stromal cells and glands at different depths in the endometrium have been reported Gaide Chevronnay et al.

Several groups have used transcriptomics to search for the molecular diagnosis of the different phases of the human endometrium Carson et al.

Indeed, despite the historical relevance of traditional histologic endometrial dating criteria defined by Noyes (7, 8), its accuracy, Received September 28, ; revised October 31, ; accepted December 3, ; published online January 8,

It is asserted that examination of the endometrium during the secretory phase yields more information about the time of ovulation, degree of progestational change, and normality of the endometrium than any other test used in sterility studies. Attention to qualitative changes in 8 morphological factors is most useful in dating the endometrial biopsy.

During the 1st week of luteal activity, attention should be focused on changes occurring in gland epithelium: During the 2nd week , stromal changes including edema , predecidual reaction, stromal mitosis, and leukocytic infiltration are the key criteria. Tissue from the fundus of the uterus gives the most reliable information. These critera were used in sterility biopsies taken from normally menstruating women over a 3-year period.

Absence of organic endometrial disease and availability of accurate menstrual history were the only selection criteria. To test the validity of the dating criteria, change in basal body temperature was used to correlate endometrial dating with ovulation rather than onset of menstruation. To determine whether biopsy caused early menstruation, the secretory phases of the 25 patients who had recorded temperatures in at least 2 cycles in addition to that in which the biopsy was taken were examined.

Endometrial receptivity array: Clinical application Mahajan N

Inadequate uterine receptivity is responsible for approximately two-thirds of implantation failures, whereas the embryo itself is responsible for only one-third of these failures Slide 6 Human embryo implantation is a three-stage process apposition, adhesion and invasion Implantation involves embryo apposition and adhesion to the endometrial epithelium penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast and the decidua of the endometrium.

Slide 9 Endometrial morphological features classical work describing the dating of the endometrium is done by Noyes et al. Pinopod expression is limited to a brief period of maximum 2 days in the menstrual cycle corresponding to the putative window of implantation Pinopods appear progesterone dependant Slide 12 Function of Pinopods the receptors required for blastocyst adhesion are located on the pinopod surface.

Histological criteria have been used since the s to date the endometrium (Noyes et al. , ). However, morphological criteria have major limitations for predicting endometrial receptivity, as shown in randomized studies (Coutifaris et al. ; Murray et al. ).

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract The impact of a premature elevation of serum progesterone level, the day of hCG administration in patients under controlled ovarian stimulation during IVF procedure, on human endometrial receptivity is still debated. In the present study, we investigated the endometrial gene expression profile shifts during the prereceptive and receptive secretory stage in patients with normal and elevated serum progesterone level on the day of hCG administration in fifteen patients under stimulated cycles.

Then, specific biomarkers of endometrial receptivity in these two groups of patients were tested. Endometrial biopsies were performed on oocyte retrieval day and on day 3 of embryo transfer, respectively, for each patient. This was confirmed by the functional annotation of the differentially expressed genes as it showed downregulation of cell cycle-related genes.

Conversely, the profile of endometrial receptivity was comparable in both groups. Premature progesterone rise alters the endometrial gene expression shift between the prereceptive and the receptive stage but does not affect endometrial receptivity. Introduction The impact of premature serum progesterone elevation at the end of the follicular phase under controlled ovarian stimulation COS cycle for in vitro fertilization IVF is still debated.

While several studies reported lower pregnancy rates in patients with high progesterone concentration on the day of human chorionic gonadotropin hCG administration [ 1 — 9 ], one found a favourable effect on pregnancy outcome [ 10 ] and others failed to demonstrate any association [ 11 — 21 ]. Although the mechanism by which premature serum progesterone elevation might alter the embryo transfer outcome is still unclear, there are accumulated data suggesting a negative impact on endometrium [ 22 , 23 ].

Elevated progesterone levels might induce premature endometrial maturation and, as a consequence, earlier opening of the implantation window that leads to asynchronization of the crosstalk between embryo and endometrium. Accelerated endometrial maturation following COS has been clearly demonstrated by histological dating on the day of oocyte retrieval [ 24 — 27 ], but this is not the case during the implantation window [ 22 ].

Human Endometrial Transcriptomics: Implications for Embryonic Implantation

The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain. Design Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years. Setting University-based infertility practices.

Patient s Volunteer subjects recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20—39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study.

CONTEXT: Endometrial maturation, important in the diagnosis of infertile couples, has been evaluated since using the Noyes criteria. Nevertheless, there is no consensus regarding the most suitable period of the luteal phase for performing the biopsy. OBJETIVE: This study evaluated the.

In , children were admitted to the Noyes Home, with 50 percent admitted for emergency shelter reasons. There are four types of admissions at the Noyes Home: Children who have become homeless are placed in the safe keeping of the Noyes Home by family members who have lost their home. Families who experience emergencies and do not have a place where their children can stay can also utilize the services of the Noyes Home.

These children are referred to us by parents who might be experiencing a short-term problem or are in great need of time to regain their coping skills. These children are placed with the Noyes Home on a temporary basis until a foster care home is secured or they are returned to their home. Children in this category are referred to the Noyes Home by parents, mental health facilities, schools and social workers. They may be having problems at home, in school or both — but children with violent behaviors are referred to other community resources who are specially trained to help with this type of challenge.

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Macklon Nick , K. Fauser Bart , H. Classen-Linke The feasibility of a less invasive method to assess endometrial maturation – Comparison of simultaneously obtained uterine secretion and tissue biopsy Publication BJOG: To compare the assessment of endometrial maturation parameters in endometrial secretion samples obtained by a novel minimally invasive technique with those assessed in tissue biopsies. Healthy female volunteers attending a gynaecological outpatient clinic.

Endometrial secretion fluid and tissue sampling 5 days after a spontaneous ovulation assessed with ultrasound.

the endometrial region–specific implantation frequency of blastocysts via anatomic dissection or ultrasonography (17–20). These studies collectively suggest that the cornual that limit the precision of histologic dating with the use of Noyes criteria (22), we limited our use of histologic dating.

A retrospective analysis of data. Ongoing pregnancy was defined as pregnancy over 12 weeks. Primary end point for group III was percentage of nonreceptive to receptive endometrium. Patient population was divided into three groups. Patients were in the age group of 25—46 years The average body mass index in the three groups was Number of previous IVF failures ranged from 2 to 6.

Only those previous cycles where embryo grading was available for scrutiny were included. These failed cycles had been done in good ART centers with an in-house embryologist and good quality control in the laboratory. Exclusion criteria Patients with uncorrected uterine and adnexal pathology, e. Apart from the routine infertility work-up a hysteroscopy when not done earlier , oral glucose tolerance test, and thyroid profile were done for all patients.

For RIF patients karyotypes of both partners, thrombophilia profile, lupus anticoagulant, and anticardiolipin antibodies IgG and IgM, were carried out and were normal. Patients in this retrospective analysis were negative for endometrial Koch’s. Transvaginal ultrasound was done on the 2nd day of the period and after ensuring that the endometrium had shed completely HRT was started.

Dating the endometrial biopsy.

Ello siempre que las condiciones de su desarrollo in vitro sean las adecuadas y no supongan un deterioro de esta capacidad. Practicaron ICSI a ovocitos, de los cuales 81 alcanzaron el estadio de blastocisto, siendo transferidos 54 1 a 3 blastocistos por transferencia. Se produjo el nacimiento de 16 fetos vivos. Concluyeron apoyando el desarrollo rutinario a bastocisto utilizando medios comerciales.

En el mismo sentido se pronunciaron Shapiro y cols

Human embryo implantation is a three-stage process (apposition, adhesion and invasion) Implantation involves embryo apposition and adhesion to the endometrial epithelium penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma.

This specific type of embryo transfer includes two embryos at different developmental stage—one cleavage stage Day 3 embryo and one blastocyst Day 5 —that are transferred together in one frozen embryo transfer procedure in an unstimulated cycle. To the best of our knowledge, this is the first report of an implemented mixed embryo transfer after the diagnosis of variable WOI.

In July , a year-old woman attended our hospital reporting 6 consecutive unsuccessful IVF attempts and a 5-year history of primary infertility. In this period, lasting approximately two days, a 6—8 day human embryo has a chance to be attached into the surface endometrial layer, composed of epithelial cells and to be implanted into the stromal cell layer [3]. This atypical condition that was rarely observed in other patients urged an alternative problem-solution approach. Endometrial cycle dating based on Noyes et al.

Most of them were found to have their WOI shifted later in the cycle and the endometrium of these women was characterized as prereceptive.

Noyes Criteria Endometrial Dating

Abstract Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity ER has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation WOI.

Use of this test in patients with recurrent implantation failure RIF has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer pET on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in After pET, the overall ongoing pregnancy rate was

Diagnosis of Endometrial-Factor Infertility: Current Approaches and New Avenues for Research In Noyes et al. histologically defined the endometrial dating criteria for evaluating the endometrium. ,, questioned the accuracy and reproducibility of the Noyes method to diagnose endometrial receptivity or fertility status.

Their use is also known for immobilizing nucleic acids which are complementary to a variety of genes, being applied to the field of chemistry, biology, medicine and medical diagnostics US 6, , B1. Microarrays are currently being used to make comparisons based on genomic data and to research different systems. There are different patent and non-patent literature publications on this subject. Microarray technology has allowed globally studying the gene expression of the endometrium under physiological conditions during the different phases of the menstrual cycle in the natural cycle Ponnampalam et al.

With respect to the human window of implantation, gene expression profiles of the endometrium in the natural cycle have been described Borthwick et al. The gene expression profile of the endometrium during the window of implantation in stimulated cycles has also been analyzed Mirkin et al. The refractory profile of the human endometrium in the presence of an intrauterine device IUD during the window of implantation has also been studied Horcajadas et al.

All these works have recently been reviewed by the authors of the present application Horcajadas et al.


To examine the relationship between endometrial histological maturation and reproductive hormones, we studied 11 fertile women, aged 18—37 yr. All participants had had at least 1 previous pregnancy and cycled regularly, every 25—35 days. Women collected daily, first morning voided urine for measurement of estradiol and progesterone metabolite excretion, estrone conjugates E1c , and pregnanediol glucuronide Pdg , respectively, throughout the cycle of study. Hormones were normalized for creatinine.

Endometrial dating by assessment of the protein patterns of endometrial secretion fluids did not significantly correlate to that based on the combination of Noyes criteria and immunohistochemical PR and Ki‐67 staining patterns.

References Abstract Over the last decade, research to improve success rates in reproductive medicine has focused predominantly on the understanding and optimization of embryo quality. However, the emergence of personalized medicine in ovulation induction and embryology has shifted the focus to assessing the individual status of the endometrium. The endometrium is considered receptive during an individually defined period, the window of implantation WOI , when the mother permits a blastocyst to attach and implant.

This individual receptivity status can now be objectively diagnosed using the endometrial receptivity array ERA developed in The ERA, together with a computational algorithm, detects the unique transcriptomic signature of endometrial receptivity by analyzing differentially expressed genes and reliably predicting the WOI.

We and others have illustrated the utility of this personalized diagnostic approach to discriminate between individual physiological variation in endometrial receptivity and unknown endometrial pathology, deemed as causal in recurrent implantation failure RIF. NCT is underway to determine the clinical value of this endometrial diagnostic intervention in the work-up for reproductive care. In this review, we analyse the current clinical practice in the diagnosis of the endometrial factor together with new avenues of research.

My Endometrial Biopsy Experience