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The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer; the.
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It is clear that more stringent criteria are needed to improve the precision of timing with endometrial dating. Graph illustrating the Noyes method of endometrial dating, which highlights the uncertainty in timing introduced during the post-ovulatory period, the mid-luteal phase and by measuring the LH surge. The distribution over time of many observed changes is too diffuse to allow precise endometrial dating, for example 2 days of the post-ovulatory period and 4—5 days in the mid-luteal phase.

Using the luteinizing hormone LH surge to predict ovulation is one approach that has been investigated, although there would still remain a degree of uncertainty in timing, as the LH surge occurs over a period of 30 h Acosta et al. Electron microscopy allows the examination of endometrial ultrastructures present during the implantation window, such as pinopodes and nucleolar channels, which may prove useful markers of endometrial receptivity Bentin-Ley et al. Methods that associate morphology and function e.

Unfortunately, immunohistochemistry suffers from the same problems as morphological assessments. Furthermore, the most promising molecular candidates for markers of the implantation window have, so far, failed as predictors of endometrial status Acosta et al. However, other markers may be more successful e.

In the future, laser capture microdissection may be coupled with gene expression analysis, providing another useful tool that could be used to link endometrial morphology and function Yanaihara et al. Another key consideration when using endometrial dating is that it disregards the status of the embryo.

Ensuring the endometrium is receptive is of little use if a poor-quality embryo is introduced. Therefore, to ensure optimal conditions for implantation, endometrial dating should not be used in isolation, but should be combined with other techniques that provide information about embryo quality. Progesterone and estrogen are the dominant hormonal modulators of endometrial development. Ovarian estrogen and progesterone condition the uterus for implantation, and knowledge about the precise temporal action of these hormones within the menstrual cycle has allowed the development of hormone-based contraception.

Both the epithelial and stromal compartments express progesterone and estrogen receptors, and the response depends on the levels of these receptors as well as on the concentration of the hormones themselves. The interactions of progesterone and estrogen with estrogen receptors ER during endometrial development are illustrated in Fig. It is apparent that the appropriate cyclical pattern of receptor expression is crucial for achieving endometrial receptivity and successful implantation Lessey, ; Ma et al.

The roles of progesterone and estrogen E 2 ; E 3 , estriol and estrogen receptors ER during endometrial development. Changes in the expression of progesterone receptors PRA, PRB in glandular epithelial cells and stromal cells during the different phases of the menstrual cycle. Adapted with permission from Mote et al.

Although progesterone and estrogen are the key modulators of endometrial maturation, their roles in this process are complex and sophisticated Punyadeera et al. Hormonal activity depends on not only the levels of progesterone, estrogen and their receptors, but also on the rates of progesterone and estrogen metabolism e. The activities of progesterone and estrogen are also influenced by the effects of co-activators and repressors Punyadeera et al. Furthermore, both hormones regulate the expression of numerous endometrial proteins paracrine signalling Cooke et al. In addition to progesterone and estrogen, a number of other endocrinological factors are known to mediate endometrial function Kodaman and Taylor, In rodents, prostaglandins PGs are thought to facilitate increased vascular permeability during implantation Kennedy, , and enzymes involved in PG production COX-1 and COX-2 shown cyclical changes in expression Chakraborty et al.

The effects of androgens are often overlooked in the female reproductive cycle. However, androgen receptors are present on stromal and epithelial cells in the endometrium, and both androstenedione and testosterone induce changes in endometrial function that may be important during implantation Kodaman and Taylor, Endometrial factors are critical mediators of all phases of the implantation process Fig.

Once the embryo reaches the uterus, the first cells it encounters are the epithelial cells of the endometrium. These cells secrete a range of factors into the uterine lumen, which may affect embryonic attachment as well as further development of the early placenta and embryo. However, the precise roles of individual factors as well as the molecular interactions involved have mostly not been elucidated for humans, and the current understanding of these processes stems primarily from research in rodents reviewed in Dimitriadis et al. Factors regulated during the early stages of implantation. Adapted with permission from Dimitriadis et al.

In humans, one factor that has attracted particular interest is leukaemia-inhibitory factor LIF , which is an interleukin IL -6 cytokine expressed in endometrial epithelial cells at the appropriate time for which receptors are present on preimplantation embryos. Studies in mice demonstrate that LIF plays a role in implantation and may also promote embryonic development.

Observational studies in humans are suggestive of a possible role for LIF in humans Robb et al. Indeed, infertility in some women has been associated with the dysregulation of LIF, and also of IL, which is produced in the same manner in the endometrial glands during the receptive phase Dimitriadis et al.

However, the importance of LIF in implantation is still under debate, as promising results in animal models have failed to translate to humans Kimber, With the increasing trend towards single embryo transfer in ART Vilska et al. Over the years, with an improving understanding of embryonic development and advances in in vitro culture techniques, the developmental stage at which an embryo can be transferred has become more advanced, and embryo selection criteria have evolved accordingly.

However, no single method of embryo selection has emerged, with some groups selecting blastocyst stage embryos, and others still opting to select at the 2PN stage or cleavage stage De Neubourg et al. Furthermore, it is recognized that morphological assessment of embryo quality is still highly subjective and, therefore, a number of alternative approaches are currently being explored, such as assessment of the embryo culture medium to detect nutrient uptake or metabolite secretion Sakkas and Gardner, Preimplantation genetic diagnosis PGD was initially developed as a preconception test for couples carrying genetic disorders who were at risk of having a child affected by the disorder Thornhill et al.

However, more recently, the technique has been used extensively in the context of optimizing IVF outcomes in infertile patients who are not carriers of a heritable disease Sermon et al. Chromosomal analysis of human gametes and embryos has revealed that chromosome aberrations occur at high frequency in the early preimplantation embryo.

At later stages, genetic testing can be performed on one or two blastomeres from the cleavage stage embryo day 3 , or on trophectoderm tissue of the blastocyst day 5 Staessen et al. Although data are emerging from clinical studies investigating the use of PGS in cleavage stage embryos and blastocysts Staessen et al. Furthermore, mosaicism presence of both aneuploid and euploid cells in an embryo is commonly found in cleavage-stage embryos, although the clinical relevance of this phenomenon remains unclear Bielanska et al. Another key issue in ART protocols that is still under debate is the timing of embryo transfer.

Whereas in an unselected patient population a clinical benefit of day-5 transfer blastocyst transfer with respect to live-birth rate and multiple-pregnancy rate has not been shown Blake et al. Blastocyst transfer gives the option to select the morphologically best embryo, whereas it has also been indicated that good-quality blastocysts have a decreased incidence of aneuploidy Fig. Relationship between chromosomal abnormalities and developmental stage on A day 3 or B day 5 of embryonic development.

The Endometrium: Conditions and Its Role in Pregnancy

Figure reproduced with permission from Staessen et al. Failure of the blastocyst to release from the zona pellucida has been identified as a potential cause of implantation failure in assisted cycles, particularly in older women Seif et al. A potential solution to this is artificial disruption of the zona pellucida or assisted hatching.

A systematic review of studies investigating the effects of this technique on conception found that assisted hatching significantly improved pregnancy rates, but had no effect on live-birth rates or spontaneous abortion rates, and multiple-pregnancy rates were significantly increased Seif et al. Unfortunately, there were insufficient data for this analysis to investigate the impact of assisted hatching on a number of other important outcomes, such as monozygotic twinning, embryo damage, congenital and chromosomal abnormalities and in vitro blastocyst development.


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When optimizing ART procedures to mimic nature as closely as possible, it is important to remember that controlled ovarian stimulation itself interrupts natural physiological processes and is likely to alter key parameters such as the rate of embryonic development and the extent and timing of endometrial receptivity.

Artificial stimulation affects the levels of progesterone and estrogen, the ratio between these two hormones and endometrial expression of their receptors Beckers et al. There is evidence that supraphysiological steroid levels impair the luteal phase, and this is true, even when stimulation is started in the late follicular phase Bourgain et al. Therefore, if the luteal phase is not supplemented, premature luteolysis can occur and pregnancy may not be achieved Beckers et al.

In ART cycles, the aim is to produce multiple mature follicles, which leads to elevated levels of progesterone and estrogen compared with natural cycles, and this can induce changes in the endometrium Bourgain and Devroey, that can be detected using standard histological techniques Garcia et al. To overcome some of the effects potentially associated with hormonal stimulation, various modified stimulation protocols have been investigated. For example, milder stimulation regimens have been studied, in which gonadotrophins were administered at a lower dose, or later in the cycle, or that used gonadotrophin-releasing hormone antagonists for pituitary downregulation Macklon and Fauser, b ; Hohmann et al.

The implantation process itself has never been observed directly in vivo in humans Lee and DeMayo, However, studies in animals, primarily rodents, sheep and primates, have provided clues about the hormonal and morphological changes that might occur in women prior to and during implantation Lee and DeMayo, Indeed, the three stages of endometrial development observed in animals endometrial neutrality, receptivity and refractoriness are also thought to occur in humans Rogers, It is recognized that different species show a wide variety of mechanisms by which implantation occurs Ringler and Strauss, and, therefore, different animals may be more suited as models for particular steps in the human implantation process.

For example, pigs and sheep are potential candidates for the study of the early stages of implantation, as they have extended apposition and attachment phases Lee and DeMayo, Conversely, macaques and humans have similar mechanisms for trophoblast invasion and, therefore, macaques are a suitable model for studying the later phases of implantation Lee and DeMayo, Although information about the physiology of implantation has been gained from a range of different animal models, the current understanding about this process on a molecular level results largely from studies in mice Lee and DeMayo, However, the mechanisms of implantation in mice and humans are quite distinct.

EDITOR DISCLOSURES AT TIME OF PUBLICATION

During implantation in mice, the luminal epithelium forms an invagination that surrounds the trophoblast eccentric mechanism and is subsequently shed by apoptosis, whereas in humans, the trophoblast invades the stroma by penetrating the luminal epithelium interstitial mechanism Wimsatt, Studies on LIF illustrate how promising findings in mice have translated to disappointing results in humans. Targeted mutagenesis studies in mice clearly established an essential role for LIF in mouse implantation, prompting intensive investigation into its role in humans. Collectively, these data question an essential role for LIF in human implantation and are cause for reflection as to the translatability of animal studies to human biology.

This issue of translatability has important implications for future research, as rodent models are best suited for testing the functional role of genes and proteins. Consequently, animal studies should be validated using alternative in vivo models, including primates, and in vitro systems that can reproduce critical stages of the implantation process with fidelity, prior to the initiation of large-scale clinical trials or development of methods to assess endometrial receptivity or improve implantation rates.

To address this need, a number of in vitro models using human cell culture systems have been developed to study various aspects of embryo—endometrial interaction. Bentin-Ley et al. Using this model, they demonstrated that human blastocysts attach preferentially to pinopode-presenting areas on the endometrial surface Bentin-Ley et al. Another group cultured a complete endometrial biopsy of the upper functional layer of the endometrium onto collagen gel Landgren et al.

Simon et al.

In the apposition model, embryos obtained after ovarian superovulation and insemination IVF or intracytoplasmic sperm injection were co-cultured with luteal phase endometrial epithelial cells. This model resulted in a clinical programme where embryos could be co-cultured with epithelial cells until blastocyst stage and transferred back to the mother Mercader et al.

6.1 Role and functional anatomy of the endometrium

For the adhesion model, a 3D culture was prepared, comprising epithelial and stromal cells cultured from endometrial biopsies. These models have provided information about the embryonic regulation of endometrial epithelial molecules such as anti-adhesion molecules Meseguer et al.


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An in vitro model has also been developed to study the process of blastocyst invasion Carver et al. Carver et al. Advances in biotechnology have lead to the development of new techniques that allow the examination of changes in the endometrium and embryo at the molecular level. DNA microarrays enable analysis of the simultaneous expression of thousands of genes in a single sample.

Endometrial Hyperplasia

These genomic and proteomic techniques have been used to study changes occurring throughout the cycle, examine the impact of artificial stimulation and determine the patterns of gene expression in different cell types. The expression of many endometrial genes has been shown to change over the course of the menstrual cycle Ponnampalam et al. However, some of these expression patterns do not appear to associate with histopathological changes occurring in the endometrium Ponnampalam et al.

Possibly, gene expression may be a better marker of the biological phases and may be a more reliable predictor of endometrial receptivity than morphology.

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To date, five studies have examined changes in endometrial gene expression during the receptive phase and all have reported genes that are strongly up- or down-regulated when the endometrium is receptive Carson et al. One striking observation is that only a single gene osteopontin was differentially expressed up-regulated in all five of these studies Carson et al.

This finding highlights the need for standardization of methodology if meaningful conclusions are to be made from genomic and proteomic studies. Microarray studies comparing natural and stimulated cycles indicate that controlled ovarian stimulation has a profound effect on endometrial gene expression during the window of implantation 7 days after the LH surge compared with 2 days; Fig. Over genes were differentially expressed in stimulated cycles Horcajadas et al.

Studies have also examined gene expression changes in human endometrial cells in vitro during decidualization Popovici et al. Principle component analyses PCA of endometrial gene expression showing clustering of samples from A 2 versus 7 days after the LH surge or B natural versus stimulated cycles. Adapted with permission from Riesewijk et al. Laser capture microdissection coupled with gene expression analysis enables accurate comparison of gene expression patterns between different cell types from the same tissue.

To date, one study has used this technique to examine differences in normal human endometrial tissues from the secretory phase Yanaihara et al. A total of 28 genes were found to be differentially expressed in epithelial and stromal cells, and a number of these genes have known immunological functions Yanaihara et al.

As well as array technologies being used to study gene expression, methods are also being developed to study proteomic changes occurring during implantation. Endometrial secretion aspiration is one such approach and enables the measurement of protein changes in the uterine lumen during treatment cycles van der Gaast et al.


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A key advantage of this approach is that the technique itself does not appear to have an adverse effect on implantation van der Gaast et al.