The impact of progesterone levels and timing of progesterone exposure on human endometrial receptivity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146777 | GEO | 2020/03/12
REPOSITORIES: GEO
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Project description:The impact of progesterone levels and timing of progesterone exposure on human endometrial receptivity
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Project description:Embryo implantation is a key step in establishing pregnancy and a major limiting factor in IVF. Implantation requires the endometrium, the inner lining of the uterus, to transform from a non-receptive to a receptive state, to allow embryos to attach to the surface and enter into the tissue. However, the fundamental mechanisms governing receptivity are not well understood. Here we show that transmembrane protein podocalyxin is a major and clinically significant factor regulating human endometrial receptivity. Podocalyxin is expressed in all endometrial epithelial cells in the non-receptive state but is selectively down-regulated in the luminal epithelium at receptivity. We present evidence that podocalyxin critically governs the barrier function of the endometrial epithelium, likely as an intrinsic protective mechanism, rendering it non-receptive to an embryo. In addition, podocalyxin suppresses genes promoting receptivity (eg LIF, CSF1) but stimulates those inhibiting implantation (eg WNT7A, LEFTY2). Down-regulation of podocalyxin in the luminal epithelium, likely mediated by progesterone, selectively converts the endometrial surface to a more adhesive state that facilitates embryo attachment and penetration. Furthermore, inadequate down-regulation of podocalyxin in the endometrial luminal epithelium is associated with poorer implantation rates in IVF. We thus propose that podocalyxin promotes the barrier function of human endometrial epithelial cells and critically regulates receptivity for embryo implantation.
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Project description:Successful embryo implantation into a receptive endometrium requires mutual endometrial-embryo communication. Recently, the function of extracellular vehicles (EVs) in cell-to-cell interaction in embryo-maternal interactions has been investigated. We explored isolated endometrial derived EVs, using RL95-2 cells as a model of a receptive endometrium, influenced by menstrual cycle hormones estrogen (E2; proliferative phase) progesterone (P4; secretory phase) and estrogen plus progesterone (E2P4; the receptive phase). EV sized particles were isolated by differential centrifugation and size exclusion chromatography. Nanoparticle tracking analysis was used to examine the different concentration and size of particles and EV proteomic analysis per-formed using shotgun label-free mass spectrometry. Our results showed that although endome-trial derived EVs were secreted in numbers independent of hormonal stimulation, EVs sizes were statistically modified by it. Proteomics analysis showed that hormone treatment changes affect the endometrial EVs proteome, with proteins enhanced within the EV E2P4 group shown to be in-volved in different processes such as embryo implantation, endometrial receptivity, and embryo development, supporting the concept of a communication system between the embryo and the maternal endometrium via EVs.
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Project description:Receptivity of the uterus is essential for embryo implantation and progression of pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from its non-receptive state at ovulation, to its receptive state four days later. The precise molecular mechanisms underlying this transition remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the uterine transcriptome in the peri-ovulatory and peri-implantation states, and to define the differences between them, in the mouse. High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of C57Bl/6 female mice on day 3.5 post-coitum after mating with BALB/c males, compared to the endometrium of unmated estrous females (n=3-4 biological replicates). RNA-sequencing and analysis using Ingenuity Pathway Analysis software revealed that, compared to the endometrium at estrus, 388 genes were differentially expressed in the endometrium on day 3.5 post-coitum (FDR ≤ 0.05). Several upstream regulators are implicated in the transition to receptivity including several cytokines, steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. The transcriptional changes indicate substantial changes in the uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. This analysis confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes and regulatory pathways not previously associated with implantation. This dataset will serve as a valuable tool and resource for future research on the molecular mechanisms of uterine receptivity.
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Project description:Progesterone (P) action is essential for embryo implantation, but the P concentration required for normal receptivity remains unclear. We use an in vivo model in normal women that abolishes detectable endogenous P production, allowing experimental provision of P. Endometrial samples on the 10th day of varying doses of P exposure are compared structurally and functionally with each other and with mid-secretory endometrium of natural cycles, using histological and microarray analysis. At 2.5mg/day of P, a delayed appearance of morphological features is seen. Higher sub-physiological levels of P result in normal morphology, but aberrant gene expression. These studies prove that low P levels can result in histological delay, consistent with clinical expectations. However, P levels required for consistent histological delay are lower than those seen in all ovulatory women. These studies also demonstrate that gene expression abnormalities can occur at higher sub-physiological P concentrations, without a change in morphology, a functional-morphological disassociation. The expression of some endometrial receptivity associated genes is multiphasic, with peak expression between the lowest and highest doses, suggesting sustained supraphysiological doses seen in fertility treatment cycles may not be optimal. These findings provide a scientific underpinning to previous studies that questioned the value of endometrial morphology as a marker for receptive endometrium and suggest potential new strategies for understanding endometrial P action. Total RNA obtained endometrium of women treated with progesterone at different doses (2.5 mg (n=4); 5 mg (n=4); 10mg (n=5_); 40 mg (n=5); Control no drug (n=9))
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Project description:Impaired endometrial receptivity is one of the major causes of recurrent implantation failure (RIF), and the underlying molecular mechanism has not been fully elucidated. We demonstrated that Chromodomain Y like (CDYL) was highly expressed in the endometrium at mid-secretory phase during the normal menstrual cycles. However, the expression of CDYL was down-regulated in the endometrial tissues obtained from women with RIF, consistently with the protein level of LIF, which is the marker of endometrial receptivity. Knockdown of CDYL significantly decreased the cell migration of human endometrial Ishikawa cells and primary endometrial cells. Genomic analyses revealed that CDYL gene silencing resulted in decreased expression of many genes associated with cytoskeleton and migration regulation.
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Project description:Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies among fertile women. PCOS patients have been confirmed to be accompanied by an increased risk of pregnancy complication, and the exact cause is still unclear. Many factors may cause this situation, and impaired endometrial receptivity could be responsible for adverse pregnancy outcomes in PCOS. Unfortunately, there were still few researches about the molecular mechanisms regarding impaired endometrial receptivity. So we designed this study to explore the secretory endometrial proteome in PCOS patients.
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Project description:We find that the Endometrial Blood Vessel Generation is an important part ofthe establishment of Endometrial Receptivity. We have demonstrated inprevious experiments: Acupuncture in IVF-ET treatment can effectively improve Endometrial Receptivity and improve the pregnancy rate, therefore, we proposea VEGF signaling pathway in Acupuncture can improve Endometrial receptivity, thus improving the success rate of IVF-ET Hypothesis. Around the hypothesisintends to adopt the rat model of IVF-ET, through methods of acupuncture, acupuncture combined with blocker, research the related indexes effect performance that acupuncture on the VEGF signaling pathway in endometrial. Using experimental techniques such as Morphological observation, ELIAS, Immunohistochemistry, Real-time quantitative PCR, Methylation-sensitive high-resolution melting curve method(MS-HRM), to complete the research ofobserving the Effect of acupuncture interference IVF-ET, Blocking the impaction VEGF to the effect, the relationship VEGF or gene methylation inits receptors with effect. From the molecular level clarify the adverse effects and mechanism action that acupuncture will improve IVF-ET superovulation of endometrial receptivity, through adjust VEGF signaling pathway, to provide a scientific basis for acupuncture in IVF-ET treatment
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