Markers Of Uterine Receptivity Research Articles

The activation of cGAS-STING pathway causes abnormal uterine receptivity in aged mice.

Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. Invitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.

Consistency and synchronization of AMPK-glycogen in endometrial epithelial cells are critical to the embryo implantation.

Uterine receptivity to the embryo is crucial for successful implantation. The establishment of uterine receptivity requires a large amount of energy, and abnormal energy regulation causes implantation failure. Glucose metabolism in the endometrium is tissue specific. Glucose is largely stored in the form of glycogen, which is the main energy source for the endometrium. AMP-activated protein kinase (AMPK), an important energy-sensing molecule, is a key player in the regulation of glucose metabolism and its regulation is also tissue specific. However, the mechanism of energy regulation in the endometrium for the establishment of uterine receptivity remains to be elucidated. In this study, we aimed to investigate the energy regulation mechanism of mouse uterine receptivity and its significance in embryo implantation. The results showed that the AMPK, p-AMPK, glycogen synthase 1, and glycogen phosphorylase M levels and the glycogen content in mouse endometrial epithelium varied in a periodic manner under regulation by the ovarian hormone. Specifically, progesterone significantly activated AMPK, promoted glycogenolysis, and upregulated glycogen phosphorylase M expression. AMPK regulated glycogen phosphorylase M expression and promoted glycogenolysis. AMPK was also found to be activated by changes in the energy or glycogen of the endometrial epithelial cells. The inhibition of AMPK activity or glycogenolysis altered the uterine receptivity markers during the window of implantation and ultimately interfered with implantation. In summary, consistency and synchronization of AMPK and glycogen metabolism constitute the core regulatory mechanism in mouse endometrial epithelial cells involved in the establishment of uterine receptivity.

A Transient Mystery: Nucleolar Channel Systems.

The nucleus is a complex organelle with functions beyond being a simple repository for genomic material. For example, its actions in biomechanical sensing, protein synthesis, and epigenomic regulation showcase how the nucleus integrates multiple signaling modalities to intricately regulate gene expression. This innate dynamism is underscored by subnuclear components that facilitate these roles, with elementsof the nucleoskeleton, phase-separated nuclear bodies, and chromatin safeguarding by nuclear envelope proteins providingexamplesof this functional diversity. Among these, one of the lesser characterized nuclear organelles is the nucleolar channel system (NCS), first reported several decades ago inhuman endometrial biopsies. This tubular structure, believed to be derived from the inner nuclear membrane of the nuclear envelope, was first observed in secretory endometrial cells during a specific phase of the menstrual cycle. Reported as a consistent, yet transient, nuclear organelle, current interpretations of existing data suggest that it serves as a marker of a window for optimal implantation. In spite of this available data, the NCS remains incompletely characterized structurally and functionally, due in part to its transient spatial and temporal expression. As a further complication, evidence exists showing NCS expression in fetal tissue, suggesting that it may not act exclusively as a marker of uterine receptivity, but rather as a hormone sensor sensitive to estrogen and progesterone ratios. To gain a better understanding of the NCS, current technologies can be applied to profile rare cell populations or capture transient structural dynamics, for example, at a level of sensitivity and resolution not previously possible. Moving forward, advanced characterization of the NCS will shed light on an uncharacterized aspect of reproductive physiology, with the potential to refine assisted reproductive techniques.

Cisplatin decreases HOXA13 and alphaVBeta3 integrin levels in the uterus

ObjectiveTo examine the effects of cisplatin on uterine histology and implantation molecules and the possible protective role of recombinant Klotho administration on uterine histology and uterine receptivity in mice exposed to cisplatin. Materials and methodsThis study was conducted using thirty-two adult female mice assigned to four groups with 8 mice in each group. Saline was given to the 1st group, cisplatin to the 2nd group, recombinant mouse Klotho to the 3rd group and recombinant mouse Klotho plus cisplatin to the 4th group. Uterine tissues were examined for damage histologically and immunobiologically for the uterine receptivity markers HOXA13 and alphaVBeta3 integrin. ResultsApoptosis, degeneration, decrease in uterine thickness and uterine absence of gland scores were higher in the cisplatin group (3rd group) compared to the saline group (1st group) (cisplatin vs. saline p < 0.0001 for all parameters). In the recombinant Klotho plus cisplatin group (4th group), scores of apoptosis, degeneration, reduction in uterine thickness and uterine absence of gland were lower than the group receiving only cisplatin (cisplatin plus recombinant Klotho vs cisplatin, p = 0.006 for apoptosis; p = 0.017 for degeneration; p = 0.011 for the reduction in uterine thickness; p = 0.002 for the absence of gland). However, HOXA13 and alphaVBeta3 integrin staining levels were not different between the cisplatin group (group 3) and the cisplatin plus recombinant Klotho group (group 4) (p = 0.980 and p = 0.762, respectively.) ConclusionCisplatin has adverse effects on the uterus. Administration of recombinant Klotho was found to attenuate the cisplatin-induced damage but failed to preserve levels of the implantation molecules HOXA13 and alphaVbeta3. Further studies examining the effect of cisplatin toxicity using other implantation markers along with functional studies are needed.

Protective effects of quercetin on uterine receptivity markers and blastocyst implantation rate in diabetic pregnant mice

ObjectiveDiabetic women have different reproductive problems. In pregnant diabetic women, high rates of perinatal mortality, spontaneous abortion and congenital anomalies are observed. We hypothesized that quercetin, as an antidiabetic and phytoestrogen, might have protective effects on the embryo implantation in pregnant diabetic mice. We investigated the ameliorative effects of quercetin on the levels of serum estrogen and progesterone, rate of blastocyst implantation, and uterine receptivity markers in diabetic mice. Materials and methodsDiabetic and healthy female mice were treated with quercetin (30 mg/kg/day) four weeks before pregnancy. Plasma sex-steroid levels were determined on day 4 of pregnancy. Also, uteri were harvested for investigation of protein and mRNA expression changes. In another set of our study, implantation rate was determined on day 5 of pregnancy. ResultsOur results indicated that quercetin was significantly reduced blood glucose levels in diabetic mice. The number of implantation sites as well as serum estradiol level was reduced in diabetic mice, and then treatment with quercetin significantly increased both. On the other hand, insulin like growth factor1, integrin αvβ3, and cyclooxygenase2 mRNA expression in the uterus of diabetic mice were significantly reduced, and quercetin treatment augmented the expression level of these genes. Besides, the level of inactive β-catenin protein level in the uterus of diabetic mice was higher than normal group; treatment with quercetin reduced the level of inactive β-catenin protein as compared to diabetic mice. ConclusionWe conclude that administration of quercetin before pregnancy can probably alleviate reproductive problems in diabetic women likely via its estrogenic and antihyperglycemic effects.

Receptivity markers in endometrial mesenchymal stem cells of recurrent implantation failure and non-recurrent implantation failure women: A pilot study.

Endometrial mesenchymal stem cells (eMSC) have a vital role in regeneration of endometrium during menstrual cycles. Since it has been suggested that (eMSC) likely play a role in uterine receptivity and establishment of pregnancy, we aimed to evaluate the expression levels of five most known receptivity markers-Integrin (ITG) β1, Rac1, HoxA11, ITGβ3 and Noggin-in eMSC of recurrent implantation failure (RIF) and non-RIF women. Human eMSC were isolated from menstrual blood (MB) of RIF and non-RIF women. The isolated eMSC characterized based on their morphological and behavioral characteristics, expression of MSC-specific surface CD markers and their capacity of differentiation into osteocytes and adipocytes. The expression levels of the five mentioned receptivity markers were analyzed with real time reverse transcription polymerase chain reaction. Our findings revealed that RIF and non-RIF eMSC expressed all tested genes at different levels. ITGb1 expression in RIF eMSC was lower than its expression in non-RIF cells. On the other hand, all the other markers were expressed at higher levels in RIF eMSC than in non-RIF cells although only HOXA11 and ITG β3 showed statistically significant (P < 0.05) higher expression levels. This pilot study on determination of the expression levels of uterine receptivity markers in eMSC interestingly indicated that RIF and non-RIF eMSC were different regarding the expression of these markers. Future studies using these findings can brighten up more the role of eMSC in the endometrium receptivity and establishment of pregnancy.

Uterine Dnmt3a is not Required for Mouse Embryo Implantation

Recent studies have demonstrated that endometrial DNA methylation is essential for embryo implantation during early pregnancy. Dnmt3a is one of the key enzymes for DNA methylation and could be expressed in the endometrium regularly at this stage. In this study, we conditionally ablated uterine Dnmt3a using progesterone receptor-cre (Pgrcre) to define the physiological roles of Dnmt3a in female reproduction. We found that ovarian function was not apparently altered and the number of embryo implantation sites in Dnmt3aloxP/loxP Pgrcre/+ (cKO) was not significantly varied during early pregnancy. Western blotting and immunohistochemistry results showed no difference in expression or location of the estrogen receptor α (ERα) and mucin 1 (Muc1), the marker of uterine receptivity. Although the expression of decidual markers, matrix metalloproteinase-2 (Mmp2), matrix metalloproteinase-9(Mmp9), and bone morphogenetic protein-2 (Bmp2), was slightly decreased in Dnmt3a cKO females, the gross morphology of mice uteri during decidualization was not significantly influenced. In the artificial induction of the decidualization model, there was also no remarkable difference in visually observed morphology or uterine weight in Dnmt3a cKO. Lastly, a continuous breeding study showed that the fertility of Dnmt3a cKO female mice was not strikingly altered. Overall, these results demonstrated that although some decidual markers are expressed abnormally, conditional knockout of Dnmt3a in the uterus did not significantly affect the endometrial function during embryo implantation; the embryo could implant into the endometrium normally.

Association of mental health diagnoses and uterine endometrial thickness in women undergoing in-vitro fertilization

To assess the association between mental health diagnoses and uterine receptivity, operationalized as endometrial thickness. Due to the lack of data regarding the impact of mental health diagnoses on intermediate outcomes of in vitro fertilization (IVF), we performed an exploratory retrospective cohort study of women undergoing IVF at an academic medical center from 2018 to 2019. A total of 101 patients undergoing IVF were recruited and underwent controlled ovarian hyperstimulation with an antagonist protocol. Women on clomiphene or letrozole, those seeking fertility preservation and those with uterine factor were excluded. Mental health diagnoses and medications were abstracted from chart review. Endometrial thickness was assessed via transvaginal ultrasound on the final day of stimulation. We used linear regressions to assess the associations between 1) anxiety 2) depression 3) any psychiatric diagnosis 4) current treatment with antidepressant or anxiolytic medications. Of the 101 women, 12 (11.9%) had previously been diagnosed with anxiety, 10 (9.9%) had been diagnosed with depression, of these women 15 (14.9%) were currently being treated with antidepressants or anxiolytic medications. Women had a mean of 35.1±4.0 years of age, a mean BMI of 26.3±5.6 kg/m2, and a mean endometrial thickness of 10.3±2.7 mm. Women self-reported as Caucasian (52.5%), Asian (24.8%), or African American (15.8%). A mental health diagnosis (p=.01) and use of antidepressants or anxiolytic medications (p=.002) were negatively associated with endometrial thickness. All associations remained significant after controlling for BMI. Endometrial thickness was not associated with cycle characteristics (peak estradiol level, total gonadotropin dose, or number of oocytes retrieved). Mental health diagnoses and current antidepressant or anxiolytic treatment are associated with a thinner endometrial thickness, a marker of uterine receptivity. Prior studies have indicated women with history of anxiety and depression may have lower live birth rates; this is perhaps due to the influence of stress on endometrial thickness and interaction with the reproductive hormonal axis. These findings are important given the strong association of mental health diagnoses and infertility, with anxiety and depression often exacerbated by the stress of fertility treatment. Future studies will examine biochemical markers of stress to further explore the mechanism behind this finding.

Fucosyltransferase gene expression in goat endometrium during the estrous cycle and early pregnancy

Regulation of the expression of the alpha(1,2)fucosyltransferase (FUT) genes and their enzymatic products, including the H-type 1 antigen (HT1), on the luminal surface of the uterus is believed to be critical for establishment of pregnancy in mammals. The FUT1 gene is a marker for conception rates in dairy cows and HT1 is a marker for uterine receptivity in rodents. To determine the spatiotemporal expression patterns of FUT1 and FUT2 genes in goats, endometrial tissues were obtained on six days spanning the estrous cycle (Days 5, 11, 13, 15, 17 and 19) and seven days spanning early pregnancy (Days 5, 11, 13, 15, 17, 19 and 25). In all data, we found no effect of status (cyclic or pregnant; P > 0.1) and pooled data where appropriate. We cloned FUT1 cDNA from goat endometrium and made probes from it for Northern and slot blot analyses. The analyses indicated that FUT1 gene expression was high until Day 13, and then declined. In situ hybridization revealed a change in the cell-specificity of FUT1 gene expression over the estrous cycle and early pregnancy. In situ hybridization signal intensity scores indicated that FUT1 expression by uterine epithelium was high on Day 5, moderate on Day 11, and minimal on subsequent days. In situ hybridization signals in uterine glandular epithelial cells remained high from Day 5 to Day 13, with weaker signals thereafter. Quantitative reverse transcription-PCR (RT-qPCR) assays were used for quantitation of FUT1 and FUT2 mRNAs. Quantitative RT-qPCR data were generated from endometrium collected from cyclic and pregnant animals on Days 5, 11 and 17. Relative levels of FUT1 mRNA were high on Days 5 and 11, but then fell 5-fold by Day 17 (P < 0.01). FUT2 mRNA concentrations were below the accurate detectable limit of the assay. High levels of HT1 were observed on the apical surface of uterine luminal epithelia on Days 5, 15, 17 and 19, with much lower levels on Days 11 and 13. Thus, data suggests that FUT1 is the primary enzyme responsible for the high levels of HT1 antigen present on the uterine luminal epithelium between Days 5 and 11 of the estrous cycle and early pregnancy. But changes in the expression of the FUT1 gene does not directly correlate to HT1 staining, which increased from Day 13–15. Future studies are required to understand the regulation of the HT1 antigen on the luminal surface of endometrium.

Alterations in the Calcitonin and Calcitonin modulated proteins, E-cadherin and the enzyme tissueTransglutaminase II during the window of implantation in a baboon model of endometriosis

Endometriosis is a gynecological condition associated with infertility. We have previously demonstrated dysregulation of several molecular markers of uterine receptivity in a baboon model of induced endometriosis. Specifically, reduced levels of endometrial progesterone receptor (PR) and progesterone (P)-regulated genes, HOXA10 and FKBP52 were observed during the window of uterine receptivity in baboons with endometriosis, suggesting that this disease results in the development of an endometrial P resistance. In this study calcitonin (CALC) and CALC-modulated proteins, E-cadherin (E-Cad) and tissue Transglutaminase (tTgase-2) were evaluated in the eutopic endometrium of endometriotic animals throughout disease progression. Endometriosis was induced in normal cycling baboons by intraperitoneal inoculation of menstrual endometrium. Eutopic and ectopic endometrium was harvested consecutively from each animal at 1, 6 and 15 months of disease, during the window of receptivity. Control eutopic endometrium was s...

Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment.

The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrALsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre) or uterine epithelium (Wnt7acre) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), was maintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibited PGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRA is inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoform at the window of receptivity is necessary for the attenuation of hedgehog signaling, transcriptional activation of LIF signaling, and modulation of solutes and fluid, producing a receptive environment for the attaching embryo.

Influence of hyaluronan on endometrial receptivity and embryo attachment in sheep.

An increasing number of reports suggests a role of hyaluronan (HA) in female reproduction and interest in its application in assisted reproduction is rising. However, there are contrasting data about the effectiveness of adding HA to the embryo-transfer medium on improving pregnancy rates. Using sheep as an experimental model, the studies reported here analysed the impact of HA infusion into the uterus on embryo attachment to uterine luminal epithelium (LE) and expression of selected markers of uterine receptivity. On Day 14 after natural mating (pre-attachment), uterine horns were infused with either (n=4 each): PBS (control), HA (1mg mL-1), HA+hyaluronidase 2 (Hyal2; 300IU mL-1) or 4-methyl-umbelliferone (HA-synthesis inhibitor; 4MU, 1mM). HA immunostaining on uterine sections collected on Day 17 was negative in the 4MU group and weak in the HA+Hyal2 group. In contrast to 4MU, which resulted in 100% attachment, HA infusion blocked embryo attachment in all treated animals. This was accompanied by the disappearance of mucin 1 and increased expression of osteopontin and CD44v6 in the LE of uteri with attached embryos. In conclusion, the presence of HA at the embryo-maternal interface during embryo implantation resulted in reduced endometrial receptivity and inhibited the interaction of trophoblasts with the LE, whereas clearance of HA favoured embryo attachment.

Calcineurin-dependent induction of markers of uterine receptivity by angiotensin II in rat endometrial stromal cells. The role of the trophoblast renin-angiotensin-system

The decidualization of uterine endometrial stromal cells (ESCs) is critical for the successful establishment and maintenance of pregnancy and involves extensive cell proliferation and differentiation. A newly established signaling pathway, the Hippo/Yes-associated protein (YAP) pathway, plays a critical role in these proliferation processes. Our previous study demonstrated that YAP is expressed in human ESCs. However, its role in decidualization remains unclear. The objective of the present study was to explore the role of YAP in the decidualization of human ESCs.The expression of YAP was first investigated in the endometrium of non-pregnant women and in the decidua of pregnant women. The role of YAP was investigated by transfecting ESCs with mRNA silencing constructs and observing the negative effects of this action upon decidualization induced in vitro.Our results revealed that the expression of YAP was higher in decidual cells from early pregnant decidua compared with ESCs from non-pregnant endometrium. The expression levels of YAP and TEA domain 1 (TEAD1) were both increased in ESCs during in vitro decidualization and the knockdown of YAP in ESCs caused negative effects upon decidualization in vitro.Our study suggests that YAP is upregulated in human decidual cells compared with ESCs and influences the decidualization of ESCs.

Traditional Chinese Medicine, the Zishen Yutai Pill, Ameliorates Precocious Endometrial Maturation Induced by Controlled Ovarian Hyperstimulation and Improves Uterine Receptivity via Upregulation of HOXA10.

Controlled ovarian hyperstimulation (COH) is widely used in assisted reproductive technology (ART), but it often leads to precocious maturation of the endometrium such that it impairs embryonic implantation and limits pregnancy rates. Previous studies have shown the traditional Chinese medicine, the Zishen Yutai pill (ZYP), to be effective in treatment of threatened as well as recurrent miscarriages, and it can improve embryonic implantation rates in patients undergoing IVF treatment. In the present study, the ZYP has been found to ameliorate precocious endometrial maturation in a mouse model of different COH. Molecular evaluations, real-time PCR, relative RT-PCR, Western blotting, and immunohistochemistry have indicated that the ZYP increased the expression of HOXA10, an important marker of uterine receptivity. Elevation of HOXA10 led to further upregulation of its target gene, integrin β3, and downregulation of EMX2, two additional markers of uterine receptivity. In this way, the ZYP may mitigate COH-induced precocious maturation of the endometrium and improve uterine receptivity by upregulating HOXA10.

Anti-inflammatory, Anti-estrogenic, and Anti-implantation Activity of Bergia suffruticosa (Delile) Fenzl.

Background:Bergia suffruticosa (Delile) Fenzl (Syn. Bergia odorata Edgew) (Elatinaceae family) is used traditionally to repair bones and is applied as a poultice on sores. It is also used for stomach troubles and as an antidote to scorpion stings. So far, very little scientific work has been reported to validate its ethnomedical uses in the alleviation of pain, bone repair, etc.,Objective:This study was designed to explore the anti-inflammatory and anti-implantation potential of n-hexane extract of B. suffruticosa whole plant in mice along with identification of its chemical constituents.Materials and Methods:n-Hexane extract of B. suffruticosa whole plant was screened for acute and chronic anti-inflammatory activity followed by an anti-estrogenic activity. Eventually, n-hexane extract was tested for anti-implantation activity by exploiting markers of uterine receptivity, lipid peroxidation, and superoxide enzyme activity. The extract was administered orally at a dose of 100 mg/kg body weight in each study.Results:Thin layer chromatography fingerprint profile of n-hexane extract revealed the presence of lupeol and β-sitosterol. The n-hexane extract reduced the edema by 80% in acute inflammation, whereas it reduced edema to 75% on the 5th day in chronic inflammation. The n-hexane extract reduced elevated malonaldehyde level from 6 to 2.5 nmol/g × 10−5 and increased superoxide dismutase enzyme activity from 0 to 350 units/g in treated animals on the 5th day of pregnancy. Moreover, extract decreased uterine weight from 0.33 to 0.2 g in estradiol treated animals.Conclusion:These results indicate that n-hexane extract of B. suffruticosa is having potent anti-inflammatory, anti-estrogenic, and anti-implantation activity. This is the first report of all the pharmacological activities of B. suffruticosa mentioned above.SUMMARY TLC fingerprint profile of n-hexane extract of Bergia suffruticosa whole plant revealed the presence of lupeol and β-sitosteroln-Hexane extract showed in vivo anti-inflammatory activity in both acute and chronic model of inflammation in ratsn-Hexane extract possess significant anti-estrogenic activityn-Hexane extract altered the levels superoxide anion radical and superoxide dismutase enzyme activity during the blastocyst implantationAnti-implantation activity of n-hexane extract is attributed to its anti-inflammatory and anti-estrogenic potential. Abbreviations used: TLC: Thin layer chromatography; LPO: Lipid peroxidation; SOD: Superoxide dismutase; B. suffruticosa: Bergia suffruticosa; TNF-α: Tumor necrosis factor-α; NO: Nitric oxide; IL-1: Interleukin-1; LIF: Leukemia inhibitory factor; CSF-1: Colony-stimulating factor; COX: Cyclooxygenase; SDS: Sodium dodecyl sulfate; IAEC: Animal House Ethics Committee; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; HBSS: Hank's balanced salt solution; MDA: Malonaldehyde; and TBA: Thiobarbituric acid.

Uterine peristalsis before embryo transfer affects the chance of clinical pregnancy in fresh and frozen-thawed embryo transfer cycles

Does uterine peristalsis influence the chance of clinical pregnancy in an embryo transfer cycle? The uterine peristaltic wave frequency before embryo transfer is inversely related to the clinical pregnancy rates in fresh and frozen-thawed embryo transfer cycles. Uterine peristalsis participates in regulating fluid migration after mock embryo transfer, but whether it could potentially influence pregnancy outcomes had remained unclear. This prospective cohort study included a total of 292 infertile women and was conducted between March 2013 and August 2013. Patients underwent fresh embryo transfer in a fresh stimulation cycle with a long down-regulation protocol, a natural frozen-thawed embryo transfer cycle or an artificial frozen-thawed embryo transfer cycle. Uterine peristaltic activity was assessed before embryo transfer by transvaginal ultrasonography. The uterine peristaltic wave frequencies of most patients were between 1.1 and 3.0 waves/min before embryo transfer (ET). The clinical pregnancy rate was the highest when <2.0 waves/min was observed and it decreased with an increasing wave frequency thereafter, with an especially dramatic decrease with >3.0 waves/min. Uterine peristaltic wave frequencies of the non-pregnant patient group were higher than that of the clinically-pregnant patient group in all types of transfer, fresh embryo transfer, natural FET or artificial FET cycle. Binary logistic regression analysis demonstrated that the association between uterine peristaltic wave frequency before embryo transfer and clinical pregnancy was independently significant (odds ratio: 0.49; 95% confidence interval: 0.34-0.70, P < 0.001). Uterine peristalsis after embryo transfer was not observed in case any possible negative effect of the observation disturbed embryo implantation or caused psychological stress. Uterine peristalsis after embryo transfer may differ from that before embryo transfer. Another limitation of the present study was the lack of uterine peristaltic wave type analysis which is also an important parameter to assess uterine activity. Patients with uterine peristalsis of <3.0 waves/min before embryo transfer had a higher chance of pregnancy compared with those with higher frequencies. This could be a promising quantitative marker of uterine receptivity and pregnancy outcome in an embryo transfer cycle. The predictive validity of the cut-off value needs to be tested in further study. The study is supported by Hunan Provincial Innovation Foundation for Postgraduates. The authors declare that they have no competing interests in this study.

Impaired flux via the pentose phosphate pathway correlates with abnormal endometrial receptivity in PCOS patients

Markers of uterine receptivity are decreased in PCOS patients. Recent work from our laboratory suggests that elevated DHEA levels in vitro inhibit the pentose phosphate pathway resulting in inhibition of endometrial decidualization. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in this pathway. As DHEA levels are elevated in 50% of PCOS patients, alterations in the pentose phosphate pathway may contribute to impaired endometrial function and thus subfertility.

The Transcription Factor C/EBPβ is a Marker of Uterine Receptivity and Expressed at the Implantation Site in the Primate

During early pregnancy, the endometrium undergoes pronounced hormone-dependent functional changes in preparation for embryo implantation. Local autocrine-paracrine signaling at the fetal-maternal interface is crucial for the establishment of pregnancy. We previously reported that the transcription factor C/ EBPbeta, which is expressed at the implantation sites (ISs) in pregnant mice, acts as a key mediator of steroid hormone responsiveness in the endometrium. Mice lacking C/EBPbeta fail to support implantation due to defects in epithelial proliferation and stromal cell differentiation. In the current study, C/EBPbeta expression was dramatically stimulated in the endometrium of baboons (Papio anubis) during the window of uterine receptivity in response to a local infusion of chorionic gonadotropin, an embryonic signal. A robust induction of C/EBPbeta expression was also seen at the IS in the baboon and the human. Collectively, our results indicate that C/EBPbeta is a biomarker of endometrial receptivity and plays a conserved functional role during implantation in the primate.

Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility

Successful embryo implantation depends on the quality of the embryo, as well as on the receptivity of the endometrium. The aim of this study was to investigate the endometrial gene expression profile in women with unexplained infertility in comparison with fertile controls at the time of embryo implantation in order to find potential predictive markers of uterine receptivity and to identify the molecular mechanisms of infertility. High-density oligonucleotide gene arrays, comprising 44 000 gene targets, were used to define the endometrial gene expression profile in infertile (n = 4) and fertile (n = 5) women during the mid-secretory phase (day LH + 7). Microarray results were validated using real-time PCR. Analyses of expression data were carried out using non-parametric methods. Hierarchical clustering and principal component analysis showed a clear distinction in endometrial gene expression between infertile and fertile women. In total we identified 145 significantly (>3-fold change) up-regulated and 115 down-regulated genes in infertile women versus controls. Via Database for Annotation, Visualization and Integrated Discovery functional analysis we detected a substantial number of dysregulated genes in the endometria of infertile women, involved in cellular localization (21.1%) and transport (18.8%) and transporter activity (13.1%) and with major localization in extracellular regions (19.2%). Ingenuity Pathways Analysis of the gene list showed dysregulation of gene pathways involved in leukocyte extravasation signalling, lipid metabolism and detoxification in the endometria of infertile women. In conclusion, endometrial gene expression in women with unexplained infertility at the time of embryo implantation is markedly different from that in fertile women. These results provide new information on genes and pathways that may have functional significance as regards to endometrial receptivity and subsequent embryo implantation.

Effects of variations in serum estradiol concentrations on secretory endometrial development and function in experimentally induced cycles in normal women

Eighteen normal women underwent pituitary down-regulation with leuprolide, followed by a 10-day treatment with 0.2 mg/d transdermal estradiol (E(2)) with subsequent allocation to one of two 10-day estradiol regimens plus 40 mg daily intramuscular P: supraphysiologic (0.2 mg/d transdermal E(2) mg/d vaginal micronized E(2)) or subphysiologic (no exogenous E(2) treatment). Average E(2) and P in the supraphysiologic, physiologic, and subphysiologic groups were 1,175.9 pg/mL and 17.5 ng/mL, 136.9 pg/mL and 21.2 pg/mL, and 23.8 ng/mL and 22.0 ng/mL, respectively, and there were no differences between groups in endometrial histology or expression of biomarkers of receptivity.