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Background: Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of implantation (WOI) displacement, particularly in patients with recurrent implantation failure (RIF). Therefore, a reliable diagnostic tool for identifying the optimal WOI is essential. Previous data has suggested that a novel RNA-Seq-based endometrial receptivity testing (ERT) can diagnose WOI, guide personalized embryo transfer (pET), and improve pregnancy outcomes in patients with RIF compared to standard embryo transfer (sET). However, there is still a lack of evidence from randomized controlled trials (RCT) with sufficient power to determine whether pET based on ERT can increase the rate of live births as the primary outcome., Methods: This trial is a prospective, single-blind, parallel-group RCT (1:1 ratio of pET versus sET). Infertile women with RIF who intend to undergo frozen-thawed embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) with the availability of at least one euploid blastocyst for transfer will be enrolled and assigned into two parallel groups randomly. Participants in the intervention group will undergo ERT and then pET based on the results of ERT, while those in the control group will undergo sET. The primary outcome is live birth rate., Discussion: The findings of this study will provide evidence for the effect of pET guided by ERT on pregnancy outcomes in patients with RIF., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100049041. Registered on 20 July 2021., (© 2024. The Author(s).)

Research Question: What is the expression pattern of platelet-derived growth factor BB (PDGF-BB), and its receptors, across the menstrual cycle in healthy control women and those with abnormal uterine bleeding-endometrial disorder (AUB-E)?, Design: Immunohistochemical staining for PDGF-BB, platelet-derived growth factor receptor alpha (PDGFRα) and platelet-derived growth factor beta (PDGFRβ) was performed in control and AUB-E endometrium from the proliferative, early, mid- and late secretory phases of the menstrual cycle (n = 5 each group). Control proliferative phase endometrium was cultured in PDGF-BB (0, 10 ng/ml) and vascular maturation assessed (n = 3). Endothelial cell to vascular smooth muscle cell (VSMC) association was assessed after treatment with PDGF-BB (0, 1, 10 ng/ml). Secretion of angiogenic growth factors by endothelial cells or VSMC was determined., Results: Endothelial cell immunoreactivity for PDGF-BB was reduced in the mid and late secretory phases in AUB-E (P = 0.008). PDGFRα was also reduced in mid secretory phase endothelial cells, proliferative and early secretory phase glandular epithelium in AUB-E (P = 0.008). PDGFRβ expression was not altered. Treatment of proliferative phase endometrium with PDGF-BB (10 ng/ml) reduced the percentage of vessels expressing contractile VSMC markers. PDGF-BB had no effect on angiogenic growth factor secretion by endothelial cells or VSMC in vitro and did not affect their association in an in-vitro endothelial cell-VSMC association assay., Conclusions: Reduced endothelial cell expression of PDGF-BB in the AUB-E endometrium may contribute to the reduced vascular maturation previously observed in these women., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine whether increased endometrial B-cell lymphoma 6 (BCL6) expression is associated with live birth in a normal responder in vitro fertilization (IVF) population., Design: Case-control study., Setting: University-affiliated infertility center., Patient(s): Two groups of women undergoing IVF with preimplantation genetic testing for aneuploidy followed by warmed, single, euploid embryo transfer. Group 1 consisted of women who failed to achieve live birth, and group 2 consisted of women who achieved live birth., Intervention(s): None., Main Outcome Measure(s): Endometrial BCL6 expression measured by immunohistochemistry in endometrial tissue samples. Overexpression was defined by mean HSCORE with a cutoff of positivity of >1.4, as previously described in the literature., Result(s): Twenty-seven patients who achieved live birth and 23 patients who failed to achieve live birth were included. B-cell lymphoma 6 expression/HSCORE and live birth rate were not associated (Odds ratio [OR], 0.78 [0.24-2.55]). Using a cutoff of >1.4 for positivity, 8 of 23 samples were positive for BCL6 in the no live birth group, whereas 7 of 27 were positive in the live birth group. There was no significant association between BCL6 positivity and live birth (OR, 0.66 [0.19-2.21])., Conclusion(s): The proportion of patients with BCL6 positivity did not significantly differ between those who achieved live birth and those who did not. In the population of patients at our center, who compromise of women who respond normally to IVF stimulation, BCL6 overexpression was not associated with IVF success. Physicians implementing BCL6 testing as a diagnostic tool for clinical decision making should counsel patients that results may have limited utility in predicting IVF outcomes in this population., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Women with chronic abnormal uterine bleeding-ovulatory dysfunction (AUB-O) are at increased risk of endometrial neoplasia. We conducted a non-inferiority randomized controlled trial to determine the effectiveness of two cyclic-progestin regimens orally administered 10 d/month for 6 months on endometrial protection and menstruation normalization in women with AUB-O. There were 104 premenopausal women with AUB-O randomized to desogestrel (DSG 150 µg/d, n = 50) or medroxyprogesterone acetate (MPA 10 mg/d, n = 54) group. Both groups were comparable in age (44.8 ± 5.7 vs. 42.5 ± 7.1 years), body mass index (24.8 ± 4.7 vs. 24.9 ± 4.7 kg/m 2 ), and AUB characteristics (100% irregular periods). The primary outcome was endometrial response rate (the proportion of patients having complete pseudodecidualization in endometrial biopsies during treatment cycle-1). The secondary outcome was clinical response rate (the proportion of progestin withdrawal bleeding episodes with acceptable bleeding characteristics during treatment cycle-2 to cycle-6). DSG was not inferior to MPA regarding the endometrial protection (endometrial response rate of 78.0% vs. 70.4%, 95% CI of difference - 9.1-24.4%, non-inferiority limit of - 10%), but it was less effective regarding the menstruation normalization (acceptable bleeding rate of 90.0% vs 96.6%, P = 0.016).Clinical trial registration: ClinicalTrials.gov (NCT02103764, date of approval 18 Feb 2014)., (© 2022. The Author(s).)

The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells (UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin-eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair., (© 2022. The Author(s).)

The establishment of endometrial receptivity is a prerequisite for successful pregnancy. Women with adenomyosis possess a lower chance of clinical pregnancy after assisted reproductive technology, which is partially due to impaired endometrial receptivity. The establishment of endometrial receptivity requires the participation of multiple processes, and proper endometrial epithelial cell (EEC) proliferation is indispensable. Monoamine oxidase A (MAOA) is a key molecule that regulates neurotransmitter metabolism in the nervous system. In the present study, we demonstrated a novel role for MAOA in the establishment of endometrial receptivity in women with adenomyosis and in an adenomyotic mouse model. Attenuated MAOA impairs endometrial receptivity by promoting inappropriate proliferation of EECs via the downregulation of FOXO1 during the window of implantation. These results revealed that MAOA plays a vital role in endometrial receptivity in female reproduction., (© Crown copyright 2021.)

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The purpose of this American Society for Reproductive Medicine Practice Committee report is to provide clinicians with principles and strategies for the evaluation and treatment of couples with infertility associated with obesity. This revised document replaces the Practice Committee document titled "Obesity and reproduction: an educational bulletin" last published in 2015 (Fertil Steril 2015;104:1116-26)., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study whether endometrial epithelial podocalyxin (PCX) inhibits implantation of human embryos in vitro and in patients undergoing in vitro fertilization (IVF)., Design: We have recently identified PCX as a key negative regulator of endometrial epithelial receptivity. Podocalyxin is expressed in all epithelial cells in the nonreceptive endometrium, but is selectively downregulated in the luminal epithelium (LE) for receptivity. In the current study, we first investigated whether high levels of PCX in Ishikawa monolayer inhibit attachment and/or penetration of human blastocysts in in vitro models. We then examined PCX by immunohistochemistry in putative receptive endometrial tissues biopsied from 81 IVF patients who underwent frozen embryo transfer in the next natural cycle and retrospectively analyzed the association between PCX staining in LE and clinical pregnancy as a proxy of successful implantation., Setting: RMIT University, Australia; Vrije Universiteit Brussel, Belgium., Patient(s): In vitro fertilization patients undergoing frozen/thawed embryo transfer., Intervention(s): N/A., Main Outcome Measure(s): Endometrial epithelial PCX inhibits implantation of human embryos in vitro and in IVF patients., Result(s): High levels of PCX in Ishikawa monolayer significantly inhibited blastocyst attachment and penetration. Among the 81 putative receptive tissues, 73% were negative, but 27% were heterogeneously positive for PCX in LE. The clinical pregnancy rate was 53% in those with a PCX-negative LE but only 18% in those with a PCX-positive LE. If LE was positive for PCX, the odds ratio of no clinical pregnancy was 4.95 (95% Confidence interval, 1.48-14.63)., Conclusion(s): Podocalyxin inhibits embryo implantation. Assessment of PCX may aid the evaluation and optimization of endometrial receptivity in fertility treatment., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Innate and adaptive immune systems have a crucial role in initiating and progressing some pregnancy disorders such as preeclampsia (PE), which is one of the pregnancy-specific disorders that could result in neonatal and maternal morbidity and mortality. The dysregulation of the spiral artery and inadequate trophoblast invasion lead to PE symptoms through producing various inflammatory cytokines and anti-angiogenic factors from the placenta. T lymphocytes play a special role in the epithelium and stroma of the human endometrium. CD4+ T helper (Th) cells, Th1/Th2, and Th17/T regulatory (Treg) balance mainly contribute to the establishment of a pregnancy-favorable environment. This review examined the dysregulation of some cytokines produced from T cells, the dysregulation of the transcription factors of Th cells, the expression of chemokine receptors on T cells, as well as the effects of some factors including vitamin D on the activity of T cells, and finally, the dysregulation of various miRNAs related to T cells, which could cause PE., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recurrent pregnancy loss (RPL) is a common and severe pathological pregnancy, whose pathogenesis is not fully understood. With the development of epigenetics, the study of DNA methylation, provides a new perspective on the pathogenesis and therapy of RPL. The abnormal DNA methylation of imprinted genes, placenta-specific genes, immune-related genes and sperm DNA may, directly or indirectly, affect embryo implantation, growth and development, leading to the occurrence of RPL. In addition, the unique immune tolerogenic microenvironment formed at the maternal-fetal interface has an irreplaceable effect on the maintenance of pregnancy. In view of these, changes in the cellular components of the maternal-fetal immune microenvironment and the regulation of DNA methylation have attracted a lot of research interest. This review summarizes the research progress of DNA methylation involved in the occurrence of RPL and the regulation of the maternal-fetal immune microenvironment. The review provides insights into the personalized diagnosis and treatment of RPL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Xiong, Qu, Bao and Zhang.)

Research Question: Presence of endometrial fluid (EF) is a poorly understood pathology and remains a challenge for clinicians, as very little data exists to explain its consequences and treatment. Our objective was to investigate risk factors for EF during IVF., Design: This retrospective cohort study included all women with a freeze all embryos cycle (FAE) for EF between 2010 and 2016 at a university-affiliated private IVF center. Controls (2:1) were randomly selected out of the database of our fresh autologous IVF cycles during the same period. Main outcome measures were possible risk factors for EF, comprising polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), previous pelvic or endometrial surgery (polypectomy or synechia removal), cesarean section, myomas and severe endometriosis. A logistic regression model was used to assess independent risk factors for EF., Results: Out of 9000 IVF cycles, 1204 were FAE cycles, among which we identified 86 EF cases. We then selected 171 controls. Independent risk factors for presence of EF were a history of previous myomectomy (adjusted odds ratio (aOR) 19.77, 95%CI [4.01-97.53]), severe endometriosis (aOR 5.97, 95%CI [2.09-17.05]), PCOS (aOR 5.72, 95%CI [2.66-12.33]) and previous cesarean section (aOR 5.17, 95%CI [1.84-14.49])., Conclusions: Our results are not only confirming the association between PCOS, severe endometriosis, previous cesarean procedure and EF, but also reporting for the first time an association between previous myomectomy and EF., Competing Interests: Declaration of Competing Interest All of the authors of this manuscript declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the predictive value of endometrial thickness (EMT) during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles for ectopic pregnancy (EP)., Methods: A total of 3068 patients with 3117 fresh IVF/ICSI cycles between January 2016 and February 2019 from the Reproductive Medicine Center of Sun Yat-Sen Memorial Hospital were included in this retrospective study. The patients were divided into an EP group (n = 92) and an intrauterine pregnancy (IUP) group (n = 3025). Multiple logistic regression analysis was conducted to evaluate the EP risk factors. Receiver operating characteristic (ROC) curves were used to evaluate the predictive value of the risk factors for EP and calculate the cutoff value of EMT for EP prediction., Results: The incidence rate of EP was 2.95 % (92/3117). After adjustment for other factors in the logistic regression model, the incidence of EP decreased by 55 % with an EMT > 10 mm compared with an EMT ≤ 10 mm (odds ratio 0.450, 95 % confidence interval 0.296-0.684, P < 0.001). The EMT in the EP group was significantly thinner than that in the live birth (n = 2540) and spontaneous abortion (n = 485) groups (p < 0.017). The cutoff value of EMT for EP prediction was 10.65 mm, with a sensitivity of 59 % and a specificity of 63 %., Conclusion: A decreased risk of EP was found among the patients with an EMT > 10 mm prior to embryo transfer. A certain EMT is needed to reduce the incidence of EP., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

It is very important to investigate the expression of endometrial receptive markers in the endometrium during implantation. Therefore, we examined whether it would be possible to analyze endometrial receptivity using cells from embryo transfer catheters. A total of 81 cycles from 81 consenting patients were enrolled in this study. The tip of the embryo transfer (ET) catheter was cut and immersed in a dedicated reagent. Confirmation of cell distribution was carried out using a Papanicolaou stain and immunocytochemistry. Protein expression was carried out by immunocytochemistry. The expressions of estrogen receptor α, progesterone receptor, and homeobox A10 mRNA were analyzed using quantitative reverse transcription-polymerase chain reaction. We analyzed the relationship between the gene expression profiles associated with pregnancy from endometrial cells. Samples collected from the ET catheter showed clear staining for endometrial cells. Most of the cells were endometrial epithelial cells. Cervical cells were not observed. The protein expression was also confirmed. Three genes were analyzed that are associated with endometrial receptivity. Progesterone receptor expression was 1.4-fold (p<0.05) and homeobox A10 was 2.8-fold (p<0.01) higher in patients who became non-pregnant group, compared to the pregnant group. Estrogen receptor α expression tended to be higher in the non-pregnant group (p=0.18). Our results suggest that endometrial receptivity can be evaluated using cells obtained from the ET catheter. This method may be useful for elucidating the cause of implantation failure by comparing a receptive and non-receptive endometrium at the time of ET., (© 2021. Society for Reproductive Investigation.)

The human endometrium plays a vital role in providing the site for embryo implantation and maintaining the normal development and survival of the embryo. Recent studies have shown that stress is a common factor for the development of unexplained reproductive disorders. The nonreceptive endometrium and disturbed early maternal-fetal interaction might lead to infertility including the repeated embryo implantation failure and recurrent spontaneous abortion, or late pregnancy complications, thereby affecting the quality of life as well as the psychological status of the affected individuals. Additionally, psychological stress might also adversely affect female reproductive health. In recent years, several basic and clinical studies have tried to investigate the harm caused by psychological stress to reproductive health, however, the mechanism is still unclear. Here, we review the relationship between psychological stress and endometrial dysfunction, and its consequent effects on female infertility to provide new insights for clinical therapeutic interventions in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Lin and Kong.)

Objective: To introduce a special case of endometrial cavity fluid (ECF), highlighting the application of hysteroscopy and laparoscopic surgical techniques in the treatment of cervical sinus tract., Design: Narrated video featuring the diagnosis and surgical management of a case of recurrent ECF. Informed consent was obtained from the patient, and approval was granted by the ethics committee of the First Affiliated Hospital of the Wenzhou Medical University., Setting: Academic tertiary hospital., Patient(s): A 36-year-old woman, gravida 0, had menstrual spotting for 13 years after abdominal myomectomy of a 104 × 86 × 111-mm myoma on the posterior uterine wall near the cervix. She failed to conceive after her marriage for 10 years, and 5 operations, including hysteroscopy and laparoscopy, were performed to increase pregnancy opportunities. She also underwent in vitro fertilization and embryo transfer procedures many times, but failed. Transvaginal sonography preoperatively suggested that ECF sometimes appeared and sometimes disappeared. The local echo of the posterior wall of the cervix was enhanced. A 40-mm cystic dark area was found beside the right ovary, which seemed to connect with the cervical hyperechoic part. Additionally, a solid mass of the right adnexa with abundant blood supply was detected., Intervention(s): First, hysteroscopy was performed to explore the ECF. A deep and narrow cervical sinus with a steady stream of accumulated blood overflowed in the lower part of the cervix, and a normal uterine cavity was found. Laparoscopic adhesiolysis and enucleation of the cystic structure that connected to the sinus tract then were performed. Hysteroscopy was repeated to determine the thinnest cervical region by the light transmission test. A horizontal incision was made on the thinnest layer. Scar tissues were removed. The incision was sutured in full layer intermittently and continuously under laparoscopy. The postoperative thickness of the muscular layer in the sinus was confirmed by light transmission test of hysteroscopy. The patient was discharged on the third day after operation, uneventfully. Histopathologic examination showed that the cystic structure and scar tissue contained smooth muscle tissue and were covered by both mucinous columnar epithelium of the cervical canal and endometrial glandular epithelium., Main Outcome Measure(s): Restoration of normal anatomy, removal of uterine effusion, and symptomatic relief., Result(s): At the 6-month follow-up, the patient's menstrual cycles returned to normal without the recurrence of menstrual spotting. The ultrasound scan also showed a symmetrical uterus without ECF., Conclusion(s): Patients with ECF who underwent assisted reproductive surgeries were related to the poor prognosis. However, the treatment should be different according to the causes, appearance time, and accumulation amount, including expectant treatment, postponement of embryo transfer, transvaginal aspiration, laparoscopic salpingectomy, or proximal tubal occlusion. For patients with recurrent ECF and/or special appearance on ultrasound, endoscopic examination is necessary. In addition, patients with large myomas at difficult locations required a uniform strategy to reduce the intraoperative and postoperative complications, especially for the nulligravida women., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the predictive value of endometrial thickness (EMT) for live birth when a lower threshold of EMT is not employed for embryo transfer (ET)., Design: Retrospective study SETTING: Academic assisted reproduction center PATIENT(S): All women who underwent fresh or frozen-thawed ET at the Koç University Hospital Assisted Reproduction Unit between October 2016 and August 2019 INTERVENTION(S): After ruling out endometrial pathology, blastocyst transfer was planned regardless of the EMT in the absence of increased serum progesterone level on the trigger day in fresh embryo transfer cycles or before commencing progesterone treatment in artificially prepared frozen-thawed ET cycles., Main Outcome Measure(s): The primary outcome was live birth. Live birth and miscarriage rates per ET were stratified according to fresh and frozen-thawed ET cycles for each millimeter of endometrial thickness. Receiver operator characteristic curve analyses were performed to evaluate the predictive value of EMT for live birth., Result(s): A total of 560 ET cycles, 273 fresh and 287 frozen-thawed, were included in the study. Relevant patient characteristics as well as EMTs were similar between women who achieved a live birth and those who did not after fresh or frozen-thawed ET. There was no linear association between EMT and live birth or miscarriage rates. Area under the curve values for EMT to predict live birth after fresh, frozen-thawed, and all ETs were 0.56, 0.47, and 0.52, respectively., Conclusion(s): Our results showed that the EMT was not predictive for live birth in either fresh or frozen-thawed ET cycles. Once intracavitary pathology and inadvertent progesterone exposure were excluded, women with thinner EMTs should not be denied their potential for live birth because it is comparable to that of those with thicker EMT., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To identify predictor microRNAs (miRNAs) from patients with repeated implantation failure (RIF)., Design: Systemic analysis of miRNA profiles from the endometrium of patients undergoing in vitro fertilization (IVF)., Setting: University research institute, private IVF center, and molecular testing laboratory., Patient(s): Twenty five infertile patients in the discovery cohort and 11 patients in the validation cohort., Interventions(s): None., Main Outcome Measure(s): A signature set of miRNA associated with the risk of RIF., Result(s): We designed a reproductive disease-related PanelChip to access endometrium miRNA profiles in patients undergoing IVF. Three major miRNA signatures, including hsa-miR-20b-5p, hsa-miR-155-5p, and hsa-miR-718, were identified using infinite combination signature search algorithm analysis from 25 patients in the discovery cohort undergoing IVF. These miRNAs were used as biomarkers in the validation cohort of 11 patients. Finally, the 3-miRNA signature was capable of predicting patients with RIF with an accuracy >90%., Conclusion(s): Our findings indicated that specific endometrial miRNAs can be applied as diagnostic biomarkers to predict RIF. Such information will definitely help to increase the success rate of implantation practice., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Glandular epithelial cells (GE) in the endometrium are thought to support the elongation and survival of ruminant embryos by secreting histotrophs. In the present study, the gene expression of bovine endometrial epithelial cells cultured in matrigel was analyzed and examined whether it could be an in vitro model of GE. Bovine endometrial epithelial cells (BEE) and stromal cells (BES) were isolated from the slaughterhouse uteri and cultured in DMEM/F12 + 10% FBS. BEE showed the gland-like structure morphological changes when cultured in 15% matrigel but could not be identified in higher concentrations of the matrigel (30% or 60%). The expression of typical genes expressed in GE, SERPINA14 and GRP, was substantially high in matrigel-cultured BEE than in monolayer (P  <  0.05). P4 and INFα have no significant effect on the SERPINA14 expression of BEE cultured in matrigel without co-culture with BES. On the other hand, when BEE were co-cultured with BES in matrigel culture, the expression of FGF13 was increased by the P4 treatment (P  <  0.05). Furthermore, SERPINA14 and TXN expressions were increased by P4 + IFNα treatment (P  <  0.05). These results demonstrate the appropriate conditions for BEE to form glandular structures in matrigel and the effect of co-culture with BES. The present study highlighted the possible use of matrigel for the culture of BEE to investigate the expression of cell-specific glandular epithelial genes as well as P4 and type-I IFN as factors controlling endometrial function during the implantation period., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Endometrial laminin subunit beta-3 (LAMB3) is a candidate gene whose expression distinguishes the endometrial window of receptivity (WOR) in human. This study aims to examine endometrial LAMB3 levels in patients with repeated implantation failure (RIF), in order to assess the ability of LAMB3 to predict pregnancy outcome., Methods: Endometrial biopsies were taken during the WOR from 21 healthy volunteers in natural menstrual cycles and from 50 RIF patients in mock cycles prior to frozen embryo transfer (FET) cycles. Immunohistochemistry (IHC) staining of LAMB3 was performed, and the H-score was correlated with the pregnancy outcome in subsequent FETs., Results: In healthy volunteers, endometrial LAMB3 was demonstrated to be highly expressed during the WOR with the staining exclusively in the cytoplasm of the epithelial cells. In a discovery set of RIF patients, the LAMB3 expression level was found to be significantly higher in those who conceived compared to those who did not in subsequent FETs. A receiving operator characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.7818 (95% confidence interval 59.92-96.44%) with an H-score cutoff of 4.129 to differentiate cases with positive or negative pregnancy outcomes. This cutoff achieved an accuracy of 75% in pregnancy prediction in a following validation set of RIF patients, in which the pregnancy rate in subsequent FETs was three-fold higher when the mock cycle LAMB3 H-score was ≥ 4.129 compared to < 4.129., Conclusions: IHC measurement of endometrial LAMB3 expression could be a promising prognostic method to predict pregnancy outcome for RIF patients undergoing FETs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Uterine inflammation is a very common and serious pathology in domestic animals, the development and progression of which often result from disturbed myometrial contractility. We investigated the effect of inflammation on the protein expression of galanin (GAL) receptor subtypes (GALR)1 and GALR2 in myometrium and their role in the contractile amplitude and frequency of an inflamed gilt uterus. The gilts of the E. coli and SAL groups received E. coli suspension or saline in their uteri, respectively, and only laparotomy was performed (CON group). Eight days later, the E. coli group developed severe acute endometritis and lowered GALR1 protein expression in the myometrium. Compared to the pretreatment period, GAL (10 -7 M) reduced the amplitude and frequency in myometrium and endometrium/myometrium of the CON and SAL groups, the amplitude in both stripes and frequency in endometrium/myometrium of the E. coli group. In this group, myometrial frequency after using GAL increased, and it was higher than in other groups. GALR2 antagonist diminished the decrease in amplitude in myometrium and the frequency in endometrium/myometrium (SAL, E. coli groups) induced by GAL (10 -7 M). GALR1/GALR2 antagonist and GAL (10 -7 M) reversed the decrease in amplitude and diminished the decrease in frequency in both examined stripes (CON, SAL groups), and diminished the drop in amplitude and abolished the rise in the frequency in the myometrium ( E. coli group). In summary, the inflammation reduced GALR1 protein expression in pig myometrium, and GALR1 and GALR2 participated in the contractile regulation of an inflamed uterus.

BMI-1 is a key component of stem cells, which are essential for normal organ development and cell phenotype maintenance. BMI-1 expression is deregulated in cancer, resulting in the alteration of chromatin and gene transcription repression. The cellular signaling pathway that governs BMI-1 action in the ovarian carcinogenesis sequences is incompletely deciphered. In this study, we set out to analyze the immunohistochemical (IHC) BMI-1 expression in two different groups: endometriosis-related ovarian carcinoma (EOC) and non-endometriotic ovarian carcinoma (NEOC), aiming to identify the differences in its tissue profile., Methods: BMI-1 IHC expression has been individually quantified in epithelial and in stromal components by using adapted scores systems. Statistical analysis was performed to analyze the relationship between BMI-1 epithelial and stromal profile in each group and between groups and its correlation with classical clinicopathological characteristics., Results: BMI-1 expression in epithelial tumor cells was mostly low or negative in the EOC group, and predominantly positive in the NEOC group. Moreover, the stromal BMI-1 expression was variable in the EOC group, whereas in the NEOC group, stromal BMI-1 expression was mainly strong. We noted statistically significant differences between the epithelial and stromal BMI-1 profiles in each group and between the two ovarian carcinoma (OC) groups., Conclusions: Our study provides solid evidence for a different BMI-1 expression in EOC and NEOC, corresponding to the differences in their etiopathogeny. The reported differences in the BMI-1 expression of EOC and NEOC need to be further validated in a larger and homogenous cohort of study.

Objective: To investigate the association of endometrium preparation with perinatal outcomes., Design: Retrospective cohort study., Setting: University-affiliated fertility center., Patient(s): Twenty-one thousand six hundred and forty-eight women who underwent frozen single-blastocyst transfer from January 2013 to March 2019., Intervention(s): None., Main Outcome Measure(s): Cesarean delivery, preterm delivery (PTD), vaginal PTD, very preterm delivery (VPTD), postterm delivery, low birth weight (LBW), macrosomia, small for gestational age (SGA), large for gestational age (LGA), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), premature rupture of membrane (PROM), placenta previa, and congenital abnormality., Result(s): Compared with natural cycles, hormone replacement cycles were associated with an increased risk of PTD, VPTD, cesarean delivery, macrosomia, PROM, and HDP. There was a trend toward an increased risk of vaginal PTD and LGA in hormone replacement cycles. Stimulated cycles were associated with an increased risk of postterm delivery and GDM. There was no statistically significant difference in the rate of SGA, placenta previa, or congenital abnormality among the three endometrium preparation methods., Conclusion(s): Hormone replacement cycles are associated with an increased risk of PTD, VPTD, cesarean delivery, LBW, macrosomia, PROM, and HDP. Stimulated cycles are associated with an increased risk of postterm delivery and GDM., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

It has been suggested that impaired venous drainage and endometrial vascular ectasia (EMVE), secondary to increased intramural pressure, explains abnormal bleeding in fibroid uteri. Striking EMVE with extravasated red blood cells (ecchymosis) has also been seen in uteri with grossly obvious myometrial hyperplasia (MMH), suggesting that increased intramural pressure can cause EMVE in the absence of fibroids. EMVE with MMH may explain the century old association of clinically enlarged uteri with abnormal bleeding, and this same mechanism may be operative in myopathic uteri with grossly obvious adenomyosis. EMVE with associated thrombosis, ecchymosis, and/or stromal breakdown is commonly seen in random sections of hysterectomies for bleeding. EMVE may also be associated with endothelial hyperplasia, consistent with a reaction to endothelial injury due to impaired venous drainage. This further supports the theory that EMVE bleeds when thrombosis occurs, due to Virchow's Triad (stasis, endothelial injury, and hypercoagulability). EMVE may be "the lesion for which surgery was performed" in hysterectomies with otherwise unexplained bleeding., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Uterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

Differentiation of endometrial stromal cells (ESCs) into secretory decidualized cells (dESCs) is essential for embryo implantation. Adenomyosis is a common benign gynecological disease that causes infertility. However, whether adenomyosis affects decidualization of human ESCs is elusive. Primary eutopic ESCs were obtained from patients with adenomyosis (n = 9) and women with nonendometrial diseases (n = 12). We determined the capacity of decidualization of human ESCs by qRT-PCR, Edu proliferation assay, cytokine array, and ELISA assay. We found that the expression of decidualization markers (IGFBP1 and PRL) in ESCs of adenomyosis was reduced, concomitant with increased cell proliferation. Differential secretion of cytokines in dESCs, including CXCL1/2/3, IL-6, IL-8, MCP-1, VEGF-A, MIP-3α, OPN, SDF-1α, HGF, and MMP-9, was observed between adenomyosis and nonadenomyosis. Moreover, the expression of decidualization regulators (HOXA10 at both mRNA and protein levels, FOXO1, KLF5, CEBPB, and HAND2 at mRNA levels) in the eutopic endometrium of adenomyosis was lower than that of nonadenomyosis. We propose that ESCs from adenomyosis have defected ability to full decidualization, which may lead to a nonreceptive endometrium., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Endometrial-related disorders including Asherman's syndrome, thin endometrium, pelvic organ prolapse, and cesarean scar pregnancies can be accompanied by different symptoms such as amenorrhea, infertility, abnormal placental implantation and recurrent miscarriage. Different methods have been introduced to overcome these problems such as surgery and hormonal therapy but none of them has shown promising outcomes. On the other hand, the development of novel regenerative therapeutic strategies has opened new avenues for the treatment of endometrial-related deficiencies. In this regard, different types of scaffolds, acellular matrices and also cell therapy with adult or stem cells have been investigated for the treatment of endometrial-related deficiencies. In this paper, we review the current status of cell-based endometrium regeneration using scaffold dependent and scaffold-free methods and future perspectives in this field. Moreover, we discuss the endometrial diseases that can be candidates for cell-based treatments. Also, the cells with the potential for endometrial regeneration are explained.

Abstract: To study the efficacy of using amniotic membrane, balloon and intrauterine device (IUD) as barrier therapy to prevent re-adhesion after hysteroscopic adhesiolysis.A total of 45 patients diagnosed with intrauterine adhesions in Changzhou Maternal and Child Health Hospital from June 2014 to December 2017 were included in this retrospective case control study. According to different postoperative isolation barrier methods, the patients were divided into group A (Foley balloon + fresh amniotic membrane Day1 + IUD Day7) (22 cases) and group B (Foley balloon Day1 + IUD Day7) (23 cases). Three months after the surgery, the second hysteroscopy was performed to observe the condition of the uterine cavity and the improvement of menstruation, and to monitor the thickness of the endometrium.The efficacy of hysteroscopic procedure in group A was significantly higher than that of group B (P < .05). After 3 months of treatment, the improvement rate of menstruation was significantly higher in group A than in group B (P < .05). Endometrial thickness in both group A and B was significantly increased compared with that before the surgery (P < .05). The postoperative endometrium of group A was significantly thicker than that of group B (P < .05).Amniotic membrane-mediated sequential double-barrier method is clinically feasible for preventing recurrent intrauterine adhesions., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The endometrium is an essential component of the female uterus which provides the environment for pregnancy establishment and maintenance. Abnormalities of the endometrium not only lead to difficulties in establishing and maintaining pregnancy but also play a causative role in diseases of endometrial origin including endometriosis and endometrial cancer. Non-coding RNAs are proposed to play a role in regulating the genome in both normal endometrial physiology and pathophysiology. In this review, we first provide a general overview of non-coding RNAs and reproductive physiology of the endometrium. We then discuss the role on non-coding RNAs in normal endometrial physiology and pathophysiology of endometrial infertility. We then conclude with non-coding RNAs in the pathophysiology of endometriosis and endometrial cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hydrosalpinx is a disease characterized by the obstruction of the salpinx, with progressive accumulation in the shape of a fluid-filled sac at the distal part of the tuba uterina, and closed to the ovary. Women with hydrosalpinges have lower implantation and pregnancy rates due to a combination of mechanical and chemical factors thought to disrupt the endometrial environment. Evidence suggests that the presence of hydrosalpinx reduces the rate of pregnancy with assisted reproductive technology. The main aim of the present is review to make an overview of the possible effects of hydrosalpinx on in vitro fertilization (IVF). We conducted a literature search on the PubMed, Ovid MEDLINE, and Google Scholar data bases regarding hydrosalpinx and IVF outcomes. Hydrosalpinx probably has a direct toxic effect on sperm motility and on the embryos. In addition, the increasing liquid inside the salpinges could alter the mechanisms of endometrial receptivity. The window of endometrial receptivity is essential in the implantation of blastocysts, and it triggers multiple reactions arising from the endometrium as well as the blastocysts. Hydrosalpinx could influence the expression of homeobox A10 ( HOXA10 ) gene, which plays an essential role in directing embryonic development and implantation. Salpingectomy restores the endometrial expression of HOXA10 ; therefore, it may be one mechanism by which tubal removal could result in improved implantation rates in IVF. In addition, salpingectomy does not affect the ovarian response, nor reduces the antral follicle count. Further studies are needed to establish the therapeutic value of fluid aspiration under ultrasonographic guidance, during or after oocyte retrieval, in terms of pregnancy rate and ongoing pregnancy., Competing Interests: The authors have no conflict of interests to delcare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Purpose: To determine the utility of the endometrial receptivity analysis (ERA) in women with prior failed embryo transfers (ET)., Methods: This was a retrospective study of patients who underwent an ERA test with a subsequent frozen ET. Women were classified based on their indication for an ERA test: (1) ≥ 1 prior failed ET (cases), or (2) as a prophylactic measure (controls). A subset analysis of women with ≥ 3 prior failed transfers was performed. Pregnancy outcomes of the subsequent cycle were examined, including conception, clinical pregnancy, and ongoing pregnancy/live birth., Results: A total of 222 women were included, 131 (59%) women with ≥ 1 prior failed ET and 91 (41%) controls. Among the 131 women with ≥ 1 prior failed ET, 20 women (9%) had ≥ 3 prior failed ETs. The proportion of non-receptive ERA tests in the three groups were the following: 45% (≥ 1 prior failed ET), 40% (≥ 3 prior failed ETs), and 52% (controls). The results did not differ between cases and controls. The pregnancy outcomes did not differ between women with ≥ 1 prior failed ET and controls. In women with ≥ 3 prior failed ETs, there was a lower ongoing pregnancy/live birth rate (28% vs 54%, P = 0.046)., Conclusion: Women with ≥ 1 prior failed ET and ≥ 3 prior failed ETs had a similar prevalence of non-receptive endometrium compared to controls. Women with ≥ 3 prior failed ETs had a lower ongoing pregnancy/live birth rate despite a personalized FET, suggesting that there are additional factors in implantation failure beyond an adjustment in progesterone exposure.

Type 2 diabetes mellitus (T2DM) is a disease characterized by hyperglycemia resulting from insulin resistance. In recent years, the incidence of T2DM has been increasing. Women with T2DM often suffer from infertility and early miscarriage; however, the underlying mechanisms remain unclear. Insulin is the most important regulatory hormone of glycogen metabolism. In addition, 5' adenosine monophosphate-activated protein kinase (AMPK) is an important regulator of glycogen metabolism. Patients with T2DM have inhibited AMPK expression in the liver, which leads to impaired glucose metabolism. However, the role of AMPK in endometrial glycogen metabolism has not been reported. In this study, a mouse model of T2DM was established to investigate whether altered endometrial glucose metabolism affects early embryo implantation. Metformin and insulin were used for therapy; the resulting changes to glycogen metabolism and embryo implantation were examined. The results indicate that the concentrations of glycogen decreased significantly in T2DM mice, resulting in insufficient energy supplies for proper endometrial function, and thereby impeding embryonic implantation. Interestingly, endometrial AMPK was not found to be overactivated. Insulin treatment was found to partially resolve the embryo implantation defects in T2DM mice. Metformin improved blood glucose but did not have a significant effect on local endometrial glucose metabolism. This study explored the changes in endometrial glucose metabolism in T2DM mouse, and the effects of these changes on embryo implantation. We found that insulin, but not metformin, significantly resolved embryo implantation problems. These findings will help to increase our understanding of the pathomechanisms of infertility and early miscarriage in women with T2DM.

Recurrent pregnancy loss (RPL), defined as two to three spontaneous pregnancy terminations occurring before 12 weeks of gestation, affects approximately 1% of the general population. The causes may include congenital factors that originate with the quality of the gametes (sperm or oocyte) or the resulting embryo, or factors that originate within the uterus. Alterations of endometrial receptivity from endometriosis and/or endometritis, which are associated with impaired action of progesterone, have also been implicated in RPL. Finally, immunologic factors and thrombophilia, congenital and acquired, have also been suspected to cause RPL., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The objective of this research is to study the effects of TGF-β1 inhibition on endometrial receptivity and pregnancy outcomes in mice with adenomyosis. Experiments were done using a mouse model of adenomyosis which took place in a hospital-affiliated laboratory. The mouse model used for this research is ICR mouse. Adenomyosis was induced by oral gavage of tamoxifen (TAM) from postnatal days (PNDs) 1 to 4 in ICR mice. Bilateral intrauterine injection of anti-TGF-β1-neutralizing antibody or isotype IgG or PBS was performed at PND42. The mice were then either sacrificed or mated at PND64 followed by sacrificing at gestational day (GD) 4 or proceeding to delivery. Implantation numbers, rate of dams with live birth, live birth numbers, survival at 1 week old, and pup mortality rate after weaning were recorded. Collagen was demonstrated by Masson's trichrome and Van Gieson's stains. Uterine expression of a receptivity marker, leukemia inhibitory factor (LIF), was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC). Anti-TGF-β1 treatment increased the mean implantation numbers, fecundity rate, the rate of dams with live birth, pup survival rate at 1 week old, and pup mortality rate after weaning. Collagen expression in uteri with adenomyosis was attenuated by anti-TGF-β1 treatment. Increased LIF expression by anti-TGF-β1 treatment was detected by qRT-PCR, Western blot, and IHC. The results suggest that inhibition of TGF-β1 improves pregnancy outcomes by restoring endometrial receptivity in mice with adenomyosis.

Chronic inflammatory processes affecting the endometrium, as encountered in endometriosis, adenomyosis, and chronic endometritis, alter endometrial receptivity. These disorders are associated with early pregnancy losses and possibly recurrent pregnancy losses (RPL). In the cases of endometriosis, other factors associated with the disease also are susceptible of causing miscarriages and possibly RPL, such as an impact of intrapelvic inflammatory processes affecting the oocyte and embryo in case of natural conception. Conversely these latter effects obviously are bypassed in case of assisted reproductive technology. Chronic inflammation of the endometrium in the condition known as chronic endometritis also causes early pregnancy losses and RPL with beneficial effects achieved when specific treatment is undertaken., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Repeated implantation failure (RIF) is a common endocrine disease that causes female infertility and the etiology is unknown. The abnormal expression of key proteins and hormones at the maternal-fetal interface affected the maternal-fetal communication and leads to adverse pregnancy outcomes. The expression of anti-Mullerian hormone (AMH) and AMH receptor II (AMHRII) was observed in the endometrium. This study aimed to investigate the expression of AMH and AMHRII at the human endometrium, decidual tissue, and blastocyst. Furthermore, the expression of AMH and AMHRII were examined in the RIF patients using immunohistochemistry and quantitative real-time PCR to test the AMHRII expression. The results demonstrated that AMH and AMHRII were present in healthy endometrium and AMHRII was highly expressed in mid-luteal phase. In addition, AMHRII expression was detected throughout the pregnancy and AMHRII's highest expression was in the second trimester. AMHRII was expressed in the blastocysts; however, AMH was not observed. The positive expression rate for AMHRII was significantly higher in the endometrium from RIF. Estrogen receptor (ER), insulin-like growth factor binding protein 1(IGFBP1), and prolactin (PRL) were significantly less expressed in RIF with high expression of AMHRII. The apoptosis was significantly higher in patients with high expression of AMHRII than in patients with normal expression of AMHRII. Our data suggests that AMHRII had an effect on RIF via the AMH and AMHRII signaling pathway. It participated in the development of RIF by interfering with endometrial decidualization and apoptosis.

The endometrial injury usually results in intrauterine adhesions (IUAs). However, there is no effective treatment to promote the regeneration of the endometrium currently. The decellularized amnion membrane (AM) is a promising material in human tissue repair and regeneration due to its biocompatibility, biodegradability, as well as the preservation of abundant bioactive components. Here, an innovative drug-delivering system based on human amniotic extracellular matrix (HAECM) scaffolds were developed to facilitate endometrium regeneration. The 17β-estradiol (E 2 ) loaded PLGA microspheres (E 2 -MS) were well dispersed in the scaffolds without altering their high porosity. E 2 released from E 2 -MS-HAECM scaffolds in vitro showed a decreased initial burst release followed with a sustained release for 21 days, which coincided with the female menstrual cycle. Results of cell proliferation suggested E 2 -MS-HAECM scaffolds had good biocompatibility and provided more biologic guidance of endometrial cell proliferation except for mechanical supports. Additionally, the mRNA expression of growth factors in endometrial cells indicated that HAECM scaffolds could upregulate the expression of EGF and IGF-1 to achieve endometrium regeneration. Therefore, these advantages provide the drug-loaded bioactive scaffolds with new choices for the treatments of IUAs.

Research Question: What is the prevalence of disrupted markers of endometrial function among women experiencing recurrent implantation failure (RIF), and does the prevalence differ from a control cohort?, Design: Prospective controlled cohort study. In total, 86 women with a history of RIF and 37 women starting their first fertility treatment were recruited for this study. Endometrial and blood profiling were carried out in a hormone-substituted cycle using oestradiol and progesterone. Endometrial biopsies were analysed by histology, immune cell profiling, and the endometrial receptivity array (ERA®) test (Igenomix, Valencia, Spain). The vaginal microbiome was analysed using a NGS-based technology (ArtPRED, Amsterdam, the Netherlands). Blood tests included oestradiol, progesterone, prolactin, thyroid-stimulating hormone, vitamin D and anti-phospholipid antibody levels., Results: Patients who had experienced RIF produced a range of test abnormalities. Compared with controls, women with RIF had a higher prevalence of chronic endometritis (24% versus 6%), a lower vitamin D level and a borderline lower progesterone level. Women who had experienced RIF had a more favourable vaginal microbiome compared with controls. Although the RIF cohort was older than the controls (mean age 33.8 years versus 30.2 years), no differences between the groups were observed in immune cell profiling and the ERA test., Conclusion: These data demonstrate that a single test or treatment for the endometrial factor in RIF is unlikely to be clinically effective. Diagnosing the endometrium in women with RIF permits targeted rather than blind interventions. Relative vitamin D deficiency, lower mid-luteal progesterone and chronic endometritis are ready targets for treatment. Understanding the role and treatment of an unfavourable vaginal microbiome in RIF needs further investigation., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

For patients with recurrent implantation failure in IVF, histologic or transcriptomic testing of the endometrium during the mid-secretory phase is often considered. Histological dating of endometrial biopsies (Noyes criteria) can determine if endometrial morphology is consistent with the period of receptivity. Alternatively, endometrial tissue can be sent for a commercial Endometrial Receptivity Array (ERA) test which characterizes the gene expression of the endometrium using a panel of 238 genes that have been implicated in endometrial receptivity. This study aimed to compare the two tests to assess their concordance and to examine the ability of the ERA to successfully predict implantation and pregnancy in a subsequent personalized embryo transfer. A retrospective review was done of 97 patients with a history of implantation failure who underwent an ERA, 35 of whom had histologic dating on the same sample. ERA and histology were classified as 'concordant' when samples were receptive by both tests or non-receptive by both tests. The ERA result was then used to personalize the embryo transfer day, and pregnancy rates from the first subsequent frozen transfer cycle were analyzed. The results indicated that there is poor concordance between ERA and histological dating with only 40.0% agreement and a kappa (95%CI) = -0.18 (-0.50, 0.14). According to the ERA, 48.5% of biopsies were receptive, 47.4% were non-receptive and 2.01% were insufficient tissue for analysis. The clinical pregnancy rate in patients shown to be receptive by ERA was 26.7% and non-receptive was 22.5% following the subsequent personalized ET (p = 0.66). This study concludes that there is a high degree of discordance between histological dating of the endometrium and molecular analysis by ERA. There was no evidence of clinical benefit when embryo transfer was personalized according to ERA in patients with a history of implantation failure.

Aim: The imbalance of Th17/Treg cells has been recently suggested as a new risk factors for recurrent implantation failure (RIF). Furthermore Th17/Treg cells are involved in immune regulation in peripheral blood and endometrial tissue of patients with RIF. In this research, we investigated the effects of Hydroxychloroquine (HCQ) on the level and function of Th17 and Treg cells in women with RIF. It may be possible to improve pregnancy outcomes by modulating high cytokine levels., Methods: Women with RIF received oral HCQ ( n  = 60) on day 4 of the menstrual cycle and continued until day 20 of the menstrual cycle and 2 days before embryo transfer and continued until the day of the pregnancy test, for a total of 16 days in another cycle. The serum levels of IL-17 and IL-10, the expression of transcription factors related to Th17 and Treg cells and the immune-reactivity of IL-17, IL-21 as Th17 related cytokines and IL-10, TGF- β as Treg related cytokines in endometrial tissues were evaluated by ELISA, real-time PCR, and fluorescent immunohistochemistry respectively., Results: Treatment with HCQ down-regulated Th17 related cytokines and function and up-regulated Treg related cytokines and function significantly ( p  < .001). RORγt, the Th17 transcription factor, expression was down-regulated and FOXP-3, the T-reg transcription factor, expression was up-regulated. The biochemical pregnancy rate was not significantly different in RIF patients before and after treatment., Conclusion: Our results demonstrated that the administration of HCQ in RIF women with immune cell disorders during pregnancy could affect the Th17/Treg ratio and enhance Treg and diminish Th17 responses which may be associated with successful pregnancy outcomes. However, significant difference in pregnancy outcomes was not observed in the present study.

Aims: This study aims to investigate the effects of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on a thin-endometrium rat model., Main Methods: Twenty rats in two groups of 10 were used. Group I was perfused with normal saline (NS) in the right uterine horn and 95% ethanol in the left one. Group II was bilaterally perfused with 95% ethanol into the uterine horns. After three estrous cycles, Group II was perfused with NS in the right uterine horn and G-CSF (30 μg/kg) in the left one. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to detect changes in endometrial thickness and expression of cytokeratin 19 (CK19) and vimentin (Vim). The relative expression levels of vascular endothelial growth factor (Vegf) and leukemia inhibitory factor (Lif) were also tested via reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and Western-blot analyses., Key Findings: G-CSF treatment significantly increased the thickness of the endometrium in the 95% ethanol-induced thin-endometrium rat model. The expression levels of endometrial glandular epithelial cell marker for CK19 and stromal cell marker Vim were augmented in the G-CSF-treated group compared with the control group. Moreover, G-CSF treatment stimulated the expression of VEGF and LIF in the 95% ethanol-induced thin-endometrium rat model., Significance: G-CSF intrauterine perfusion improved endometrial receptivity in the thin-endometrium rat model by stimulating endometrial proliferation and angiogenesis., (Copyright © 2020. Published by Elsevier Inc.)

Intrauterine adhesions (IUAs) are characterized by the injury of endometrium due to curettage and/or endometritis. The loss of functional endometrium in uterine cavity usually results in hypomenorrhea, amenorrhea, infertility, and/or recurrent pregnancy loss. Recently, stem cell transplantation has been applied to promote the endometrial regeneration. Human amnion epithelial cells (hAECs) have been shown to have stem cell characteristics. In this study, we found that PKH26-labeled hAECs were mainly distributed in the basal layer of endometrium after transplantation, and hAEC transplantation, including uterine injection and tail vein injection, could increase pregnancy rate and the number of embryos in rat model of IUAs. Moreover, hAEC transplantation was demonstrated to increase the endometrial thickness, promote the proliferation of glands and blood vessels, and decrease fibrotic areas in the endometrium. The immunohistochemical and quantitative polymerase chain reaction analysis showed the upregulated expression of growth factors, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) after hAEC transplantation; and the downregulated expression of collagen type I alpha 1 (COL1A1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-β (TGF-β), all of which are associated with the extracellular matrix (ECM) deposition after hAEC transplantation. The mRNA sequencing indicated that platelet-derived growth factor-C (PDGF-C), thrombospondin-1 (THBS1), connective tissue growth factor (CTGF), Wnt5a, and Snai2 were significantly modulated in treatment groups. These results indicate that hAEC transplantation promotes endometrial regeneration and the restoration of fertility in rat model of IUAs.

Over the last years, increasing evidence has focused on crucial pathogenetic role of PRL on malignant, premalignant and benign uterine diseases. Studies in animals and humans have documented that PRL receptors (PRL-Rs) are widely expressed on uterine cells and that PRL is directly synthesized by the endometrium under the stimulatory action of progesterone. Uterine PRL secretion is finely modulated by autocrine/paracrine mechanisms which do not depend on the same control factors implied in the regulation of PRL secretion from pituitary. On the other hand, PRL is synthesized also in the myometrium and directly promotes uterine smooth muscle cell growth and proliferation. Therefore, PRL and PRL-Rs appear to play an important role for the activation of signaling pathways involved in uterine cancers and preneoplastic lesions. Circulating PRL levels are reportedly increased in patients with cervical or endometrial cancers, as well as uterine premalignant lesions, and might be used as discriminative biomarker in patients with uterine cancers. Similarly, increased PRL levels have been implicated in the endometriosis-induced infertility, albeit a clear a causative role for PRL in the pathogenesis of endometriosis is yet to be demonstrated. This evidence has suggested the potential application of dopamine agonists in the therapeutic algorithm of women with malignant, premalignant and benign uterine lesions. This review focuses on the role of PRL as tumorigenic factor for uterus and the outcome of medical treatment with dopamine agonists in patients with malignant and benign uterine disease., (Copyright © 2020 Auriemma, Del Vecchio, Scairati, Pirchio, Liccardi, Verde, de Angelis, Menafra, Pivonello, Conforti, Alviggi, Pivonello and Colao.)

This study aimed to assess the endometrial receptivity during implantation window in women with unexplained infertility. A prospective study recruited 168 women with unexplained infertility and 169 fertile women. Ultrasonic parameters and biomarkers in the uterine fluid were detected. The endometrial vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly higher in fertile women as compared with unexplained infertile women, and the integrin αvβ3, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and leukemia inhibitory factor (LIF) levels in uterine fluid were significantly higher in fertile women. The biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate in fertile women were 20.12%, 18.34%, and 17.75%, respectively, which were significantly higher compared with unexplained infertile women (7.14%, 5.36%, and 4.17%, respectively). Endometrial thickness (ET), endometrial volume (EV), VI, FI, and VFI measured by ultrasound, and the integrin αvβ3, VEGF, TNF-α, and LIF levels in uterine fluid were all significantly higher in pregnant women as compared with nonpregnant women. The best parameters of ultrasonic indicators for predicting endometrial receptivity in women with unexplained infertility were FI(AUC = 0.894, sensitivity 93.8%, and specificity 83.1%). Integrin αvβ3 had the best predictive value for endometrial receptivity among biomarkers in the uterine fluid (AUC = 0.921, sensitivity 96.7%, and specificity 89.5%). Women with unexplained infertility present declined endometrial receptivity. Endometrial ultrasonic parameters detected by three-dimensional power Doppler and biomarkers in the uterine fluid may be effective indicators to predict endometrial receptivity.

Vaginal bleeding can occur shortly after delivery in 3%-5% of newborns as a consequence of placental hormone withdrawal . Although usually benign, its differential diagnosis includes central precocious puberty, tumours and other pathological conditions. A girl born at 26 weeks of gestation presented with five episodes of vaginal bleeding, each lasting less than a week, initiated at 4 months of age. Luteinising hormone and oestradiol levels were in the pubertal range. Later, she exhibited breast development, with no other pubertal signs. An ultrasonography test revealed an impregnated endometrium and a right ovarian cyst with 43 mm of diameter. A cranioencephalic MRI was unremarkable. Clinicians adopted expectant management and there was clinical, hormonal and radiological resolution in 3 months. The spontaneous resolution suggested mini-puberty of infancy. This is usually an asymptomatic condition, but to date, four cases of an exacerbated form in extremepremature infants have been reported. Long-term follow-up data are missing.A girl born at 26 weeks of gestation presented with five episodes of vaginal bleeding, each lasting less than a week, initiated at 4 months of age. Luteinising hormone and oestradiol levels were in the pubertal range. Later, she exhibited breast development, with no other pubertal signs. An ultrasonography test revealed an impregnated endometrium and a right ovarian cyst with 43 mm of diameter. A cranioencephalic MRI was unremarkable. Clinicians adopted expectant management and there was clinical, hormonal and radiological resolution in 3 months. The spontaneous resolution suggested mini-puberty of infancy. This is usually an asymptomatic condition, but to date, four cases of an exacerbated form in extremepremature infants have been reported. Long-term follow-up data are missing., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Final maturation of follicles has, in connection with ovarian stimulation and infertility treatment, traditionally been achieved by the administration of a human chorionic gonadotropin (hCG) bolus trigger of 5,000 to 10,000 IU. This trigger serves two purposes: induce oocyte maturation; and serve as luteal phase support owing to its long half-life. It now appears that the hCG bolus trigger is unable to support both these two purposes optimally. In particular, after an hCG trigger, the early luteal phase is hormonally abnormal and different from conditions observed in the natural menstrual cycle: the timing of the initiation of hCG and progesterone rise is much faster after an hCG trigger than in a natural menstrual cycle; the maximal concentrations of hCG and progesterone considerably exceed those naturally observed; and the timing of the peak progesterone concentration after an hCG trigger is advanced several days compared with the natural cycle. Furthermore, the hCG trigger without any follicle-stimulating hormone activity may induce oocyte maturation less efficiently than the combined luteinizing hormone and follicle-stimulating hormone surge normally seen. Collectively, the endometrium is likely to be advanced after an hCG trigger, and the implantation potential is probably not optimal. The precise effect on pregnancy rates after the different progressions of hCG and progesterone concentrations during the early luteal phase has not yet been determined, but more individualized methods using more physiological approaches are likely to improve reproductive outcomes., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)