Bushen Zhuyun Decoction Improves Endometrial Receptivity by Inhibiting NF-κB/NLRP3 Signaling Pathway.

OBJECTIVE: Bushen Zhuyun Decoction (BSZY), a traditional Chinese herbal prescription has shown promising effects on gynecological infertility, but the mechanism for endometrial receptivity is still unclear. This study aimed to investigate the regulatory effects of BSZY on endometrial receptivity, which plays a key role in colonization of embryo, and its regulatory mechanisms associated with NF- κB/NLRP3 pathway. METHODS: SD rats at reproductive age with affected endometrial receptivity was established using mifepristone (RU486), and the regulatory effects of BSZY on endometrial receptivity were evaluated by H&E staining, and changes in sex hormones by ELISA and Western blot. Moreover, human endometrial RL95-2 cells were treated with H2O2, and inflammatory cytokines in rats and RL95-2 cells were analyzed by ELISA. The activation of NF-κB/NLRP3 signaling pathway in RL95-2 cells were characterized using immunofluorescence and Western blot. Mitochondrial morphology and function in RL95-2 cells were observed by transmission electron microscope and cell mitochondrial stress test. RESULTS: BSZY increased uterine endometrial thickness and attenuate histopathological changes induced by RU486. BSZY can regulate endometrial estrogen receptor and progesterone receptor, and the levels of sex hormones and inflammatory cytokines in pregnant rats. BSZY-containing serum also showed strong anti-inflammatory and cytoprotective effects in vitro. In addition, BSZY-containing serum inhibited the activation of NF-κB/NLRP3 signaling pathway, and improve mitochondrial morphology and function in RL95-2 cells. CONCLUSION: BSZY can improve endometrial receptivity, potentially by improving mitochondrial morphology and function to inhibit the activation of NF-κB/NLRP3 signaling pathway in endometrial cells, thus regulate inflammation to improve endometrial receptivity.

Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? SUMMARY ANSWER: EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). WHAT IS KNOWN ALREADY: EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. STUDY DESIGN SIZE DURATION: A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. PARTICIPANTS/MATERIALS SETTING METHODS: The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). LIMITATIONS REASONS FOR CAUTION: Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. WIDER IMPLICATIONS OF THE FINDINGS: In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. STUDY FUNDING/COMPETING INTERESTS: H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. REGISTRATION NUMBER: PROSPERO CRD42022378464.

The Impact of Progesterone Administration Routes on Endometrial Receptivity and Clinical Outcomes in Assisted Reproductive Technology Cycles.

Introduction Assisted reproductive technologies (ART) rely on endometrial receptivity (ER) for successful embryo implantation. This study aimed to compare the impact of different progesterone administration routes on ER assessed using optimal time for endometrial receptivity analysis (OpERA) and clinical outcomes in ART cycles. Methods A retrospective cohort analysis was conducted on 281 infertile women who underwent in vitro fertilization (IVF). Patients were stratified based on progesterone administration routes: oral and vaginal progesterone (Group 1) vs. intramuscular progesterone (Group 2). OpERA was performed on 257 patients to assess ER. Clinical outcomes, including biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), implantation rate (IR), and abortion rate (AR), were compared between the groups. Results OpERA results showed no significant differences between Group 1 and Group 2 in receptive (51.2% vs. 52.0%, p = 0.857), pre-receptive (44.1% vs. 44.6%, p = 0.933), or post-receptive (4.7% vs. 3.1%, p = 0.496) states. Clinical outcomes, including BPR (59.9% vs. 60.9%, p = 0.903), CPR (50.0% vs. 56.5%, p = 0.463), IR (52.5% vs. 55.3%, p = 0.748), and AR (44.3% vs. 45.6%, p = 0.882), did not significantly differ between the groups. Conclusion Progesterone administration routes did not significantly affect ER or clinical outcomes, highlighting the need to prioritize understanding and enhancing ER instead of solely focusing on progesterone delivery methods. Identifying molecular pathways or biomarkers could improve receptivity and optimize ART, ultimately improving pregnancy outcomes.

An Approach to Improve Endometrial Receptivity: Is It Beneficial to Flush The Uterine Cavity with Follicular Fluid and Granulosa Cells? A Phase III Randomised Clinical Trial.

BACKGROUND: The follicular fluid (FF) of mature oocytes contains a high concentration of growth factors and cytokines that have the potential to influence implantation in either a paracrine or autocrine manner. During the physiological processes of ovulation, FF enters the fallopian tubes in conjunction with the oocyte. The purpose of this study is to evaluate implantation and clinical pregnancy rates following uterine flushing with FF and granulosa cells in infertile women with moderate male factor infertility after ovum retrieval for intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: This phase III randomised clinical trial enrolled 140 women with moderate male factor infertility who intended to undergo ICSI at Royan Infertility Clinic (Tehran, Iran). A computer-generated program and opaque sealed envelopes were used to randomly allocate patients to either an intervention group (n=70) or a control group (n=70). Participants in the intervention group received 2 ml of clear FF (without blood contamination) from 2 to 3 dominant follicles after oocyte retrieval. The control group only underwent uterine cavity catheterisation. RESULTS: The intervention group had a clinical pregnancy rate of 38.5% (25/65) compared to the control group [42.9% (27/63); P=0.719] and an implantation rate of 24.1% compared to the control group (27%; P=0.408). These rates did not differ between the groups. There were no statistically significant differences between the intervention and control groups in terms of pregnancy-related complications-ectopic pregnancy, blighted ovum or anembryonic pregnancy, and abortion. CONCLUSION: Uterine cavity flushing with FF from mature follicles following oocyte retrieval had no effect, either positively or negatively, on clinical pregnancy or implantation rates in women with moderate male factor infertility (registration number: NCT04077970).

[Effect of Intrauterine Perfusion of Granulocyte Colony-Stimulating Factor on Endometrium and Blood Flow Parameters in Patients With Thin Endometrium: A Prospective Controlled Clinical Trial]. / å®«è ”çŒæ³¨ç²’ç»†èƒžé›†è½åˆºæ¿€å› å­æ”¹å–„è–„åž‹å­å®«å† è†œæ‚£è€ å† è†œåŠè¡€æµå‚æ•°çš„å‰çž»æ€§ä¸´åºŠå¯¹ç §è¯•éªŒ.

Objective: To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF) on the endometrial thickness, volume, and blood flow parameters of patients with thin endometrium and their clinical outcomes. Methods: We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer (FET) at Mianyang Central Hospital between September 1, 2021 and September 1, 2023. They were divided into two groups, an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment. The general data and the clinical outcomes of the two groups were analyzed and compared. The endometrial thickness, volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed. Results: The clinical data of 83 patients were included in the study. The experimental group included 51 cases, while the control group included 31 cases. There were no significant differences in the baseline data between the two groups. The clinical pregnancy rate of the experimental group (56.86%) was higher than that of the control group (50.00%) and the rate of spontaneous abortion in the experimental group (27.59%) was lower than that in the control group (37.50%), but the differences were not statistically significant (P>0.05). In the experimental group, the postperfusion endometrial thickness ([0.67±0.1] cm) was greater than the preperfusion endometrial thickness ([0.59±0.09] cm), the postperfusion ([1.84±0.81] cm3) was greater than the preperfusion endometrial volume ([1.54±0.69] cm3), and the postperfusion vascularization flow index (VFI) (1.97±2.82) was greater than the preperfusion VFI (0.99±1.04), with all the differences being statistically significant (P<0.05). Conclusion: Intrauterine perfusion with G-CSF can enhance the endometrial thickness, volume, and some blood flow parameters in patients with thin endometrium.

Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER.

The Molecular Link between Obesity and the Endometrial Environment: A Starting Point for Female Infertility.

Female infertility constitutes a growing health problem in developing countries and could be associated with several possible causes including reproductive disorders, congenital malformations, infections and hormonal dysfunction. Nonetheless, a series of additional factors can also negatively impact female fertility and are represented by chronic exposure to environmental pollutants, stress, unhealthy lifestyle choices such as cigarette smoking and, among others, obesity. Excess weight is associated with several chronic diseases, and growing evidence demonstrates that it can compromise reproductive physiology due to its influence on endometrial gene expression and receptivity. Thus, the current review of the literature mainly focused on how obesity can impair uterine receptivity, mostly from a molecular point of view throughout the window of implantation (WOI) period at an endometrial level. It was also highlighted that an obesity-related increase in adipose tissue may lead to a modulation in the expression of multiple pathways, which could cause a hostile endometrial environment with a consequent negative impact on the uterine receptivity and the establishment of pregnancy. Thanks to the use of the endometrial receptivity assay (ERA), a specific microarray that studies the expression of a series of genes, it is now possible to evaluate the endometrial status of patients with infertility problems in a more detailed manner. Moreover, female fertility and endometrial receptivity could be affected by endometriosis, a chronic benign gynecological disease, whose cause-and-effect relationship to obesity is still uncertain. Therefore, further investigations would be required to better elucidate these mechanisms that govern embryo implantation and could be potentially useful for the generation of new strategies to overcome implantation failure and improve the pregnancy rates in obese women.

Platelet-Rich Plasma (PRP) for Endometrial Treatment Efficacy and Safety in Assisted Reproductive Technology: A Comprehensive Review.

Platelet-rich plasma (PRP) is among the new ground-breaking methods called for endometrial disorders detected in assisted reproductive technology (ART). This research work takes account of both a systematic literature review and an exploration of the molecular connections. The report aims to present the capabilities and benefits of the PRP in ART and the nonconformance and dangers involved in its use in ART. However, all these stages of ART need conducive endometrium, live micro embryo, and coordinated interaction between the blastocyst and the uterus. Despite all ART has achieved, implantation failure still exists as a problem having one quarter being attributed to the absence of the endometrial receptivity level. The review points to a corresponding increase in the role of autologous PRP in promoting cell proliferation, neo-angiogenesis, and anti-inflammatory effects to facilitate effective endometrial receptivity. The outcome of prior trials with the PRP approach proved to be positive for women with adenomyosis, thin endometrial lining, recurring implantation failure, chronic endometritis, and Asherman's syndrome. Challenges still exist in the proper placement of PRP for all women with infertility problems as well as how it works for individuals with blood disorders and infections. This study will look into the safest number of doses, the time of acting, and the possible future health hazards that both mother and child may face.

Acupuncture combined with gonadotropin-releasing hormone agonists improves endometrial receptivity and pregnancy outcome in patients with recurrent implantation failure of in vitro fertilization-embryo transfer.

OBJECTIVE: Gonadotropin-releasing hormone agonists (GnRHa), combined with other auxiliary treatments, can improve pregnancy outcomes in in vitro fertilization-embryo transfer (IVF-ET). This research investigated the effect of acupuncture combined with GnRHa in patients with recurrent implantation failure (RIF) of IVF-ET. METHODS: A total of 164 patients who intended to undergo frozen-thawed embryo transfer after RIF of IVF-ET were selected for experiments and then divided into the control (received conventional hormone replacement therapy (HRT) for endometrial preparation) and study groups (received a combination of acupuncture, GnRHa, and HRT for endometrial preparation) (n = 82). Endometrial thickness (EMT), endometrial morphological classification, submucosal uterine blood flow classification, clinical pregnancy rate, embryo implantation rate, and early abortion rate for each transfer cycle were compared between the two groups. RESULTS: EMT of the study group was higher than that of the control group 1 day before transfer. There were more patients with linear endometrium (A + B type) in the study group on the day of endometrial transformation than in the control group. The number of patients with type I submucosal uterine blood flow in the study group was decreased and the number of patients with type III was increased compared with the control group on the day of endometrial transformation. The clinical pregnancy rate and embryo implantation rate of the study group were higher than those of the control group. CONCLUSION: Acupuncture combined with GnRHa improves the endometrial receptivity of patients with RIF of IVF-ET, thereby increasing clinical pregnancy rates and improving pregnancy outcomes.

LnCRNAs in the Regulation of Endometrial Receptivity for Embryo Implantation.

The development of endometrial receptivity is crucial for successful embryo implantation and the initiation of pregnancy. Understanding the molecular regulatory processes that transform the endometrium into a receptive phase is essential for enhancing implantation rates in fertility treatments, such as in vitro fertilization (IVF). Long non-coding RNAs (lncRNAs) play a pivotal role as gene regulators and have been examined in the endometrium. This review offers current insights into the role of lncRNAs in regulating endometrial receptivity. Considering the significant variation in endometrial remodeling among species, we summarize the key events in the human endometrial cycle and discuss the identified lncRNAs in both humans and other species, which may play a crucial role in establishing receptivity. Notably, there are 742 lncRNAs in humans and 4438 lncRNAs that have the potential to modulate endometrial receptivity. Additionally, lncRNAs regulating matrix metalloproteinases (MMPs) and Let-7 have been observed in both species. Future investigations should explore the potential of lncRNAs as therapeutic targets and/or biomarkers for diagnosing and improving endometrial receptivity in human fertility therapy.

Feasible Influence of G-CSF on Clinical Pregnancy Outcome in Oocyte Donation Cycles for Patients with Recurrent Implantation Failure.

Background and Objectives: The aim of our single-center cohort study was the determination of the influence of the intrauterine lavage of granulocyte colony-stimulating growth factor (G-CSF) on clinical pregnancy rate in patients with a history of implantation failure older than 40 years. Materials and Methods: The study was conducted in Ferticare Prague SE between May 2018 and June 2020. Overall, 115 patients were distributed into two arms, with 48 subjects in the experimental and 67 in the control arm. All women have had a previous history of unsuccessful history of infertility treatment with their own genetic material and at least one ineffective cycle with the donated oocytes. The experimental arm underwent the intrauterine lavage of 0.5 mL of pure G-CSF from 120 to 48 h prior to embryo transfer. Results: The clinical pregnancy rate was 63.3% in the experimental arm and 47.8% in the control arm (p = 0.097 for Pearsonߣs χ2, and p = 0.133 for Fisher's exact test). However, the mean endometrial thickness on the day of embryo transfer did not appear to be statistically different (p = 0.139). Only the difference in endometrium thickness growth was statistically significant (p = 0.023). The increase in pregnancy rate is still encouraging for the future, even if it is not significant. Conclusion: Our study suggests the trend of increased pregnancy rate after the intrauterine G-CSF lavage in the interval of 120-48 h prior to embryo transfer.

Modified Hongteng Baijiang decoction enema improves sequelae of pelvic inflammatory disease by regulating the LIF/JAK2/STAT3 pathway and gut microbiota.

OBJECTIVE: The sequelae of pelvic inflammatory disease (SPID) are major causes of secondary infertility. Modified Hongteng Baijiang decoction (MHTBD) has produced positive results in the treatment of patients with chronic pelvic inflammatory disease; however, its role in SPID remains elusive. Therefore, this study clarified the role of MHTBD in SPID pathogenesis. METHODS: The main components in MHTBD were analyzed by using liquid chromatography‒mass spectrometry (LC/MS). An SPID rat model was established, and the rats were treated with different doses of MHTBD (0.504 g of raw drug/kg, 1.008 g of raw drug/kg, and 2.016 g of raw drug/kg). Endometrial pinopodes were observed via scanning electron microscopy, endometrial thickness and inflammatory cell infiltration were assessed via HE staining, and the expression of estrogen receptor (ER), progesterone receptor (PR), integrin ß3 (ITGB3), and CD31 in the endometrium was detected by using immunohistochemistry. Western blot analysis was used to detect the protein expression of LIF, JAK2, p-JAK2, STAT3, and p-STAT3 in the endometrium. Moreover, the changes in the gut microbiota were analyzed via 16S rRNA sequencing. RESULTS: MHTBD improved endometrial receptivity, attenuated endometrial pathologic damage, reduced inflammatory cell infiltration, decreased ER and PR expression in the endometrium, and promoted the expression of LIF, p-JAK2, and p-STAT3 in the endometrium (p < .05) in SPID rats. Additionally, MHTBD treatment affected the composition of the gut microbiota in SPID rats. Furthermore, MHTBD attenuated endometrial receptivity and pathological damage in SPID rats by promoting the LIF/JAK2/STAT3 pathway. CONCLUSION: MHTBD attenuates SPID in rats by promoting the LIF/JAK2/STAT3 pathway and improving the composition of the gut microbiota. MHTBD may be a valuable drug for SPID therapy.

A modified flexible GnRH antagonist protocol using antagonist early cessation and a gonadotropin step-down approach improves live birth rates in fresh cycles: a randomized controlled trial.

STUDY QUESTION: Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin (Gn) step-down approach with cessation of GnRH antagonist on the day of hCG administration (hCG day) in patients with normal ovarian response? SUMMARY ANSWER: The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on the hCG day is effective in improving live birth rates (LBRs) per fresh eSET cycle. WHAT IS KNOWN ALREADY: Currently, there is no consensus on optimal GnRH antagonist regimens. Studies have shown that fresh GnRH antagonist cycles result in poorer pregnancy outcomes than the long GnRH agonist (GnRHa) protocol. Endometrial receptivity is a key factor that contributes to this phenomenon. STUDY DESIGN, SIZE, DURATION: An open label randomized controlled trial (RCT) was performed between November 2021 and August 2022. There were 546 patients allocated to either the modified GnRH antagonist or the conventional antagonist protocol at a 1:1 ratio. PARTICIPANTS/MATERIALS, SETTING, METHODS: Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen from the partner, or from frozen donor ejaculates. The primary outcome was the LBRs per fresh SET cycle. Secondary outcomes included rates of implantation, clinical and ongoing pregnancy, miscarriage, and ovarian hyperstimulation syndrome (OHSS), as well as clinical outcomes of ovarian stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline demographic features were not significantly different between the two ovarian stimulation groups. However, in the intention-to-treat (ITT) population, the LBRs in the modified antagonist group were significantly higher than in the conventional group (38.1% [104/273] vs. 27.5% [75/273], relative risk 1.39 [95% CI, 1.09-1.77], P = 0.008). Using a per-protocol (PP) analysis which included all the patients who received an embryo transfer, the LBRs in the modified antagonist group were also significantly higher than in the conventional group (48.6% [103/212] vs. 36.8% [74/201], relative risk 1.32 [95% CI, 1.05-1.66], P = 0.016). The modified antagonist group achieved significantly higher implantation rates, and clinical and ongoing pregnancy rates than the conventional group in both the ITT and PP analyses (P < 0.05). The two groups did not show significant differences between the number of oocytes retrieved or mature oocytes, two-pronuclear zygote (2PN) rates, the number of embryos obtained, blastocyst progression and good-quality embryo rates, early miscarriage rates, or OHSS incidence rates (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study was that the subjects were not blinded to the treatment allocation in the RCT trial. Only women under 40 years of age who had a good prognosis were included in the analysis. Therefore, use of the modified antagonist protocol in older patients with a low ovarian reserve remains to be investigated. In addition, the sample size for Day 5 elective SET was small, so larger trials will be required to strengthen these findings. WIDER IMPLICATIONS OF THE FINDINGS: The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on hCG day improved the LBRs per fresh eSET cycle in normal responders. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by grant 2022YFC2702503 from the National Key Research & Development Program of China and grant 2021140 from the Beijing Health Promotion Association. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453. TRIAL REGISTRATION DATE: 21 November 2021. DATE OF FIRST PATIENT'S ENROLLMENT: 23 November 2021.

In Vitro Human Endometrial Cells and In Vivo Rat Model Studies Suggest That Ulipristal Acetate Impacts Endometrial Compatibility for Embryo Implantation.

BACKGROUND: Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. AIMS: To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. METHODS: In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. RESULTS: Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. CONCLUSIONS: These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

Corrigendum: An endometrial receptivity scoring system evaluated by ultrasonography in patients undergoing frozen-thawed embryo transfer: a prospective cohort study.

[This corrects the article DOI: 10.3389/fmed.2024.1354363.].

The therapeutic effects of vitamin D3 administration on the embryo implantation.

Various adjuvants have been tested clinically for patients with problems with embryo implantation during in vitro fertilization (IVF)-embryo transfer (ET). Vitamin D3, an essential modulator of various physiological processes, has received attention as an important adjuvant for successful pregnancy, as many studies have shown a strong association between vitamin D deficiency and implantation failure and fetal growth restriction. However, vitamin D has been widely utilized in different protocols, resulting in non-reproducible and debatable outcomes. In the present study, we demonstrated that cyclic intrauterine administration of vitamin D3 increased endometrial receptivity and angiogenesis, which could be attributed to increased recruitment of uterus-resident natural killer cells. In particular, cyclic treatment of vitamin D3 promoted stable attachment of the embryo onto endometrial cells in vitro, suggesting its merit during the early stage of embryo implantation to support the initial maternal-fetal interactions. Our findings suggest that women with repeated implantation failure may benefit from the use of vitamin D3 as a risk-free adjuvant prior to IVF-ET procedures to improve the uterine environment, and make it favorable for embryo implantation.

Excessive proliferating cell nuclear antigen attenuates endometrial adhesive capacity and decidualization in patients with recurrent implantation failure.

STUDY QUESTION: Does the expression of proliferating cell nuclear antigen (PCNA) in the endometrium regulate endometrial receptivity in patients with recurrent implantation failure (RIF)? SUMMARY ANSWER: A high abundance of PCNA attenuates endometrial adhesive capacity and decidualization in patients with RIF. WHAT IS KNOWN ALREADY: Aberrant expression of PCNA has been discovered in multiple infertility-related disorders. However, the expression pattern and role of PCNA in the establishment of endometrial receptivity and endometrial decidualization in patients with RIF remain unclear. STUDY DESIGN, SIZE, DURATION: We analysed the expression of PCNA in mid-secretory endometrial tissues from 24 patients with RIF and 24 healthy women. Additionally, PCNA expression levels were measured in proliferative and mid-secretory phase endometrial tissue samples from women with regular menstrual cycles and in decidual tissue samples taken from ten women during normal early pregnancy (n = 10 per phase for each group). The function and regulatory mechanisms of PCNA in endometrial adhesive capacity and endometrial decidualization were investigated using BeWo spheroids, Ishikawa cells, and human endometrial stromal cells (HESCs). PARTICIPANTS/MATERIALS, SETTING, METHODS: The expression of PCNA in mid-secretory endometrial tissues of patients with RIF and women with normal endometrium and in endometrial tissue at different stages of the menstrual cycle and in decidualized tissues was analysed by RT-qPCR, western blot, and immunohistochemistry staining (IHC). Furthermore, the number of BeWo spheroids directly attached to the Ishikawa cell monolayers, and the potential molecular mechanisms involved, were compared between cells overexpressing PCNA and a control group. Additionally, the effect and regulatory mechanisms of PCNA on the decidualization of HESCs in vitro were investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Our findings indicated that the abundance of PCNA was dramatically greater in mid-secretory endometrial tissues from patients with RIF than in those from women with healthy endometrium. The expression of PCNA increased in the proliferative phase of the menstrual cycle but decreased gradually in the mid-secretory phase and in decidual tissues. Interestingly, PCNA was expressed in both human endometrial epithelial cells (HEECs) and HESCs. In Ishikawa cells, PCNA overexpression dramatically reduced the endometrial adhesive capacity by inhibiting the expression of adhesion molecules (E-cadherin and integrin ß3) and activating the FAK/paxillin signalling pathway. Furthermore, in HESCs, PCNA overexpression attenuated endometrial decidualization by activating the AKT/ß-catenin signalling pathway and increasing tight junctions between cells by upregulating ZO-1 and occludin expression. In addition, PCNA-ELAVL1 interactions were confirmed by coimmunoprecipitation in decidualized HESCs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The functional analysis of PCNA was limited by the number of human endometrial tissues. A larger sample size is required to further explore the potential roles of PCNA during embryo implantation. Moreover, the present results should be taken with caution, as only a few of the embryos that were transferred in RIF patients population underwent preimplantation genetic testing for embryonic chromosome aneuploidies (PGT-A), despite embryo ploidy testing being significant in the diagnosis of unexplained RIF. WIDER IMPLICATIONS OF THESE FINDINGS: High PCNA expression attenuates endometrial adhesive capacity and decidualization in patients with RIF. These findings provide new insights into the potential mechanisms underlying the occurrence of implantation failure. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82101698), Shandong Provincial Natural Science Foundation (ZR2021MH012), and the Science and Technology Plan of Yantai (2023YD021 and 2022YD031). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Personalized embryo transfer guided by rsERT improves pregnancy outcomes in patients with repeated implantation failure.

Introduction: Embryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal causes for embryo implantation failure [especially repeated implantation failure (RIF)] when biopsied good-quality euploid embryos are transferred. An RNA-seq-based endometrial receptivity test (rsERT) was previously established to precisely guide successful embryo implantation. In this study, we aimed to evaluate the effect of personalized embryo transfer (pET) via rsERT on the clinical outcomes in patients with RIF. Methods: A total of 155 patients with RIF were included in the present retrospective study and were divided into two groups: 60 patients who underwent rsERT and pET (Group rsERT) and 95 patients who underwent standard frozen embryo transfer (FET) without rsERT (Group FET). Reproductive outcomes were compared for patients who underwent rsERT-guided pET and standard FET. Results: Forty percent (24/60) of the patients who underwent rsERT were receptive, and the remaining 60% (36/60) were non-receptive. The positive human chorionic gonadotropin (ß-hCG) rate (56.3% vs. 30.5%, P = 0.003) and clinical pregnancy rate (43.8% vs. 24.2%, P = 0.017) were significantly higher in Group rsERT patients than in FET group patients. Additionally, Group rsERT patients also showed a higher implantation rate (32.1% vs. 22.1%, P = 0.104) and live birth rate (35.4% vs. 21.1%, P = 0.064) when compared with FET patients, although without significance. For subpopulation analysis, the positive ß-hCG rate, clinical pregnancy rate, implantation rate, and live birth rate of receptive patients were not statistically significant different from those of non-receptive patients. Conclusions: The rsERT can significantly improve the pregnancy outcomes of RIF patients, indicating the clinical potential of rsERT-guided pET.

Endometriosis, staging, infertility and assisted reproductive technology: time for a rethink.

How endometriosis causes infertility, with the exception of tubal dysfunction caused by adhesions, is unclear. The inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible factors. Anatomical staging systems fail to predict the fertility status of endometriosis patients. Data from assisted reproductive technology cycles consistently suggest that oocytes from patients with endometriosis have a normal potential to develop into euploid blastocysts. Moreover, oocyte or embryo recipients with endometriosis seem to have similar or slightly lower pregnancy and live birth rates compared with recipients without endometriosis, suggesting that eutopic endometrium is not or is only minimally affected, which may be caused by undiagnosed adenomyosis. In-vivo observations from women with endometriomas provide evidence against a detrimental effect of endometriomas on oocytes. Combined with the absence of an obvious improvement in fertility following the surgical destruction or excision of peritoneal endometriosis or from temporary medical suppression of the disease and the associated inflammation, the available evidence makes endometriosis-associated infertility questionable in the absence of tubal dysfunction caused by adhesions. It is likely that no anatomical staging will correlate with fertility beyond assessing tubal function. In patients with endometriosis assisted reproductive technology is as effective as for other indications.