暂无摘要。

Introduction: Numerous strategies have been investigated for addressing recurrent implantation failure (RIF) and enhancing endometrial receptivity, yet agreement on the optimal intervention remains elusive. Our investigation endeavors to assess the effect of low-level laser therapy (LLLT) on pregnancy outcomes in individuals who have undergone a minimum of three unsuccessful embryo transfer cycles (ET). Methods: In our randomized single-blinded clinical trial, we enrolled thirty females with a medical history of RIF who were eligible for frozen-thawed embryo transfer (FET). Through a random allocation sequence, the participants were divided into two groups. The LLLT was performed one cycle before blastocyst transfer in 15 cases using a New Age BIOLASER device (New Age Co., Italy) with a 900-milliwatt power output and an 850-nm wavelength. The irradiation sessions were conducted transabdominal on the hypogastric area. The considered outcomes were biochemical pregnancy, identified by a positive blood pregnancy test, and clinical pregnancy, confirmed through visualization of the gestational sac using ultrasonography. Results: The mean age of the subjects was 34.17 years, and they had undergone three to seven previous embryo transfers. There was no significant difference in basic characteristics between the group undergoing laser treatment and the control group. However, the laser-treated group exhibited elevated rates of both biochemical and clinical pregnancies compared to the control group (46.7% vs. 33.3%; P==0.710 and 33.3% vs. 20.0%; P=0.682 respectively). Conclusion: To our knowledge, this study represents the first single-blinded randomized clinical trial to assess the effectiveness of LLLT pretreatment in individuals with RIF. The findings propose that LLLT may potentially enhance biochemical and clinical pregnancy rates among RIF patients.

OBJECTIVE: In contemporary society, socially active women are increasingly planning their fertility for later in life. The fertility outcomes for advanced-age patients, even with egg donation, are often suboptimal due to endometrial aging. Recurrent implantation failure (RIF) is one of the core problems for assisted reproductive technology (ART), especially for advanced-age patients. High-quality, euploid embryos and synchronization between the embryonic stage and the uterine endometrial lining are crucial for positive outcomes. The study aims to improve ART outcomes with personalized embryo transfer (pET) according to endometrial receptivity analysis (ERA) in advanced-age patients with challenging reproductive histories, and RIF by utilizing, donor oocytes and preimplantation genetic testing for aneuploidy (PGT-A) for embryo testing.
METHODS: A randomized, controlled observational follow-up study was conducted from 2020 to 2023. After obtaining informed consent, 320 patients with RIF were selected. Patients were allocated into the study group and control group 1 based on consistent application of randomization principles, while control group 2 was selected separately. The study group included patients undergoing PGT-A and ERA, aged 35-45 years, with a mean age of 40.5±3.7 years. Control group 1 comprised patients undergoing PGT-A, aged 35-45 years, with a mean age of 40±4.2 years. Control group 2 consisted of patients undergoing PGT-A and ERA, aged less than 35 years, with a mean age of 31.6±2.2 years.
RESULTS: Results suggest that ERA may improve implantation and pregnancy outcomes in advanced-age patients, particularly those with RIFs. The pregnancy rate was significantly higher in the study group (77.9%), compared to control group 1 (57.6%) (p=0.0007), and no significant difference compared to control group 2 (77.3%) (p=0.94). The implantation rate was higher in the study group (54.1%) than in control group 1 (39.4%) (p=0.0009), and there was no significant difference between the study group and control group 2 (50%, p=0.87). The live birth rate was also higher in the study group (71.3%), compared to control group 1 (39.4%) (p<0.0001). There were no significant differences between the study group and control group 2 (65.9%, p=0.50).
CONCLUSIONS: pET guided by ERA significantly improves pregnancy, implantation, and live birth rates in advanced-age patients with challenging reproductive histories. pET provides ART outcomes with no significant difference between advanced-age patients and younger patients with pET guided by ERA.

OBJECTIVE: Does the expression of proliferating cell nuclear antigen (PCNA) in the endometrium regulate endometrial receptivity in patients with recurrent implantation failure (RIF)?
CONCLUSIONS: A high abundance of PCNA attenuates endometrial adhesive capacity and decidualization in patients with RIF.
BACKGROUND: 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.
METHODS: 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).
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.
RESULTS: 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 β3) and activating the FAK/paxillin signalling pathway. Furthermore, in HESCs, PCNA overexpression attenuated endometrial decidualization by activating the AKT/β-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.
METHODS: N/A.
CONCLUSIONS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
BACKGROUND: N/A.

暂无摘要。

Recurrent implantation failure (RIF) poses a significant challenge in assisted reproductive technology (ART) outcomes. The endometrium plays a crucial role in embryo implantation, and its protein expression profile is integral in determining receptivity. Proteomics has emerged as a valuable tool in unraveling the molecular intricacies underlying endometrial receptivity and RIF. The aim of the present review is to analyze the contribution of proteomics to the understanding of endometrial protein expression in women with RIF, based on the results of significant proteomic studies. Medline/Pubmed databases were searched using keywords pertaining to proteomics combined with terms related to RIF. 15 studies were included in the present review. Several proteins have been found to exbibit differential expression in endometrial biopsies and fluid samples between fertile women and women with RIF during the receptive endometrial phase. The profile of endometrial proteins varied significantly among the studies. Nevertheless, similar changes in the expression levels of annexin-6, progesterone receptor, MMP-2, and MMP-9 in the endometrium of women with RIF, were found in more than one study indicating that certain proteins could potentially be effective biomarkers of endometrial receptivity. Proteomics contributes significantly to the understanding of protein expression in the endometrium of women with RIF and the analysis of proteins in endometrial fluid are promising for improving the clinical management of RIF.

The maternal-fetal interaction has been hypothesized to involve the human leucocyte antigen (HLA). It has been suggested that excessive HLA antigen sharing between spouses is a mechanism causing maternal hyporesponsiveness to paternal antigens encountered during pregnancy and thus leading to a miscarriage. Participants in this retrospective study are RIF and RPL couples who visited Gunasheela Surgical and Maternity Hospital, Bangalore, India from November 2019 to September 2022. A total of 40 couples with RIF and 195 couples with RPL are included in the study. We observed that the DQB1*02:01:01 allele is associated with an increase in risk of both RIF and RPL, while the C*12:02:01 allele increases risk of only RPL. On the contrary, DQB1*02:02:01 and DQB1*06:03 alleles appear to be protective against both RPL and RIF. In addition, the C*07:02:01 allele was observed to be protective against RPL. In conclusion, C*12:02:01 and DQB1*02:01:01 could play a major role in RPL which is consistent with other studies, while DQB1*02:01:01 is the risk allele in our RIF group. The protective alleles C*07:02:01 in the RPL group, DQB1*02:02:01, and DQB1*06:03 in both RIF and RPL, were discovered for the first time. Allele frequencies will vary in population-based studies depending on the ethnicities of the cohort. Meta-analysis and antibody testing will provide additional insights on whether and how this data can be adopted into clinical practices.

The molecular mechanisms underlying window of implantation (WOI) displacement in patients with recurrent implantation failure (RIF) remain unclear. This study aims to explore the transcriptomic signatures of endometrium with normal and displaced WOIs and to identify the causes of endometrial receptivity (ER) abnormalities and WOI displacement in RIF patients.
In this study, 40 RIF patients were recruited and underwent personalized embryo transfer (pET) guided by the predicted results of endometrial receptivity diagnosis (ERD) model. Transcriptome analysis of endometrium from patients with clinical pregnancies after pET was performed to identify differentially expressed genes (DEGs) associated with WOI displacement. Gene expression data from HRT and natural cycle endometrium were compared to identify specific gene expression patterns of ER-related genes during WOI.
The ERD results indicated that 67.5% of RIF patients (27/40) were non-receptive in the conventional WOI (P+5) of the HRT cycle. The clinical pregnancy rate in RIF patients improved to 65% (26/40) after ERD-guided pET, indicating the effectiveness of transcriptome-based WOI prediction. Among the 26 patients with clinical pregnancy, the gene expression profiles of P+5 endometrium from advanced (n=6), normal (n=10) and delayed (n=10) WOI groups were significantly different from each other. Furthermore, 10 DEGs identified among P+5 endometrium of 3 groups were involved in immunomodulation, transmembrane transport and tissue regeneration, which could accurately classify the endometrium with different WOIs. Additionally, a large number of ER-related genes showed significant correlation and similar gene expression patterns in P+3, P+5, and P+7 endometrium from HRT cycles and LH+5, LH+7, and LH+9 endometrium from natural cycles.
Our study shows that ER-related genes share similar gene expression patterns during WOI in both natural and HRT cycles, and their aberrant expression is associated with WOI displacements. The improvement of pregnancy outcomes in RIF patients by adjusting ET timing according to ERD results demonstrates the importance of transcriptome-based endometrial receptivity assessment and the clinical efficiency of ERD model.

Recurrent implantation failure (RIF) is one of the core problems for assisted reproductive technology (ART). High-quality, euploid embryos and synchronization between the embryonic stage and the uterine endometrial lining are crucial for positive outcomes. Molecular biology techniques have significantly transformed assisted reproductive technology (ART). Numerous couples facing infertility issues have successfully achieved the birth of healthy infants through the application of molecular biology methods: preimplantation genetic testing for aneuploidy (PGT-A) and endometrial receptivity analysis (ERA). Exploring the impact of age on endometrial assays like the endometrial receptivity assay (ERA) yields valuable insights, including the determination of the implantation window and the development of personalized strategies. The authors present the case of a 42-year-old woman who has experienced RIF with euploid embryos, coupled with a hereditary thrombophilia homozygous mutation in the MTHFR genes: A1298C and C677T.

OBJECTIVE: To observe the effects of acupuncture combined with Chinese herbal medication on pregnancy outcomes in patients with recurrent implantation failure (RIF) infertility of kidney deficiency and blood stasis, and to explore its effects on the protein expression of serum p38MAPK and JAK/STAT.
METHODS: Sixty-two patients with RIF infertility of kidney deficiency and blood stasis who were scheduled for artificial cycle frozen-thawed embryo transfer were randomly divided into an observation group (31 cases, 4 cases dropped out) and a control group (31 cases, 3 cases were eliminated). The patients in the control group were treated with conventional artificial cycle frozen-thawed embryo transfer. On the basis of the control group, the patients in the observation group were treated with acupuncture combined with Chinese herbal medication. Acupuncture was applied at Baihui (GV 20), Guanyuan (CV 4) and bilateral Neiguan (PC 6), Zigong (EX-CA 1), Guilai (ST 29), Zusanli (ST 36), Taichong (LR 3), Shenshu (BL 23), Ciliao (BL 32), with each session lasting for 30 minutes, once every other day. Chinese herbal medication was administered to Bushen Huoxue (tonifing the kidney and activating blood circulation) decoction, with one dose per day, starting from the 3rd to 5th day of the menstrual cycle and continuing until 1 day before embryo transfer. Clinical pregnancy rate, embryo implantation rate, live birth rate, and biochemical pregnancy rate were compared between the two groups. TCM symptom score, platelet count (PLT), and plasma D-dimer level were assessed before treatment and 1 day before embryo transfer. Western blot method was used to detect the expression of serum P38MAPK, JAK, and STAT proteins before treatment and 1 day before embryo transfer.
RESULTS: In the observation group, the clinical pregnancy rate, embryo implantation rate, and live birth rate were higher (P<0.05), while the biochemical pregnancy rate was lower (P<0.05) than those in the control group. One day before embryo transfer, both groups showed a decrease in TCM symptom scores, PLT, and plasma D-dimer levels compared to those before treatment (P<0.05), and the observation group had lower TCM symptom scores and plasma D-dimer levels than the control group (P<0.05). One day before embryo transfer, the expression levels of serum p38MAPK, JAK, and STAT proteins in both groups were lower than those before treatment (P<0.05), and the observation group had lower serum p38MAPK protein expression than the control group (P<0.05).
CONCLUSIONS: Acupuncture combined with Chinese herbal medication can improve the clinical pregnancy rate, embryo implantation rate, live birth rate, and reduce the biochemical pregnancy rate in RIF infertility patients of kidney deficiency and blood stasis. Its mechanism of action may be related to down-regulating plasma D-dimer level and protein expression of serum p38MAPK.
目的: 观察针刺联合中药对反复种植失败（RIF）不孕患者妊娠结局及血清p38丝裂原活化蛋白激酶（MAPK）、Janus激酶（JAK）/信号转导和转录激活因子（STAT）蛋白表达的影响。方法: 将62例拟行人工周期冻融胚胎移植的肾虚血瘀型RIF不孕患者随机分为观察组（31例，脱落4例）和对照组（31例，剔除3例）。对照组予人工周期冻融胚胎移植常规方案治疗。在对照组基础上，观察组予针刺联合中药治疗，针刺穴取百会、关元，双侧内关、子宫、归来、足三里、太冲、肾俞、次髎，每次30 min，隔日1次；中药予补肾活血方，每日1剂。于月经第3~5天开始，治疗至移植前1 d。比较两组患者临床妊娠率、胚胎种植率、活产率、生化妊娠率，治疗前及移植前1 d中医症状评分、血小板计数（PLT）、血浆D-二聚体含量。于治疗前及移植前1 d采用Western blot法检测两组患者血清p38MAPK、JAK、STAT蛋白表达。结果: 观察组临床妊娠率、胚胎种植率、活产率高于对照组（P<0.05），生化妊娠率低于对照组（P<0.05）。移植前1 d，两组中医症状评分、PLT、血浆D-二聚体含量较治疗前降低（P<0.05），观察组中医症状评分、血浆D-二聚体含量低于对照组（P<0.05）。移植前1 d，两组患者血清p38MAPK、JAK、STAT蛋白表达均少于治疗前（P<0.05），观察组血清p38MAPK蛋白表达少于对照组（P<0.05）。结论: 针药结合能提高肾虚血瘀型RIF不孕患者的临床妊娠率、胚胎种植率、活产率，降低生化妊娠率，其作用机制可能与降低血浆D-二聚体含量及下调血清p38MAPK蛋白表达有关。.