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Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes

Science China(Life Sciences) 2022年第8期65卷 1578-1589页

作者： Haiyan Xu Jingyi Li Luyang Jin Dan Zhang Bin Chen Xinmei Liu Xianhua Lin Yiting Huang Zhanghong Ke Juan Liu Lin Gao Jianzhong Sheng Hefeng Huang Reproductive Medicine Center Ningbo First HospitalNingbo 315100China Key Laboratory of Reproductive Genetics Ministry of Education(Zhejiang University)Hangzhou 310058China Department of Reproductive Endocrinology Women’s HospitalZhejiang University School of MedicineHangzhou 310006China Department of Pathology&Pathophysiology Zhejiang University School of MedicineHangzhou 310058China Shanghai Key Laboratory of Embryo Original Diseases Shanghai 200030China

Diabetes is a complex metabolic disorder which can adversely affect reproductive function. SGK1 is found to be up-regulated in multiple tissues of diabetic patients. However, the effects of diabetes on endometrial SGK1 expression and endometrial receptivity remain unknown. In this study, we established a streptozotocin-induced diabetic mouse model and observed reduced implantation sites, retarded development of pinopodes, increased SGK1, and aberrant expression of LIF and MUC1 in the endometrial epithelium. We injected the uterine lumen of normal mice with high-glucose solution and cultured endometrial cells in high-glucose medium to mimic intrauterine hyperglycemia. Both studies provided compelling evidence that hyperglycemia could lead to diminished embryo implantation and dysregulated SGK1, LIF and MUC1. Additionally, through over-expression of SGK1 in vivo and in vitro, we found that enhanced SGK1 also decreased LIF expression, increased MUC1 expression, and attenuated embryo implantation rate. We further identified that hyperglycemia-activated SMAD2/3 might be responsible for the enhancement of SGK1 and verified directly the interaction between SMAD3 and corresponding SMAD binding elements within SGK1 promoter. Taken together, our study confirmed the association between diabetes-related hyperglycemia and endometrial receptivity defects. Hyperglycemia-induced SGK1 has a tremendous role in this pathological process, rendering it as an attractive therapeutic target for diabetes-related reproductive disorders.

关键词： diabetes endometrial receptivity hyperglycemia serum/glucocorticoid-regulated kinase

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Value of Intrauterine Autologous Platelet-Rich Plasma Therapy on endometrial receptivity:A Literature Review

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Current Medical Science 2023年第6期43卷 1075-1083页

作者： Chu-jun LI Ya-dou ZHAN Xian-li ZHOU Jie YANG Ling DENG Xue-lan LI Xin CHEN Reproductive Medicine Center Shunde Hospital of Southern Medical University(The First People’s Hospital of Shunde)Shunde528300China

endometrial receptivity is an important factor that influences embryo implantation.Thus,it is important to identify an applicable approach to improve endometrial receptivity in women undergoing assisted reproductive technology.Recently,growing evidence has indicated that intrauterine platelet-rich plasma(PRP)infusion is an effective method to obtain a satisfactory reproductive outcome by increasing endometrial thickness and improving endometrial receptivity.Therefore,the present review aims to outline the possible mechanisms of PRP on endometrial receptivity and summarize the present literature on the effects of PRP therapy in improving endometrial receptivity.

关键词： platelet-rich plasma intrauterine perfusion endometrial thickness endometrial receptivity

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Effect of Acupuncture on endometrial Blood Flow in Women Undergoing in vitro Fertilization Embryo Transfer: A Single Blind, Randomized Controlled Trial

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Chinese Journal of Integrative Medicine 2024年第1期30卷 10-17页

作者： DONG Hao-xu Wu Xiao ZHOU Qin HUANG Dong-mei ZHANG Ming-min HUANG Guang-ying YANG Wei Department of Integrated Traditional Chinese and Western Medicine Tongji HospitalHuazhong University of Science and TechnologyWuhan(430030)China Department of Obstetrics and Gynecoiogy Tongji HospitalHuazhong University of Science and TechnologyWuhan(430030)China Institute of Integrated Traditional Chinese and Western Medicine Tongji HospitalHuazhong University of Science and TechnologyWuhan(430030)China Department of Reproductive Medicine Tongji HospitalHuazhong University of Science and TechnologyWuhan(430030)China

Objective: To evaluate the effect of manual acupuncture on endometrial blood flow parameters by three-dimensional(3D) power Doppler ultrasound in women undergoing in vitro fertilization embryo transfer(IVF-ET). Methods: Seventy patients undergoing IVF-ET were equally randomized into traditional or sham acupuncture treatment group for totally 4 days(from the day of oocyte aspiration to the day of embryo transfer) of treatment by random envelope method at the Reproductive Medicine Center and Outpatient Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology from January 2013 to December 2015. Patients in the traditional acupuncture group accepted traditional acupuncture methods with manual acupuncture, and Zhongji(CV3), Qihai(CV 6), Sanyinjiao(SP6), Taichong(LR 3), Tianshu(ST 25), Guilai(ST 29) and Zusanli(ST 36) were chosen. Patients at the sham acupuncture group accepted shallow acupuncture methods at 4 non-meridian points at each shoulder and upper arm. Outcome measures included endometrial ultrasonic indices such as vascularization index(VI), flow index(FI) and vascularization flow index(VFI), endometrial thickness and volume, subendometrial VI(sVI), subendometrial FI(sFI), subendometrial VFI(sVFI), implantation rate, clinical pregnancy rate, abortion rate, live birth rate and number of live births. Results: Finally, 34 patients in the traditional acupuncture group and 35 in the sham acupuncture group completed this trial. VI, FI and VFI of the traditional acupuncture group were significantly higher than those in the sham acupuncture group(Pendometrial thickness, endometrial volume, sVI, sFI, sVFI, implantation rate, clinical pregnancy rate, abortion rate, live birth rate and number of live births(P>0.05). Conclusions: Manual acupuncture performed after oocyte aspiration and before transplantation improved the endometrial blood flow parametersVI, RI and VFI in women

关键词： acupuncture endometrial blood flow endometrial receptivity in vitro fertilization randomized controlled trial

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Rhizoma Drynariae Improves endometrial receptivity in a Mus Model of Dysfunctional Embryo Implantation

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World Journal of Traditional Chinese Medicine 2023年第1期9卷 94-100页

作者： Yue Shi Yan-Feng Liu Jia-Mei Wang Jing Jiang Bo-Lin He Guo-Hua Mu Fang Liu Ya-Hui Li Ting Qiao Jing Lu Department of Traditional Chinese Medicine Haidian District Maternal and Child Health Care HospitalHaidian DistrictBeijingChina Department of Ggynaecology Dongzhimen Hospital Beijing University of Chinese MedicineDongchen DistrictBeijingChina

Background: Rhizoma drynariae is a traditional Chinese medicine used in orthopedics and traumatology, but its effect on endometrial receptivity remains unknown. Aims and Objectives: To observe effect of Rhizoma drynariae and its main components on endometrial receptivity in a mus model of dysfunctional embryo implantation. Materials and Methods: Mus models were established by the Gn RHa+HMG+HCG method. Normal mus receiving saline were used as controls and the remaining six groups were: model receiving saline, progynova, aspirin, Rhizoma drynariae, osteopractic total flavone, and naringin. Pinopodes in uterine endometrium were examined by scanning electron microscopy. Stem cell factor(SCF) m RNA expressions was determined by real-time RT-PCR, and estrogen receptor α(ERα), progesterone receptor(PR) by immunohistochemistry. Results: In the model group, surface morphology of endometrium was heterogeneous, without obvious pinopodes. In the Rhizoma drynaria and progynova groups, pinopodes were abundant. Compared with the blank group, model group had lower levels of SCF(-47%), ERα(-63%) and PR(-50%)(all Pendometrial receptivity of mouse models of dysfunctional embryo implantation as shown by increased numbers of pinopodes and higher levers of SCF, ERα, PR compared with the model group.

关键词： endometrial receptivity naringin rhizoma drynariae stem cell factor total flavone

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Use of biological and chemical molecules in regulating embryo implantation and endometrial receptivity

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Reproductive and Developmental Medicine 2022年第4期6卷 234-242页

作者： Xian Chen Shu-Ya Sun Ernest Hung-Yu Ng Raymond Hang-Wun Li William Shu-Biu Yeung Kai-Fai Lee Department of Obstetrics and Gynaecology LKS Faculty of Medicinethe University of Hong KongHong Kong SARChina Shenzhen Key Laboratory of Fertility Regulation the University of Hong Kong-Shenzhen HospitalShenzhen 518053China

This review summarizes the drugs and chemicals that may modulate embryo implantation.Non-hormonal molecules,including aspirin,improved endometrial blood flow,while low molecular weight heparin,vitamin E,sildenafil,and atosiban modulated the expression of endometrial genes.Hormonal factors,including human chorionic gonadotropin and growth hormones,can regulate the expression of endometrial receptivity markers.Other immunomodulatory molecules,including granulocyte colony-stimulating factor,peripheral blood mononuclear cells,autologous platelet-rich plasma,and intralipid and intravenous immunoglobulins,may improve implantation rate by modulating endometrial immune functions.Medicinal extracts of the Chinese herbs Paeonia lactiflora and Perilla frutescens increased the expression of leukemia inhibitory factors in endometrial epithelial cells.Recently,the use of the commercially available Library of Pharmacologically Active Compounds with a high-throughput screening method has provided an approach to screen for compounds that may potentially enhance or suppress embryo implantation.Whether these biomedical findings translate into clinical effects that enhance or suppress embryo implantation requires further investigation.

关键词： Embryo implantation endometrial receptivity fertilization Repeated implantation failure Birth control Emergency contraception

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Impact of Luteinized Unruptured Follicles on endometrial receptivity

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2011年第2期31卷 181-184页

作者：徐望明杨菁蒋蕾胡静 Department of Reproductive Medical Center Renmin Hospital of Wuhan University

This study examined the impact of luteinized unruptured follicle （LUF） on endometrial receptivity. The menstrual cycle of 17 LUF patients （LUF group） and 13 ovulatory women （control group） was monitored by measuring LH level in urine and by ultrasonic examination. An endometrial biopsy at the sixth to tenth day after LH surge was taken in all the patients. The expressions of endometrial ER, PR and integrin ανβ3 were immunohistochemically determined. At the same time, the serum levels of E2 and P were detected by chemiluminescence. The results exhibited that （1） The mean serum P level in LUF group （7.32±2.56 ng/mL） was significantly lower than that in control group （11.17±3.17 ng/mL）（P0.01）. But there was no significant difference in the mean serum E2 levels between LUF group （179.35±81.60 pg/mL） and the control group （198.58±75.23 pg/mL）（P0.05）; （2） The mean expression intensities of ER, PR in endometrium of LUF group （183.86±2.43, 167.94±3.04） were significantly higher than those in control group （109.35±6.31, 105.98±4.07）（P0.01）; （3） The mean expression intensities of integrin ανβ3 in endomtrium of LUF patients （114.90±11.38） were significantly lower than those in control group （191.34±1.82）（P0.01）; （4） The change profile of integrin ανβ3 expression in the endometrium of LUF patients was in positive relation with serum P level （r=0.77, P0.01）, but bore no significant relationship with serum E2 level （r=0.01, P0.05）. It was concluded that the depression of serum P levels in LUF patients was closely related to the failure of the down-regulation of ER and PR, and the low expressions of integrin ανβ3 also suggested that the delayed implantation and the impaired endometrial receptivity had impact on embryonic implantation.

关键词： luteinized unruptured follicle endometrial receptivity progesterone integrin ανβ3

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EFFECT OF MIFEPRISTONE (RU486)ON MARKERS OF endometrial receptivity

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Journal of Pharmaceutical Analysis 2003年第1期15卷 89-92,106页

作者：武捷王龙生程捷王介东 Department of Histology & Embryology National Research Institute for Family Planning

Objective To study the effect of single and low dose of RU486 on endometrial receptivity of healthy women. Methods A total of 5 healthy women were followed for one control and one treatment cycle. In the treatment cycle, a dose of 10 mg RU486 was administered on day luteinizing hormone (LH)-2. In both the control and treatment cycle, an endometrial biopsy was obtained on LH+7. These biopsies were assessed by immunohistochemical analysis to find the difference in expression of integrins and progesterone receptor (PR) between the control and treatment cycle. Results The treatment with RU486 increased the expression of α 1 and α 4 subunits of integrin in glandular epithelial cells, but did not influence β 3 subunit. Moreover, the normal down regulation of PR in epitherial cell nuclei was inhibited by 10 mg RU486. Conclusion Single dose of 10 mg RU486 impairs the establishment of endometrial receptivity on time.

关键词： mifepristone (RU486) integrin progesterone receptor (PR) endometrial receptivity

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Assessment of Uterine receptivity by endometrial and Subendometrial Blood Flows Measured by Vaginal Color Doppler Ultrasound in Women Undergoing IVF Treatment

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Journal of Reproduction and Contraception 2007年第3期18卷 205-212页

作者： Min-zhi GAO Xiao-ming ZHAO Wen-ying LI Gui-mei LIU Xiao-feng JIA Hui-qin ZHANG Reproductive Medicine Center of Renji Hospital Medical College of Jiao Tong University Shanghai 200001 China Shanghai Institution of Planned Parenthood Research Shanghai 200032 China

Objective To evaluate endometrial and subendometrial blood flows measured by vaginal color Doppler ultrasound as a predicator of endometrial receptivity in women undergoing IVF treatment. Methods A total of 119 infertile patients undergoing the first IVF/ICSI-ET cycle were recruited. Three groups were divided according to a color Doppler ultrasound examination performed on the day of hCG injection. Group A, endometrial and subendometrial blood flows were 2 branches and below; group B, endometrial and subendometrial blood flows were between 3 and 4 branches; group C, endometrial and subendometrial blood flows were 5 branches and above. Patients were transferred 1-3 embryos each. Demographic data, ovarian responses, endometrial thickness, PI, RI, development of embryo and IVF result among groups were compared. Results Demographic data, ovarian responses, endometrial thickness, PI, RI and development of embryo among groups have no significant difference. The pregnancy rate of group A was significantly lower than that of group B （P〈0.05） and group C （P〈0.01）. The implantation rate of group A was significantly lower than than of group C （P〈0.01）. There was no significant difference of the rate of pregnancy and implantation between group B and group C （P〉0.05）. Conclusion endometrial and subendometrial blood flows measured by vaginal color Doppler ultrasound is a good predicator of pregnancy during IVF treatment. A good endometrial and subendometrial blood flows is benefit for the result of IVF.

关键词： endometrial and subendometrial blood flows endometrial receptivity in vitro fertilization-embryo transfer （IVF） color Doppler ultrasound

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Role of microRNAs in embryo–endometrial interactions:biological functions and clinical applications

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Reproductive and Developmental Medicine 2023年第4期7卷 238-251页

作者： Shiwen Qi Suranga P.Kodithuwakku Ronald T.K.Pang Philip C.N.Chiu Mary H.Y.Tang Kai-Fai Lee Department of Obstetrics and Gynaecology School of Clinical MedicineLKs Faculty of MedicineThe University of Hong KongHong Kong SARChina Department of Animal Science Faculty of AgricultureUniversity of PeradeniyaPeradeniya 20400Sri Lanka Shenzhen Key Laboratory of Fertility Regulation The University of Hong Kong-Shenzhen HospitalShenzhenGuangdongChina.

The human endometrium and embryo both produce microRNAs(miRNAs),which are involved in various physiological activities.Accumulating evident suggested that endometrial miRNAs are regulated by steroid hormones that modulate endometrial functions,whereas embryo-derived miRNAs play vital roles in maternal–embryo communication.The aberrant expression of endometriumor embryo-derived miRNAs can cause early pregnancy and gestational disorders,including repeated implantation failure,recurrent miscarriage,and pathological conditions such as endometriosis.miRNAs are,therefore,ideal candidates for conducting clinicopathological tests.Potential diagnostic and prognostic tests using miRNAs are under development;however,the therapeutic applications of miRNAs in regulating gestational disorders require further investigation.

关键词： MicroRNAs endometrial receptivity Diagnostic biomarkers Therapeutic targets

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endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure

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Chinese Medical Journal 2017年第5期130卷 566-573页

作者： Cheng Shi Huan Shen Li-Juan Fan Jing Guan Xin-Bang Zheng Xi Chen Rong Liang Xiao-Wei Zhang Qing-Hua Cui Kun-Kun Sun Zhu-Ran Zhao Hong-Jing Han Reproductive Medical Center Peking University People's Hospital Beijing 100044 China Department of Urology Peking University People's Hospital Beijing 100044 China Department of Biomedical Informatics School of Basic Medical Sciences Peking University Beijing 100191 China Department of Pathology Peking University People's Hospital Beijing 100044 China Department of Paediatrics Peking University People's Hospital Beijing 100044 China

Background： At present, a diagnostic tool with high specificity for impaired endometrial receptivity, which may lead to implantation failure, remains to be developed. We aimed to assess the different endometrial microRNA （miRNA） signatures for impaired endometrial receptivity by microarray analysis. Methods： A total of 12 repeated implantation failure （RIF） patients and I0 infertile patients, who conceived and delivered after one embryo transfer attempt, were recruited as RIF and control groups, respectively. endometrial specimens from the window of implantation （WOI） were collected from these two groups. MiRNA microarray was conducted on seven and five samples from the RIF and control groups, respectively. Comparative, functional, and network analyses were performed for the microarray results. Quantitative real-time polymerase chain reaction （PCR） was performed on other samples to validate the expression of specific miRNAs. Results： Compared with those in the control group, the expression levels of 105 miRNAs in the RIF group were found to be significantly up- or down-regulated （at least 2-fold） by microarray analysis. The most relevant miRNA functional sets of these dysregulated miRNAs were miR-30 family, human embryonic stern cell regulation, epithelial-mesenchymal transition, and miRNA tumor suppressors by tool for annotations ofmicroRNA analysis. Network regulatory analysis found 176 miRNA-mRNA interactions, and the top 3 core miRNAs were has-miR-4668-5p, has-miR-429, and has-miR-5088. Expression levels of the 18 selected miRNAs in new samples by real-time PCR were found to be regulated with the same trend, as the result ofmicroarray analysis. Conclusions： There is a significant different expression of certain miRNAs in the WOI endometrium for RIF patients. These miRNAs may contribute to impaired endometrial receptivity.

关键词： Embryo Implantation endometrial receptivity MicroRNA Microarray Repeated Implantation Failure Window of Implantation

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