| Objectives:1 Systematic evaluation of the effectiveness and safety of traditional Chinese medicine intervention in the treatment of low endometrial receptivity provides the best evidence for clinical treatment of low endometrial receptivity.2 Observe the effects of Erbuzhuyu decoction on patients with repeated IVF-ET failures(with 2 or more times superior embryo transfer),menstrual conditions,TCM syndromes,hormone levels,ultrasound parameters,blood rheology parameters,as well as the clinical pregnancy rate and embryo implantation rate.3 To study the effect of Erbuzhuyu decoction on endometrial receptivity of embryo implantation dysfunction mice,and to explore the mechanism and new target for improving the endometrial receptivity in terms of endometrial morphology and angiogenesis.Methods:1 Searching for a randomized controlled trial of repeated IVF-ET failures because of endometrial receptivity with Chinese herbal medicine treatment to January 2018.Two investigators screened independently and will be included in the study literature for evaluation,using the Revman5.3 provided by Cochrane to statistical analysis and descriptive analysis of data extracted from the literature.2 Using self-contrast test,we collected 30 cases with 2 or more times embryo transplantation failed(32 cases in total,of which 1 case was lost,1 case was not adhered to treatment).The patients with kidney deficiency and blood stasis syndrome,who were treated with Erbuzhuyu decoction for 1-3 treatment courses(1 menstrual cycle for a course of treatment,do not stop during the period).The patients' menstrual conditions and TCM syndromes were evaluated by scales.The menstrual conditions(quantity,colour,clot)scores and TCM syndrome scores before and after treatment were compared;the serum hormone levels,ultrasound parameters,and hemorheology indexes were compared before and after treatment.And the embryo implantation rate and clinical pregnancy rate of the patient who do IVF-ET again were observed.3 Indomethacin was used for embryo implantation dysfunciton mouse model.The animals were divided into the blank group,the model group,(low-dose,medium-dose,high-dose)Erbuzhuyu decoction groups,the progynova group and the aspirin group.Light microscope and electron microscope were used to observe the morphology of endometrium,endometrial ultrastructure and pinopodes in each group.qPCR,western blot and immunohistochemistry were used to detect the endometrial miR-126,PI3K mRNA,Akt mRNA,eNOS mRNA and VEGF mRNA in each group,and the expression and localization of p-PI3K,p-Akt and p-eNOS proteins;nitrate reductase techniques were used to test the expression of NO in mice in each group.Results:1 In the systematic evaluation of the effectiveness of traditional Chinese medicine for repeated IVF-ET failure of endometrial receptivityA total of 915 articles were retrieved,and the final 6 articles were included in the study,with 483 cases.The statistical results showed that the clinical pregnancy rate of Chinese medicine intervention group(OR=2.70,95%CI=1.81-4.01,P<0.00001),embryo implantation rate(OR=2.52,95%CI=1.59-3.99,P<0.0001),biochemistry Pregnancy rate(OR=3.60,95%CI=1.76-7.35,P=0.0005),endometrial thickness(WMD=0.68,95%CI=0.06-1.30,P=0.03)were higher than non-TCM intervention groups.Significantly;endometrial RI(WMD=-0.19,95%CI=-0.30--0.19,P=0.001)was lower than non-TCM intervention group;TCM syndrome was significantly improved compared with non-TCM intervention group(WMD=4.14,95%CI=2.63-5.66,P<0.00001).There was no significant difference in the rate of miscarriage,the proportion of type A and B endometrium,endometrial PI,and serum E2,P,and E2/P levels at the day of embryo transfer.None of the included studies described adverse drug reactions.2 Clinical study of Erbuzhuyu decoction on endometrial receptivity in patients with repeated IVF-ET failures(1)Menstruation condition and TCM syndroms:Erbuzhuyu decoction can improve menstruation condition(P<0.001)and kidney-deficiency and blood-stasis syndromes(P<0.05);(2)Serum hormone levels:Erbuzhuyu decoction can reduce the level of FSH,and increase the level of E2 in patients,but there is no significant difference(P>0.05);(3)Ultrosound parameters:Erbuzhuyu decoction can increase the thickness of the endometrium,proportion of type A endometrium,subendometrial blood flow and Salle scores(P<0.001).Bilateral uterine artery PI,RI and left uterine artery S/D were significantly lower than before treatment(P<0.001).(4)Hemorheology indexes:the prethrombotic state of 19 patients was detected.13 cases(68.42%,13/19)had abnormal increase of PAgT before treatment,and 1 case(5.26%,1/19)of D-Dimer increased abnormally.After treatment with Erbuzhuyu decoction,PAgT and D-Dimer decreased significantly(P<0.05),and AT-? increased compared with that before treatment,but there was no significant difference(P>0.05).(5)Embryo implantation rate and clinical rate:the embryo implantation rate was 40%,and clinical pregnancy rate was 33.33%.3 Experimental research of Erbuzhuyu decoction on endometrial receptivity in mouse model of embryo implantation dysfunction(1)Pregnancy rate and average number of implantation sites:there was no significant difference in the pregnancy rate of mice in each group(P>0.05);the number of mouse embryo implantation sites in the model group was less than that in the blank group(P<0.05),suggesting successful modeling.The average number of implantation sites in the medium-dose and high-dose groups of Erbuzhuyu decoction was higher than that in the model group(P<0.05),and there was no significant difference among Erbuzhuyu decoction groups,progynova group and aspirin group(P>0.05).(2)Morphology:Light microscopy and electron microscopy showed that the mouse endometrium in the model group became thin,the glands and blood vessels decreased,the ultrastructure of epithelial cells was destroyed,and the expression of pinopodes decreased or immature.Erbuzhuyu decoction can improve the endometrial morphology and the ultrastructure of endometrial epithelial cells during embryo implantation window,promote the expression and development of pinopodes.The scores of pinopodes in the medium-dose group of Erbuzhuyu decoction and the aspirin group were significantly higher than those in the model group(P<0.05).(3)miR-126,PI3K/Akt/eNOS pathway:? The expression of miR-126 in endometrium of mice in each group was not significantly different(P>0.05).The expression of PI3K mRNA and Akt mRNA in the model group was lower than that in the blank group,Erbuzhuyu decoction groups,progynova group,and aspirin group,of which low-dose group of Erbuzhuyu decoction had significant differences compared with the model group(P<0.05),and the expression of PI3K mRNA in low-dose group was significantly higher than that in the progynova group and the aspirin group(P<0.05),there was no significant difference in the expression of Akt mRNA among Erbuzhuyu decoction groups,the progynova group and the aspirin group(P>0.05).There was no significant difference in the expression of eNOS mRNA in the endometrium of each group(P>0.05).?The expression of p-PI3K,p-Akt and p-eNOS protein in the model group was significantly lower than that in the blank group(P<0.05).The p-PI3K,p-Akt,and p-eNOS protein levels in low-dose,medium-dose and high-dose groups of Erbuzhuyu decoction,the progynova group,and the aspirin group were higher than that in the model group(P<0.05),and the expression level of the p-Akt protein in the high-dose group was significantly higher than in the progynova group and the aspirin group(P<0.05).There were no significant differences in PI3K and eNOS protein levels between Erbuzhuyu decoction groups,the progynova group and the aspirin group(P>0.05).?Protein localization:The p-PI3K,p-Akt,and p-eNOS proteins in the model group showed weak positive expression in endometrial luminal epithelial cells,but no obvious expression in endometrial glandular cells and vascular epithelial cells.Proteins in the blank group,the Erbuzhuyu decoction groups,the progynova group,and the aspirin group were positively expressed in the endometrial cavity epithelium and vascular epithelium.(4)VEGF mRNA,NO:The expression of VEGF mRNA was lower in the model group than in the blank group,and the middle-dose group of Erbuzhuyu decoction was significantly higher than the model group(P<0.05),but there was no significant difference between the Erbuzhuyu decoction groups,the progynova group and the aspirin group(P>0.05).NO expression in the model group was significantly lower than that in the blank group(P<0.001),NO expression in low-dose group and high-dose group were significant higher than that in the model group(P<0.05),and there was no significant difference among Erbuzhuyu decoction groups,the progynova group and the aspirin group(P>0.05).Conclusion:1 In the systmatic review,the results showed that traditional Chinese medicine as an important adjuvant therapy can improve the clinical pregnancy outcome and endometrial receptivity of IVF-ET patients with repeated IVF-ET failure.However,due to the low quality of the included literature and lack of strong evidence,the results of this study need to be further verified in high-quality evidence.2 In the clinical studies,the results showed that Erbuzhuyu decoction did not significantly affect the level of hormones in patients,it can significantly improve menstruation in patients with recurrent IVF-ET failuers,make kidney deficiency and blood stasis syndrome better,increase endometrial thickness and blood supply,correct the prethrombosis status,improve successful rate of IVF-ET.3 In the experimental studies,the results showed that the Erbuzhuyu decoction can improve the uterine morphology in implantation window of mice with embryo implantation dysfunction,activate the PI3K/AKt/eNOS signaling pathway,increase the expression of NO and VEGF,promote angiogenesis at the maternal-fetal interface,and increase the endometrial capacity,which were beneficial to the implantation of embryos. |
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