A Multicenter,randomized,double-blind,placebo-controlled Trial And Metabolomics Study On The Intervention Of TCM To Improve IVF Outcome In Advanced-age Patients

Objective: To observe the clinical efficacy of Qiziyusi Pills(QZ)using a multi-center,prospective,randomized,double-blind,placebocontrolled trial research method.And explore its possible mechanism from the perspective of targeted metabolomics.Methods: Subjects in this trial came from 5 reproductive centers in China.A total of 124 cases both undertook controlled ovulation stimulation with a short-acting long-term protocol.The test group was given QZ While the control group was given a placebo from the day of down-regulation till the day of egg retrieval.Unblinding the group belonging 35 days after embryo transfer,and analyze the data,compare the differences between two groups.The UPLC-MS/MS metabolomics platform was used to analyze and identify changes in the expression and content of specific metabolites in the follicular fluid of the two groups of patients.Key metabolic pathways were analyzed with Met PA.Results: 1.In terms of efficacy of TCM syndromes,scores of kidney Qi deficiency symptom were significantly lower than that in the control group.The difference was statistically significant(P<0.05).Such as lumbosacral soreness,dizziness and tinnitus,neurolysis,leucorrhea Increased,pale urine and increased urine output.Compared with the control group,the symptoms of decreased libido and scanty menstruation were improved,but the difference was not statistically significant.The total clinical effective rate of TCM syndrome of the test group was significantly higher than that of the control group.The difference was statistically significant(P<0.01).2.In terms of IVF outcomes,the cumulative pregnancy rate in the test group was significantly higher than that in the control group.The difference was statistically significant(P<0.05).The endometrial thickness at trigger day and the number of retrieved oocytes of the test group was significantly higher than that of the control group.The difference was statistically significant(P<0.05).IVF fertilization rate,ICSI fertilization rate,and quality embryo rate were better than the control group,but the difference was not statistically significant(P>0.05).3.Follicular fluid targeted metabolomics analysis confirmed 26 related metabolites,mainly divided into 6 categories of vitamins,amino acids,hormones,nucleotides,lipids,and protein degradation fragments.10 substances up-regulated,including Indoxyl,P-Cresol sulfate,Lyso PC161,Lthreonine,Inosine,Dehydroepiandrosterone sulfate,Citicoline＿2,13-Hydroxy-a-tocopherol,11-carboxy-α-chromanol,2-Acyl-sn-glycero-3-phosphocholine.And 16 substances down-regulated,including Lactate,Lformyl kynurenine,Pyruvic acid,Uric acid,Retinol acetate,Retinoic acid,Retinal,Progesterone,Indoleacetic acid,Leucine＿2,Hydroxy Retinoic acid),Glyoxylic acid,Creatine,Decanoyl carnitine,25-Hydroxyvitamin D3,2-Formylaminobenzaldehyde.4.Pathway analysis found the mechanism of TCM to improve the outcome of IVF assisted pregnancy mainly involves Glycine,serine and threonine metabolism,Pyruvate metabolism,Glycolysis/gluconeogenesis.Conclusion: QZ is significantly better than placebo for improving pregnancy outcomes in elderly patients with IVF.It is speculated that the mechanism is related to the regulation of the metabolism of some substances in follicular fluid.Mainly involves amino acid metabolism and energy metabolism.