Affect And Mechanism Of TGF-β1 In The Development Of PCOS

Background: Polycystic ovary syndrome(PCOS)causes complex and diverse symptoms.It is one of the main diseases causing infertility in women of childbearing age,mainly characterized by sparse ovulation or disturbance of glycolipid and sex hormone metabolism.Ovarian stroma fibrosis,thickening of the capsule,and abnormal follicular dysplasia are the main pathological changes that cause ovulation disorders,and the mechanism is still unclear.Current status of research: Previous studies have shown that Transforming growth factor-β1(TGF-β1)signaling pathway might be involved in various pathological changes of PCOS.Genetic studies have found that certain nucleotide polymorphisms in the TGF-β1 gene are associated with risk of PCOS.There is no evidence that TGF-β1 signaling pathway and related molecules are involved in PCOS ovarian fibrosis yet.Current evidence is not enough to prove that DPP4 inhibitor effects TGF-β1pathway in PCOS.Objectives: 1.To investigate the mechanism of regulation on TGF-β1 signaling pathway for PCOS by analyzing the effects of TGF-β1 signaling pathway on reproductive,metabolic and pathological changes in PCOS rats;2.To investigate the effects of TGF-β1 single nucleotide polymorphism(SNP)on PCOS by analyzing the genotype frequency and allele frequency of TGF-β1 gene rs4803457.Methods: 1.30 female rats were divided into blank control group,PCOS model group and Siglitin treatment group.After execution,the ovaries were analysed including the cell morphology and the proportion of collagen fibers in the interstitium.the serum of sex hormones,blood glucose and lipid were detected,including anti-Müllerian hormone(AMH),Luteinizing hormone(LH),Testosterone(T),follicle-stimulating hormone(FSH),Glucose(Glu),Insulin(INS)、Low density lipoprotein(LDL),High density lipoprotein(HDL),Triglyceride(TG)、Total Cholesterol(TC).The protein and mRNA expression of Dipeptidyl peptidase-4(DPP4),TGF-β1,Smad2/3 and Connection tissue growth factor(CTGF)in different ovarian cells were detected too.2.205 PCOS women and 207 healthy controls were selected.The genotype frequency and allele frequency of TGF-β1 gene rs4803457 in DNA were determined.Biochemical indicators(Glu,TC,INS)and sex hormones(T,LH,FSH)were detected.Results: 1.Structural disorder of ovarian were observed in rat model group.The tissue appeared typical polycystic changes.while the ovarian structure in treatment group is more regular.The proportion of type III collagen in each group of ovaries was higher than that of type I.The percentage of type III and type I collagen fibers in the model group was significantly higher than that in the control group and the treatment group.2.DPP4,TGF-β1,Smad2/3,CTGF protein can be expressed in rat ovarian stroma,ovarian membrane and granulosa cells,mainly in ovarian stroma,especially in model group;DPP4,TGF-β1,CTGF mRNA level in the model group was significantly higher than that in the control group and the treatment group.For the whole ovary,there was no significant difference in Smad2/3 protein and mRNA levels.However,in the ovarian stroma,the expression of Smad2/3 in the model group was significantly increased.The intensity of Smad3 expression was significantly attenuated in treatment group.3.There were no significant differences in TC,TG,LDL and LH/FSH between the three groups.The levers of AMH and T in the model group were higher than the control group,and the HDL was lower than the control group.Glu,INS,HOMA,and T in the treatment group were lower than those in the model group,and HDL was higher than the model group.4.The OR of TGF-β1 rs4803457 CC genotype was 1.903 and 95% CI(1.025-3.530)in obesity and non-obesity patients in PCOS group.Conclusions and prospects: The results suggest that TGF-β1 participates in the progress of PCOS ovarian pathology through TGF-β1/Smad2/3/CTGF signaling pathway,and DPP4 inhibitors can block this pathway,thereby reversing ovarian fibrosis and promoting ovulation,alleviate islet resistance and regulate the role of sex hormones.The single nucleotide polymorphism of TGF-β1 gene rs4803457 is associated with PCOS,and CC genotype may be a risk factor for PCOS obesity.