补肾中药对超排卵周期子宫内膜容受性及整合素β3/骨桥蛋白时序表达的影响
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摘要
目的:观察补肾中药二至天癸颗粒对超排卵周期子宫内膜容受性、小鼠围着床期子宫内膜整合素β3及其配体骨桥蛋白时序表达的影响,探讨补肾中药改善子宫内膜容受性的机理。
方法:临床研究将64例进入体外受精-胚胎移植治疗周期的不孕患者随机分为两组,选用控制性超排卵方案,分别用二至天癸颗粒联合促性腺激素(治疗组,31例)和单用促性腺激素(对照组,33例)治疗,对两组患者中医证候积分变化、促性腺激素用量及用药天数、子宫内膜厚度及分型、子宫动脉搏动指数和阻力指数、子宫内膜血流、血清激素水平、优质卵率、受精率、优质胚胎率、移植胚胎数及临床妊娠率进行评定。实验研究以性成熟昆明种小鼠为研究对象,随机分为试验组(超排卵加二至天癸颗粒),对照组(超排卵)和正常组,于合笼第0天、第2天、第4天、第6天、第8天五个时间点取小鼠子宫内膜,采用原位杂交法,检测整合素β3及其配体骨桥蛋白mRNA的时序表达。
结果:
临床研究:治疗组与对照组,治疗前后中医肾虚证候积分差值比较,有统计学差异(P<0.01);两组促性腺激素用量及用药天数、人绒毛膜促性腺激素(HCG)注射日子宫内膜厚度比较,差异无统计学意义(P>0.05);两组HCG注射日子宫内膜分型、内膜及内膜下血流、子宫动脉搏动指数和阻力指数比较,差异有统计学意义(P<0.05);两组HCG注射日血清激素水平、优质卵率、受精率、优质胚胎率、移植胚胎数比较,差异无统计学意义(P>0.05);两组临床妊娠率比较,差异有统计学意义(P<0.05)。
实验研究:1.正常组小鼠整合素β3及其配体骨桥蛋白mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠之后逐渐上升,妊娠第4天(即小鼠胚胎着床当天)达到峰值,与其他时点比较有统计学意义(P<0.05),之后表达逐渐下降,妊娠第8天仍高于合笼日水平。2.对照组小鼠整合素β3 mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠第2天达到峰值,与其他时点比较有统计学意义(P<0.05),之后随着妊娠天数的增加而下降,妊娠第8天仍高于合笼日水平。3.对照组小鼠骨桥蛋白mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠之后逐渐上升,在妊娠第4天达到峰值,与其他时点比较有统计学意义(P<0.05),之后在子宫内膜的表达迅速下降,妊娠第6、8天降到较低水平。4.试验组小鼠整合素β3及其配体骨桥蛋白mRNA在围着床期子宫内膜上的时序表达规律类似于正常组,峰值较正常组略低,但差异无统计学意义(P>0.05)。5.对照组小鼠妊娠第2天整合素β3mRNA表达明显高于正常组,差异有统计学意义(P<0.01);第4、6天明显低于正常组,差异有统计学意义(P<0.05);第8天对照组略低于正常组,但差异无统计学意义(P>0.05)。6.对照组小鼠妊娠第4、6、8天骨桥蛋白mRNA表达明显低于正常组,差异有统计学意义(P<0.01)。7.正常组和试验组小鼠骨桥蛋白mRNA与整合素β3mRNA时序表达上呈正相关,二者峰值表达及曲线拟合一致;对照组骨桥蛋白mRNA与整合素β3mRNA整体上无相关性,二者峰值表达及曲线拟合不一致。
结论:1.在IVF-ET的控制性超排卵过程中,应用补肾中药二至天癸颗粒,在不影响临床诱导排卵疗效的前提下,可明显改善患者肾虚症状,增加子宫内膜血流灌注,改善子宫内膜容受性,进而提高临床妊娠率。2.整合素β3及其配体骨桥蛋白在围着床期子宫内膜的表达呈时间上高度一致性,二者协调表达可作为子宫内膜容受性建立和着床期开放的重要标志之一。3.超排卵可能影响整合素β3及其配体骨桥蛋白mRNA的时序表达,使整合素β3表达峰值提前,破坏整合素β3与骨桥蛋白表达的内在协调关系,从而影响子宫内膜容受性的建立。4.补肾中药可能通过调整整合素β3及其配体骨桥蛋白mRNA的时序表达,改善超排卵周期子宫内膜的容受性。5.研究结果为补肾中药在IVF-ET领域的应用提供科学依据,揭示了中医学“肾主生殖”的理论内涵。
Objective: To observe the effect of Erzhi Tiangui Granules(ETG) on endometrial reception and the temporal expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation in controlled ovarian hyperstimulation(COH) of mice,and explore the mechanism of Tranditional Chinese Medcine(TCM) nourishing the kidney in improving endometrial reception.
Method: 64 infertil women undergoing In vitro Fertilization and Embryo Transfer (IVF-ET) were randomized into test group,treated with ETG and gonadotropin (Gn)(31 cases),and control group,treated with Gn only(33 cases),to evaluate the syndrome points of TCM,the dose and days of Gn,thickness and type of endometrium,pulsatility index (PI) and resistent index (RI) of uterous artery,endometrial blood stream,hormone level in serum,high-quality oocyte rate,fertility rate,high-quality embryo rate,implanted embryo rate and the clinical pregnancy rate of both. In empirical study,sex mature Kunming female mice were randomized into test group,treated with COH and ETG,control group,treated with COH only,and normal group. Obtain the endometrium on day 0、2、4、6、8 of pregnancy(Pd0、Pd2、Pd4、Pd6、Pd8) apart to detect the temporal expression of endometrial beta3-integrin and its ligand osteopontin messenger ribonucleic acid (mRNA)in the way of in situ hybridization (ISH).
Results:
Clinical study:There are statistical significance before and after the treatment in the syndrome points of Kidney-deficiency(P<0.05),type of endometrium,PI and RI of uterous artery,endometrial and under- endometrial blood stream on HCG day(P<0.05), and the clinical pregnancy rate(P<0.05)of two groups;while not in the thickness of endometrium, dose and days of Gn,hormone level on HCG day,high-quality oocyte rate, fertility rate,high-quality embryo rate and implanted embryo rate(P>0.05).
Empirical study:1.The rule of expression of beta3-integrin and its ligand osteopontin mRNA on the peri-implantational endometrium of normol group mice: comparing to the low expression in non-pregnancy,it rised after pregnancy,topped on Pd4(i.e.the day of nidation) with statistical significance contrast with other time points(P<0.05)and decreased after that.The expression on Pd8 is still higher than that of non-pregnancy. 2.The rule of expression of beta3-integrin mRNA on the peri-implantational endometrium in control group:it was low in non-pregnancy,topped on Pd2 with statistical significance contrast with other time points(P<0.05)and decreased gradually according to the pregnancy and the expression on Pd8 is still higher than that of non-pregnancy.3.The rule of expression of osteopontin mRNA on the peri-implantational endometrium in control group: contrast with the low expression in non-pregnancy,it rised after pregnancy,topped on Pd4 with statistical significance contrast with other time points(P<0.05) and decreased gradually to a much lower level on Pd6 and Pd8.4.The rule of the temporal expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation in control group is similar to that of the normal group,the top was a little lower with no statistical significance.5.The expression of beta3-integrin mRNA of control group was obviously higher on Pd2,lower on Pd4 and Pd6 than normal group with statistical significance(P<0.05)and a little lower on Pd8 with no statistical significance(P>0.05).6.The expression of osteopontin mRNA was much lower in control group on Pd4,Pd6 and Pd8 than normal group with statistical significance(P<0.01).7.The temporal expression of osteopontin mRNA and beta3-integrin mRNA in normal group and test group are of positive correlation,the top expression and curve fitting of both are in concordance;while the osteopontin mRNA and beta3-integrin mRNA in control group have no correlation,and the top expression and curve fitting of both are in no concordance.
Conclusions: 1.The use of ETG in the COH of IVF-ET can improve syndroms of kidney-deficiency, increase blood supply of endometrium, ameliorate endometrial reception, raise the clinical pregnancy rate with no effect on the clinial COH.2.The expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation have high concordance in time,and the coordination of the two can be used as one marker of the endometrial reception.3.COH may have some effect on the temporal expression of endometrial beta3-integrin mRNA and its ligand osteopontin mRNA during peri-implantation , it can bringing forward the top of endometrial beta3-integrin expression,broke the inner coordination of beta3-integrin and its ligand osteopontin thus affected the establishment of endometrial reception.4.TCM nourishing the kidney can regulate the expression of endometrial beta3-integrin and its ligand osteopontin to improve endometrial reception in COH.5.Provide evidence for the application of TCM in IVF-ET.
方法:临床研究将64例进入体外受精-胚胎移植治疗周期的不孕患者随机分为两组,选用控制性超排卵方案,分别用二至天癸颗粒联合促性腺激素(治疗组,31例)和单用促性腺激素(对照组,33例)治疗,对两组患者中医证候积分变化、促性腺激素用量及用药天数、子宫内膜厚度及分型、子宫动脉搏动指数和阻力指数、子宫内膜血流、血清激素水平、优质卵率、受精率、优质胚胎率、移植胚胎数及临床妊娠率进行评定。实验研究以性成熟昆明种小鼠为研究对象,随机分为试验组(超排卵加二至天癸颗粒),对照组(超排卵)和正常组,于合笼第0天、第2天、第4天、第6天、第8天五个时间点取小鼠子宫内膜,采用原位杂交法,检测整合素β3及其配体骨桥蛋白mRNA的时序表达。
结果:
临床研究:治疗组与对照组,治疗前后中医肾虚证候积分差值比较,有统计学差异(P<0.01);两组促性腺激素用量及用药天数、人绒毛膜促性腺激素(HCG)注射日子宫内膜厚度比较,差异无统计学意义(P>0.05);两组HCG注射日子宫内膜分型、内膜及内膜下血流、子宫动脉搏动指数和阻力指数比较,差异有统计学意义(P<0.05);两组HCG注射日血清激素水平、优质卵率、受精率、优质胚胎率、移植胚胎数比较,差异无统计学意义(P>0.05);两组临床妊娠率比较,差异有统计学意义(P<0.05)。
实验研究:1.正常组小鼠整合素β3及其配体骨桥蛋白mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠之后逐渐上升,妊娠第4天(即小鼠胚胎着床当天)达到峰值,与其他时点比较有统计学意义(P<0.05),之后表达逐渐下降,妊娠第8天仍高于合笼日水平。2.对照组小鼠整合素β3 mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠第2天达到峰值,与其他时点比较有统计学意义(P<0.05),之后随着妊娠天数的增加而下降,妊娠第8天仍高于合笼日水平。3.对照组小鼠骨桥蛋白mRNA在围着床期子宫内膜的表达规律:合笼日表达较低,妊娠之后逐渐上升,在妊娠第4天达到峰值,与其他时点比较有统计学意义(P<0.05),之后在子宫内膜的表达迅速下降,妊娠第6、8天降到较低水平。4.试验组小鼠整合素β3及其配体骨桥蛋白mRNA在围着床期子宫内膜上的时序表达规律类似于正常组,峰值较正常组略低,但差异无统计学意义(P>0.05)。5.对照组小鼠妊娠第2天整合素β3mRNA表达明显高于正常组,差异有统计学意义(P<0.01);第4、6天明显低于正常组,差异有统计学意义(P<0.05);第8天对照组略低于正常组,但差异无统计学意义(P>0.05)。6.对照组小鼠妊娠第4、6、8天骨桥蛋白mRNA表达明显低于正常组,差异有统计学意义(P<0.01)。7.正常组和试验组小鼠骨桥蛋白mRNA与整合素β3mRNA时序表达上呈正相关,二者峰值表达及曲线拟合一致;对照组骨桥蛋白mRNA与整合素β3mRNA整体上无相关性,二者峰值表达及曲线拟合不一致。
结论:1.在IVF-ET的控制性超排卵过程中,应用补肾中药二至天癸颗粒,在不影响临床诱导排卵疗效的前提下,可明显改善患者肾虚症状,增加子宫内膜血流灌注,改善子宫内膜容受性,进而提高临床妊娠率。2.整合素β3及其配体骨桥蛋白在围着床期子宫内膜的表达呈时间上高度一致性,二者协调表达可作为子宫内膜容受性建立和着床期开放的重要标志之一。3.超排卵可能影响整合素β3及其配体骨桥蛋白mRNA的时序表达,使整合素β3表达峰值提前,破坏整合素β3与骨桥蛋白表达的内在协调关系,从而影响子宫内膜容受性的建立。4.补肾中药可能通过调整整合素β3及其配体骨桥蛋白mRNA的时序表达,改善超排卵周期子宫内膜的容受性。5.研究结果为补肾中药在IVF-ET领域的应用提供科学依据,揭示了中医学“肾主生殖”的理论内涵。
Objective: To observe the effect of Erzhi Tiangui Granules(ETG) on endometrial reception and the temporal expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation in controlled ovarian hyperstimulation(COH) of mice,and explore the mechanism of Tranditional Chinese Medcine(TCM) nourishing the kidney in improving endometrial reception.
Method: 64 infertil women undergoing In vitro Fertilization and Embryo Transfer (IVF-ET) were randomized into test group,treated with ETG and gonadotropin (Gn)(31 cases),and control group,treated with Gn only(33 cases),to evaluate the syndrome points of TCM,the dose and days of Gn,thickness and type of endometrium,pulsatility index (PI) and resistent index (RI) of uterous artery,endometrial blood stream,hormone level in serum,high-quality oocyte rate,fertility rate,high-quality embryo rate,implanted embryo rate and the clinical pregnancy rate of both. In empirical study,sex mature Kunming female mice were randomized into test group,treated with COH and ETG,control group,treated with COH only,and normal group. Obtain the endometrium on day 0、2、4、6、8 of pregnancy(Pd0、Pd2、Pd4、Pd6、Pd8) apart to detect the temporal expression of endometrial beta3-integrin and its ligand osteopontin messenger ribonucleic acid (mRNA)in the way of in situ hybridization (ISH).
Results:
Clinical study:There are statistical significance before and after the treatment in the syndrome points of Kidney-deficiency(P<0.05),type of endometrium,PI and RI of uterous artery,endometrial and under- endometrial blood stream on HCG day(P<0.05), and the clinical pregnancy rate(P<0.05)of two groups;while not in the thickness of endometrium, dose and days of Gn,hormone level on HCG day,high-quality oocyte rate, fertility rate,high-quality embryo rate and implanted embryo rate(P>0.05).
Empirical study:1.The rule of expression of beta3-integrin and its ligand osteopontin mRNA on the peri-implantational endometrium of normol group mice: comparing to the low expression in non-pregnancy,it rised after pregnancy,topped on Pd4(i.e.the day of nidation) with statistical significance contrast with other time points(P<0.05)and decreased after that.The expression on Pd8 is still higher than that of non-pregnancy. 2.The rule of expression of beta3-integrin mRNA on the peri-implantational endometrium in control group:it was low in non-pregnancy,topped on Pd2 with statistical significance contrast with other time points(P<0.05)and decreased gradually according to the pregnancy and the expression on Pd8 is still higher than that of non-pregnancy.3.The rule of expression of osteopontin mRNA on the peri-implantational endometrium in control group: contrast with the low expression in non-pregnancy,it rised after pregnancy,topped on Pd4 with statistical significance contrast with other time points(P<0.05) and decreased gradually to a much lower level on Pd6 and Pd8.4.The rule of the temporal expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation in control group is similar to that of the normal group,the top was a little lower with no statistical significance.5.The expression of beta3-integrin mRNA of control group was obviously higher on Pd2,lower on Pd4 and Pd6 than normal group with statistical significance(P<0.05)and a little lower on Pd8 with no statistical significance(P>0.05).6.The expression of osteopontin mRNA was much lower in control group on Pd4,Pd6 and Pd8 than normal group with statistical significance(P<0.01).7.The temporal expression of osteopontin mRNA and beta3-integrin mRNA in normal group and test group are of positive correlation,the top expression and curve fitting of both are in concordance;while the osteopontin mRNA and beta3-integrin mRNA in control group have no correlation,and the top expression and curve fitting of both are in no concordance.
Conclusions: 1.The use of ETG in the COH of IVF-ET can improve syndroms of kidney-deficiency, increase blood supply of endometrium, ameliorate endometrial reception, raise the clinical pregnancy rate with no effect on the clinial COH.2.The expression of endometrial beta3-integrin and its ligand osteopontin during peri-implantation have high concordance in time,and the coordination of the two can be used as one marker of the endometrial reception.3.COH may have some effect on the temporal expression of endometrial beta3-integrin mRNA and its ligand osteopontin mRNA during peri-implantation , it can bringing forward the top of endometrial beta3-integrin expression,broke the inner coordination of beta3-integrin and its ligand osteopontin thus affected the establishment of endometrial reception.4.TCM nourishing the kidney can regulate the expression of endometrial beta3-integrin and its ligand osteopontin to improve endometrial reception in COH.5.Provide evidence for the application of TCM in IVF-ET.
引文
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