温肾活血方联合电针治疗肾虚血瘀型反复种植失败的随机对照研究

Effect of Wenshen Huoxue Decoction Combined with Electro-acupuncture in Treating Recurrent Implantation Failure Patients with Shen Deficiency Blood Stasis Syndrome:a Randomized Controlled Trial

目的 观察温肾活血方及电针对肾虚血瘀型反复种植失败(RIF)患者冻融胚胎移植周期妊娠结局的影响,探讨其对子宫内膜蜕膜化标记物的影响。方法 选取自2019年5月—2020年5月于上海市第一妇婴保健院生殖医学科行体外授精及解冻胚胎移植的肾虚血瘀证RIF患者,将符合纳入标准的160例患者按随机数字+信封法分为中药组、电针组、针药组及对照组,每组各40例。对照组选用自然周期或来曲唑促排或激素替代方案进行内膜准备,中药组在内膜准备阶段每日口服温肾活血方,电针组在内膜准备阶段隔日1次电针,针药组在内膜准备阶段予中药口服及电针治疗。比较4组种植窗期雌二醇(E2)和孕酮(P)及子宫内膜厚度、子宫内膜血流、移植后着床率、临床妊娠率及早期流产率,检测4组移植日宫腔组织中孕激素受体(PR)、同源框基因10(Hox10)及骨形态发生蛋白2(BMP2) mRNA表达水平,评价治疗前后生殖质量与中医证候积分。结果 针药组临床妊娠率、着床率均显著高于对照组(P<0.05)。35岁患者针药组临床妊娠率、着床率均显著高于对照组(P<0.05),中药组临床妊娠率明显高于对照组(P<0.05)。>35岁患者中电针组临床妊娠率、着床率均高于其余3组,但差异无统计学意义(P>0.05)。3个中西医结合治疗组流产率均低于对照组,但差异均无统计学意义(P>0.05)。治疗后4组种植窗口期E2及P水平差异均无统计学意义(P>0.05),子宫内膜厚度3个中西医结合治疗组均显著高于对照组(P<0.05),其中,针药组子宫内膜较中药组、电针组明显增厚(P<0.05)。治疗后3个中西医结合治疗组种植窗口期A型内膜比例均高于对照组,但差异无统计学意义(P>0.05)。3个中西医结合治疗组内膜下血管支数均高于对照组(P<0.05),其中针药组、电针组血管支数均高于中药组(P<0.05)。移植日宫腔内组织PR、Hox10、BMP2 mRNA相对表达量均高于对照组(P<0.05),其中针药组、电针组表达量明显高于中药组(P<0.05)。治疗前后3个中西医结合治疗组生殖质量评分与中医证候积分的差值均明显高于对照组(P<0.05)。结论 在内膜准备阶段给予温肾活血方联合电针疗法可以改善子宫内膜厚度及血供,中医肾虚血瘀症状及患者生育生活质量,提高RIF患者的着床率及临床妊娠率,降低流产风险。其机制可能与中医药治疗提高种植窗口期PR、Hox10及BMP2的表达,增强子宫内膜蜕膜化程度有关。

Objective To observe the effects of Wenshen Huoxue Decoction(WSHXD) combined with electro-acupuncture therap(EA) on the outcomes of frozen thawed embryo transfer and endometrial decidualization in recurrent implantation failure(RIF) patients with Shen deficiency blood stasis syndrome(SDBSS).Methods Totally 160 RIF patients with SDBSS at Reproductive Medicine Center of Shanghai First Maternity and Infant Hospital from May 2019 to May 2020 were randomly assigned to four groups:Herb group,EA group,Herb&EA group,and Control group,40 in each group.Patients in Control group chose natural cycle or letrozole cycle or hormone replacement cycle for endometrium preparation.Those in Herb group received WSHXD every day during endometrium preparation time.Those in EA group received EA therapy once every 2 days during endometrium preparation time.Those in Herb&EA group took WSHXD and received EA in the endometrial preparation stage.Estradiol(E2) and progesterone(P) levels,endometrial thickness,endometrial blood flow,implantation rate,clinical pregnancy rate,and early abortion rate were compared among the four groups.mRNA expressions of progesterone receptor(PR),homeobox genes10(Hox10),and bone morphogenetic protein2(BMP2) in uterine tissue of the four groups on the transplantation day were detected,and reproductive quality and TCM syndrome score before and after treatment were evaluated.Results The clinical pregnancy rate and implantation rate of Herb&EA group were significantly higher than those in Control group(P<0.05).In patients equal to or younger than 35,they were significantly higher in Herb&EA group than in Control group(P<0.05).When patients aged over 35 years,the implantation rate and clinical pregnancy rate were higher in EA group,but with no statistical differences as compared with the rest 3 groups(P>0.05).The abortion rate of the three TCM treatment groups was lower than that of Control group,but with no statistical difference(P>0.05).There were no significant differences in E2 or P levels in the four groups during the implantation window after treatment(P>0.05).The endometrial thickness in the three TCM treatment groups was significantly higher than that in Control group(P<0.05).Among them,endometrial thickness obviously thickened more in Herb&EA group than in Herb and EA group(P<0.05).After treatment the proportion of type A endometrium in the three TCM treatment groups was higher than that in Control group in the implantation window period,but with no statistical difference(P>0.05).The number of spiral arteries under endometrium in the three TCM groups was higher than that in Control group(P<0.05).Among them,the number of blood vessels of Herb and EA group was higher than Herb&EA group(P<0.05).The mRNA relative expression levels of PR,Hox10 and BMP2 in intrauterine tissue on transplantation day were higher than those in Control group(P<0.05).They were higher in EA group and Herb&EA group than in Herb group(P<0.05).Before and after treatment,the difference between reproductive quality score and TCM syndrome score in the three TCM treatment groups were significantly higher than those in Control group(P<0.05).Conclusions During the endometrial preparation stage,the combination of WSHXD and EA therapy improved the endometrial thickness and blood supply,the symptoms of SDBSS,and patients’ reproductive quality and quality of life,elevated the implantation rate and clinical pregnancy rate,and lowered the risk of abortion.The mechanism might be related to enhancing the expressions of PR,Hox10,and BMP2 during the implantation window period and accelerating decidualization of endometrium.