肾虚不孕IVF-ET卵泡液与子宫内膜相关细胞因子表达的研究
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摘要
生殖是人类生存延续的永恒主题,但由于近代各种因素的相互作用使生命之源的产生发生障碍,为了生殖过程的延续,辅助生育技术应运而生,并在二十多年的发展中日新月异,通过改进超排卵方案、提高卵子质量、发展实验室培养系统、开拓分子生物学技术等方面,以达到提高妊娠率,减少并发症,出生健康婴儿的辅助生育技术的最终目的。近五年来,中医药渗透入辅助生殖的各个环节,在诱导排卵,提高子宫内膜容受性,提高妊娠率,并有效地降低西药毒、副作用等方面有了长足的发展。二至天癸颗粒是经临床实践筛选出的促卵泡发育的有效中药方剂,具有补肾益天癸,养血调冲任之效。本课题以该方与现代辅助生殖技术相结合,采用现代生殖医学的相关观察指标,从临床研究和动物实验两个方面,对二至天癸颗粒在IVF-ET中应用的临床疗效及作用机理进行了系统探讨。
临床研究
背景:不孕不育症是影响育龄夫妇双方身心健康的世界性问题,据统计,在我国约有10%的育龄夫妇存在着生殖障碍,并有逐渐增加的趋势,体外受精-胚胎移植(IVF-ET)及其衍生技术为千万不孕不育夫妇带来了福音。但其临床妊娠率却一直未能尽如人意,徘徊于30%～40%之间。如何提高IVF-ET过程中卵细胞质量及改善子宫内膜容受性,进而提高临床妊娠率已成为众多学者关注的焦点问题。中医药在不孕不育的治疗方面有着悠久的历史,随着现代科学和医学的发展,临床研究日趋深入,研究的方法更加客观,治疗的手段更加科学。在大量总结前人经验,挖掘祖国医学医药宝库的基础上,不断探索新的途径。近年来结合现代辅助生殖技术,在诱导排卵、改善子宫内膜容受性,提高妊娠率,并有效地降低西药毒副作用等方面有了长足的发展,使中医药在辅助生殖中的应用,从理论和临床两方面均得到进一步丰富和完善。二至天癸颗粒是经临床实践筛选出的促卵泡发育的有效中药方剂,具有补肾益天癸,养血调冲任之效。前期研究显示,能提高卵细胞质量及改善子宫内膜容受性。
目的:采用生殖医学的相关观察指标,对二至天癸颗粒在IVF-ET中应用的临床疗效及作用机理进行了系统探讨。
方法:遵循随机对照原则,对符合纳入标准的66例因输卵管因素行IVF-ET的患者进行系统的临床观察,其中治疗组33例,33个治疗周期;对照组33例,33个治疗周期。采用IVF-ET治疗中目前常规应用的控制性超排卵长方案,治疗组在IVF治
Clinical StudyBackground: Along with social development, physical and mental infertility increasingly trouble couples worldwide. According to statistics, around the world there are 50-80 million persons with infertility. In our country, there are about 10% of couples of reproductive defects, and the incidence is showing a tendency to increase. Assisted reproductive technology (ART) including artificial insemination (AI), in vitro fertilization and embryo transfer (IVF-ET), and other derivative technologies, had been treated as "Gospel" by many infertile couples. Currently in the most advanced treatment centers, pregnancy rate of IVF is hovering between 30% and 40%, Britain and other developed countries are no exception. How to promote oocyte quality and endometrial receptivity has frequently become the focus of specialist's attention. Traditional Chinese Medicine (TCM) has a long history in treating infertility. Along with the development of modern science and medicine, the clinical studies on treating infertility with TCM tend to deepen every day. The way of study is more objective, the means of treatment more scientific. Combined with ART in recent years by inducing ovulation, improving endometrial receptivity, TCM had achieved considerable development. Erzhi Tiangui Granules is recipe made for treating infertility. It is efficacious in tonifying kidney, benefiting tiangui, nourishing blood and tonifying the Chong and Ren channels. It can promote oocyte quality and improve
endometrial receptivity in earlier study and has healed a lot of patients single or associated with western medicine. The long term clinical practice has proved that the medicine is effective for infertility, but combined with ART its exact mechanism remains further investigation.Object i ve: To explore the clinical effect and mechanism of Erzhi Tiangui Granules in infertility patients of Shenxu undergoing IVF-ET.Methods: Sixty-six infertile patients with tubal factors undergoing IVF-ET were divided into two groups at random, 33 cases in the study group treated with Erzhi Tiangui Granules and western medicine, and 33 cases in the control group were treated with gonadotropin-releasing hormone agonist (GnRH-a) and gonadotropin (Gn) alone. The long term protocol was adopted. The expression of IL-lp and IL-6 in follicular fluid on the day of retrieving oocyles were detected by EL1SA. and symptom scores, number of retrieved oocytcs. fertilization rate, high quality embryo rate and pregnancy rate were evaluated.Results: Symptoms of Shenxu in study group had been significantly improved. Fertilization rate in the two groups were similar, but high quality embryo rale and clinical pregnancy rate were significantly higher in study group. TCM can reduce the ampoules of Gn, regulate the expression of IL-lp in follicular fluid and improve the blood perfusion in endometrium and follicular theca.Cone I us i on: There are many western drugs used to ovarian stimulation in IVF-ET, which do indeed have good therapeutic effects, but many side effects can ensue. By treating the disease with combination of TCM and western medicine, not only can obtain better effects than that of western medicine alone, but also avoid the side effects which result from prolonged use of western medicine. The methods are simple and convenient. The cost is cheap and is easily accepted by the patients. According to symptom-sign differentiation, mechanism of down regulation in controlled ovarian hyperstimulation is ascribed as follows: The leading mechanism is insufficient of kidney Yin, blood stasis can be the production of the pathology. It is showed that Erzhi Tiangui Granules can promote oocyte quality and improve endometrial receptivity. The possible mechanism of combined therapy is that: ? Promoting oocyte maturation by regulating the level of IL-1 P expression in
follicular fluid: ! 2,Balancing the reproductive endocrine environment in controlled ovarian hyperstimulation cycle: (3)Benefiting follicular theca and endometrium perfusion in long term protocol.Experimental StudyBackground: Cytokines, a group of widespread heterogeneity secretion of the protein, are closely associated with functions of reproductive endocrine system through an autocrine/ paracrine manner. Studies found that there exists many cytokines in the follicular fluid. They regulate reproductive and immune response;play an important role in the oocyte maturation and ovulation. Recently, the study of embryo implantation has aroused reproductive biologists' special interest, and has been becoming a focal point and unsolved problem of the field of reproductive medicine. Cytokines are essential for oocyte development and embryo implantation may mediate the roles of ovarian estrogen and progesterone, regulate endometrial receptivity and embryo' implantation process. The expression of Interleukin-1 (IL-1) and leukemia inhibitory factor (LIF) in reproductive system are generally accepted as the markers to evaluate oocyte quality, fertilization and endometrial receptivity. IL-1 represents two polypeptides, IL-1 a and IL-lp\ It regulates the physiological functions of ovary, mediates the interaction between preimplantation embryo and uterus, and participates in embryonic implantation, decidualization and parturition. LIF was first found in 60s. In 1988, that LIF can inhibit differentiation of embryonic stem cells that have multi-directional growth potentials was proved. From then on, large amount of researchers were made in order to find out its special functions in reproduction.The researchers have focused their attention on the macro mechanism of TCM in treating infertility, such as the effect on HPOA. Reports that concerned with the factors of ovary and endometrium are fewer. From the perspective of cytokines, our study want to answer two questions: On the one hand , combined with ART, TCM has a satisfactory regulating effect on reproductive system with multifunction and unique advantage;on the
other hand, the traditional Chinese Gynecology theory can be made a extensive study to molecular level and the research approach will be abundance by ART.Objective: To study the effect of Erzhi Tiangui Granules combined with ovarian stimulation on the expression of IL-l(3mRNA and LIFmRNA in mouse and the molecular mechanism of TCM in improving endometrial receptivity.Methods: Thirty mice were allocated into three groups randomly, ?normal group (group NS), performed abdomen injection with 0.9% salt solution of same volume as model group and study group on the same time schedule;?model group (group HMG+HCG), HMG and HCG were given for ovarian stimulation;(3) study group (group TCM+HMG+HCG): Erzhi Tiangui Granules combined with HMG and HCG were given. After cohabiting, vaginal plug was found on the second morning. It can be seen as pregnant 1 day (Di). On pregnant 4 days (D4), the samples of mice endometrium were collected, endometrial thickness, the size of gland and glandular lumen were investigated by light microscope with computerized multi-functional image analyzer, and the expression of LIFmRNA and IL-ipmRNA in the endometrium of D4 mice was detected by reverse transcription polymerase chain reaction analysis (RT-PCR).Results: CDThere was no significantly difference in endometrial thickness between three groups. Comparing to the normal group, delayed endometrial maturation was frequently found in group of HMG+HCG, the non-synchronistic development of gland epithelium and stroma cells, namely, pesudostratified glandular epithelium and predecidual changes of stroma cells were seen at same time in model group. Combined with Erzhi Tiangui Granules, the size of gland and glandular lumen were significantly larger than those in model group, and were similar to normal group. Therefore the protocol with HMG had a negative effect on endometrial histological structure, and Chinese medicine of tonifying kidney can down regulate this effection. (2) It showed that the level of IL-ipmRNA expression in the endometrium during implantation window was 0.41+0.17 in model group, significantly lower than that in normal group (0.62 + 0.18), but without a significant difference between the study group (0.59 + 0.22). It maybe was related to the small sample size and requires further study. (3) RT-PCR showed that the relative quantity of LIFmRNA
expression was 0.32 + 0.14 in model group, significantly lower than that in the normal group (0.56 + 0.12) , with a significant difference between the study group, and without a significant difference between the study group and the normal groups. Erzhi Tiangui Granules can effectively increase the LIFmRNA expression in mice endometrium during implantation window, and the mechanism may be related to the endocrine of endometrium though a paracrine manner.Conclusion: It showed that TCM can improve the morphological index in mice endometrial tissue during implantation window under stimulation and increase LIFmRNA expression in mice endometrium during implantation window though a paracrine manner. Chinese herbs of tonifying kidney had a satisfactory global regulating effect on the reproductive system with multifunction and unique advantage. It can ameliorate genital-endocrine environment and adjust potential homeostasis in patients under going IVF. The information obtained from this experiment would be beneficial to understand the Tiaojingzhongzi theory of traditional Chinese Gynecology. Erzhi Tiangui Granules could play its effect synergistically with gonadotropins under IVF procedures. The use of TCM provides a new^pproach to ART and is a new trend in treating infertility which has shown a higher clinical value. TCM has the broad prospects in this field, and it is worthy of further studying.
临床研究
背景:不孕不育症是影响育龄夫妇双方身心健康的世界性问题,据统计,在我国约有10%的育龄夫妇存在着生殖障碍,并有逐渐增加的趋势,体外受精-胚胎移植(IVF-ET)及其衍生技术为千万不孕不育夫妇带来了福音。但其临床妊娠率却一直未能尽如人意,徘徊于30%～40%之间。如何提高IVF-ET过程中卵细胞质量及改善子宫内膜容受性,进而提高临床妊娠率已成为众多学者关注的焦点问题。中医药在不孕不育的治疗方面有着悠久的历史,随着现代科学和医学的发展,临床研究日趋深入,研究的方法更加客观,治疗的手段更加科学。在大量总结前人经验,挖掘祖国医学医药宝库的基础上,不断探索新的途径。近年来结合现代辅助生殖技术,在诱导排卵、改善子宫内膜容受性,提高妊娠率,并有效地降低西药毒副作用等方面有了长足的发展,使中医药在辅助生殖中的应用,从理论和临床两方面均得到进一步丰富和完善。二至天癸颗粒是经临床实践筛选出的促卵泡发育的有效中药方剂,具有补肾益天癸,养血调冲任之效。前期研究显示,能提高卵细胞质量及改善子宫内膜容受性。
目的:采用生殖医学的相关观察指标,对二至天癸颗粒在IVF-ET中应用的临床疗效及作用机理进行了系统探讨。
方法:遵循随机对照原则,对符合纳入标准的66例因输卵管因素行IVF-ET的患者进行系统的临床观察,其中治疗组33例,33个治疗周期;对照组33例,33个治疗周期。采用IVF-ET治疗中目前常规应用的控制性超排卵长方案,治疗组在IVF治
Clinical StudyBackground: Along with social development, physical and mental infertility increasingly trouble couples worldwide. According to statistics, around the world there are 50-80 million persons with infertility. In our country, there are about 10% of couples of reproductive defects, and the incidence is showing a tendency to increase. Assisted reproductive technology (ART) including artificial insemination (AI), in vitro fertilization and embryo transfer (IVF-ET), and other derivative technologies, had been treated as "Gospel" by many infertile couples. Currently in the most advanced treatment centers, pregnancy rate of IVF is hovering between 30% and 40%, Britain and other developed countries are no exception. How to promote oocyte quality and endometrial receptivity has frequently become the focus of specialist's attention. Traditional Chinese Medicine (TCM) has a long history in treating infertility. Along with the development of modern science and medicine, the clinical studies on treating infertility with TCM tend to deepen every day. The way of study is more objective, the means of treatment more scientific. Combined with ART in recent years by inducing ovulation, improving endometrial receptivity, TCM had achieved considerable development. Erzhi Tiangui Granules is recipe made for treating infertility. It is efficacious in tonifying kidney, benefiting tiangui, nourishing blood and tonifying the Chong and Ren channels. It can promote oocyte quality and improve
endometrial receptivity in earlier study and has healed a lot of patients single or associated with western medicine. The long term clinical practice has proved that the medicine is effective for infertility, but combined with ART its exact mechanism remains further investigation.Object i ve: To explore the clinical effect and mechanism of Erzhi Tiangui Granules in infertility patients of Shenxu undergoing IVF-ET.Methods: Sixty-six infertile patients with tubal factors undergoing IVF-ET were divided into two groups at random, 33 cases in the study group treated with Erzhi Tiangui Granules and western medicine, and 33 cases in the control group were treated with gonadotropin-releasing hormone agonist (GnRH-a) and gonadotropin (Gn) alone. The long term protocol was adopted. The expression of IL-lp and IL-6 in follicular fluid on the day of retrieving oocyles were detected by EL1SA. and symptom scores, number of retrieved oocytcs. fertilization rate, high quality embryo rate and pregnancy rate were evaluated.Results: Symptoms of Shenxu in study group had been significantly improved. Fertilization rate in the two groups were similar, but high quality embryo rale and clinical pregnancy rate were significantly higher in study group. TCM can reduce the ampoules of Gn, regulate the expression of IL-lp in follicular fluid and improve the blood perfusion in endometrium and follicular theca.Cone I us i on: There are many western drugs used to ovarian stimulation in IVF-ET, which do indeed have good therapeutic effects, but many side effects can ensue. By treating the disease with combination of TCM and western medicine, not only can obtain better effects than that of western medicine alone, but also avoid the side effects which result from prolonged use of western medicine. The methods are simple and convenient. The cost is cheap and is easily accepted by the patients. According to symptom-sign differentiation, mechanism of down regulation in controlled ovarian hyperstimulation is ascribed as follows: The leading mechanism is insufficient of kidney Yin, blood stasis can be the production of the pathology. It is showed that Erzhi Tiangui Granules can promote oocyte quality and improve endometrial receptivity. The possible mechanism of combined therapy is that: ? Promoting oocyte maturation by regulating the level of IL-1 P expression in
follicular fluid: ! 2,Balancing the reproductive endocrine environment in controlled ovarian hyperstimulation cycle: (3)Benefiting follicular theca and endometrium perfusion in long term protocol.Experimental StudyBackground: Cytokines, a group of widespread heterogeneity secretion of the protein, are closely associated with functions of reproductive endocrine system through an autocrine/ paracrine manner. Studies found that there exists many cytokines in the follicular fluid. They regulate reproductive and immune response;play an important role in the oocyte maturation and ovulation. Recently, the study of embryo implantation has aroused reproductive biologists' special interest, and has been becoming a focal point and unsolved problem of the field of reproductive medicine. Cytokines are essential for oocyte development and embryo implantation may mediate the roles of ovarian estrogen and progesterone, regulate endometrial receptivity and embryo' implantation process. The expression of Interleukin-1 (IL-1) and leukemia inhibitory factor (LIF) in reproductive system are generally accepted as the markers to evaluate oocyte quality, fertilization and endometrial receptivity. IL-1 represents two polypeptides, IL-1 a and IL-lp\ It regulates the physiological functions of ovary, mediates the interaction between preimplantation embryo and uterus, and participates in embryonic implantation, decidualization and parturition. LIF was first found in 60s. In 1988, that LIF can inhibit differentiation of embryonic stem cells that have multi-directional growth potentials was proved. From then on, large amount of researchers were made in order to find out its special functions in reproduction.The researchers have focused their attention on the macro mechanism of TCM in treating infertility, such as the effect on HPOA. Reports that concerned with the factors of ovary and endometrium are fewer. From the perspective of cytokines, our study want to answer two questions: On the one hand , combined with ART, TCM has a satisfactory regulating effect on reproductive system with multifunction and unique advantage;on the
other hand, the traditional Chinese Gynecology theory can be made a extensive study to molecular level and the research approach will be abundance by ART.Objective: To study the effect of Erzhi Tiangui Granules combined with ovarian stimulation on the expression of IL-l(3mRNA and LIFmRNA in mouse and the molecular mechanism of TCM in improving endometrial receptivity.Methods: Thirty mice were allocated into three groups randomly, ?normal group (group NS), performed abdomen injection with 0.9% salt solution of same volume as model group and study group on the same time schedule;?model group (group HMG+HCG), HMG and HCG were given for ovarian stimulation;(3) study group (group TCM+HMG+HCG): Erzhi Tiangui Granules combined with HMG and HCG were given. After cohabiting, vaginal plug was found on the second morning. It can be seen as pregnant 1 day (Di). On pregnant 4 days (D4), the samples of mice endometrium were collected, endometrial thickness, the size of gland and glandular lumen were investigated by light microscope with computerized multi-functional image analyzer, and the expression of LIFmRNA and IL-ipmRNA in the endometrium of D4 mice was detected by reverse transcription polymerase chain reaction analysis (RT-PCR).Results: CDThere was no significantly difference in endometrial thickness between three groups. Comparing to the normal group, delayed endometrial maturation was frequently found in group of HMG+HCG, the non-synchronistic development of gland epithelium and stroma cells, namely, pesudostratified glandular epithelium and predecidual changes of stroma cells were seen at same time in model group. Combined with Erzhi Tiangui Granules, the size of gland and glandular lumen were significantly larger than those in model group, and were similar to normal group. Therefore the protocol with HMG had a negative effect on endometrial histological structure, and Chinese medicine of tonifying kidney can down regulate this effection. (2) It showed that the level of IL-ipmRNA expression in the endometrium during implantation window was 0.41+0.17 in model group, significantly lower than that in normal group (0.62 + 0.18), but without a significant difference between the study group (0.59 + 0.22). It maybe was related to the small sample size and requires further study. (3) RT-PCR showed that the relative quantity of LIFmRNA
expression was 0.32 + 0.14 in model group, significantly lower than that in the normal group (0.56 + 0.12) , with a significant difference between the study group, and without a significant difference between the study group and the normal groups. Erzhi Tiangui Granules can effectively increase the LIFmRNA expression in mice endometrium during implantation window, and the mechanism may be related to the endocrine of endometrium though a paracrine manner.Conclusion: It showed that TCM can improve the morphological index in mice endometrial tissue during implantation window under stimulation and increase LIFmRNA expression in mice endometrium during implantation window though a paracrine manner. Chinese herbs of tonifying kidney had a satisfactory global regulating effect on the reproductive system with multifunction and unique advantage. It can ameliorate genital-endocrine environment and adjust potential homeostasis in patients under going IVF. The information obtained from this experiment would be beneficial to understand the Tiaojingzhongzi theory of traditional Chinese Gynecology. Erzhi Tiangui Granules could play its effect synergistically with gonadotropins under IVF procedures. The use of TCM provides a new^pproach to ART and is a new trend in treating infertility which has shown a higher clinical value. TCM has the broad prospects in this field, and it is worthy of further studying.
引文
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