多囊卵巢综合征内皮细胞损伤及活血化瘀法对其影响
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摘要
【研究目的】
多囊卵巢综合征(polycystic ovarian syndrome,PCOS)长期以来被公认是一个异质性综合征,主要表现为无排卵型月经异常、不育、多毛、痤疮、肥胖和卵巢多囊性变。PCOS近期引起月经失调、多毛、肥胖、不孕等临床后果,并导致产科结局不良:自然流产、妊娠糖尿病、妊娠高血压疾病、多胎妊娠等;远期增加心血管疾病、非胰岛素依赖性糖尿病和子宫内膜癌等疾病的发生率。PCOS的远期并发症主要与胰岛素异常及高雄激素水平有关。现胰岛素的血管活性作用已引起人们的广泛关注,一旦血管内皮细胞受损,内皮细胞内分泌功能紊乱,机体就有可能产生血液循环障碍、血栓形成等病理状态。
中医药对于PCOS临床应用研究很多,但直接观察内皮损伤以及舒缩功能的研究尚匮乏。导师张玉珍教授致力于中医药治疗PCOS研究多年,根据大量的临床实践总结出在辨证施治的同时,适当佐以活血化瘀,有助于提高疗效。因此,在导师的指导下,本研究旨在从临床观察和实验两个途径,寻求PCOS存在血瘀的微观证据,从细胞水平探讨PCOS血瘀发生与活血化瘀机理,观察中药对PCOS内皮细胞的影响,以便从内皮细胞的角度,探讨中医辨证治疗PCOS对于预防其远期并发症的重要意义,从而进一步体现“未病先防,已病防变”的思想。
【研究方法】
1.临床研究根据纳入病例标准和排除病例标准选择PCOS患者58例,其中肥胖者18例,非肥胖者40例。肾虚证18例,痰湿阻滞证18例,肝经郁火证16例,气滞血瘀证6例。选择月经规律的健康成年女性15例作为正常对照组。在辨证基础上选加活血化瘀药当归、川芎、桃仁等。肾虚证组予益肾调冲活血,基础方选归肾丸合桃红四物汤加减;痰湿阻滞证组予补肾健脾、化痰活血,方选苍附导痰丸加减;肝经郁火组予泻肝清热、活血调经,方选丹栀逍遥散加减;气滞血瘀证组予理气活血、祛瘀通经,方选膈下逐瘀汤加减。观察治疗前后患者月经周期、妊娠情况的变化;采用电化学发光法测定治疗前后血清卵泡刺激素(FSH)、黄体生成素(LH)、雌二醇(E_2)、总睾酮(T);用放射免疫分析法(RIA)测定治疗前后胰岛素(INS)、血浆内皮素(ET)水平。
2.实验研究依照Poretsky法建立PCOS大鼠模型,观察归肾丸合桃红四物汤对PCOS大鼠模型主动脉血管内皮细胞形态、超微结构态及功能的影响,并设立归肾丸组、二甲双胍组作对照。测定各组血清FSH、LH、T、INS及血浆ET、PAI-1的水平,光镜观察卵巢病理改变,电镜观察内皮细胞形态及超微结构变化。
[Objective]PCOS is a syndrome characterized by anovulation irregular or absent menstruation], infertility, obesity, excess hair growth, and acne. The causes of PCOS are compLicated, there are various theories about etiology, none of which can elucidate the abnormal manifestations of PCOS. Insulin resistance accompanied by compensatory hyperinsulinemia as well as hyperandrogenism are believed to be the main characteristics of PCOS.PCOS can cause symptoms of irregular menstrual cycle, infertility, hirsutism, and obesity ect. Causing obstetrical disorders such as natural abortion, gestational diabetes mellitus, raising the risk of cardiovascular disease, noninsulin-dependent diabetes mellitus and endometrial carcinoma. Morbid insulin and hyperandrogenism are associated with some potential complications. The vasoactive action of insulin has been extensively focused on . The damage of endothelial cell in the vessels will lead to disorders of endocrine function, thus resulting in such pathological conditions as disturbed blood circulation and thrombosis, ect.TCM, which has been studied a lot in the clinical treatment of pcos, is still lack of study on direct observation of endothelial damage and vasoactive function. Professor zhang yu-zhen has been addressing herself to the treatment of PCOS with Chinese herbs for many years, and has summarized that treatment based on syndrome differentiation accompanied by using Chinese herbs for activating blood stasis could improve the clinical efficiency. This study aims to seek the microscopic evidence of blood stasis in PCOS, discuss the mechanism of blood stasis causing PCOS and stimulate circulation to end stasis, observe the effect of Chinese herbs on endothelial cells, so as to detect the significance of TCM treating PCOS and preventing its complications, as well as reflecting a theory in TCM of preventive treatment disease.
[method]1.58 cases with PCOS were selected, 18 of whom were overweight, 40 nonoverweight. According to syndrome differentiation, 18 cased are of kidney asthenia, 18 cases of phlegm and dampness, 16 of dampness heat accumulating the liver, 6 stagnation of qi and blood. 15 healthy female adults with regular menstruation were grouped into the control group. The kidney asthenia group were treated with modified yougui bolus with taohong siwu decoction, which is composed of tusizi duzhong shudi gouqizi danggui fuling shanyao shanyurou chuanxiong taoren. The therapeutic method of invigorating the kidney and spleen, reducing phlegm and activate blood was used in treating phlegm and dampness group, with modified cangfu daotan Bolus composed of cangzhu xiangfu banxia fuling chenpi huangqi danggui xianlingpi chuanxiong.The group of damp heat accumulating the liver were treated with modified danzhixiaoyao powder functioning to clear liver fire and remove damp, which is composed of danpi zhizi danggui shengdi baishao fuling zaojiaoci chaihu taoren etc. The group of qi stagnation and blood stasis were treated with modified gexiazhuyu decoction functioning to regulating qi and blood , which is composed of danggui chaunxiong chishao taoren zhiqiao xiangfu wuyao gancao etc. Observe the changes before and after the treatment of the patients;measure the serum level of FSH, LH, E2, T with electro-chemiluminescence and assay the concentration of insulin and plasma ET before and after treatment with radioimmunoassay.2.rat models of PCOS have been established according Poretsky, with the purpose of observing the effect of Guishen Bolus and Taohongsiwu Decoction on the shape and function of the endothelial cells in rat aorta. Cemitidine and Taohongsiwu Decoction was used in the control group. Measure the serum level of FSH, LH, T, INS and plasma ET PAI-1, and observe the endothelial cell morph.[results]1.clinical results(1)20 cases regain their normal menstruation, 14 of whose menstrual period is within 40days, 9 within 3months, 15 cases without any changes, the total efficiency rate is 74.1%;the rate of regaining normal BBT is 46. 9%. The results show that Chinese herbs can efficiently correct the menstrual irregularity, stimulate the ovulation, thus raising the pregnancy rate and lowering the
incidence of natural abortion after conception.(2)After treatment based on syndrome differentiation, the level of LH, T, LH/ T, INS, ET in each group decreased obviously and the level of E2 increased obviously, both of which showed the significant difference (KO. 05)2. experimental results(l)In the control group, group of Guishen bolus and Taohongsiwu Decoction, the endothelial cells appear flat, arranging along the long axis of the blood vessels, normal endothelial cell integrity with scanty cytoplasm and the microscopic appearance shows highly developed golgiosome rough endoplasmic reticulum and smooth endoplasmic reticulum. In the model group, Cemitidine group and Taohongsiwu Decoction group, the endothelia cells of the rat aorta were contracted, with discontinuous basement membrane, inflated chondriosome, the middle layer smooth muscles tending to move inside and out of the normal shape of intraendothelial junction.(2)The groups which were respectively treated with Taohongsiwu Decoction and Cemitidine have a significantly lower serum level of L^ T> INS> PAI-I ET than those of the model group(KO. 05). There were no significant difference between the healthy group and the group of Taohongsiwu Decoction(/>0.05);and were significant difference between the model group and the group of Taohongsiwu Decoction(/<0. 05). Compared to the model group, the decreased level of INS in Cemitidine treatment group showed the significant difference (K0. 05), compared to the high-dosage group of Taohongsiwu Decoction , it showed no significant difference (/M). 05). Respectively compared to the model group and the group of Taohongsiwu Decoction with Guishen Bolus, the decreased level of PAI-I> ET in Cemitidine treatment group showed the significant difference (K0.05).^conclusion!1. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can effectively correct irregular menstruation and stimulate ovulation, thus raising the possibility of pregnancy.2. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can improve the endocrine function of patients with PCOS and lower the serum level of LH, T, LH, FSH., which indicate that
Chinese herbs can regulate the endocrine function of the ovaries and be helpful in promoting pregnancy.3. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can regulate the serum level of INS ET, which indicates that Chinese herbs has the function of correcting insulin resistance and preventing the endothelial cells from injury.4. The morphologic changes of the endothelial cells and increase of ET INS are found in the PCOS model rat, indicating blood stasis is one pathogenesis of PCOS.5. Guishen Bolus and Taohongsiwu Decoction , which morphologically repair damaged endothelial cells, regulate their functions, and correct insulin resistance , are of great importance for complication prevention.This study mainly discusses blood stasis involved in pcos in the light of endothelium and detect the effect of Chinese herbs on endothelial cells in pcos for the first time, results show that Chinese herbs have the function of regulating the menstruation to raise the possibility of pregnacncy, repairing the damaged endothelial cells as well as preventing the potential compications of pcos.
多囊卵巢综合征(polycystic ovarian syndrome,PCOS)长期以来被公认是一个异质性综合征,主要表现为无排卵型月经异常、不育、多毛、痤疮、肥胖和卵巢多囊性变。PCOS近期引起月经失调、多毛、肥胖、不孕等临床后果,并导致产科结局不良:自然流产、妊娠糖尿病、妊娠高血压疾病、多胎妊娠等;远期增加心血管疾病、非胰岛素依赖性糖尿病和子宫内膜癌等疾病的发生率。PCOS的远期并发症主要与胰岛素异常及高雄激素水平有关。现胰岛素的血管活性作用已引起人们的广泛关注,一旦血管内皮细胞受损,内皮细胞内分泌功能紊乱,机体就有可能产生血液循环障碍、血栓形成等病理状态。
中医药对于PCOS临床应用研究很多,但直接观察内皮损伤以及舒缩功能的研究尚匮乏。导师张玉珍教授致力于中医药治疗PCOS研究多年,根据大量的临床实践总结出在辨证施治的同时,适当佐以活血化瘀,有助于提高疗效。因此,在导师的指导下,本研究旨在从临床观察和实验两个途径,寻求PCOS存在血瘀的微观证据,从细胞水平探讨PCOS血瘀发生与活血化瘀机理,观察中药对PCOS内皮细胞的影响,以便从内皮细胞的角度,探讨中医辨证治疗PCOS对于预防其远期并发症的重要意义,从而进一步体现“未病先防,已病防变”的思想。
【研究方法】
1.临床研究根据纳入病例标准和排除病例标准选择PCOS患者58例,其中肥胖者18例,非肥胖者40例。肾虚证18例,痰湿阻滞证18例,肝经郁火证16例,气滞血瘀证6例。选择月经规律的健康成年女性15例作为正常对照组。在辨证基础上选加活血化瘀药当归、川芎、桃仁等。肾虚证组予益肾调冲活血,基础方选归肾丸合桃红四物汤加减;痰湿阻滞证组予补肾健脾、化痰活血,方选苍附导痰丸加减;肝经郁火组予泻肝清热、活血调经,方选丹栀逍遥散加减;气滞血瘀证组予理气活血、祛瘀通经,方选膈下逐瘀汤加减。观察治疗前后患者月经周期、妊娠情况的变化;采用电化学发光法测定治疗前后血清卵泡刺激素(FSH)、黄体生成素(LH)、雌二醇(E_2)、总睾酮(T);用放射免疫分析法(RIA)测定治疗前后胰岛素(INS)、血浆内皮素(ET)水平。
2.实验研究依照Poretsky法建立PCOS大鼠模型,观察归肾丸合桃红四物汤对PCOS大鼠模型主动脉血管内皮细胞形态、超微结构态及功能的影响,并设立归肾丸组、二甲双胍组作对照。测定各组血清FSH、LH、T、INS及血浆ET、PAI-1的水平,光镜观察卵巢病理改变,电镜观察内皮细胞形态及超微结构变化。
[Objective]PCOS is a syndrome characterized by anovulation irregular or absent menstruation], infertility, obesity, excess hair growth, and acne. The causes of PCOS are compLicated, there are various theories about etiology, none of which can elucidate the abnormal manifestations of PCOS. Insulin resistance accompanied by compensatory hyperinsulinemia as well as hyperandrogenism are believed to be the main characteristics of PCOS.PCOS can cause symptoms of irregular menstrual cycle, infertility, hirsutism, and obesity ect. Causing obstetrical disorders such as natural abortion, gestational diabetes mellitus, raising the risk of cardiovascular disease, noninsulin-dependent diabetes mellitus and endometrial carcinoma. Morbid insulin and hyperandrogenism are associated with some potential complications. The vasoactive action of insulin has been extensively focused on . The damage of endothelial cell in the vessels will lead to disorders of endocrine function, thus resulting in such pathological conditions as disturbed blood circulation and thrombosis, ect.TCM, which has been studied a lot in the clinical treatment of pcos, is still lack of study on direct observation of endothelial damage and vasoactive function. Professor zhang yu-zhen has been addressing herself to the treatment of PCOS with Chinese herbs for many years, and has summarized that treatment based on syndrome differentiation accompanied by using Chinese herbs for activating blood stasis could improve the clinical efficiency. This study aims to seek the microscopic evidence of blood stasis in PCOS, discuss the mechanism of blood stasis causing PCOS and stimulate circulation to end stasis, observe the effect of Chinese herbs on endothelial cells, so as to detect the significance of TCM treating PCOS and preventing its complications, as well as reflecting a theory in TCM of preventive treatment disease.
[method]1.58 cases with PCOS were selected, 18 of whom were overweight, 40 nonoverweight. According to syndrome differentiation, 18 cased are of kidney asthenia, 18 cases of phlegm and dampness, 16 of dampness heat accumulating the liver, 6 stagnation of qi and blood. 15 healthy female adults with regular menstruation were grouped into the control group. The kidney asthenia group were treated with modified yougui bolus with taohong siwu decoction, which is composed of tusizi duzhong shudi gouqizi danggui fuling shanyao shanyurou chuanxiong taoren. The therapeutic method of invigorating the kidney and spleen, reducing phlegm and activate blood was used in treating phlegm and dampness group, with modified cangfu daotan Bolus composed of cangzhu xiangfu banxia fuling chenpi huangqi danggui xianlingpi chuanxiong.The group of damp heat accumulating the liver were treated with modified danzhixiaoyao powder functioning to clear liver fire and remove damp, which is composed of danpi zhizi danggui shengdi baishao fuling zaojiaoci chaihu taoren etc. The group of qi stagnation and blood stasis were treated with modified gexiazhuyu decoction functioning to regulating qi and blood , which is composed of danggui chaunxiong chishao taoren zhiqiao xiangfu wuyao gancao etc. Observe the changes before and after the treatment of the patients;measure the serum level of FSH, LH, E2, T with electro-chemiluminescence and assay the concentration of insulin and plasma ET before and after treatment with radioimmunoassay.2.rat models of PCOS have been established according Poretsky, with the purpose of observing the effect of Guishen Bolus and Taohongsiwu Decoction on the shape and function of the endothelial cells in rat aorta. Cemitidine and Taohongsiwu Decoction was used in the control group. Measure the serum level of FSH, LH, T, INS and plasma ET PAI-1, and observe the endothelial cell morph.[results]1.clinical results(1)20 cases regain their normal menstruation, 14 of whose menstrual period is within 40days, 9 within 3months, 15 cases without any changes, the total efficiency rate is 74.1%;the rate of regaining normal BBT is 46. 9%. The results show that Chinese herbs can efficiently correct the menstrual irregularity, stimulate the ovulation, thus raising the pregnancy rate and lowering the
incidence of natural abortion after conception.(2)After treatment based on syndrome differentiation, the level of LH, T, LH/ T, INS, ET in each group decreased obviously and the level of E2 increased obviously, both of which showed the significant difference (KO. 05)2. experimental results(l)In the control group, group of Guishen bolus and Taohongsiwu Decoction, the endothelial cells appear flat, arranging along the long axis of the blood vessels, normal endothelial cell integrity with scanty cytoplasm and the microscopic appearance shows highly developed golgiosome rough endoplasmic reticulum and smooth endoplasmic reticulum. In the model group, Cemitidine group and Taohongsiwu Decoction group, the endothelia cells of the rat aorta were contracted, with discontinuous basement membrane, inflated chondriosome, the middle layer smooth muscles tending to move inside and out of the normal shape of intraendothelial junction.(2)The groups which were respectively treated with Taohongsiwu Decoction and Cemitidine have a significantly lower serum level of L^ T> INS> PAI-I ET than those of the model group(KO. 05). There were no significant difference between the healthy group and the group of Taohongsiwu Decoction(/>0.05);and were significant difference between the model group and the group of Taohongsiwu Decoction(/<0. 05). Compared to the model group, the decreased level of INS in Cemitidine treatment group showed the significant difference (K0. 05), compared to the high-dosage group of Taohongsiwu Decoction , it showed no significant difference (/M). 05). Respectively compared to the model group and the group of Taohongsiwu Decoction with Guishen Bolus, the decreased level of PAI-I> ET in Cemitidine treatment group showed the significant difference (K0.05).^conclusion!1. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can effectively correct irregular menstruation and stimulate ovulation, thus raising the possibility of pregnancy.2. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can improve the endocrine function of patients with PCOS and lower the serum level of LH, T, LH, FSH., which indicate that
Chinese herbs can regulate the endocrine function of the ovaries and be helpful in promoting pregnancy.3. Treatment based on syndrome differentiation combined with Chinese herbs for activating blood stasis can regulate the serum level of INS ET, which indicates that Chinese herbs has the function of correcting insulin resistance and preventing the endothelial cells from injury.4. The morphologic changes of the endothelial cells and increase of ET INS are found in the PCOS model rat, indicating blood stasis is one pathogenesis of PCOS.5. Guishen Bolus and Taohongsiwu Decoction , which morphologically repair damaged endothelial cells, regulate their functions, and correct insulin resistance , are of great importance for complication prevention.This study mainly discusses blood stasis involved in pcos in the light of endothelium and detect the effect of Chinese herbs on endothelial cells in pcos for the first time, results show that Chinese herbs have the function of regulating the menstruation to raise the possibility of pregnacncy, repairing the damaged endothelial cells as well as preventing the potential compications of pcos.
引文
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