养血补肾方治疗卵巢早衰动物实验研究
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摘要
目的:卵巢早衰(Premature Ovarian Failure,简称POF)是女性在40岁之前由于卵巢内卵泡耗竭或医源性损伤等原因导致的卵巢功能衰竭的一种妇科内分泌疾病。它以低雌激素及高促性腺激素为特征,其主要临床表现为闭经,不孕,常伴有烘热汗出、情绪不稳、失眠健忘、白带量少、阴道干涩、生殖器官及第二性征退化等围绝经期症状。目前西医认为该病与多种因素有关,包括自身免疫功能异常、遗传因素、染色体异常、代谢异常、医源性因素(药物、放疗、化疗、手术等)及感染性因素等。治疗上,多采用性激素补充疗法(HRT),外源性补充性激素,模拟卵巢的周期性变化给予雌孕激素替代治疗。该疗法虽然能在短期内缓解患者的主要临床症状,但其远期疗效不确定且有较大的副作用。中医在本病的治疗方面具有独特优势,我们从“女子以血为本”,“精血同源”,“经水出诸肾”,后天之精化生、滋养先天之精的认识出发,认为本病的病因病机是血虚肾亏,治疗当以养血补肾填髓为原则,自拟“养血补肾方”,在临床治疗上取得一定效果。本研究旨在通过动物实验,探讨养血补肾方对卵巢早衰的影响及其作用机理。
方法:本实验选取60只健康雌性、动情周期规律的SD大鼠,将其随机分为两组,空白对照组15只,模型组45只。用自身免疫法,经过三次间断性异体卵巢组织液多点注射免疫,建立卵巢功能早衰的大鼠模型,待造模成功2周后,处死空白对照组及模型组大鼠各5只,将模型组剩余40只大鼠随机分为4组(模型对照组、中药高剂量组、中药低剂量组、西药组)每组各10只,中药组给予养血补肾方灌胃(高剂量组3ml/250g,每毫升药液含4.5g生药,低剂量组1ml/250g,每毫升药液含4.5g生药),西药组给予雌激素灌胃(2ml/250g,每毫升溶液含己烯雌酚0.17mg),模型组及空白对照组给予正常饮食。分别于造模前后及治疗前后观察各组大鼠的一般情况、动情周期、血清性激素(FSH\LH\ E2)水平、卵巢组织学变化。
结果:造模前大鼠活动频繁,对刺激反应灵敏,皮毛润泽,动情周期规律一般为4-5天。造模后大鼠活动频度减少,对刺激反应迟缓,皮毛干枯,动情周期紊乱,造模后大鼠血清中的FSH水平明显高于造模前水平(P<0.01),LH水平高于造模前水平(P<0.05),而E2水平则明显低于造模前水平(P<0.01)。光镜下观察大鼠的卵巢组织,造模后大鼠的卵巢体积与造模前相比明显缩小(P<0.01),卵巢组织中生长期卵泡的数量和黄体数量明显减少,闭锁细胞明显增多。经治疗后,中药高剂量组大鼠的血清激素FSH水平与模型对照组相比较有显著性差异(P<0.01),血清激素LH水平与模型对照组相比较有差异(P<0.05), E2水平较模型对照组有所升高(P<0.05);西药组大鼠的血清激素FSH水平与模型对照组相比较有差异(P<0.05),血清激素LH水平与模型对照组相比较有差异(P<0.05), E 2水平较模型对照组明显升高(P<0.01);中药低剂量组大鼠的血清激素FSH水平与模型对照组相比较有差异(P<0.05),血清激素LH水平与模型对照组相比较无差异(P>0.05), E2水平较模型对照组有所升高(P<0.05)。中药高剂量组大鼠经治疗后其活动频繁,对刺激反应较灵敏,皮毛润泽,动情周期逐渐趋于正常。光镜下观察,中药高剂量组大鼠的卵巢体积增大与模型对照组大鼠的卵巢体积相比有显著性差异(P<0.01),卵巢组织中的生长期卵泡和黄体数量显著增多,闭锁细胞数量显著减少。中药低剂量组大鼠的卵巢体积也有所增大,与模型对照组大鼠的卵巢体积相比有差异(P<0.05),卵巢组织中的生长期卵泡、黄体、闭锁细胞的情况与模型组比较变化不明显。西药组卵巢体积和卵巢组织细胞的变化介于两者之间。
结论:
1.模型组大鼠的动情周期紊乱,血清性激素水平及卵巢组织病理学改变等证实卵巢功能降低,自身免疫性卵巢功能衰退的大鼠动物模型成功建立。
2.中药治疗组大鼠血清性激素及卵巢组织学改变表明养血补肾方能够促进卵巢早衰大鼠的卵泡生长,激发和改善受损卵巢的内分泌功能。
3.通过对三个治疗组的治疗结果进行统计分析,三组大鼠病情均有好转,其中中药高剂量组的疗效最优,西药组疗效次之。
Objective: The premature ovarian failure (POF)is a kind of the decay of the ovarial function before the woman is 40.It shows to last amenorrhea, the estrin descends and the antophysin heightens, accompanying with the symptoms of climacteric syndrome. At present, we have not known its etiological factor, and the treatment is not satisfied. The hormonal therapy is usually used in western medicine ,but it can bring to a series of side effect, and it does not get at the root. We based on traditional medicine, have presumed that the etiological factor and pathogenesis of this kind of disease be renal deficiency and hemophthsis. So we base on supporting blood and invigorating kidney and makes out a prescription named as“Yangxuebushenfang”. By the clinical usage of this prescription ,the pathogenesis further that Yangxuebushenfang treats POF by observing oophoric histomorphology and detecting blood biochemical indicator at two aspects of clinical observation and experiment study.
Methods: In this experiment study ,60 healthy, female SD rats were classified into two groups randomly .One is control group which has 15 rats, the other is model group with 45 rats. The estrous cycle was regularity to set up the model of POF through the autogenous immunization. When the model set up successfully, killed 5 rats each group. The 40 rats in model group would be divided into 4 groups randomly, the model control group, the high dose of traditional Chinese medicine group, the low dose of traditional Chinese medicine group and the western medicine group. Each group has 10 rats. The rats in traditional Chinese medicine groups were fed with Yangxuebushenfang (the quantity of high dose traditional Chinese medicine group is 3ml/250g, every milliliter contains 4.5g drug and the quantity of low dose traditional Chinese medicine group is 1ml/250g, every milliliter contains4.5g drug). The rats in western medicine group were intragastric admimistration with the man-made cycle method, the rats in model group and control group were fed with normal food. At both before and after making model , before and after treating, we observe the general state of health, the level of gonadal hormone in serum (FSH/LH/E2)and the appearance changes of the ovaries cytology of the rats in each group.
Result: In experiment study, the activity of pre-modeled rats is multifarious, their respond is intelligent, hair color is sheen, feel attracted a period 4-5days once. After building model, the activity degree of rats is little, heir respond is cool, and hair has no sheen. Their feeling attracted periods prolong even disorder. FSH level increase significantly compared with pre-modeled(P<0.01). LH level increase compared with pre-modeled(P<0.05). E2 level decline significantly compared with pre-modeled(P<0.01).Though the microscopy opticaling, growing follicecs and corpus luteums reduced significantly in POF model rats. After high dose of traditional Chinese medicine group treated, atretic follicles increase significantly. Activities of rats rise multifarious and their hair color become sheen. FSH level decline significantly compared with model group(P<0.01). LH level also decline compared with model group (P<0.05). E2 level increase compared with model group(P<0.05). The light mirror descends growing follicecs and corpus luteums increased significantly, yellow ovarian volume is big, atretic follicles reduced significantly.After western medicine group treated, FSH level decline compared with model group(P<0.05). LH level also decline compared with model group (P<0.05). E2 level increase significantly compared with model group(P<0.01).The change of rats general situation and ovarian tissue are not so distinct than high dose traditional Chinese medicine group. After low dose of traditional Chinese medicine group treated, atretic follicles increase unsignificantly. The change of activities and rats hair color are not distinct . FSH level decline compared with model group(P<0.05). LH level not decline compared with model group (P>0.05). E2 level increase compared with model group(P<0.05).
Conclusions
1.The decrease of ovarian function, injury of organization pathology proved that the animal model of autoimmunity ovarian function decline had successfully founded.
2.Changes of ovaries histology indicate that YXBSF can promote ovarian follicle and improve ovaries function.
3.Through analyse the results of 3 treat groups, they make rats up in different levels. The effect of high dose traditional Chinese medicine group is best, the western medicine group is second.
方法:本实验选取60只健康雌性、动情周期规律的SD大鼠,将其随机分为两组,空白对照组15只,模型组45只。用自身免疫法,经过三次间断性异体卵巢组织液多点注射免疫,建立卵巢功能早衰的大鼠模型,待造模成功2周后,处死空白对照组及模型组大鼠各5只,将模型组剩余40只大鼠随机分为4组(模型对照组、中药高剂量组、中药低剂量组、西药组)每组各10只,中药组给予养血补肾方灌胃(高剂量组3ml/250g,每毫升药液含4.5g生药,低剂量组1ml/250g,每毫升药液含4.5g生药),西药组给予雌激素灌胃(2ml/250g,每毫升溶液含己烯雌酚0.17mg),模型组及空白对照组给予正常饮食。分别于造模前后及治疗前后观察各组大鼠的一般情况、动情周期、血清性激素(FSH\LH\ E2)水平、卵巢组织学变化。
结果:造模前大鼠活动频繁,对刺激反应灵敏,皮毛润泽,动情周期规律一般为4-5天。造模后大鼠活动频度减少,对刺激反应迟缓,皮毛干枯,动情周期紊乱,造模后大鼠血清中的FSH水平明显高于造模前水平(P<0.01),LH水平高于造模前水平(P<0.05),而E2水平则明显低于造模前水平(P<0.01)。光镜下观察大鼠的卵巢组织,造模后大鼠的卵巢体积与造模前相比明显缩小(P<0.01),卵巢组织中生长期卵泡的数量和黄体数量明显减少,闭锁细胞明显增多。经治疗后,中药高剂量组大鼠的血清激素FSH水平与模型对照组相比较有显著性差异(P<0.01),血清激素LH水平与模型对照组相比较有差异(P<0.05), E2水平较模型对照组有所升高(P<0.05);西药组大鼠的血清激素FSH水平与模型对照组相比较有差异(P<0.05),血清激素LH水平与模型对照组相比较有差异(P<0.05), E 2水平较模型对照组明显升高(P<0.01);中药低剂量组大鼠的血清激素FSH水平与模型对照组相比较有差异(P<0.05),血清激素LH水平与模型对照组相比较无差异(P>0.05), E2水平较模型对照组有所升高(P<0.05)。中药高剂量组大鼠经治疗后其活动频繁,对刺激反应较灵敏,皮毛润泽,动情周期逐渐趋于正常。光镜下观察,中药高剂量组大鼠的卵巢体积增大与模型对照组大鼠的卵巢体积相比有显著性差异(P<0.01),卵巢组织中的生长期卵泡和黄体数量显著增多,闭锁细胞数量显著减少。中药低剂量组大鼠的卵巢体积也有所增大,与模型对照组大鼠的卵巢体积相比有差异(P<0.05),卵巢组织中的生长期卵泡、黄体、闭锁细胞的情况与模型组比较变化不明显。西药组卵巢体积和卵巢组织细胞的变化介于两者之间。
结论:
1.模型组大鼠的动情周期紊乱,血清性激素水平及卵巢组织病理学改变等证实卵巢功能降低,自身免疫性卵巢功能衰退的大鼠动物模型成功建立。
2.中药治疗组大鼠血清性激素及卵巢组织学改变表明养血补肾方能够促进卵巢早衰大鼠的卵泡生长,激发和改善受损卵巢的内分泌功能。
3.通过对三个治疗组的治疗结果进行统计分析,三组大鼠病情均有好转,其中中药高剂量组的疗效最优,西药组疗效次之。
Objective: The premature ovarian failure (POF)is a kind of the decay of the ovarial function before the woman is 40.It shows to last amenorrhea, the estrin descends and the antophysin heightens, accompanying with the symptoms of climacteric syndrome. At present, we have not known its etiological factor, and the treatment is not satisfied. The hormonal therapy is usually used in western medicine ,but it can bring to a series of side effect, and it does not get at the root. We based on traditional medicine, have presumed that the etiological factor and pathogenesis of this kind of disease be renal deficiency and hemophthsis. So we base on supporting blood and invigorating kidney and makes out a prescription named as“Yangxuebushenfang”. By the clinical usage of this prescription ,the pathogenesis further that Yangxuebushenfang treats POF by observing oophoric histomorphology and detecting blood biochemical indicator at two aspects of clinical observation and experiment study.
Methods: In this experiment study ,60 healthy, female SD rats were classified into two groups randomly .One is control group which has 15 rats, the other is model group with 45 rats. The estrous cycle was regularity to set up the model of POF through the autogenous immunization. When the model set up successfully, killed 5 rats each group. The 40 rats in model group would be divided into 4 groups randomly, the model control group, the high dose of traditional Chinese medicine group, the low dose of traditional Chinese medicine group and the western medicine group. Each group has 10 rats. The rats in traditional Chinese medicine groups were fed with Yangxuebushenfang (the quantity of high dose traditional Chinese medicine group is 3ml/250g, every milliliter contains 4.5g drug and the quantity of low dose traditional Chinese medicine group is 1ml/250g, every milliliter contains4.5g drug). The rats in western medicine group were intragastric admimistration with the man-made cycle method, the rats in model group and control group were fed with normal food. At both before and after making model , before and after treating, we observe the general state of health, the level of gonadal hormone in serum (FSH/LH/E2)and the appearance changes of the ovaries cytology of the rats in each group.
Result: In experiment study, the activity of pre-modeled rats is multifarious, their respond is intelligent, hair color is sheen, feel attracted a period 4-5days once. After building model, the activity degree of rats is little, heir respond is cool, and hair has no sheen. Their feeling attracted periods prolong even disorder. FSH level increase significantly compared with pre-modeled(P<0.01). LH level increase compared with pre-modeled(P<0.05). E2 level decline significantly compared with pre-modeled(P<0.01).Though the microscopy opticaling, growing follicecs and corpus luteums reduced significantly in POF model rats. After high dose of traditional Chinese medicine group treated, atretic follicles increase significantly. Activities of rats rise multifarious and their hair color become sheen. FSH level decline significantly compared with model group(P<0.01). LH level also decline compared with model group (P<0.05). E2 level increase compared with model group(P<0.05). The light mirror descends growing follicecs and corpus luteums increased significantly, yellow ovarian volume is big, atretic follicles reduced significantly.After western medicine group treated, FSH level decline compared with model group(P<0.05). LH level also decline compared with model group (P<0.05). E2 level increase significantly compared with model group(P<0.01).The change of rats general situation and ovarian tissue are not so distinct than high dose traditional Chinese medicine group. After low dose of traditional Chinese medicine group treated, atretic follicles increase unsignificantly. The change of activities and rats hair color are not distinct . FSH level decline compared with model group(P<0.05). LH level not decline compared with model group (P>0.05). E2 level increase compared with model group(P<0.05).
Conclusions
1.The decrease of ovarian function, injury of organization pathology proved that the animal model of autoimmunity ovarian function decline had successfully founded.
2.Changes of ovaries histology indicate that YXBSF can promote ovarian follicle and improve ovaries function.
3.Through analyse the results of 3 treat groups, they make rats up in different levels. The effect of high dose traditional Chinese medicine group is best, the western medicine group is second.
引文
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22刘敏如,谭万信.中医妇产科学[M].北京:人民卫生出版社,2001:25- 35
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26李吾川,周文隆,蒋常林.胎儿卵巢薄片异体移植治疗卵巢早衰[J].南京铁道医学院学报, 1999, 18(1):55256
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28姚石安.卵巢早衰中医证治需注意哪些方面[J].中医杂志,1998, 39 (5):313
29安胜军,李姚,李恩.补肾方药对绝经后妇女卵巢功能和骨密度的影响[J].中国骨质疏松杂志, 2000, 6(2): 55
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20 Harlow BL, Signorello LB Factors associated with early menopause[J].Maturiras,2000,35(1):3
21夏天,韩冰.卵巢早衰的中西医结合研究进展[J].辽宁中医杂志, 2004, 31(8):707
22刘敏如,谭万信.中医妇产科学[M].北京:人民卫生出版社,2001:25- 35
23朱玲,罗颂平.卵巢早衰的病因病机及其证治[J].中医药学刊,2003,21(1):143
24莫中福,徐素欣.卵巢早衰病因及诊治的研究进展.河北医科大学学报,2006,27(3):233
25俞琳,李美芝.高促性腺激素闭经的研究进展[J].国外医学.计划生育分册, 1999,18(4):2202224
26李吾川,周文隆,蒋常林.胎儿卵巢薄片异体移植治疗卵巢早衰[J].南京铁道医学院学报, 1999, 18(1):55256
27庄广伦.卵巢功能局部调节的研究现状及展望[J].中华妇产科杂志,1997,32(10):5792581
28姚石安.卵巢早衰中医证治需注意哪些方面[J].中医杂志,1998, 39 (5):313
29安胜军,李姚,李恩.补肾方药对绝经后妇女卵巢功能和骨密度的影响[J].中国骨质疏松杂志, 2000, 6(2): 55
30王璇.仙乐雄胶囊治疗卵巢早衰闭经47例临床观察[J].基层中药杂志,1999,13(4):55
31陆建明.骨质疏松症[M].北京:化学工业出版社1992,607
32张振雯.中药助孕方和西药激素疗法治疗不孕症86例[J].新中医, 1995,27(12):35-36
33周华,赵春梅.中西医治疗卵巢早衰临床研究述略[J].中医药学刊,2004 ,51(22):903
34温鸿雁.卵巢早衰的中西医研究近况[J].中医药研究,2001,6 , (17 ):49-51
35陈秀芳.辨证治疗卵巢早衰22例[J].四川中医,2000 ,18 (1):35
36李云君,姜惠中.姜惠中治疗卵巢早衰的经验[J].湖北中医杂志,2006 ,28(6):28-29
37周华,赵春梅.中西医治疗卵巢早衰临床研究述略[J].中医药学刊,2004,5(22):903
38陈国姿,徐虹.中药人工周期疗法治疗卵巢功能早衰继发性闭经32例[J].Guangdong Medical Journal ,1999,(10): 782—783
39赵建春,徐萍.巢衰复元汤治疗卵巢早衰38例临床观察[J].北京中医药大学学报(中医临床版), 2006,13, (6) :23-25
40徐萍.巢衰汤治疗卵巢早衰例报告[J].甘肃中医,2003 ,16(6) :31
41梁雪雯,苏建芬.逍遥助卵煎治疗卵巢早衰30例[J].上海中医药杂志,2006,40(2):31-32
42施艳秋,时燕萍.乌鳖口服液治疗卵巢功能早衰的临床与实验研究总结[J].中华实用中西医杂志,2004,4(17): 424-427
43朱玲.左归丸对免疫性卵巢早衰小鼠抗卵巢抗体的影响[J].现代中西医结合杂志,2006,15(4) :435-438
44王璇.仙乐雄胶囊治疗卵巢早衰闭经47例临床观察[J].基层中医杂志,1999,13(4) :55
45邢翠玲,杨玉荣.中西医结合治疗卵巢早衰症310例[J].国医论坛, 1995, 10 (3) : 20
46赵建春,徐萍,宋亚光.中西医结合治疗卵巢早衰40例观察[J].四川中医, 2004, 22 (7) : 69-70
47沙桂娥,赵文民,马仁海.针灸治疗卵巢早衰76例临床研究[J].中国针灸,1999,19(4) : 199-201
48何文扬.针刺治疗卵巢早衰症157例[J].中国针灸, 2000, 20(7) : 399
49刘炳权.针灸治疗继发性闭经86例[J].针灸临床杂志,2003, 19 (2) : 16
50浦蕴星.针灸治疗闭经疗效分析[J].上海针灸杂志, 1994,13 (6) : 257-258